Pharmacokinetics
Safety and Pharmacokinetics of Single and Multiple Intravenous Bolus Doses of Diclofenac Sodium Compared With Oral Diclofenac Potassium 50 mg: A Randomized, Parallel-Group, Single-Center Study in Healthy Subjects
The Journal of Clinical Pharmacology 2016, 56(1) 87–95 © 2015, The American College of Clinical Pharmacology DOI: 10.1002/jcph.575
Sagar Munjal, MD, MS1, Anirudh Gautam, MPharm2, Franklin Okumu, PhD2, James McDowell, PhD3, and Kent Allenby, MD, FACP2
Abstract In a randomized, parallel-group, single-center study in 42 healthy adults, the safety and pharmacokinetic parameters of an intravenous formulation of 18.75 and 37.5 mg diclofenac sodium (DFP-08) following single- and multiple-dose bolus administration were compared with diclofenac potassium 50 mg oral tablets. Mean AUC0–inf values for a 50-mg oral tablet and an 18.75-mg intravenous formulation were similar (1308.9 [393.0]) vs 1232.4 [147.6]). As measured by the AUC, DFP-08 18.75 mg and 37.5 mg demonstrated dose proportionality for extent of exposure. One subject in each of the placebo and DFP-08 18.75-mg groups and 2 subjects in the DFP-08 37.5-mg group reported adverse events that were considered by the investigator to be related to the study drug. All were mild in intensity and did not require treatment. Two subjects in the placebo group and 1 subject in the DFP-08 18.75-mg group reported grade 1 thrombophlebitis; no subjects reported higher than grade 1 thrombophlebitis after receiving a single intravenous dose. The 18.75- and 37.5-mg doses of intravenous diclofenac (single and multiple) were well tolerated for 7 days. Additional efficacy and safety studies are required to fully characterize the product.
Keywords safety, pharmacokinetics, diclofenac, intravenous, oral
Nonsteroidal anti-inflammatory drugs (NSAIDs) are mainstays in the medical treatment of acute pain, and diclofenac—an amino phenylacetic acid derivative that inhibits prostaglandin biosynthesis to produce analgesic, antipyretic, and anti-inflammatory activity—is among the most widely used agents in the class.1 Frequently prescribed for oral administration (as a tablet or water-soluble powder) to relieve pain and reduce inflammation, diclofenac for intravenous injection may be preferable in a number of clinical situations, such as when a rapid onset of relief is required; when reduction`s in systemic availability and variability due to hepatic first-pass metabolism will have clinical consequences; when dysphagia or ileal/ gastrointestinal (GI) sensitivity preclude the use of oral agents; or when opioids are contraindicated due to issues with tolerability or misuse, and an equianalgesic2 intervention is needed. A number of randomized, well-controlled clinical trials have demonstrated the safety, efficacy, and opioid-sparing effects of intravenous diclofenac in subjects with acute pain following dental surgery,3 abdominal surgery,4 laparoscopic surgery,5 orthopedic procedures,6,7 and general postoperative pain.8,9 In the United States,
diclofenac sodium for intravenous injection was recently approved for management of mild to moderate pain and moderate to severe pain alone or in combination with opioid analgesics.10 A reformulation of diclofenac administered by intravenous bolus as an oil-in-water emulsion of 37.5 mg diclofenac sodium per milliliter of vehicle (DFP-08) is being investigated for clinical use. During pharmaceutical and preclinical toxicology development, DFP-08 was
1 Senior Director/Head of Neurology Clinical Development and Medical Affairs, Proprietary Products, Dr. Reddy’s Laboratories, Princeton, NJ, USA 2 Dr. Reddy’s Laboratories, Princeton, NJ, USA 3 Premier Research Group, Austin, TX, USA
Submitted for publication 21 April 2015; accepted 15 June 2015. Corresponding Author: Sagar Munjal, MD, MS, Senior Director/Head of Neurology Clinical Development and Medical Affairs, Proprietary Products, Dr. Reddy’s Laboratories, 107 College Road East, Princeton, NJ 08540 Email: [email protected]
88 examined for in-life findings, injection site reactions, clinical pathology observations, and formulation stability characteristics that might influence clinical use. No new adverse nonclinical pathology findings were observed, and pharmaceutical development data support a stable intravenous preparation suitable for human use. Previous clinical trial experience and routine clinical use of other intravenous formulations of diclofenac outside the United States suggest a benefit-risk assessment that favors further development of DFP-08 as a viable intravenous diclofenac option for patients. Objectives The objectives of the present study were to assess the safety and pharmacokinetic (PK) parameters of DFP-08 following single- and multiple-dose bolus administration compared with diclofenac potassium 50-mg oral tablets (CataflamTM; Novartis Pharmaceuticals Corp, East Hanover, New Jersey).
Methods Design This was a randomized, parallel-group, single-center PK study in 42 healthy adults. The Chesapeake Institutional Review Board in Columbia, Maryland, reviewed and approved the protocol and protocol amendments, informed consent form, and related subject information and recruitment materials. The study was conducted in accordance with Good Clinical Practice requirements and all applicable regulations. Subjects Male and female subjects were eligible to participate if they were able to understand the requirements of the study, willing and able to give written informed consent, between 18 and 45 years of age (inclusive), and in good general health; had a body weight 50 kg and a body mass index 18 and 30 kg/m2; agreed to use no other medication (including over-the-counter products), herbal products, or vitamin or dietary supplements (including St. John’s wort) during the 7 days prior to the first dose of the study and continuing until after the final visit (excluding hormonal contraceptives and hormone replacement therapy); were free of any systemic disorder that could interfere with the study results in the opinion of the investigator; were not of childbearing potential or practicing a medically acceptable method of birth control. Subjects were excluded from participation for any of the following reasons: history of allergic reaction or clinically significant intolerance to acetaminophen, aspirin, or any NSAID, including diclofenac; history of NSAID-induced bronchospasm (subjects with the triad of asthma, nasal polyps, and chronic rhinitis are at greater risk for bronchospasm and were considered carefully);
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hypersensitivity, allergy, or significant reaction to any ingredients in the study drug; pregnant or nursing or planning to become pregnant during the study; participated in a trial involving any investigational product in the 30 days before the screening visit; had a clinically significant history of respiratory, gastrointestinal, hepatic, renal, hematologic, endocrinal, oncologic, immunologic, GI, neurologic, drug or alcohol abuse (within the last 2 years), or psychiatric disorders or any other disease or medical condition that would interfere with the study; a known history of vasculitis, phlebitis, or any other condition predisposing to venous inflammation events more readily than the general population; history of intravenously induced cellulitis, intravenous drug abuse, or clotting disorder; abnormal laboratory results at screening; history of blood or plasma donation within 90 days before the first day of dosing; were unable to participate or cooperate with the study procedures for any reason. Treatments DFP-08 was provided in 2-mL vials containing 75 mg diclofenac sodium as a yellowish, translucent, or semitransparent oil-in-water emulsion for intravenous bolus administration. Each milliliter contained 3.75% diclofenac sodium, 10% phospholipids, 5% medium-chain triglycerides, 0.0055% ethylenediaminetetraacetic acid disodium dehydrate, 5% sucrose in water for injection. Diclofenac potassium was provided as 50-mg oral tablets, and vehicle was provided in the form of an emulsion for intravenous bolus administration that was visually identical to the active treatments. All study drugs were protected from light and stored in a tightly closedlight-resistant container at 2°C to 8°C. Protocol The study was divided into a screening period, administration of oral diclofenac potassium 50-mg tablet (period 1), a washout period, a treatment period (period 2), and a safety follow-up visit. The screening period took place within 21 days before administration of the diclofenac potassium 50-mg oral tablet on day 1. Subjects provided written informed consent before any procedures or evaluations were completed, and they were evaluated against protocolspecified inclusion and exclusion criteria to determine their eligibility for participation. During period 1, eligible subjects were admitted to the clinical research unit (CRU) on day -1. All subjects underwent at least a 10-hour overnight fast. The following morning (day 1), subjects received a single oral diclofenac potassium 50-mg tablet with 240 mL of water. The fast was maintained until the first meal given 4 hours after dosing. Subjects were confined to the CRU until at least 24 hours after study drug administration.
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During period 2, after completing a washout period (days 2 to 4), subjects underwent at least a 10-hour overnight fast. The following morning (day 5), based on a computer-generated randomization schedule, subjects were randomized equally to receive a single intravenous bolus dose of diclofenac sodium 18.75 mg in 0.5 mL, diclofenac sodium 37.5 mg in 1 mL, or placebo in 1 mL over a duration of 1 minute to characterize the single-dose intravenous bolus PK profile on day 5 over 24 hours. To account for the difference in volume between DFP-08 37.5 mg and DFP-08 18.75 mg and placebo, all intravenous treatments were administered by unblinded study center staff who did not participate in the safety assessments. Syringes used to administer study drugs were covered with white tape to maintain the blind for patients, the investigator, and all other study staff. Intravenous catheters for administration of the study drug were placed in a nondominant forearm location, avoiding the hand and antecubital fossa, if possible. Intravenous access sites were maintained in a sterile, aseptic fashion, flushed every 4–6 hours with normal saline, and changed at least every 72 hours. If additional intravenous access sites were required because of clotting, infection, or intolerable irritation, the number of changes and the reasons for each change were documented for each subject. On days 5 (single-dose intravenous bolus PK profile) and 6, at 2 minutes after dosing, a 4-mL blood sample for complete blood count was drawn to inspect for evidence of hemolysis. If there was no evidence of hemolysis, then intravenous bolus multiple doses administered every 6 hours were started on day 6 and continued to the final dose on the morning of day 12 (multiple-dose intravenous bolus PK profile). Subjects received a total of 25 doses of their assigned intravenous bolus treatment by intravenous pushover 1 minute. On the evening of day 11, subjects underwent at least a 10-hour overnight fast. The final dose of the study drug was administered at the end of the overnight fast on the morning of day 12 to characterize the multiple-dose intravenous bolus PK profile at steady state. Standardized meals were provided. On day 5 (single-dose PK profile) and day 12 (multiple-dose PK profile), the fast was maintained until the first meal given 4 hours after the dosing. On days 6 to 11, the meals (breakfast, lunch, snack, dinner) were provided at the same time each day. Subjects were discharged from the CRU after completing all protocol-specified procedures scheduled for day 13. Subjects returned to the CRU on day 17 ( 2 days) for the safety follow-up visit. Pharmacokinetic and Safety Variables Pharmacokinetics. Blood samples (approximately 5 mL each) for PK analysis from all administered treatments were collected on days 1 (single-dose oral profile), 5 (single-dose intravenous bolus profile), and
89 12 (multiple-dose intravenous bolus profile) at the following times: before dosing (time 0); 2, 5, 10, 15, and 20 minutes after dosing; and 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, and 24 hours after dosing. For intravenous diclofenac treatment, sampling times were calculated from the start of the 1-minute intravenous bolus. The predose sample was obtained within 30 minutes before dosing. Postdose PK blood samples collected at times 0.5 hours after dosing were obtained within 1 minute of the scheduled sampling time; samples collected at times > 0.5 hours were obtained within 2 minutes of the scheduled sampling time. The PK blood sample collected 24 hours after dosing was obtained within 5 minutes of the scheduled sampling time. The concentration of diclofenac in plasma samples was determined using high-performance liquid chromatography with mass spectrometric detection. The method used was validated for a lower concentration range of 2.50 to 750 ng/mL and a higher range of 30 to 1500 ng/mL to cover the expected concentration range of the samples from this multidose study. The accuracy (%Bias) and precision (%CV) of quality control samples ranged from 0.00% to -3.5% and 3.8% to 6.1%, respectively, across the 2 concentration ranges. Safety Safety was assessed largely on the basis of local tolerance (venous irritation, phlebitis, and/or thrombophlebitis), which was the primary safety end point. Only injectionsite reactions not evaluated as these end points (ie, other than phlebitis, vasculitis, cellulitis, and other dermal findings at the intravenous access site) were reported as adverse events (AEs) of special interest. Safety was also evaluated by the incidence of treatment-emergent AEs (TEAEs), clinical laboratory test results, and changes in vital signs. Additional AEs of special interest included GI complaints (specifically GI bleeding) and any cardiovascular complications and outcomes, including cardiac death, myocardial infarction, ischemia, and stroke. Thrombophlebitis was assessed using a 6-point Likert-type scale11 (0 ¼ no reaction, 1 ¼ tenderness along the vein, 2 ¼ continuous tenderness or pain with redness, 3 ¼ palpable swelling or thrombosis within the length of the cannula, 4 ¼ palpable swelling or thrombosis beyond the length of the cannula, 5 ¼ as for grade 4, with overt infection) predose (after the intravenous catheter was placed and before each bolus was administered), immediately after each intravenous dose, every 6 hours after the initial intravenous dose on day 5 and continuing through day 12, immediately before and after each change or discontinuation of intravenous access site during the inpatient phase, on day 13, and at the follow-up visit. The Thrombophlebitis Assessment was performed at each discontinued intravenous site every 6 hours through day 12.
90 Statistical Methods Analysis Populations. Two analysis populations were defined for this study. The safety population included all subjects who received any amount of the study drug. The PK population included all subjects in the safety population who had at least 1 quantifiable diclofenac concentration after dosing. Pharmacokinetic Parameter Estimation. All PK parameters were estimated with Phoenix WinNonlin, version 6.3, using actual elapsed sampling times from the time of drug administration to the time of sample collection. The diclofenac potassium oral tablet doses were characterized using an extravascular administration single-dose model, and the intravenous bolus doses were characterized using an intravenous administration single- or multiple-dose model as appropriate. Observed peak concentration parameters included the maximum concentration (Cmax) and its time of collection (Tmax) for the oral diclofenac potassium administration and back-extrapolated concentration at time of administration (C0) for the DFP-08 intravenous bolus administrations. The observed extent of systemic availability was measured by AUC to the last concentration and then extrapolated to infinity (AUC0–inf) for the single-dose administrations of diclofenac potassium tablets and DFP-08 and by AUC0–tau for the multipledose DFP-08 administration. Clearance (CL) was calculated from the dose and the AUC0–tau for the multiple-dose DFP-08 administration. Additional PK parameters were calculated when the elimination rate constant (kel) could be estimated. These included the coefficient of determination (Rsq), half-life (t1/2) and its associated AUC%Extrap, CL (CL/F for oral), Vd (Vd/F for oral), and the AUC%BackExt associated with the C0. The only additional parameter from the multiple-dose administration was Vd. Pharmacokinetic Parameter Analysis. All PK parameter analyses (except for PK parameter estimation) were performed using SAS software, version 9.3. The AUC0–t and AUC0–inf for single-dose intravenous bolus DFP-08 were compared with the corresponding single-dose oral diclofenac (diclofenac potassium) AUC measures using a mixed analysis of variance (ANOVA) model with terms for sequence, subject within sequence, and treatment. The ANOVA models were run on the natural log-transformed values. The least-squares means and the standard error values from the analyses were used to construct the 90% confidence intervals (CIs) for the relative bioavailability evaluations. The dose proportionality of the 18.75- and 37.5-mg single- and multiple-dose profiles of DFP-08 was assessed. The dose-normalized AUC0–tau, AUC0–t, and C0 were logarithmically transformed and analyzed by computing the ratios of the geometric means by using the least-squares mean and standard error values from an ANOVA model with a term for treatment. Dose
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proportionality was demonstrated if the 90%CIs for the ratios of geometric means were within the 80% to 125% range. The sample size was considered sufficient to provide adequate valid data to meet the study objectives. To accommodate possible dropouts, withdrawals, or both, 42 subjects (14 per arm) entered the study to obtain valid data on at least 36 subjects (12 per arm). Discontinued subjects were not replaced. Safety Analysis. Adverse events were coded using the Medical Dictionary for Regulatory Activities, version 16.0. All AEs were summarized by frequencies and percentages of subjects. Local tolerance (venous irritation, phlebitis, and/or thrombophlebitis) was the primary safety end point, as quantified by the Thrombophlebitis Assessment. In addition to frequencies and percentage of subjects reporting any thrombophlebitis within the first 6 hours, exact 95%CIs for the proportion of subjects with phlebitis at each grade were calculated by treatment and for the pooled active treatment arms (37.5- and 18.75-mg doses). The proportions of subjects with a grade 2 or higher severe reaction were summarized and reported along with the 95%CIs. Similar analyses were presented for the multiple-dosing phase of the study.
Results A total of 42 subjects were randomized into the study, including the PK and safety populations. Of these, 3 subjects (2 [14.3%] in the placebo group and 1 subject [3.6%] in the DFP-08 37.5-mg group) were discontinued from the study prematurely because of procedurerelated study noncompliance (Figure 1). Overall, a majority of the subjects were female (57.1%, 24 of 42 subjects) and black or African American (66.7%, 28 of 42 subjects); 2 subjects (28.6%) were Hispanic or Latino. Subjects’ mean age was 31.1 (7.9) years. Their mean (SD) weight was 75.5 (12.8) kg, mean (SD) height was 173.0 (10.2) cm, and mean (SD) body mass index was 25.0 (2.4) kg/m2. Pharmacokinetics As shown in Figure 2, the initial measurable diclofenac concentrations appeared at 10 minutes in 47.6% of subjects (20 of 42) after single-dose oral diclofenac potassium administration, at 2 minutes in 96.4% of subjects (27 of 28) after the single-dose intravenous bolus and was present for 100% of subjects (27 of 27) at the 5-minute predose sample for the multiple-dose intravenous bolus. No measureable concentrations were reported 24 hours after administration of any dose. One subject mistakenly received a subcutaneous dose rather than an intravenous bolus dose of DFP-08 18.75 mg. The error was discovered when results showed absorption rates that would not be possible after
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Figure 1. Disposition of subjects.
administration of an intravenous bolus dose of DFP-08 18.75 mg. Specifically, unlike the other 13 subjects who were given DFP-08 18.75 mg, each of whom had a concentration exceeding 1000 mg/mL at 5 minutes postdose, the concentration profile for this subject first appeared at 34.4 ng/mL. Because 4 concentrations
Figure 2. Mean diclofenac concentrations over time.
confirmed the aberrant pattern of absorption, this particular intravenous bolus administration appears to have missed the vein. As a result, data from this subject are not reported. The PK parameters for the single-dose oral tablet and the single-and multiple-dose intravenous bolus admin-
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Safety. No deaths, SAEs, or discontinuations of the study drug because of TEAEs occurred during the study. The only TEAEs that were reported in more than 1 subject overall were erythema, presyncope, and abdominal pain, none of which was judged by the investigator to be severe. As shown in Table 3, 1 subject each in the placebo and DFP-08 18.75-mg groups and 2 subjects in the DFP-08 37.5-mg group reported TEAEs that were considered by the investigator to be related to the study drug. All were mild in intensity and did not require treatment. After the single-dose intravenous bolus treatment, 3 subjects (2 subjects [14.3%] in the placebo group and 1 subject [7.1%] in the DFP-08 18.75-mg group) reported grade 1 thrombophlebitis. No subjects in any group reported higher than grade 1 thrombophlebitis after receiving a single intravenous dose. The incidence of grade 1 thrombophlebitis after the multiple-dose phase ranged from 28.6% (DFP-08 18.75 and 37.5 mg) to 35.7% (placebo). Of the 9 subjects who reported grade 2 or higher thrombophlebitis, 2 subjects (14.3%) each were in the placebo and DFP-08 37.5-mg groups, and 5 (35.7%) were in the DFP-08 18.75-mg group (Table 4). On day 13 during discharge assessments, 1 subject (a 28-year-old Asian man) in the DFP-08 37.5-mg group had an aspartate transaminase (AST) of 55 U/L (normal range, 15–46 U/L) and an alanine aminotransferase (ALT) of 115 U/L (normal range, 11–65 U/L). These AEs were considered by the investigator to be probably or possibly related to the study drug. The follow-up visit scheduled 5 days after discharge (day 18) showed an AST of 110 U/L and ALT of 147 U/L; the AST and ALT for the second
istrations of diclofenac are summarized in Table 1. Mean AUC0–inf values for 50-mg oral tablet and 18.75 mg intravenously were similar (1308.9 [393.0] vs 1232.4 [147.6]), but both were lower than DFP-08 37.5 mg intravenously (2582.2 [426.6]). Tmax values for the singledose diclofenac 50-mg oral tablet ranged from 20 minutes to 4 hours, with a median of 0.8 hours. Results for half-life were similar across all dosage forms (1.2–2.4 hours), but the observed half-life of DFP-08 18.75 mg increased by 0.5 hours and DFP-08 37.5 mg by 0.7 hours after multiple dosing. Close examination of the 10-hour sample in the semilog insert (Figure 2) suggests that the 37.5 mg DFP-08 single dose may have been unduly influenced by that sampling time. The CL and Vd values were similar across all DFP-08 administrations. In the single-dose comparisons of the 2 intravenous bolus treatments to the oral diclofenac 50-mg treatment, the 18.75-mg intravenous bolus of DFP-08 had an AUC0–t ratio point estimate of 107.5% (90%CI, 95.8%–120.7%), and DFP-08 37.5 mg had an AUC0–t ratio point estimate of 187.3% (90%CI, 167.6%–209.4%). For the AUC0–inf ratio comparisons, the 18.75-mg intravenous bolus had a ratio point estimate of 107.1% (90%CI, 95.5%–120.2%), and the 37.5-mg intravenous bolus had a ratio point estimate of 186.5% (90%CI, 166.9%–208.4%). Dose proportionality was demonstrated for the AUC measures from the 2 DFP-08 doses (18.75 and 37.5 mg), but not for the C0 comparisons (Table 2). The C0 point estimates were 94.4% and 95.0% for the single- and multiple-dose comparisons, respectively. The C0 had a % CV that ranged from 41% to 50%.
Table 1. Diclofenac PK Parameters for the Oral Tablet and the Single- and Multiple-Dose Intravenous Bolus Administrations Diclofenac Sodium Single Dose
Parameter AUC0–tau (ng h/mL) Mean (SD) AUC0–inf (ng h/mL) Mean (SD) Cmax or C0 (ng/mL) Mean (SD) Tmax (h) Median (min, max) t1/2 (h) Mean (SD) CL or CL/F (mL/min/kg) Mean (SD) Vd or Vd/F (L/kg) Mean (SD)
Diclofenac Potassium 50 mg (n ¼ 42)
18.75 mga (n ¼ 13)
Multiple Dose 37.5 mg (n ¼ 14)
18.75 mg (n ¼ 14)
37.5 mg (n ¼ 14)
1142.7 (179.5)
2305.5 (297.8)
1308.9 (393.0)
1232.4 (147.6)
2582.2 (426.6)
1041.4 (607.4)
6143.6 (2503.5)
11 702.0 (5029.8)
6024.8 (3014.3)
10 914.9 (4506.8)
2.1 (0.8)
1.3 (0.2)
1.8 (0.4)
1.7 (0.3)
2.5 (0.9)
9.3 (2.6)
3.4 (0.5)
3.3 (0.4)
3.7 (0.5)
3.7 (0.5)
1.66 (0.7)
0.37 (0.1)
0.51 (0.1)
0.54 (0.1)
0.79 (0.3)
0.8 (0.3, 4.0)
AUC0–tau, area under the concentration–time curve from time 0 to the end of the treatment period (tau ¼ 6 hours); AUC0–inf, area under the concentration– time curve from time 0 to the last quantifiable concentration, then extrapolated to infinity; C0, initial plasma concentration; CL, clearance; Cmax, maximum concentration; SD, standard deviation; t1/2, terminal half-life; Tmax, time to maximum concentration; Vd, volume of distribution based on the terminal phase. a Data for subject 16 were excluded from this table because this subject did not receive an intravenous dose.
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Table 2. Dose Proportionality of DFP-08a
Comparisons between different dosage forms with different routes of administrations (intravenous bolus vs oral tablet) are not normally expected to exhibit similar PK profiles. However, comparisons of the extent of diclofenac exposure after the single-dose treatment indicate that the exposure of DFP-08 18.75 mg is similar to oral diclofenac 50 mg. The 18.75- and 37.5-mg doses of DFP-08 demonstrated dose proportionality for exposure as measured by the AUC. The C0 comparisons did not show proportionality in this study, but because recording was done to the minute and calculations were made 2 and 5 minutes after the start of the 1-minute bolus administration, accuracy of dosing and sampling times affected more than the typical measure of Cmax from an oral preparation. This methodological limitation may have increased the variability of initial plasma concentrations and inflated the 90%CI. The PK results align with expectations and indicate that DFP-08 will be clinically useful in the treatment of a variety of patients with pain and inflammation. In hospitalized patients, DFP-08 may provide a safe and effective nonoral therapy with a rapid onset of action and minimal risk of the central nervous system and GI side effects associated with opioids. Among patients who are transitioning to outpatient care, the comparable diclofenac exposure of DFP-08 18.75 mg with single-dose diclofenac 50-mg oral tablets will simplify switching to an oral NSAID regimen. Finally, the linear PK of DFP-08 will provide simplified dosing in patients receiving multimodal analgesia or other types of polypharmacy. Safety results were similar to those seen in previous research with intravenous diclofenac,12 and no new concerns were identified. All TEAEs were mild in intensity and required no treatment. Overall, both the 18.75- and 37.5-mg doses of DFP-08 were well tolerated. The cause of the elevated liver enzymes in 1 subject (a 28-year-old Asian man) treated with DFP-08 is unknown. At screening, AST was 18 U/L (normal range, 15–46 U/L), and ALT was 20 U/L (normal range, 11–65 U/L). Medical history revealed no chronic illnesses or liver abnormalities, and a creatinine phosphokinase test on the original sample
DFP-08 Parameter
Ratiob
90%CI
AUC0–inf (ng h/mL) C0 (ng/mL)
104.1 94.4
94.5 to 114.7 69.2 to 128.8
AUC0–tau (ng h/mL) C0 (ng/mL)
101.3 95.0
92.0 to 111.4 68.6 to 131.8
Single dose
Multiple dose
AUC0–inf, area under the concentration–time curve from time 0 to the last quantifiable concentration then extrapolated to infinity; AUC0–tau, area under the concentration–time curve from time 0 to the end of the treatment period (tau ¼ 6 hours); CI, confidence interval; C0, initial plasma concentration. a Data for subject 16 for the single intravenous bolus dose were excluded because this subject did not receive an intravenous dose. b The ratios were 37.5/18.75 mg; 90% confidence intervals for the treatment difference.
follow-up visit (day 22, 9 days after discharge) were 26 and 66 U/L, respectively. After this report, the protocol for the study was amended to provide additional information on liver function: blood samples for chemistry laboratory tests were collected on day -1 and from day 4 through day 12, inclusive; the blood volumes required for each study day were updated, and daily monitoring via chemistry blood draw from day 4 until the end of the study was implemented. After the change in protocol, no increases in liver enzyme tests were observed for the remaining subjects. All other changes from baseline in clinical laboratory and vital sign results were considered not clinically significant.
Discussion This phase 1 study in healthy adult subjects compared the safety and PK parameters of intravenous diclofenac sodium following single- and multiple-dose bolus administration with single-dose diclofenac potassium 50-mg oral tablets. It represents the first exposure of the DFP-08 formulation of diclofenac in humans.
Table 3. Treatment-Emergent Drug-Related Adverse Events in >1 Subject DFP-08 Diclofenac Potassium
Placebo
Preferred Term
(n ¼ 42) n (%)
(n ¼ 14) n (%)
Any event Related Infusion site pain Alanine aminotransferase increased Aspartate aminotransferase increased Erythema
2 0 0 0 0 0
6 1 0 0 0 1
(4.8) (0.0) (0.0) (0.0) (0.0) (0.0)
(42.9) (7.1) (0.0) (0.0) (0.0) (7.1)
Total 18.75 mg (n ¼ 14) n (%) 1 1 1 0 0 1
(7.1) (7.1) (7.1) (0.0) (0.0) (7.1)
37.5 mg (n ¼ 14) n (%)
Total (n ¼ 28) n (%)
(N ¼ 42) n (%)
2 2 0 1 1 1
3 3 1 1 1 2
10 4 1 1 1 3
(14.3) (14.3) (0.0) (7.1) (7.1) (7.1)
(10.7) (10.7) (3.6) (3.6) (3.6) (7.1)
(23.8) (9.5) (2.4) (2.4) (2.4) (7.1)
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94 Table 4. Summary of Treatment-Emergent Thrombophlebitis
Event Severity Single dose Grade 0 Grade 1 Multiple doses Grade 0 Grade 1 Grade 2 Grade 3 Grade 4 Grade 2 or higher n
Placebo (n ¼ 14) n (%, 95% CI)a
DFP-08 18.75 mg (n ¼ 14) N (%, 95% CI)a
DFP-08 37.5 mg (n ¼ 14) N (%, 95% CI)a
DFP-08 Total (N ¼ 28) N (%, 95% CI)a
12 (85.7, 57.2–98.2) 2 (14.3, 1.8–42.8)
13 (92.9, 66.1–99.8) 1 (7.1, 0.2–33.9)
14 (100, 76.8–100) 0
27 (96.4, 81.7–99.9) 1 (3.6, 0.1–18.3)
7 (50.0, 23.0–77.0) 5 (35.7, 12.8–64.9) 2 (14.3, 1.8–42.8) 0 0
5 (35.7, 12.8–64.9) 4 (28.6, 8.4–58.1) 3 (21.4, 4.7–50.8) 2 (14.3, 1.8–42.8) 0
8 (57.1, 28.9–82.3) 4 (28.6, 8.4–58.1) 0 1 (7.1, 0.2–33.9) 1 (7.1, 0.2–33.9)
13 (46.4, 27.5–66.1) 8 (28.6, 13.2–48.7) 3 (10.7, 2.3–28.2) 3 (10.7, 2.3–28.2) 1 (3.6, 0.1–18.3)
2 (14.3, 1.8–42.8)
5 (35.7, 12.8–64.9)
2 (14.3, 1.8–42.8)
7 (25.0, 10.7–44.9)
CI, confidence interval. Grade 0, no reaction; grade 1, tenderness along the vein; grade 2, continuous tenderness or pain with redness; grade 3, palpable swelling or thrombosis within length of the cannula; grade 4, palpable swelling or thrombosis beyond the length of the cannula; and grade 5, as for grade 4, with overt infection. The frequency and percentage of subjects reporting any thrombophlebitis within the same day following the initial dose are presented by grade. Percentages are n/N 100. The grade shown is the greatest grade reported per event for a particular subject (0 < 1 < 2 < 3 < 4 < 5). a Exact confidence intervals are from Clopper-Pearson intervals for binomial proportions.
to check for rhabdomyolysis was within the normal range. The results for the follow-up visits on days 18 and 22 demonstrated a downward trend. Because there were no clinically significant laboratory, vital sign, or ECG results, and daily measurements showed no change in liver enzymes in any of the other subjects, it is possible this individual is among the subset of patients who experience elevated liver enzymes during treatment with diclofenac. A review of the medical literature published on phlebitis associated with intravenous catheters revealed that phlebitis develops in about 30% of patients (range, 4%–45%), with an average incidence of 30% per catheter (range, 25%–35%).13,14 With 12 evaluable subjects in the active treatment arms, the proportion of phlebitis using a 95%CI was estimated with a precision of 26% within both active treatment arms. Pooling both active treatment arms (24 subjects), the proportion of phlebitis using a 95% CI was estimated with a precision of 18%. DFP-08 uses the same active ingredient, dosing and route of administration as a recently approved formulation of diclofenac sodium for intravenous injection.10,14,15 However, DFP-08 contains no hydroxypropyl-beta-cyclodextrin (HPbCD), a cyclic glucose-derived oligomer used to enhance the solubility of diclofenac.14 In a conventional carcinogenesis study, rats treated with HPbCD 500 to 5000 mg/kg per day for 25 months had a significantly higher incidence of pancreatic hyperplasia and neoplasia, as well as adenocarcinomas of the exocrine pancreas, than untreated animals and historical controls.15 The clinical significance of these findings is unknown. The study has a few limitations. Results for grade 1 thrombophlebitis are likely to be confounded because the intravenous line was left in for 3 days per protocol requirements and the clinical unit standard of care;
these results are not reported. In addition, the intravenous AUC results of the study suggest no accumulation of DFP-08, as the 18.75-mg intravenous bolus had an AUCtau/AUCinf of 0.927, and the 37.5-mg intravenous bolus had a ratio of 0.893 based on mean values from Table 1. Because the C0 for the intravenous bolus was a back-extrapolation from the first 3 observed concentrations, it is less reliable. No additional statistical assessment of accumulation was included in the analysis plans.
Conclusions These results demonstrate that the diclofenac exposure of a single dose of intravenous diclofenac 18.75 mg is comparable to a single dose of a diclofenac potassium 50-mg oral tablet. In addition, dose proportionality was demonstrated for exposure, as measured by the AUC from the 2 intravenous diclofenac doses (18.75 and 37.5 mg), but not for the C0 extrapolations. No accumulation was apparent on multiple dosing of DFP-08 based on the exposure (AUC) values. Finally, the 18.75- and 37.5-mg doses of intravenous diclofenac (single and multiple) were well tolerated for 7 days. Declaration of Conflicting Interests S.M., A.G., F.O., and K.A. are employees of Dr. Reddy’s Laboratories, which manufactures a formulation of diclofenac sodium for intravenous injection; J.M. is a paid consultant.
Acknowledgments The authors acknowledge Kendra Gulbronson, and Alix Bennett, PhD, for assistance in the conduct of the study and preparation of the article. Medical writing services were provided by Onesta Inc.
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References 1. Derry P, Derry S, Moore RA, McQuay HJ. Single dose oral diclofenac for acute postoperative pain in adults. Cochrane Database Syst Rev. 2009;(2):CD004768. 2. Marret E, Kurdi O, Zufferey P, Bonnet F. Effects of nonsteroidal antiinflammatory drugs on patient-controlled analgesia morphine side effects: meta-analysis of randomized controlled trials. Anesthesiology. 2005;102:1249–1260. 3. Christensen K, Daniels S, Bandy D, et al. A double-blind placebocontrolled comparison of a novel formulation of intravenous diclofenac and ketorolac for postoperative third molar extraction pain. Anesth Prog. 2011;58:73–81. 4. Gan TJ, Daniels SE, Singla N, Hamilton DA, Carr DB. A novel injectable formulation of diclofenac compared with intravenous ketorolac or placebo for acute moderate-to-severe pain after abdominal or pelvic surgery: a multicenter, double-blind, randomized, multiple-dose study. Anesth Analg. 2012;115:1212– 1220. 5. Hovorka J, Kallela H, Korttila K. Effect of intravenous diclofenac on pain and recovery profile after day-case laparoscopy. Eur J Anaesthesiol. 1993;10:105–108. 6. Claeys MA, Camu F, Maes V. Prophylactic diclofenac infusions in major orthopedic surgery: effects on analgesia and acute phase proteins. Acta Anaesthesiol Scand. 1992;36:270–275. 7. Daniels S, Melson T, Hamilton DA, Lang E, Carr DB. Analgesic efficacy and safety of a novel injectable formulation of diclofenac compared with intravenous ketorolac and placebo after orthopedic
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surgery: a multicenter, randomized, double-blinded, multiple-dose trial. Clin J Pain. 2013;29:655–663. Tigerstedt I, Janhunen L, Tammisto T. Efficacy of diclofenac in a single prophylactic dose in postoperative pain. Ann Clin Res. 1987;19:18–22. Hyrk€as T, Ylipaavalniemi P, Oikarinen VJ, Paakkari I. Preoperative intravenous diclofenac for postoperative pain prevention in outpatients. Br J Oral Maxillofac Surg. 1993;31:351–354. Dyloject(diclofenac sodium) Prescribing Information. http://www. hospira.com/Images/DYLOJECT-(diclofenac_sodium)-InjectionPackage-Insert_81-95926_2.pdf. Accessed March 2, 2015. Dinley RJ. Venous reactions related to indwelling plastic cannulae: a prospective clinical trial. Curr Med Res Opin. 1976;3:607–611. Mermelstein F, Hamilton DA, Wright C, Lacouture PG, Ramaiya A, Carr DB. Single-dose and multiple-dose pharmacokinetics and dose proportionality of intravenous and intramuscular HPbCDdiclofenac (Dyloject) compared with other diclofenac formulations. Pharmacotherapy. 2013;33:1012–1021. Ahlqvist M, Berglund B, Nordstrom G, Klang B, Wiren M, Johansson E. A new reliable tool (PVC assess) for assessment of peripheral venous catheters. J Eval Clin Pract. 2010;16:1108–1115. Tagalakis V, Kahn SR, Libman M, Blostein M. The epidemiology of peripheral vein infusion thrombophlebitis: a critical review. Am J Med. 2002;113:146–151. Dyloject1 75mg/2ml Solution for Injection-PL 25053/0001. http:// www.mhra.gov.uk/home/groups/par/documents/websiteresources/ con2033165.pdf. Accessed March 2, 2015.
Safety and Pharmacokinetics of Single and Multiple Intravenous Bolus Doses of Diclofenac Sodium Compared With Oral Diclofenac Potassium 50 mg: A Randomized, Parallel-Group, Single-Center Study in Healthy Subjects
The Journal of Clinical Pharmacology 2016, 56(1) 87–95 © 2015, The American College of Clinical Pharmacology DOI: 10.1002/jcph.575
Sagar Munjal, MD, MS1, Anirudh Gautam, MPharm2, Franklin Okumu, PhD2, James McDowell, PhD3, and Kent Allenby, MD, FACP2
Abstract In a randomized, parallel-group, single-center study in 42 healthy adults, the safety and pharmacokinetic parameters of an intravenous formulation of 18.75 and 37.5 mg diclofenac sodium (DFP-08) following single- and multiple-dose bolus administration were compared with diclofenac potassium 50 mg oral tablets. Mean AUC0–inf values for a 50-mg oral tablet and an 18.75-mg intravenous formulation were similar (1308.9 [393.0]) vs 1232.4 [147.6]). As measured by the AUC, DFP-08 18.75 mg and 37.5 mg demonstrated dose proportionality for extent of exposure. One subject in each of the placebo and DFP-08 18.75-mg groups and 2 subjects in the DFP-08 37.5-mg group reported adverse events that were considered by the investigator to be related to the study drug. All were mild in intensity and did not require treatment. Two subjects in the placebo group and 1 subject in the DFP-08 18.75-mg group reported grade 1 thrombophlebitis; no subjects reported higher than grade 1 thrombophlebitis after receiving a single intravenous dose. The 18.75- and 37.5-mg doses of intravenous diclofenac (single and multiple) were well tolerated for 7 days. Additional efficacy and safety studies are required to fully characterize the product.
Keywords safety, pharmacokinetics, diclofenac, intravenous, oral
Nonsteroidal anti-inflammatory drugs (NSAIDs) are mainstays in the medical treatment of acute pain, and diclofenac—an amino phenylacetic acid derivative that inhibits prostaglandin biosynthesis to produce analgesic, antipyretic, and anti-inflammatory activity—is among the most widely used agents in the class.1 Frequently prescribed for oral administration (as a tablet or water-soluble powder) to relieve pain and reduce inflammation, diclofenac for intravenous injection may be preferable in a number of clinical situations, such as when a rapid onset of relief is required; when reduction`s in systemic availability and variability due to hepatic first-pass metabolism will have clinical consequences; when dysphagia or ileal/ gastrointestinal (GI) sensitivity preclude the use of oral agents; or when opioids are contraindicated due to issues with tolerability or misuse, and an equianalgesic2 intervention is needed. A number of randomized, well-controlled clinical trials have demonstrated the safety, efficacy, and opioid-sparing effects of intravenous diclofenac in subjects with acute pain following dental surgery,3 abdominal surgery,4 laparoscopic surgery,5 orthopedic procedures,6,7 and general postoperative pain.8,9 In the United States,
diclofenac sodium for intravenous injection was recently approved for management of mild to moderate pain and moderate to severe pain alone or in combination with opioid analgesics.10 A reformulation of diclofenac administered by intravenous bolus as an oil-in-water emulsion of 37.5 mg diclofenac sodium per milliliter of vehicle (DFP-08) is being investigated for clinical use. During pharmaceutical and preclinical toxicology development, DFP-08 was
1 Senior Director/Head of Neurology Clinical Development and Medical Affairs, Proprietary Products, Dr. Reddy’s Laboratories, Princeton, NJ, USA 2 Dr. Reddy’s Laboratories, Princeton, NJ, USA 3 Premier Research Group, Austin, TX, USA
Submitted for publication 21 April 2015; accepted 15 June 2015. Corresponding Author: Sagar Munjal, MD, MS, Senior Director/Head of Neurology Clinical Development and Medical Affairs, Proprietary Products, Dr. Reddy’s Laboratories, 107 College Road East, Princeton, NJ 08540 Email: [email protected]
88 examined for in-life findings, injection site reactions, clinical pathology observations, and formulation stability characteristics that might influence clinical use. No new adverse nonclinical pathology findings were observed, and pharmaceutical development data support a stable intravenous preparation suitable for human use. Previous clinical trial experience and routine clinical use of other intravenous formulations of diclofenac outside the United States suggest a benefit-risk assessment that favors further development of DFP-08 as a viable intravenous diclofenac option for patients. Objectives The objectives of the present study were to assess the safety and pharmacokinetic (PK) parameters of DFP-08 following single- and multiple-dose bolus administration compared with diclofenac potassium 50-mg oral tablets (CataflamTM; Novartis Pharmaceuticals Corp, East Hanover, New Jersey).
Methods Design This was a randomized, parallel-group, single-center PK study in 42 healthy adults. The Chesapeake Institutional Review Board in Columbia, Maryland, reviewed and approved the protocol and protocol amendments, informed consent form, and related subject information and recruitment materials. The study was conducted in accordance with Good Clinical Practice requirements and all applicable regulations. Subjects Male and female subjects were eligible to participate if they were able to understand the requirements of the study, willing and able to give written informed consent, between 18 and 45 years of age (inclusive), and in good general health; had a body weight 50 kg and a body mass index 18 and 30 kg/m2; agreed to use no other medication (including over-the-counter products), herbal products, or vitamin or dietary supplements (including St. John’s wort) during the 7 days prior to the first dose of the study and continuing until after the final visit (excluding hormonal contraceptives and hormone replacement therapy); were free of any systemic disorder that could interfere with the study results in the opinion of the investigator; were not of childbearing potential or practicing a medically acceptable method of birth control. Subjects were excluded from participation for any of the following reasons: history of allergic reaction or clinically significant intolerance to acetaminophen, aspirin, or any NSAID, including diclofenac; history of NSAID-induced bronchospasm (subjects with the triad of asthma, nasal polyps, and chronic rhinitis are at greater risk for bronchospasm and were considered carefully);
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hypersensitivity, allergy, or significant reaction to any ingredients in the study drug; pregnant or nursing or planning to become pregnant during the study; participated in a trial involving any investigational product in the 30 days before the screening visit; had a clinically significant history of respiratory, gastrointestinal, hepatic, renal, hematologic, endocrinal, oncologic, immunologic, GI, neurologic, drug or alcohol abuse (within the last 2 years), or psychiatric disorders or any other disease or medical condition that would interfere with the study; a known history of vasculitis, phlebitis, or any other condition predisposing to venous inflammation events more readily than the general population; history of intravenously induced cellulitis, intravenous drug abuse, or clotting disorder; abnormal laboratory results at screening; history of blood or plasma donation within 90 days before the first day of dosing; were unable to participate or cooperate with the study procedures for any reason. Treatments DFP-08 was provided in 2-mL vials containing 75 mg diclofenac sodium as a yellowish, translucent, or semitransparent oil-in-water emulsion for intravenous bolus administration. Each milliliter contained 3.75% diclofenac sodium, 10% phospholipids, 5% medium-chain triglycerides, 0.0055% ethylenediaminetetraacetic acid disodium dehydrate, 5% sucrose in water for injection. Diclofenac potassium was provided as 50-mg oral tablets, and vehicle was provided in the form of an emulsion for intravenous bolus administration that was visually identical to the active treatments. All study drugs were protected from light and stored in a tightly closedlight-resistant container at 2°C to 8°C. Protocol The study was divided into a screening period, administration of oral diclofenac potassium 50-mg tablet (period 1), a washout period, a treatment period (period 2), and a safety follow-up visit. The screening period took place within 21 days before administration of the diclofenac potassium 50-mg oral tablet on day 1. Subjects provided written informed consent before any procedures or evaluations were completed, and they were evaluated against protocolspecified inclusion and exclusion criteria to determine their eligibility for participation. During period 1, eligible subjects were admitted to the clinical research unit (CRU) on day -1. All subjects underwent at least a 10-hour overnight fast. The following morning (day 1), subjects received a single oral diclofenac potassium 50-mg tablet with 240 mL of water. The fast was maintained until the first meal given 4 hours after dosing. Subjects were confined to the CRU until at least 24 hours after study drug administration.
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During period 2, after completing a washout period (days 2 to 4), subjects underwent at least a 10-hour overnight fast. The following morning (day 5), based on a computer-generated randomization schedule, subjects were randomized equally to receive a single intravenous bolus dose of diclofenac sodium 18.75 mg in 0.5 mL, diclofenac sodium 37.5 mg in 1 mL, or placebo in 1 mL over a duration of 1 minute to characterize the single-dose intravenous bolus PK profile on day 5 over 24 hours. To account for the difference in volume between DFP-08 37.5 mg and DFP-08 18.75 mg and placebo, all intravenous treatments were administered by unblinded study center staff who did not participate in the safety assessments. Syringes used to administer study drugs were covered with white tape to maintain the blind for patients, the investigator, and all other study staff. Intravenous catheters for administration of the study drug were placed in a nondominant forearm location, avoiding the hand and antecubital fossa, if possible. Intravenous access sites were maintained in a sterile, aseptic fashion, flushed every 4–6 hours with normal saline, and changed at least every 72 hours. If additional intravenous access sites were required because of clotting, infection, or intolerable irritation, the number of changes and the reasons for each change were documented for each subject. On days 5 (single-dose intravenous bolus PK profile) and 6, at 2 minutes after dosing, a 4-mL blood sample for complete blood count was drawn to inspect for evidence of hemolysis. If there was no evidence of hemolysis, then intravenous bolus multiple doses administered every 6 hours were started on day 6 and continued to the final dose on the morning of day 12 (multiple-dose intravenous bolus PK profile). Subjects received a total of 25 doses of their assigned intravenous bolus treatment by intravenous pushover 1 minute. On the evening of day 11, subjects underwent at least a 10-hour overnight fast. The final dose of the study drug was administered at the end of the overnight fast on the morning of day 12 to characterize the multiple-dose intravenous bolus PK profile at steady state. Standardized meals were provided. On day 5 (single-dose PK profile) and day 12 (multiple-dose PK profile), the fast was maintained until the first meal given 4 hours after the dosing. On days 6 to 11, the meals (breakfast, lunch, snack, dinner) were provided at the same time each day. Subjects were discharged from the CRU after completing all protocol-specified procedures scheduled for day 13. Subjects returned to the CRU on day 17 ( 2 days) for the safety follow-up visit. Pharmacokinetic and Safety Variables Pharmacokinetics. Blood samples (approximately 5 mL each) for PK analysis from all administered treatments were collected on days 1 (single-dose oral profile), 5 (single-dose intravenous bolus profile), and
89 12 (multiple-dose intravenous bolus profile) at the following times: before dosing (time 0); 2, 5, 10, 15, and 20 minutes after dosing; and 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, and 24 hours after dosing. For intravenous diclofenac treatment, sampling times were calculated from the start of the 1-minute intravenous bolus. The predose sample was obtained within 30 minutes before dosing. Postdose PK blood samples collected at times 0.5 hours after dosing were obtained within 1 minute of the scheduled sampling time; samples collected at times > 0.5 hours were obtained within 2 minutes of the scheduled sampling time. The PK blood sample collected 24 hours after dosing was obtained within 5 minutes of the scheduled sampling time. The concentration of diclofenac in plasma samples was determined using high-performance liquid chromatography with mass spectrometric detection. The method used was validated for a lower concentration range of 2.50 to 750 ng/mL and a higher range of 30 to 1500 ng/mL to cover the expected concentration range of the samples from this multidose study. The accuracy (%Bias) and precision (%CV) of quality control samples ranged from 0.00% to -3.5% and 3.8% to 6.1%, respectively, across the 2 concentration ranges. Safety Safety was assessed largely on the basis of local tolerance (venous irritation, phlebitis, and/or thrombophlebitis), which was the primary safety end point. Only injectionsite reactions not evaluated as these end points (ie, other than phlebitis, vasculitis, cellulitis, and other dermal findings at the intravenous access site) were reported as adverse events (AEs) of special interest. Safety was also evaluated by the incidence of treatment-emergent AEs (TEAEs), clinical laboratory test results, and changes in vital signs. Additional AEs of special interest included GI complaints (specifically GI bleeding) and any cardiovascular complications and outcomes, including cardiac death, myocardial infarction, ischemia, and stroke. Thrombophlebitis was assessed using a 6-point Likert-type scale11 (0 ¼ no reaction, 1 ¼ tenderness along the vein, 2 ¼ continuous tenderness or pain with redness, 3 ¼ palpable swelling or thrombosis within the length of the cannula, 4 ¼ palpable swelling or thrombosis beyond the length of the cannula, 5 ¼ as for grade 4, with overt infection) predose (after the intravenous catheter was placed and before each bolus was administered), immediately after each intravenous dose, every 6 hours after the initial intravenous dose on day 5 and continuing through day 12, immediately before and after each change or discontinuation of intravenous access site during the inpatient phase, on day 13, and at the follow-up visit. The Thrombophlebitis Assessment was performed at each discontinued intravenous site every 6 hours through day 12.
90 Statistical Methods Analysis Populations. Two analysis populations were defined for this study. The safety population included all subjects who received any amount of the study drug. The PK population included all subjects in the safety population who had at least 1 quantifiable diclofenac concentration after dosing. Pharmacokinetic Parameter Estimation. All PK parameters were estimated with Phoenix WinNonlin, version 6.3, using actual elapsed sampling times from the time of drug administration to the time of sample collection. The diclofenac potassium oral tablet doses were characterized using an extravascular administration single-dose model, and the intravenous bolus doses were characterized using an intravenous administration single- or multiple-dose model as appropriate. Observed peak concentration parameters included the maximum concentration (Cmax) and its time of collection (Tmax) for the oral diclofenac potassium administration and back-extrapolated concentration at time of administration (C0) for the DFP-08 intravenous bolus administrations. The observed extent of systemic availability was measured by AUC to the last concentration and then extrapolated to infinity (AUC0–inf) for the single-dose administrations of diclofenac potassium tablets and DFP-08 and by AUC0–tau for the multipledose DFP-08 administration. Clearance (CL) was calculated from the dose and the AUC0–tau for the multiple-dose DFP-08 administration. Additional PK parameters were calculated when the elimination rate constant (kel) could be estimated. These included the coefficient of determination (Rsq), half-life (t1/2) and its associated AUC%Extrap, CL (CL/F for oral), Vd (Vd/F for oral), and the AUC%BackExt associated with the C0. The only additional parameter from the multiple-dose administration was Vd. Pharmacokinetic Parameter Analysis. All PK parameter analyses (except for PK parameter estimation) were performed using SAS software, version 9.3. The AUC0–t and AUC0–inf for single-dose intravenous bolus DFP-08 were compared with the corresponding single-dose oral diclofenac (diclofenac potassium) AUC measures using a mixed analysis of variance (ANOVA) model with terms for sequence, subject within sequence, and treatment. The ANOVA models were run on the natural log-transformed values. The least-squares means and the standard error values from the analyses were used to construct the 90% confidence intervals (CIs) for the relative bioavailability evaluations. The dose proportionality of the 18.75- and 37.5-mg single- and multiple-dose profiles of DFP-08 was assessed. The dose-normalized AUC0–tau, AUC0–t, and C0 were logarithmically transformed and analyzed by computing the ratios of the geometric means by using the least-squares mean and standard error values from an ANOVA model with a term for treatment. Dose
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proportionality was demonstrated if the 90%CIs for the ratios of geometric means were within the 80% to 125% range. The sample size was considered sufficient to provide adequate valid data to meet the study objectives. To accommodate possible dropouts, withdrawals, or both, 42 subjects (14 per arm) entered the study to obtain valid data on at least 36 subjects (12 per arm). Discontinued subjects were not replaced. Safety Analysis. Adverse events were coded using the Medical Dictionary for Regulatory Activities, version 16.0. All AEs were summarized by frequencies and percentages of subjects. Local tolerance (venous irritation, phlebitis, and/or thrombophlebitis) was the primary safety end point, as quantified by the Thrombophlebitis Assessment. In addition to frequencies and percentage of subjects reporting any thrombophlebitis within the first 6 hours, exact 95%CIs for the proportion of subjects with phlebitis at each grade were calculated by treatment and for the pooled active treatment arms (37.5- and 18.75-mg doses). The proportions of subjects with a grade 2 or higher severe reaction were summarized and reported along with the 95%CIs. Similar analyses were presented for the multiple-dosing phase of the study.
Results A total of 42 subjects were randomized into the study, including the PK and safety populations. Of these, 3 subjects (2 [14.3%] in the placebo group and 1 subject [3.6%] in the DFP-08 37.5-mg group) were discontinued from the study prematurely because of procedurerelated study noncompliance (Figure 1). Overall, a majority of the subjects were female (57.1%, 24 of 42 subjects) and black or African American (66.7%, 28 of 42 subjects); 2 subjects (28.6%) were Hispanic or Latino. Subjects’ mean age was 31.1 (7.9) years. Their mean (SD) weight was 75.5 (12.8) kg, mean (SD) height was 173.0 (10.2) cm, and mean (SD) body mass index was 25.0 (2.4) kg/m2. Pharmacokinetics As shown in Figure 2, the initial measurable diclofenac concentrations appeared at 10 minutes in 47.6% of subjects (20 of 42) after single-dose oral diclofenac potassium administration, at 2 minutes in 96.4% of subjects (27 of 28) after the single-dose intravenous bolus and was present for 100% of subjects (27 of 27) at the 5-minute predose sample for the multiple-dose intravenous bolus. No measureable concentrations were reported 24 hours after administration of any dose. One subject mistakenly received a subcutaneous dose rather than an intravenous bolus dose of DFP-08 18.75 mg. The error was discovered when results showed absorption rates that would not be possible after
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Figure 1. Disposition of subjects.
administration of an intravenous bolus dose of DFP-08 18.75 mg. Specifically, unlike the other 13 subjects who were given DFP-08 18.75 mg, each of whom had a concentration exceeding 1000 mg/mL at 5 minutes postdose, the concentration profile for this subject first appeared at 34.4 ng/mL. Because 4 concentrations
Figure 2. Mean diclofenac concentrations over time.
confirmed the aberrant pattern of absorption, this particular intravenous bolus administration appears to have missed the vein. As a result, data from this subject are not reported. The PK parameters for the single-dose oral tablet and the single-and multiple-dose intravenous bolus admin-
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Safety. No deaths, SAEs, or discontinuations of the study drug because of TEAEs occurred during the study. The only TEAEs that were reported in more than 1 subject overall were erythema, presyncope, and abdominal pain, none of which was judged by the investigator to be severe. As shown in Table 3, 1 subject each in the placebo and DFP-08 18.75-mg groups and 2 subjects in the DFP-08 37.5-mg group reported TEAEs that were considered by the investigator to be related to the study drug. All were mild in intensity and did not require treatment. After the single-dose intravenous bolus treatment, 3 subjects (2 subjects [14.3%] in the placebo group and 1 subject [7.1%] in the DFP-08 18.75-mg group) reported grade 1 thrombophlebitis. No subjects in any group reported higher than grade 1 thrombophlebitis after receiving a single intravenous dose. The incidence of grade 1 thrombophlebitis after the multiple-dose phase ranged from 28.6% (DFP-08 18.75 and 37.5 mg) to 35.7% (placebo). Of the 9 subjects who reported grade 2 or higher thrombophlebitis, 2 subjects (14.3%) each were in the placebo and DFP-08 37.5-mg groups, and 5 (35.7%) were in the DFP-08 18.75-mg group (Table 4). On day 13 during discharge assessments, 1 subject (a 28-year-old Asian man) in the DFP-08 37.5-mg group had an aspartate transaminase (AST) of 55 U/L (normal range, 15–46 U/L) and an alanine aminotransferase (ALT) of 115 U/L (normal range, 11–65 U/L). These AEs were considered by the investigator to be probably or possibly related to the study drug. The follow-up visit scheduled 5 days after discharge (day 18) showed an AST of 110 U/L and ALT of 147 U/L; the AST and ALT for the second
istrations of diclofenac are summarized in Table 1. Mean AUC0–inf values for 50-mg oral tablet and 18.75 mg intravenously were similar (1308.9 [393.0] vs 1232.4 [147.6]), but both were lower than DFP-08 37.5 mg intravenously (2582.2 [426.6]). Tmax values for the singledose diclofenac 50-mg oral tablet ranged from 20 minutes to 4 hours, with a median of 0.8 hours. Results for half-life were similar across all dosage forms (1.2–2.4 hours), but the observed half-life of DFP-08 18.75 mg increased by 0.5 hours and DFP-08 37.5 mg by 0.7 hours after multiple dosing. Close examination of the 10-hour sample in the semilog insert (Figure 2) suggests that the 37.5 mg DFP-08 single dose may have been unduly influenced by that sampling time. The CL and Vd values were similar across all DFP-08 administrations. In the single-dose comparisons of the 2 intravenous bolus treatments to the oral diclofenac 50-mg treatment, the 18.75-mg intravenous bolus of DFP-08 had an AUC0–t ratio point estimate of 107.5% (90%CI, 95.8%–120.7%), and DFP-08 37.5 mg had an AUC0–t ratio point estimate of 187.3% (90%CI, 167.6%–209.4%). For the AUC0–inf ratio comparisons, the 18.75-mg intravenous bolus had a ratio point estimate of 107.1% (90%CI, 95.5%–120.2%), and the 37.5-mg intravenous bolus had a ratio point estimate of 186.5% (90%CI, 166.9%–208.4%). Dose proportionality was demonstrated for the AUC measures from the 2 DFP-08 doses (18.75 and 37.5 mg), but not for the C0 comparisons (Table 2). The C0 point estimates were 94.4% and 95.0% for the single- and multiple-dose comparisons, respectively. The C0 had a % CV that ranged from 41% to 50%.
Table 1. Diclofenac PK Parameters for the Oral Tablet and the Single- and Multiple-Dose Intravenous Bolus Administrations Diclofenac Sodium Single Dose
Parameter AUC0–tau (ng h/mL) Mean (SD) AUC0–inf (ng h/mL) Mean (SD) Cmax or C0 (ng/mL) Mean (SD) Tmax (h) Median (min, max) t1/2 (h) Mean (SD) CL or CL/F (mL/min/kg) Mean (SD) Vd or Vd/F (L/kg) Mean (SD)
Diclofenac Potassium 50 mg (n ¼ 42)
18.75 mga (n ¼ 13)
Multiple Dose 37.5 mg (n ¼ 14)
18.75 mg (n ¼ 14)
37.5 mg (n ¼ 14)
1142.7 (179.5)
2305.5 (297.8)
1308.9 (393.0)
1232.4 (147.6)
2582.2 (426.6)
1041.4 (607.4)
6143.6 (2503.5)
11 702.0 (5029.8)
6024.8 (3014.3)
10 914.9 (4506.8)
2.1 (0.8)
1.3 (0.2)
1.8 (0.4)
1.7 (0.3)
2.5 (0.9)
9.3 (2.6)
3.4 (0.5)
3.3 (0.4)
3.7 (0.5)
3.7 (0.5)
1.66 (0.7)
0.37 (0.1)
0.51 (0.1)
0.54 (0.1)
0.79 (0.3)
0.8 (0.3, 4.0)
AUC0–tau, area under the concentration–time curve from time 0 to the end of the treatment period (tau ¼ 6 hours); AUC0–inf, area under the concentration– time curve from time 0 to the last quantifiable concentration, then extrapolated to infinity; C0, initial plasma concentration; CL, clearance; Cmax, maximum concentration; SD, standard deviation; t1/2, terminal half-life; Tmax, time to maximum concentration; Vd, volume of distribution based on the terminal phase. a Data for subject 16 were excluded from this table because this subject did not receive an intravenous dose.
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Table 2. Dose Proportionality of DFP-08a
Comparisons between different dosage forms with different routes of administrations (intravenous bolus vs oral tablet) are not normally expected to exhibit similar PK profiles. However, comparisons of the extent of diclofenac exposure after the single-dose treatment indicate that the exposure of DFP-08 18.75 mg is similar to oral diclofenac 50 mg. The 18.75- and 37.5-mg doses of DFP-08 demonstrated dose proportionality for exposure as measured by the AUC. The C0 comparisons did not show proportionality in this study, but because recording was done to the minute and calculations were made 2 and 5 minutes after the start of the 1-minute bolus administration, accuracy of dosing and sampling times affected more than the typical measure of Cmax from an oral preparation. This methodological limitation may have increased the variability of initial plasma concentrations and inflated the 90%CI. The PK results align with expectations and indicate that DFP-08 will be clinically useful in the treatment of a variety of patients with pain and inflammation. In hospitalized patients, DFP-08 may provide a safe and effective nonoral therapy with a rapid onset of action and minimal risk of the central nervous system and GI side effects associated with opioids. Among patients who are transitioning to outpatient care, the comparable diclofenac exposure of DFP-08 18.75 mg with single-dose diclofenac 50-mg oral tablets will simplify switching to an oral NSAID regimen. Finally, the linear PK of DFP-08 will provide simplified dosing in patients receiving multimodal analgesia or other types of polypharmacy. Safety results were similar to those seen in previous research with intravenous diclofenac,12 and no new concerns were identified. All TEAEs were mild in intensity and required no treatment. Overall, both the 18.75- and 37.5-mg doses of DFP-08 were well tolerated. The cause of the elevated liver enzymes in 1 subject (a 28-year-old Asian man) treated with DFP-08 is unknown. At screening, AST was 18 U/L (normal range, 15–46 U/L), and ALT was 20 U/L (normal range, 11–65 U/L). Medical history revealed no chronic illnesses or liver abnormalities, and a creatinine phosphokinase test on the original sample
DFP-08 Parameter
Ratiob
90%CI
AUC0–inf (ng h/mL) C0 (ng/mL)
104.1 94.4
94.5 to 114.7 69.2 to 128.8
AUC0–tau (ng h/mL) C0 (ng/mL)
101.3 95.0
92.0 to 111.4 68.6 to 131.8
Single dose
Multiple dose
AUC0–inf, area under the concentration–time curve from time 0 to the last quantifiable concentration then extrapolated to infinity; AUC0–tau, area under the concentration–time curve from time 0 to the end of the treatment period (tau ¼ 6 hours); CI, confidence interval; C0, initial plasma concentration. a Data for subject 16 for the single intravenous bolus dose were excluded because this subject did not receive an intravenous dose. b The ratios were 37.5/18.75 mg; 90% confidence intervals for the treatment difference.
follow-up visit (day 22, 9 days after discharge) were 26 and 66 U/L, respectively. After this report, the protocol for the study was amended to provide additional information on liver function: blood samples for chemistry laboratory tests were collected on day -1 and from day 4 through day 12, inclusive; the blood volumes required for each study day were updated, and daily monitoring via chemistry blood draw from day 4 until the end of the study was implemented. After the change in protocol, no increases in liver enzyme tests were observed for the remaining subjects. All other changes from baseline in clinical laboratory and vital sign results were considered not clinically significant.
Discussion This phase 1 study in healthy adult subjects compared the safety and PK parameters of intravenous diclofenac sodium following single- and multiple-dose bolus administration with single-dose diclofenac potassium 50-mg oral tablets. It represents the first exposure of the DFP-08 formulation of diclofenac in humans.
Table 3. Treatment-Emergent Drug-Related Adverse Events in >1 Subject DFP-08 Diclofenac Potassium
Placebo
Preferred Term
(n ¼ 42) n (%)
(n ¼ 14) n (%)
Any event Related Infusion site pain Alanine aminotransferase increased Aspartate aminotransferase increased Erythema
2 0 0 0 0 0
6 1 0 0 0 1
(4.8) (0.0) (0.0) (0.0) (0.0) (0.0)
(42.9) (7.1) (0.0) (0.0) (0.0) (7.1)
Total 18.75 mg (n ¼ 14) n (%) 1 1 1 0 0 1
(7.1) (7.1) (7.1) (0.0) (0.0) (7.1)
37.5 mg (n ¼ 14) n (%)
Total (n ¼ 28) n (%)
(N ¼ 42) n (%)
2 2 0 1 1 1
3 3 1 1 1 2
10 4 1 1 1 3
(14.3) (14.3) (0.0) (7.1) (7.1) (7.1)
(10.7) (10.7) (3.6) (3.6) (3.6) (7.1)
(23.8) (9.5) (2.4) (2.4) (2.4) (7.1)
The Journal of Clinical Pharmacology / Vol 56 No 1 2016
94 Table 4. Summary of Treatment-Emergent Thrombophlebitis
Event Severity Single dose Grade 0 Grade 1 Multiple doses Grade 0 Grade 1 Grade 2 Grade 3 Grade 4 Grade 2 or higher n
Placebo (n ¼ 14) n (%, 95% CI)a
DFP-08 18.75 mg (n ¼ 14) N (%, 95% CI)a
DFP-08 37.5 mg (n ¼ 14) N (%, 95% CI)a
DFP-08 Total (N ¼ 28) N (%, 95% CI)a
12 (85.7, 57.2–98.2) 2 (14.3, 1.8–42.8)
13 (92.9, 66.1–99.8) 1 (7.1, 0.2–33.9)
14 (100, 76.8–100) 0
27 (96.4, 81.7–99.9) 1 (3.6, 0.1–18.3)
7 (50.0, 23.0–77.0) 5 (35.7, 12.8–64.9) 2 (14.3, 1.8–42.8) 0 0
5 (35.7, 12.8–64.9) 4 (28.6, 8.4–58.1) 3 (21.4, 4.7–50.8) 2 (14.3, 1.8–42.8) 0
8 (57.1, 28.9–82.3) 4 (28.6, 8.4–58.1) 0 1 (7.1, 0.2–33.9) 1 (7.1, 0.2–33.9)
13 (46.4, 27.5–66.1) 8 (28.6, 13.2–48.7) 3 (10.7, 2.3–28.2) 3 (10.7, 2.3–28.2) 1 (3.6, 0.1–18.3)
2 (14.3, 1.8–42.8)
5 (35.7, 12.8–64.9)
2 (14.3, 1.8–42.8)
7 (25.0, 10.7–44.9)
CI, confidence interval. Grade 0, no reaction; grade 1, tenderness along the vein; grade 2, continuous tenderness or pain with redness; grade 3, palpable swelling or thrombosis within length of the cannula; grade 4, palpable swelling or thrombosis beyond the length of the cannula; and grade 5, as for grade 4, with overt infection. The frequency and percentage of subjects reporting any thrombophlebitis within the same day following the initial dose are presented by grade. Percentages are n/N 100. The grade shown is the greatest grade reported per event for a particular subject (0 < 1 < 2 < 3 < 4 < 5). a Exact confidence intervals are from Clopper-Pearson intervals for binomial proportions.
to check for rhabdomyolysis was within the normal range. The results for the follow-up visits on days 18 and 22 demonstrated a downward trend. Because there were no clinically significant laboratory, vital sign, or ECG results, and daily measurements showed no change in liver enzymes in any of the other subjects, it is possible this individual is among the subset of patients who experience elevated liver enzymes during treatment with diclofenac. A review of the medical literature published on phlebitis associated with intravenous catheters revealed that phlebitis develops in about 30% of patients (range, 4%–45%), with an average incidence of 30% per catheter (range, 25%–35%).13,14 With 12 evaluable subjects in the active treatment arms, the proportion of phlebitis using a 95%CI was estimated with a precision of 26% within both active treatment arms. Pooling both active treatment arms (24 subjects), the proportion of phlebitis using a 95% CI was estimated with a precision of 18%. DFP-08 uses the same active ingredient, dosing and route of administration as a recently approved formulation of diclofenac sodium for intravenous injection.10,14,15 However, DFP-08 contains no hydroxypropyl-beta-cyclodextrin (HPbCD), a cyclic glucose-derived oligomer used to enhance the solubility of diclofenac.14 In a conventional carcinogenesis study, rats treated with HPbCD 500 to 5000 mg/kg per day for 25 months had a significantly higher incidence of pancreatic hyperplasia and neoplasia, as well as adenocarcinomas of the exocrine pancreas, than untreated animals and historical controls.15 The clinical significance of these findings is unknown. The study has a few limitations. Results for grade 1 thrombophlebitis are likely to be confounded because the intravenous line was left in for 3 days per protocol requirements and the clinical unit standard of care;
these results are not reported. In addition, the intravenous AUC results of the study suggest no accumulation of DFP-08, as the 18.75-mg intravenous bolus had an AUCtau/AUCinf of 0.927, and the 37.5-mg intravenous bolus had a ratio of 0.893 based on mean values from Table 1. Because the C0 for the intravenous bolus was a back-extrapolation from the first 3 observed concentrations, it is less reliable. No additional statistical assessment of accumulation was included in the analysis plans.
Conclusions These results demonstrate that the diclofenac exposure of a single dose of intravenous diclofenac 18.75 mg is comparable to a single dose of a diclofenac potassium 50-mg oral tablet. In addition, dose proportionality was demonstrated for exposure, as measured by the AUC from the 2 intravenous diclofenac doses (18.75 and 37.5 mg), but not for the C0 extrapolations. No accumulation was apparent on multiple dosing of DFP-08 based on the exposure (AUC) values. Finally, the 18.75- and 37.5-mg doses of intravenous diclofenac (single and multiple) were well tolerated for 7 days. Declaration of Conflicting Interests S.M., A.G., F.O., and K.A. are employees of Dr. Reddy’s Laboratories, which manufactures a formulation of diclofenac sodium for intravenous injection; J.M. is a paid consultant.
Acknowledgments The authors acknowledge Kendra Gulbronson, and Alix Bennett, PhD, for assistance in the conduct of the study and preparation of the article. Medical writing services were provided by Onesta Inc.
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