Pharmacokinetics

Single-Dose Evaluation of Safety, Tolerability and Pharmacokinetics of Newly Formulated Hydromorphone Immediate-Release and Hydrophilic Matrix Extended-Release Tablets in Healthy Japanese Subjects Without Co-Administration of an Opioid Antagonist

The Journal of Clinical Pharmacology 2015, 55(9) 975–984 © 2015, The American College of Clinical Pharmacology DOI: 10.1002/jcph.501

Kaoru Toyama, MSc1, Naoki Uchida, MD, PhD2, Hitoshi Ishizuka, PhD1, Takehiko Sambe, MD, PhD2, and Shinichi Kobayashi, MD, PhD3

Abstract This single dose, open-label study investigated the safety, tolerability and pharmacokinetics of single oral doses of newly formulated immediate-release (IR) and hydrophilic matrix extended-release (ER) hydromorphone tablets in healthy Japanese subjects without co-administration of an opioid antagonist under fasting and fed conditions. Plasma and urinary concentrations of hydromorphone and metabolites were measured by liquidchromatography tandem mass-spectroscopy. Following administration of the ER tablet, plasma concentrations of hydromorphone slowly increased with a median tmax of 5.0 h and the Cmax decreased to 37% of the IR tablet, while the AUC0-inf was comparable with that of the IR tablet when administered at the same dose. The degree of fluctuation in the plasma concentration for the ER tablet was much lower than that of the IR tablet and certain levels of plasma concentrations were maintained after 24 h of ER dosing. The AUC0-inf and Cmax increased with food for both IR and ER tablets. The AUC0-inf of hydromorphone-3-glucoside was one-tenth of that of hydromorphone-3-glucuronide. A single oral administration of the hydromorphone tablets would be well-tolerated in healthy Japanese subjects despite a lack of co-administration of an opioid antagonist and the newly developed ER hydromorphone tablets may have the appropriate PK characteristics for once-daily dosing.

Keywords Hydromorphone, pharmacokinetics, metabolism, safety, opioid

Hydromorphone is a semi-synthetic full m-opioid receptor agonist, structurally similar to morphine. It is widely used as an alternative to morphine for the relief of acute and chronic pain and is included in several international guidelines for the treatment of pain.1 Opioid therapy frequently requires switching from one opioid to another to improve the response to analgesic therapy or to reduce adverse effects. There may be a benefit in switching to a different route of administration, drug or formulation.2,3 Various hydromorphone dosage forms and routes of administration, including immediate-release (IR) and extended-release (ER) oral formulations and intravenous and subcutaneous injections, allow a high degree of flexibility in switching from one route of administration to another, and switching to hydromorphone from other opioids. Hydromorphone has been available in over 40 countries, including the United States, Canada, and some European countries, for the management of moderate-to-severe chronic pain.4 However, currently, no hydromorphone formulation has been approved in Japan and therefore no information on efficacy, safety, tolerability or pharmacokinetics (PK) of hydromorphone has been reported in Japanese subjects.

IR hydromorphone has a relatively short t1/2 of approximately 2 to 3 h and therefore it is required to be administered every 4 to 6 h for the management of pain.5,6 A number of approaches have been taken to formulate a controlled release hydromorphone formulation to improve patient compliance with consistent pain relief. The osmotic-control release oral delivery system (OROS)

1 Translational Medicine and Clinical Pharmacology Department, Daiichi Sankyo Co., Ltd, Shinagawa-ku, Tokyo, Japan 2 Department of Clinical Pharmacology, Showa University, School of Medicine, Shinagawa-ku, Tokyo, Japan 3 Showa University Clinical Research Institute for Clinical Pharmacology and Therapeutics, Setagaya-ku, Tokyo, Japan

Submitted for publication 1 December 2014; accepted 19 March 2015. Corresponding Author: Kaoru Toyama, MSc, Translational Medicine and Clinical Pharmacology Department, Daiichi Sankyo Co., Ltd, 1-2-58, Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan Email: [email protected]

976 technology consists of an osmotic drug core surrounded by a semipermeable membrane with laser drilled holes. In an aqueous environment, the osmotic pressure of water entering the tablet pushes the active drug through the openings in the tablet. The OROS tablet products are currently on the market in various therapeutic areas, including hydromorphone, nifedipine, oxybutynin, and paliperidone.7 Hydrophilic matrix technology is another method for ER of drugs and has also been widely used for oral controlled delivery of various drugs. Due to their hydrophilic nature, the polymers begin to swell upon contact with water, forming a gel layer. The drug release is controlled by the diffusion through the layer and/or erosion mechanisms. The advantages of this technology are ease of formulation, a cost-effective manufacturing process, wide regulatory acceptance of the polymer systems, and flexibility in the control of the drug-release profiles.8 However, it is difficult to extrapolate from nonclinical data whether an ER formulation of hydromorphone using the hydrophilic matrix technology would have appropriate PK profiles to provide consistent analgesia in patients. Opioid-related adverse events (AEs), such as nausea, constipation, and vomiting are problematic in the PK studies with hydromorphone.9 A common solution is to administer naltrexone, an opioid antagonist, to reduce the likelihood of these AEs. However, naltrexone could potentially alter the PK profile of hydromorphone, because it reverses the slowing of gastric transit associated with opioids.10 In fact, naltrexone increased the mean Cmax by 39% and the median tmax occurred 4 h earlier when an OROS hydromorphone (16 mg) was administered with naltrexone under fasting conditions.11 The mean t1/2 was approximately 4.6 h shorter than that without naltrexone (10.1 vs. 14.7 h). Therefore, it is preferable to characterize the PK profiles of a newly formulated hydromorphone tablet without co-administration of an opioid antagonist. The objective of this open-label study was to evaluate the safety, tolerability and PK of single oral doses of newly formulated IR and ER hydromorphone tablets in healthy Japanese subjects without co-administration of an opioid antagonist under fasting and fed conditions. In addition, PK characteristics of the ER hydromorphone tablets were evaluated to determine if they are suitable for once-daily oral dosing.

Methods The study was conducted at the Clinical Research Institute for Clinical Pharmacology and Therapeutics at Showa University School of Medicine (Tokyo, Japan) in 2013. The study protocol, amendments and the informed consent form were approved by the institutional review boards of the study site. The study was conducted in

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accordance with the guidelines on Good Clinical Practice and with ethical standards for human experimentation established by the Declaration of Helsinki Principles. All subjects gave written informed consent. The registry’s URL and the registration number are as follows: http://www.clinicaltrials.jp/ and JapicCTI-132167. Study Participants Healthy male Japanese subjects between the age of 20 and 45 years, with normal body mass index
18.5 and < 25.0 kg/m2 were eligible for inclusion. Subjects were excluded from this study if any of the following conditions existed: evidence of organ dysfunction or any clinically significant deviation from the normal range in a physical examination, vital signs (e.g. blood pressure, heart rate and body temperature), 12-lead electrocardiogram (ECG), or clinical laboratory determinations; presence or history of severe adverse reaction to any medicine; a history of alcohol abuse or drug abuse; a positive result for either hepatitis B, hepatitis C, or HIV; a positive result for drug urinalysis; donated more than 200 mL of blood within 28 days before the screening test, or more than 400 mL of blood within 84 days, or more than 1200 mL of blood within a year, or apheresis within 14 days; receipt of an investigational agent within 120 days before the screening test; previous participation in an opioid study; refusal to use contraception; and inability to communicate satisfactorily with the investigator. Study Design This was an open-label, single-dose study. A total of 30 subjects were enrolled in this study. Each subject underwent screening assessments to confirm eligibility within 21 days before admission to the study site on Day -1 of the first treatment period. Subjects were allocated to 5 groups of 6 subjects each according to the treatment. Three cohorts were to receive a single oral dose of the IR hydromorphone tablet at doses of 1 mg (cohort 1), 4 mg (cohort 3), and the ER hydromorphone tablet (6 mg, cohort 5) under fasting conditions. All subjects fasted overnight (more than 10 h) and for 4 h after dosing. Each dose was given with 200 mL of water and water ad libitum was allowed after 2 h of administration. The subjects were prohibited from resting in a supine position for 4 h after administration. Standardized meals were served at appropriate times through the study. Each subject was discharged from the study site in the morning of Day 3, after completion of the 48-hour post-dose assessment. The final follow-up assessment was carried out after 7  1 days of the dosing. The influence of food on PK was evaluated using a twoperiod two-way crossover design. Two cohorts were to receive oral doses of hydromorphone at a dose of 2 mg of the IR (cohort 2) and ER (cohort 4) tablets. Each subject was randomly assigned to receive the tablet under fasting

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conditions and immediately after the completion of a standard breakfast in accordance with the guidelines of Japan12: For the IR tablet, less than 700 kcal, of which less than 20% of calories was derived from fat; for the ER tablet, more than 900 kcal, of which more than 35% of calories was derived from fat. There was a washout period of 7  1 days between treatments. Each subject was discharged from the study site in the morning of Day 3, after completion of the 48-hour post-dose assessment. The final follow-up assessment was carried out after 7  1 days of the last dosing. IR (1, 2, and 4 mg) and ER (2 and 6 mg) hydromorphone tablets were provided by Daiichi Sankyo Co., Ltd. (Tokyo, Japan). Blood and Urine Sampling Blood (3 mL) was collected into Vacutainers containing EDTA-2K as an anticoagulant, as follows: predose and at 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 24, 36, and 48 h after dosing in each treatment period. To evaluate tmax precisely, samples were also obtained at 0.25 h after the IR tablet dosing and 5 h after the ER tablet dosing, respectively. By centrifugation, plasma was separated and stored at 20°C until the assay. Plasma samples were analyzed for hydromorphone and hydromorphone-3-glucuronide (H3G) concentrations. In cohort 3 (IR 4 mg) and cohort 5 (ER 6 mg), additional blood (2 mL) was collected and the plasma hydromorphone-3-glucoside (H3-glu) concentration was also determined. Urine for the hydromorphone and H3G assay was collected at several intervals (04, 48, 812, 1224, 2436, and 3648 h) to evaluate the urinary excretion rate from predose to 48 h after dosing in each treatment period. For each collection period, the total urine volume was measured, and 2 mL were collected and stored at 20°C until the assay. Sample Analysis The drug concentrations in human plasma (hydromorphone, H3G and H3-glu) and urine (hydromorphone and H3G) were determined by validated sensitive and specific methods using solid phase extraction of the analyte and deuterated internal standard (hydromorphone-d6, H3G-d5 and H3-glu-d7) from plasma and urine, followed by reverse-phase high-pressure liquid chromatography with tandem mass spectrometry detection in the positive ionization mode (AB SCIEX 5500 QTRAP, Framingham, Massachusetts). The samples were analyzed using an Inertsil amide analytical column (3 mm, 100 mm x 2.1 mm id, GL Sciences, Tokyo, Japan). A gradient of 7.5 mM ammonium acetate in 0.1% acetic acid and acetonitrile was used for the mobile phase, and the flow rates for hydromorphone and H3G assay and for H3-glu assay were 0.8 and 0.6 mL/min, respectively. The mass transitions were 286-185 (m/z) for hydromorphone, 462-185 (m/z) for H3G, and 448-286 (m/z) for H3-glu, respectively.

977 Two sets of low-, medium-, and high-quality control samples were evaluated with each run of clinical samples. The lower limit of quantitation for the plasma hydromorphone, H3G and H3-glu assay were 0.05, 0.5 and 0.02 ng/mL, and the linear calibration ranges were 0.0550, 0.5100 and 0.0220 ng/mL, respectively. The coefficient of variations (CVs) for the intra-day reproducibility of the plasma quality control samples for hydromorphone, H3G and H3-glu were between 1.8% and 7.0%, between 2.5% and 4.0% and between 2.5% and 7.9%, respectively. The CVs for the inter-day reproducibility of the plasma quality control samples for hydromorphone, H3G and H3-glu were between 3.4% and 9.3%, between 2.8% and 9.2% and between 3.2% and 7.3%, respectively. The lower limit of quantifications for the urine hydromorphone and H3G assay were 2 and 10 ng/mL, and the linear calibration ranges were 21000 and 102000 ng/mL, respectively. The CVs for the intra-day reproducibility of the urine quality control samples for hydromorphone and H3G were between 2.8% and 9.0% and between 3.8% and 8.5%, respectively. The CVs for the inter-day reproducibility of the urine quality control samples for hydromorphone and H3G were between 4.9% and 9.1% and between 7.3% and 13.0%, respectively. Pharmacokinetic Analysis The pharmacokinetic parameters were calculated by a non-compartment analysis using the computer software WinNonlin Professional (version 6.2, Pharsight Corp., Sunnyvale, California) and SAS (version 9.2, SAS Institute Japan, Tokyo Japan). The maximum concentration (Cmax) and time to Cmax (tmax) were obtained by observation. The apparent elimination t1/2 was obtained by linear regression of 3 or more log-transformed data points in the terminal phase. The area under the concentration versus the time curve (AUC) up to the time of the last measurable concentration data (AUClast) was obtained by the linear trapezoidal method. The AUC values were extrapolated to infinity (AUC0-inf) using the equation AUClast þ Ctz/l, where Ctz is the last measurable concentration and l is the terminal elimination rate. The degree of fluctuation was calculated from the formula ((Cmax - C24)/Cav x 100), where C24 is the plasma concentrations after 24 h of dosing and Cav is the average plasma concentration (calculated as the ratio of AUC0-inf to the assumed dosing interval (24 h)). The urine concentrations, urine volumes from individual collection intervals, and nominal times of the collection intervals were used to calculate the cumulative amount of hydromorphone and metabolites excreted in urine. Statistical Analysis No formal sample size or power calculation was used to determine the size of each cohort. Sample sizes were based

978 on practical considerations, exposing a limited number of subjects, while obtaining the necessary tolerability, safety, and PK data. Descriptive statistics were calculated for the pharmacokinetic parameters. The 90% CI for the geometric mean ratios were derived from a general linear model analysis of variance with sequence, subjects within sequence, period, and treatment (fasting or fed) as fixed effects comparing the log transformed values for AUC0-inf and Cmax. The geometric mean ER/IR ratios and their 95% CI for AUC0-inf and Cmax under fasting conditions were used for the analysis of the relative exposure. Safety and Tolerability Each subject was confined to the study site from the previous day of dosing through to completion of the 48-hour post dose procedures. The safety and tolerability were assessed by physical examinations, the drug dependency questionnaire as a reference to the previous report,13 vital signs, oxygen saturation, 12-lead ECG and laboratory measurements (including hematology, serum chemistry and urinalysis). AEs were monitored throughout the study. Subjects were questioned concerning their well-being. Investigators evaluated all the clinical AEs in terms of intensity (mild, moderate, or severe), duration, severity, outcome, and relationship to the study drug.

Results From the 30 subjects enrolled in this study, the subjects’ age, weight, and body mass index (mean  standard deviation [SD]) were 37.3  5.2 years, 65.1  5.8 kg and 21.7  1.5 kg/m2, respectively. After the administration of the IR hydromorphone tablets under fasting conditions, hydromorphone appeared rapidly in plasma, with median values of tmax ranging from 0.5 to 1.0 h and the plasma concentrations decreased with the mean values of t1/2 of 5.3 to 18.3 h (Figure 1A and Table 1). The average AUC0-inf and Cmax for hydromorphone increased almost proportionally with the dose range of 1 to 4 mg. The mean cumulative excretion amounts of hydromorphone in urine for 48 h were 2.9% to 3.0% of the dose under fasting conditions. The plasma hydromorphone concentration profiles after single oral administration of the ER hydromorphone tablets are shown in Figure 1B. Hydromorphone appeared slowly in plasma, with median values of tmax ranging from 3.3 to 5.0 h (Table 1). The mean AUC0-inf and Cmax for hydromorphone increased proportionally with the dose. The mean values of t1/2 for 2 and 6 mg of the ER tablets under fasting conditions were 8.9 and 16.8 h, respectively. The mean cumulative excretion amounts of hydromorphone in urine for 48 h were 3.6% and 2.9% of the dose. The degree of fluctuation for 2 and 6 mg of the ER tablets under fasting conditions were 102.6% and 76.6%, respectively.

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The mean ratios of AUC0-inf and Cmax from the analysis of the ER and IR hydromorphone tablets under fasting conditions were 109.4% and 36.7%, respectively. A comparison of the mean plasma hydromorphone concentration-time profiles for the IR tablet under fasting and fed conditions are shown in Figure 1C. The mean Cmax increased when the IR tablet was administered after a meal (1.0 vs. 1.3 ng/mL) and the mean ratio of Cmax was 133.3% (Table 2). The AUC0-inf also increased with food and the mean ratio of AUC0-inf was 126.3%. Median tmax was approximately similar under fasting and fed conditions. The mean plasma hydromorphone concentration-time profiles for the ER tablet under fasting and fed conditions are shown in Figure 1D. The mean Cmax increased when the ER tablet was administered after a meal (0.4 vs. 0.6 ng/mL) and the mean ratio of Cmax was 164.9% (Table 2). The AUC0-inf also increased with food and the mean ratio of AUC0-inf was 127.2%. Median tmax was approximately similar under fasting and fed conditions. The plasma hydromorphone, H3G and H3-glu concentration profiles after a single oral administration of the IR and ER hydromorphone tablets are shown in Figure 2. The H3-glu slowly appeared in plasma with a median tmax of 2.5 h in the IR tablet (4 mg), while a median tmax of H3G was 1.0 h (Table 1). The AUC0-inf of H3-glu was approximately 3 times higher than that of hydromorphone and less than one-tenth of that of H3G in both formulations. The mean plasma t1/2 of H3-glu was almost comparable with that of hydromorphone. The number and the incidence of AEs are summarized by each treatment group in Table 3. Hydromorphone was generally well-tolerated. No serious clinical or laboratory adverse experiences nor opioid dependence were reported and no subject discontinued because of an adverse experience. No notable mean changes from the baseline were recorded in the vital signs or clinical laboratory variables, and none of the individual participant values outside the laboratory reference ranges were considered to be clinically significant. A total of 16 AEs by 14 participants were considered by the investigator to be possibly related to the study treatment; of these, 12 AEs (9 cases of somnolence, 2 cases of headache and 1 each of vertigo, hot flush, and vomiting) were reported in the IR hydromorphone groups, and 5 AEs (3 cases of somnolence, and 1 case each of headache and vomiting) were reported in the ER hydromorphone groups. All events were mild and resolved without treatment except for one case of moderate vomiting in cohort 3 (IR 4 mg). There was no clear difference in AEs between the fasting and fed conditions in cohort 2 (IR 2 mg) and cohort 4 (ER 2 mg).

Discussion This is the first report of safety and PK of hydromorphone in healthy Japanese subjects. The PK profiles of

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Figure 1. Mean plasma hydromorphone concentration-time profiles following a single oral administration of immediate-release (IR, panel A) and extended-release (ER, panel B) hydromorphone tablets under fasting conditions in healthy Japanese volunteers. Comparison of mean plasma hydromorphone concentration-time profiles under fasting and fed conditions after a single oral administration of 2 mg of IR (panel C) and ER (panel D) hydromorphone tablets. Symbols are the mean of 6 subjects per group.

hydromorphone following oral administration of the IR hydromorphone tablets in healthy Japanese subjects were generally consistent with reported values in other ethnicities.14–16 The IR hydromorphone was rapidly absorbed, reaching a maximum concentration in approximately 1 h. A linear dose-exposure relationship was observed across the dose range studied. The mean value of t1/2 of 4 mg IR tablet under fasting conditions (18.3  11.7 h) was comparable with that of the recent report (12.7  3.4 h). 16 The higher percentage of H3G than hydromorphone was excreted into urine and the ratio was not affected by the dose of hydromorphone, formulation (IR or ER) nor food conditions (fasting or fed). Hydromorphone is extensively metabolized via glucuronidation by the hepatic enzymes UGT2B7.17 Although it has been reported that the allele frequencies of UGT2B7*1

and *2 in Japanese and Caucasian populations are different, there is no functional (metabolic) difference between the alleles.18 The effects of the UGT2B7 genetic polymorphism on the PK and safety in healthy Taiwanese subjects have been evaluated during concomitant administration of naltrexone.19 This study indicated that an increasing number of UGT2B7*2 alleles resulted in a minimal increase in Cmax and AUC0–36h and had no effect on AUC0-inf of hydromorphone compared to UGT2B7*1/*1. In addition, the metabolic ratio of H3G to hydromorphone was similar for all UGT2B7 genotypes. These data indicate that ethnic differences in the PK of hydromorphone are not expected to be significant, and are consistent with the results of the study reported here. The PK of an IR hydromorphone in healthy Caucasian male and female subjects were evaluated and found that sex has little effect on the PK of hydromorphone.20 The

114  34.6 19.4  3.0 1.0 (1.0, 1.5) 17.2  17.0 29.4  2.5

Hydromorphone-3-glucuronide (H3G) AUC0-inf ng  h/mL Cmax ng/mL tmax h t1/2 h Fe % ND ND ND ND

202  41.0 35.2  7.4 1.3 (1.0, 1.5) 10.8  3.0 30.9  3.8

5.2  1.2 4.1  0.9 1.0  0.4 0.8 (0.3, 1.5) 9.2  5.9 3.0  0.6

IR 2 mg (Fasting) N¼6

ND ND ND ND

234  35.8 34.2  7.1 2.8 (1.0, 3.0) 10.9  3.7 37.3  5.0

6.8  2.4 5.7  2.1 1.3  0.5 1.3 (0.3, 2.5) 9.4  4.9 4.3  1.2

IR 2 mg (Fed) N¼6

Cohort 2

34.2  7.9 2.8  0.4 2.5 (1.5, 3.0) 16.8  3.6

384  73.6 56.0  11.7 1.0 (1.0, 1.5) 13.0  2.3 29.2  5.8

12.6  3.0 10.3  3.3 2.0  0.6 1.0 (0.5, 1.0) 18.3  11.7 2.9  0.8

IR 4 mg (Fasting) N¼6

Cohort 3

ND ND ND ND

228  34.8 12.4  2.1 4.0 (2.0, 10.0) 8.6  2.2 35.7  3.9

5.7  1.1a 5.3  1.6 0.4  0.1 5.0 (1.0, 10.0) 8.9  2.3a 3.6  0.8

ER 2 mg (Fasting) N¼6

ND ND ND ND

234  34.2 15.4  2.3 4.5 (3.0, 6.0) 10.8  3.7 36.9  6.0

7.3  1.3 6.1  1.2 0.6  0.2 4.0 (1.0, 5.0) 11.2  3.4 4.3  1.0

ER 2 mg (Fed) N¼6

Cohort 4

62.3  15.0 2.4  0.6 5.0 (2.5, 6.0) 19.0  3.2

702  97.1 39.7  7.9 2.0 (1.5, 6.0) 13.4  3.6 29.5  2.7

22.2  4.4 19.2  5.0 1.1  0.4 3.3 (1.0, 8.0) 16.8  6.7 2.9  0.6

ER 6 mg (Fasting) N¼6

Cohort 5

Values are mean  standard deviation (SD), except for tmax (median [min, max]). AUC0-inf, area under the plasma concentration-time curve to infinity; AUClast, AUC up to the time of the last measurable concentration data; Cmax, maximum plasma concentration; tmax, time to reach maximum concentration; t1/2, terminal elimination half-life; Fe, fraction excreted in urine; ND, not determined. aN ¼ 5.

Hydromorphone-3-glucoside (H3-glu) ND ND ND ND

2.3  0.7 1.8  0.6 0.7  0.3 0.5 (0.3, 1.0) 5.3  3.4 2.9  0.6

AUC0-inf ng  h/mL AUClast ng  h/mL Cmax ng/mL tmax h t1/2 h Fe %

Hydromorphone

AUC0-inf ng  h/mL Cmax ng/mL tmax h t1/2 h

IR 1 mg (Fasting) N¼6

Compound

Parameter

Cohort 1

Table 1. Pharmacokinetic Parameters of Hydromorphone, Hydromorphone-3-Glucuronide (H3G) and Hydromorphone-3-Glucoside (H3-glu) After Single Oral Administration of Immediate-Release (IR) and Extended-Release (ER) Hydromorphone Tablets in Healthy Japanese Subjects

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Table 2. Effect of Food on the Pharmacokinetic Parameters of Hydromorphone Condition Formulation and Dose

Parameter

Fasting

Fed

Ratio, % (Fed/Fasting)

90%CIs

IR 2 mg

Cmax ng/mL AUC0-inf ng  h/mL

1.0 (0.4) 5.2 (1.2)

1.3 (0.5) 6.8 (2.4)

133.3 126.3

113.8  156.2 91.6  174.2

ER 2 mg

Cmax ng/mL AUC0-inf ng  h/mL

0.4 (0.1) 5.7 (1.1)

0.6 (0.2) 7.3 (1.3)

164.9 127.2

145.1  187.3 108.1  149.7

IR, immediate-release; ER, extended-release; CI, confidence interval.

difference between two groups was less than 2% in AUC0–24h. Though the PK of hydromorphone had been evaluated only in male Japanese subjects in this study, PK characteristics of the hydromorphone tablets in males will be applicable to that in females. PK characteristics (tmax, Cmax, trough concentration, fluctuation and t1/2) of the newly manufactured ER tablets appear to be generally comparable with the OROS hydromorphone tablets. Hydromorphone appeared slowly in plasma following the administration of the ER tablets, with the median values of tmax ranging from 3.3 to 5.0 h (Table 1). The mean Cmax for 2 and 6 mg of the ER tablets (both 0.18 ng/mL/dose-normalized to 1 mg assuming dose linearity) and the plasma concentrations after 24 h of dosing (0.042 and 0.058 ng/ mL/dose-normalized to 1 mg, respectively) were slightly differentiated from the mean Cmax and Cmin of OROS hydromorphone at a steady state in patients with chronic pain (0.16 and 0.069 ng/mL/dose-normalized to 1 mg, respectively). 21 The degree of peak-to-trough fluctuation is one metric for evaluating ER dosing regimens, including opioids. The degree of fluctuation for the ER tablets (2 and 6 mg) under fasting conditions (102.6% and 76.6%, respectively) was much lower than that of the reported IR hydromorphone in healthy subjects

(172.0%), and relatively close to that of OROS hydromorphone at a steady state in healthy subjects (60.5%) and patients with chronic pain (99.6%). 21 The mean t1/2 observed in this study (6 mg ER, 16.8  6.7 h) was close to the value of 14.7  6.07 h reported following OROS hydromorphone (16 mg) under fasting conditions without naltrexone.11 Although it is possible that the t1/2 of the ER hydromorphone tablets might change with higher doses, the mean values of t1/2 were close despite the different mechanisms employed to achieve ER characteristics. These data indicate that the ER properties of the OROS hydromorphone formulation were maintained in the ER hydromorphone studied here. Moreover, existence of a significant linear relationship between hydromorphone plasma concentration and the analgesic effect on painful stimuli has been reported22 and OROS hydromorphone administered once-daily yielded effects that were comparable to the same daily dose of IR formulation administered in multiple doses.23 In this study, the mean ratio of AUC0-inf (ER/IR tablets) was 109.4%, indicating that the bioavailability may be comparable between both formulations, although 95% CIs of the ratios of AUC0-inf geometric means for the ER and IR tablets were relatively wide (79.6150.5). These data indicate that the ER hydromorphone tablets may

Figure 2. Mean plasma concentration-time profiles of hydromorphone, hydromorphone-3-glucuronide (H3G), and hydromorphone-3-glucoside (H3-glu) following a single oral administration of immediate-release (4 mg, panel A) and extended-release (6 mg, panel B) hydromorphone tablets under fasting conditions in healthy Japanese subjects. Symbols are the mean of 6 subjects per group.

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Table 3. Incidence of Drug-Related Treatment Emergent Adverse Events (TEAEs) Classified by the Primary System Organ Class and Preferred Term (MedDRA Version 16.0) IR 1 mg

System Organ Class Preferred Term Number of subjects with drug-related TEAE Nervous system disorders Headache Somnolence Ear and labyrinth disorders Vertigo Vascular disorders Hot flush Gastrointestinal disorders Vomiting

ER

2 mg

4 mg

2 mg

6 mg

Fasting

Fasting

Fed

Fasting

Fasting

Fed

Fasting

N¼6 n (%)

N¼6 n (%)

N¼6 n (%)

N¼6 n (%)

N¼6 n (%)

N¼6 n (%)

N¼6 n (%)

(33.3) (33.3) (0.0) (33.3)b (0.0) (0.0) (0.0) (0.0) (0.0) (0.0)

0 0 0 0 0 0 0 0 0 0

4 4 0 4 0 0 0 0 0 0

(66.7) (66.7) (0.0) (66.7) (0.0) (0.0) (0.0) (0.0) (0.0) (0.0)

1 1 0 1 0 0 0 0 0 0

(16.7) (16.7) (0.0) (16.7) (0.0) (0.0) (0.0) (0.0) (0.0) (0.0)

2 2 0 2 0 0 0 0 0 0

(33.3) (33.3) (0.0) (33.3) (0.0) (0.0) (0.0) (0.0) (0.0) (0.0)

3 2 2 0 1 1 1 1 1 1

(50.0) (33.3) (33.3) (0.0) (16.7) (16.7)a (16.7) (16.7)a (16.7) (16.7)a

2 2 1 1 0 0 0 0 1 1

(33.3) (33.3) (16.7) (16.7)b (0.0) (0.0) (0.0) (0.0) (16.7) (16.7)

2 2 0 2 0 0 0 0 0 0

(0.0) (0.0) (0.0) (0.0) (0.0) (0.0) (0.0) (0.0) (0.0) (0.0)

IR, immediate-release; ER, extended-release. a One subject experienced three AEs. b One subject experienced during each treatment period.

have the appropriate PK profile to relieve pain with oncedaily dosing and may also yield effects that are comparable to the same daily dose of the IR hydromorphone tablets administered in multiple doses. The clinical efficacy and safety of the IR and ER hydromorphone tablets has not been published to date, although they are currently being evaluated in four ongoing phase III studies in opioid-naive and opioid-tolerant patients with cancer pain (JapicCTI-132288, -132338, -142666, and -142667). The efficacy and safety by the conversion of IR to ER hydromorphone in Japanese patients will be evaluated in one of the phase III studies (Japic-142667). It is definitely of benefit to patients with chronic pain who need not take meals into consideration when taking an ER hydromorphone tablet. No clinically significant food effect was observed in OROS11,16 and another hydromorphone ER formulation, a multiparticulate melt-extrusion pellet capsule formulation.15 In this study, the mean AUC0-inf and Cmax increased by 127.2% and 164.9%, respectively (Table 2), when the ER tablet was administered after a meal, although the number of subjects was limited (6 subjects in each cohort). Oxymorphone ER tablets (OPANA ER) have been recommended to be taken at least 1 h before or 2 h after eating due to the potential of food to cause an increase in plasma concentrations.24 The Cmax of the oxymorphone ER tablets was approximately 50% higher under fed conditions than fasting conditions, with most of the difference in AUC occurring in the first 4 h after dosing. The information for the oxymorphone ER tablets provides a specific suggestion that the effect of food on the PK of hydromorphone and its clinical significance regarding the ER tablets should be fully confirmed in further clinical studies.

The concomitant intake of alcoholic beverages together with ER opioid formulations poses a serious safety concern, since ethanol ingestion may modify the release characteristics, where dose dumping may be an issue for patient safety.25 An ER hydromorphone was withdrawn from the US market following concern over the potential for ethanolinduced dose-dumping. The in vitro release of hydromorphone from this formulation significantly depended on the ethanol content of the surrounding bulk fluid26 and a PK study showed that co-ingestion of this formulation with 40% alcohol resulted in a higher peak hydromorphone concentration than when taken with water.27 The in vitro dissolution profile of hydromorphone from the hydrophilic matrix ER tablets in this study in 40% ethanol was not different from that in water (Daiichi Sankyo Co., Ltd., data on file). Hydrophilic polymers, which are insoluble in ethanol and expected to be unaffected when consumed together with alcohol, were used as excipients for the preparation of the ER hydromorphone tablets. Though a clinical study has not been conducted, the PK profile of the ER tablets would be minimally affected by alcohol. Though hydromorphone and morphine are structurally related, it is mentioned that unlike morphine, hydromorphone has a ketone group at the 6-position and so direct conjugation of hydromorphone with glucuronic acid at this position does not occur.28 Hydromorphone is extensively metabolized to H3G along with minor amounts of 6-hydroxy reduction metabolites and glucoside conjugate. In this study, plasma concentrations of another metabolite of hydromorphone, H3-glu, were evaluated to confirm its relative exposure compared with hydromorphone and H3G. The AUC0-inf of H3-glu was approximately 3 times higher than that of hydromorphone and less than one-tenth of that of H3G in both the IR and

Toyama et al

ER tablets. These data indicate that the exposure of H3glu is lower than 10% of the sum of exposure of three compounds (hydromorphone, H3G, and H3-glu) corrected by each molecular weight. Abuse deterrent formulations represent an intervention strategy to decrease abuse or misuse without affecting patient access. Many of these formulations propose some mechanism to discourage abusers’ attempts to render the active ingredient immediately available for abuse and conducive for use.29–31 OROS hydromorphone is a tamper resistant delivery system for oral hydromorphone. The core of the tablet has polyethylene oxide and hydroxypropyl methylcellulose that can act as gelling agents and is surrounded by a hard to crush cellulose acetate membrane. A tamper resistant system has not been actively provided to the current ER hydromorphone tablets because no hydromorphone formulation has been approved in Japan and the prescription will be confined to only patients with cancer pain for the time being. However, abuse deterrent formulations will definitely ensure the safe and effective use of opioids for the relief of chronic pain and the technology has been under consideration. Hydromorphone was well-tolerated following a single oral dose in healthy Japanese subjects. Even without coadministration of an opioid antagonist, no clinically significant changes in the physical examination, vital signs, or laboratory measurements were observed during the course of the study. No opioid dependence was reported in this study. The safety of OROS hydromorphone without coadministration of naltrexone in healthy subjects was evaluated and the most frequently occurring AEs discovered were nausea and asthenia.11 Other AEs under fasting conditions without naltrexone were consistent with those expected for an opioid agonist: dizziness, pruritus, headache and vomiting. The most commonly reported AEs in patients with chronic pain treated with OROS hydromorphone were nausea, constipation, somnolence, vomiting, headache, and dizziness.4 Though the dose in this study was relatively lower and a small number of subjects was studied to prevent healthy subjects from excess exposure to an opioid, similar AEs (somnolence, headache, and vomiting) were observed in healthy Japanese subjects. In conclusion, single oral doses of the IR (14 mg) and ER (2 and 6 mg) hydromorphone tablets were welltolerated in healthy Japanese subjects despite a lack of coadministration of an opioid antagonist, and these newly developed IR and ER hydromorphone formulations may widen options for opioid therapy. Acknowledgments The authors thank Mitsutoshi Uemori and Hiromi Okabe for the statistical analyses, and Tsunenori Nakazawa for the bioanalytical work. The authors gratefully acknowledge the contribution of Hideki Yano for valuable technical comments.

983 Funding This study was sponsored by Daiichi Sankyo Co., Ltd.

Declaration of Conflicting Interest Naoki Uchida, Takehiko Sambe, and Shinichi Kobayashi have no conflict of interest. Kaoru Toyama and Hitoshi Ishizuka are employees of Daiichi Sankyo Co., Ltd.

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