ORIGINAL ARTICLE
Therapeutic Drug Monitoring and Dose Adjustment of Posaconazole Oral Suspension in Adults With Acute Myeloid Leukemia Shelly E. Hummert, PharmD* and Myke R. Green, BS Pharm, PharmD, BCOP†‡
Background: Prophylaxis with posaconazole, an extendedspectrum triazole antifungal, has been shown to increase overall survival in adults with acute myeloid leukemia receiving intensive remission induction chemotherapy. A paucity of data exists evaluating therapeutic drug monitoring and subsequent dose adjustment based on serum concentrations in humans.
Methods: An observational study was performed in 29 adult patients with acute myeloid leukemia who initially received posaconazole oral suspension 200 mg 3 times daily and required $1 dose adjustment because of steady-state posaconazole serum concentration ,0.7 mcg/mL. Four dosing schemas were compared simultaneously. Patient records were reviewed to collect patient-related and medication-related factors that may affect serum concentrations. Results: Thirty-five percent of patients experienced subtherapeutic posaconazole serum concentrations with prophylactic dosing of posaconazole oral suspension. Increasing the dose and/or schedule of posaconazole oral suspension led to attainment of goal posaconazole serum concentrations in all groups. However, patients who received 400 mg orally 3 times daily experienced the least significant increase in serum concentration and remained subtherapeutic, despite doubling the posaconazole daily dose. Toxicities were similar to baseline within all groups. Increasing the dose and/or frequency of posaconazole oral suspension led to an increase in systemic exposure and did not appreciably increase incidence of toxicities.
Conclusions: Patients receiving posaconazole oral suspension that experience subtherapeutic posaconazole serum concentrations may benefit from increasing the frequency to 200 mg orally 4 times daily or dose to 300 mg orally 3 times daily. Key Words: posaconazole, therapeutic drug monitoring, antifungal, prophylaxis (Ther Drug Monit 2015;37:508–511)
Received for publication June 18, 2014; accepted December 1, 2014. From the *Division of Pharmacy Services, Providence St. Vincent Medical Center, Portland, Oregon; †Division of Pharmacy Services, University of Arizona Medical Center; and ‡Section of Hematology/Oncology, University of Arizona Cancer Center, Tucson. M. R. Green serves on the speakers’ bureau of Merck and Co. The other author declares no conflict of interest. Correspondence: Myke R. Green, BS Pharm, PharmD, BCOP, University of Arizona Cancer Center, 1501 N Campbell Avenue, PO Box 245009, Tucson, AZ 85724-5009 (e-mail: [email protected]). Copyright © 2014 Wolters Kluwer Health, Inc. All rights reserved.
508
INTRODUCTION Invasive fungal infections are major contributors to morbidity and mortality in adult patients with acute myeloid leukemia receiving intensive remission induction therapy.1,2 Posaconazole is an extended-spectrum triazole antifungal agent with broad activity against a wide spectrum of opportunistic fungi, including Candida and Aspergillus species.3 Clinical trials have proven the efficacy of posaconazole in preventing invasive fungal infections and improving overall survival rates versus comparator triazole antifungal agents in patients with acute myeloid leukemia (AML).4–6 The efficacy of posaconazole prophylaxis for patients with AML requires a steady-state serum concentration at least 0.7 mcg/mL, with no known toxicity threshold or upper limit of serum concentration.7 However, poor and highly variable absorption of posaconazole suspension and therapeutic drug monitoring may be necessary to attain maximal efficacy.8,9 However, the role of dose adjustment in response to subtherapeutic serum concentrations has not been evaluated in humans. Currently, a dose-adjustment algorithm based on plasma concentrations using a computer simulation model has been posited.7 The primary outcome for this study was posaconazole serum concentrations after dose adjustment in adult patients with AML receiving intensive remission induction chemotherapy. Secondary outcomes included treatmentemergent adverse effects and clinical outcomes at day 100 after first dose of posaconazole.
METHODS A retrospective chart review study was conducted at a single academic medical center after institutional review board approval. Eligibility included patients aged 18 years or older, with primary or secondary AML treated with intensive remission induction chemotherapy, received posaconazole oral suspension 200 mg orally 3 times daily as prophylaxis for $14 days (defined as $7 days predose adjustment and $7 postdose adjustment), and required at least 1 dose adjustment secondary to a subtherapeutic steady-state posaconazole serum concentration. Exclusion criteria included concurrent pharmacotherapy that is known to decrease serum posaconazole concentrations during the first 14 days of posaconazole administration, alternate indications for posaconazole, and nonadherence with posaconazole or “posaconazole bundle,” which consists of strategies to optimize absorption of posaconazole oral suspension.10 Both in predose and Ther Drug Monit Volume 37, Number 4, August 2015
Copyright © 2015 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
Ther Drug Monit Volume 37, Number 4, August 2015
Dose Adjustment of Posaconazole
postdose adjustment, all patients were carefully screened for adherence to posaconazole administration and “posaconazole bundle”; nonadherence was defined as #95% adherence with any element of “posaconazole bundle” at any time during the dosing interval. All posaconazole serum concentrations were drawn 7–10 days after posaconazole initiation or adjustment and were analyzed at The Fungus Testing Laboratory, University of Texas Health Science Center at San Antonio (San Antonio, TX). The steady-state posaconazole serum concentration was considered subtherapeutic if ,0.7 mcg/mL.8,9 Patients were stratified into 4 groups based on posaconazole dose adjustment schema chosen at the discretion of the oncologist and/or infectious diseases physician. The 4 groups consisted of group A = 200 mg 4 times daily, group B = 300 mg 3 times daily, group C = 400 mg 3 times daily, and group D = 400 mg 4 times daily (Table 1). Posaconazole was continued until absolute neutrophil count exceeded 500 cells per cubic millimeter for 2 consecutive days or breakthrough fungal infection necessitating alternate antifungal treatment.5 Patients were followed for 100 days after the first dose of posaconazole. All statistical analyses used 2-sided P values, with statistical significance set at ,0.05. Chi-squared test was used to compare gender demographic comparisons between all 4 groups, whereas analysis of variance (ANOVA) was used for age and body mass index. Baseline posaconazole serum concentrations were compared with posaconazole serum concentrations after dose adjustment in each group using paired t test and Pearson r correlation. ANOVA was used to compare posaconazole serum concentrations and the percent increase in posaconazole serum concentrations after dose adjustment between the groups. Renal and hepatic toxicities were evaluated using ANOVA and x2 test, respectively.
RESULTS Eighty-three patients were screened over a 51-month period from October 2008 to December 2012. Twenty-nine patients were included in the final analysis. Each dose adjustment was treated as a separate event with a total of 32 dose adjustments occurring in 29 adults. The causes for ineligibility were lack of need for dose adjustment because of attainment of therapeutic posaconazole serum concentration with 200 mg orally 3 times daily dosing (45 patients; 54%) and nonadherence with posaconazole and/or “posaconazole bundle” (9 patients; 11%). Patients were categorized into 4 groups (A, B, C, and D) based on posaconazole dosing and administration after dose adjustment. All 4 groups were similar at baseline (Table 1).
After $7 days of posaconazole oral suspension 200 mg 3 times daily along with a bundle shown to optimize absorption of posaconazole, 29 of 83 patients (35%) required dose increase because of subtherapeutic steady-state posaconazole serum concentration. The median baseline steady-state posaconazole serum concentration using posaconazole 200 mg orally 3 times daily was 0.41 mcg/mL (SD, 60.134; range, 0.5). Patients in groups A, B, and D displayed an increase in posaconazole serum concentrations, with median increases ranging from 124% to 212% (Table 2). The median posaconazole serum concentration achieved in these 3 groups was 0.87 mcg/mL (group A), 0.76 mcg/mL (group B), and 0.8 mcg/mL (group D), respectively (Table 2). Group C displayed an increase in posaconazole serum concentration of only 122% above baseline with a median posaconazole serum concentration that continued to be subtherapeutic (0.51 mcg/ mL). Of note, Group C follows the schema recommended by Food and Drug Administration in response to subtherapeutic serum concentration.7 After dose adjustment, posaconazole serum concentrations achieved therapeutic range in a greater percentage of patients in group A (87%) than any other group (B = 47%, C = 9%, and D = 33%) (Table 2), but this did not reach statistical significance (P = 0.35). Three of the 4 groups (A, B, and D) achieved goal median posaconazole serum concentrations, whereas group C failed to increase medial serum posaconazole concentration .0.7 mcg/mL. This did not reach statistical significance with any group compared with baseline posaconazole serum concentration (P = 0.245). All patients in this study who required more than 1 posaconazole dose adjustment were initially administered posaconazole oral suspension 400 mg 3 times daily after subtherapeutic serum concentration with posaconazole 200 mg orally 3 times daily. No clinically relevant drug– drug interactions were identified as pertinent for this analysis. All indices of hepatic and renal function did not alter significantly after modification of posaconazole administration irrespective of dose and schedule used (Table 3). All patients included in this analysis remained adherent with posaconazole and “posaconazole bundle” until recovery absolute neutrophil count exceeded 500 cells per cubic millimeter for 2 consecutive days. No patient in any group demonstrated a documented breakthrough yeast or mold infection. Favoring a preemptive antifungal strategy, routine serologic or radiographic screenings for fungal infections were not used. One patient in group C displayed symptoms and radiographic evidence of fungal pneumonia on posaconazole at day 24 with negative serum galactomannan results for which he was alive at day 100. No positive fungal culture was obtained.
TABLE 1. Baseline Patient Characteristics Demographic Category Posaconazole oral suspension dose, postdose adjustment Age, yrs BMI 6 SD, kg/m2 Female gender, %
A (N = 3) 200 mg orally 4 times daily 32 6 5 20.0 6 3.13 100
B (N = 15) 300 mg orally 3 times daily 55 6 17 32.3 6 15.6 53
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C (N = 11) 400 mg orally 3 times daily 50 6 10 30.2 6 7.14 36
D (N = 3) 400 mg orally 4 times daily 42 6 5 27.2 6 5.5 0
P — 0.056 0.468 0.405
509
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Ther Drug Monit Volume 37, Number 4, August 2015
Hummert and Green
TABLE 2. Results of Posaconazole Dose Adjustment Parameter
A (N = 3)
Posaconazole dose, postdose adjustment Observed posaconazole serum concentrations (baseline,* followed by serum concentration obtained $7 days after dose)†
200 mg orally 4 times daily 0.6, 0.5
0.6, 1.1 0.7, 1.0
Posaconazole serum concentration (median 6 SD), ng/mL Median increase in serum posaconazole concentration, % Achieved therapeutic range, postdose adjustment,‡ % Pearson r effect size (P, compared with baseline)
B (N = 15) 300 mg orally 3 times daily 0.2, 1.7
C (N = 11) 400 mg orally 3 times daily 0.26, 0.37
0.3, 0.3, 0.37, 0.4, 0.4, 0.4, 0.4, 0.5, 0.5, 0.6,
0.3 0.3 0.32 0.2 0.5 0.6 0.6 0.8 1.0 0.6
D (N = 3) 400 mg orally 4 times daily 0.3, 1.5
P — —
0.87 6 0.32
0.22, 0.42 0.3, 0.3 0.32, 0.7 0.36, 0.79 0.4, 0.67 0.41, 0.25 0.44, 0.68 0.46, 0.63 0.5, 0.8 0.5, 1.19 0.58, 0.83 0.59, 0.5 0.61, 1.2 0.64, 0.67 0.76 6 0.38
0.2, 0.3 0.5, 0.6
0.51 6 0.24
0.80 6 0.62
0.245
212
185
124
195
—
87
47
9
33
0.35
1.34 (,0.001)
0.85 (,0.001)
0.29 (0.24)
0.58 (0.007)
—
*Baseline serum level obtained after 7 days of administration of posaconazole 200 mg orally 3 times daily. †Results in bold type indicate serum posaconazole concentration after second dose adjustment in same subject. ‡Therapeutic range defined as $0.7 mcg/mL at steady state (eg, $7 days of posaconazole administration).
DISCUSSION
demonstrated subtherapeutic posaconazole serum concentration necessitating dose increase. Posaconazole dose modifications in this study ranged from 800 mg per day divided in 4 doses to 1600 mg per day divided into 4 doses. No dose modification schema emerged superior as measured by attainment of goal posaconazole serum concentrations or toxicity. Groups A, B, and D all yielded an increase in posaconazole
This is the first study analyzing therapeutic drug monitoring and dose adjustment of posaconazole oral suspension in human subjects. Although the utility of therapeutic drug monitoring is not universally recognized when using posaconazole for prophylaxis, recent data suggest clinical benefit.7–9 Greater than 1 in 3 patients included in this study TABLE 3. Postadjustment Treatment-Emergent Adverse Effects Parameter Posaconazole dose, postdose adjustment Median serum creatinine 6 SD, mg/dL AST WNL, % ALT WNL, % Total bilirubin WNL, % Gastrointestinal adverse effects (including diarrhea, constipation, nausea, vomiting)
A (N = 3) 200 mg orally 4 times daily 0.5 6 0.1 100 100 33 0
B (N = 15) 300 mg orally 3 times daily 0.8 6 0.3 87 87 93 0
C (N = 11) 400 mg orally 3 times daily 0.7 6 0.2 100 100 100 0
D (N = 3) 400 mg orally 4 times daily 0.8 6 0.1 100 67 100 0
P — 0.35 0.676 0.877 0.097 0.894
ALT, alanine aminotransferase; AST, aspartate aminotransferase; WNL, within normal limits.
510
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Ther Drug Monit Volume 37, Number 4, August 2015
serum concentration of 185% or greater. However, patients in group C (400 mg orally 3 times daily) demonstrated only a modest increase in posaconazole serum concentrations with a median posaconazole concentration of 0.51 mcg/mL, remaining below goal serum concentration. This puzzling lack of improvement in serum posaconazole concentrations for group C was explored for other factors to explain this lack of benefit, such as formulation differences, timing of procedures, and drug–drug or drug–nutrient interactions. Nothing significant was found to explain this finding, and the authors cannot provide a plausible explanation for the lack of benefit despite significant increase in posaconazole dosing. All other groups (ie, groups A, B, and D) yielded a similar median posaconazole serum concentration of 0.76–0.87 mcg/mL. These results obtained in human patients stand in contrast with the dose adjustment algorithm proposed using a computer simulation of a subset of patients with pharmacokinetic data collected from registration trials.7 This algorithm proposes an increase in dose posaconazole suspension to 400 mg orally 3 times daily when 200 mg orally 3 times daily dosing fails to produce a steady-state posaconazole serum concentration $0.7 mcg/mL. In this study, 11 of 32 dose adjustments (34%) used followed this algorithm, yet only 1 of 11 (9%) yielded a steady-state posaconazole serum concentration within goal. Although this study includes a small number of patients, it challenges the current dogma.7 No statistical difference was identified in organ function among all of the posaconazole dosing and administration groups. Patients receiving higher doses of posaconazole did not demonstrate greater rates of toxicity, including hepatic toxicity, or difficulty tolerating the increased dose and/or schedule of posaconazole oral suspension (Table 3). Because of retrospective design and limited sample number within the posaconazole dose groups, further research is required to expand on these findings. Future research should also include the use of posaconazole delayed-release tablets and/or intravenous posaconazole in patients with subtherapeutic serum concentrations achieved with standard prophylactic dosing of posaconazole oral suspension. In conclusion, it seems that there is no singular dosing schema that yields the greatest likelihood of attaining therapeutic posaconazole serum concentrations. The schema
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Dose Adjustment of Posaconazole
proposed by computerized simulation was the schema that proved the least useful in human subjects in this study.7 From cost-minimization perspective, administration of posaconazole oral suspension 200 mg 4 times daily uses the lowest daily dose of posaconazole at the expense of reduced adherence versus 3 times daily administration. Depending on patient-specific parameters, including financial and adherence to medication administration, it would be logical to choose either posaconazole suspension 200 mg orally 4 times daily or posaconazole suspension 300 mg orally 3 times daily in patients exhibiting subtherapeutic posaconazole serum concentrations while receiving 200 mg orally 3 times daily. REFERENCES 1. Cannas G, Pautas C, Raffoux E, et al. Infectious complications in adult acute myeloid leukemia: an analysis of the Acute Leukemia French Association-9802 prospective multicenter clinical trial. Leuk Lymphoma. 2012;53:1068–1076. 2. Lewis RE, Cahyame-Zuniga L, Leventakos K, et al. Epidemiology and sites of involvement of invasive fungal infections in patients with haematological malignancies: a 20-year autopsy study. Mycoses. 2013;56: 638–645. 3. Frampton JE, Scott LJ. Posaconazole: a review of its use in the prophylaxis of invasive fungal infections. Drugs. 2008;68:993–1016. 4. Cornely OA, Maertens J, Winston DJ, et al. Posaconazole vs. fluconazole or itraconazole prophylaxis in patients with neutropenia. N Engl J Med. 2007;356:348–359. 5. Vehreschild JJ, Ruping MJGT, Wisplinghoff H, et al. Clinical effectiveness of posaconazole prophylaxis in patients with acute myelogenous leukaemia (AML): a 6 year experience of the Cologne AML cohort. J Antimicrob Chemother. 2010;65:1466–1471. 6. Pechlivanoglou P, Le HH, Daenen S, et al. Mixed treatment comparison of prophylaxis against invasive fungal infections in neutropenic patients receiving therapy for haematological malignancies: a systematic review. J Antimicrob Chemother. 2014;69:1–11. 7. Jang SH, Colangelo PM, Gobburu JVS. Exposure-response of posaconazole used for prophylaxis against invasive fungal infections: evaluating the need to adjust doses based on drug concentrations in plasma. Clin Pharmacol Ther. 2010;88:115–119. 8. Dolton MJ, Ray JE, Marriott D, et al. Posaconazole exposure-response relationship: evaluating the utility of therapeutic drug monitoring. Antimicrob Agents Chemother. 2012;56:2806–2813. 9. Hoenigl M, Raggam RB, Salzer HJF, et al. Posaconazole plasma concentrations and invasive mould infections in patients with haematological malignancies. Int J Antimicrob Agents. 2012;39:510–513. 10. Green MR, Woolery JE. Optimising absorption of posaconazole. Mycoses. 2011;54:e775–e779.
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Therapeutic Drug Monitoring and Dose Adjustment of Posaconazole Oral Suspension in Adults With Acute Myeloid Leukemia Shelly E. Hummert, PharmD* and Myke R. Green, BS Pharm, PharmD, BCOP†‡
Background: Prophylaxis with posaconazole, an extendedspectrum triazole antifungal, has been shown to increase overall survival in adults with acute myeloid leukemia receiving intensive remission induction chemotherapy. A paucity of data exists evaluating therapeutic drug monitoring and subsequent dose adjustment based on serum concentrations in humans.
Methods: An observational study was performed in 29 adult patients with acute myeloid leukemia who initially received posaconazole oral suspension 200 mg 3 times daily and required $1 dose adjustment because of steady-state posaconazole serum concentration ,0.7 mcg/mL. Four dosing schemas were compared simultaneously. Patient records were reviewed to collect patient-related and medication-related factors that may affect serum concentrations. Results: Thirty-five percent of patients experienced subtherapeutic posaconazole serum concentrations with prophylactic dosing of posaconazole oral suspension. Increasing the dose and/or schedule of posaconazole oral suspension led to attainment of goal posaconazole serum concentrations in all groups. However, patients who received 400 mg orally 3 times daily experienced the least significant increase in serum concentration and remained subtherapeutic, despite doubling the posaconazole daily dose. Toxicities were similar to baseline within all groups. Increasing the dose and/or frequency of posaconazole oral suspension led to an increase in systemic exposure and did not appreciably increase incidence of toxicities.
Conclusions: Patients receiving posaconazole oral suspension that experience subtherapeutic posaconazole serum concentrations may benefit from increasing the frequency to 200 mg orally 4 times daily or dose to 300 mg orally 3 times daily. Key Words: posaconazole, therapeutic drug monitoring, antifungal, prophylaxis (Ther Drug Monit 2015;37:508–511)
Received for publication June 18, 2014; accepted December 1, 2014. From the *Division of Pharmacy Services, Providence St. Vincent Medical Center, Portland, Oregon; †Division of Pharmacy Services, University of Arizona Medical Center; and ‡Section of Hematology/Oncology, University of Arizona Cancer Center, Tucson. M. R. Green serves on the speakers’ bureau of Merck and Co. The other author declares no conflict of interest. Correspondence: Myke R. Green, BS Pharm, PharmD, BCOP, University of Arizona Cancer Center, 1501 N Campbell Avenue, PO Box 245009, Tucson, AZ 85724-5009 (e-mail: [email protected]). Copyright © 2014 Wolters Kluwer Health, Inc. All rights reserved.
508
INTRODUCTION Invasive fungal infections are major contributors to morbidity and mortality in adult patients with acute myeloid leukemia receiving intensive remission induction therapy.1,2 Posaconazole is an extended-spectrum triazole antifungal agent with broad activity against a wide spectrum of opportunistic fungi, including Candida and Aspergillus species.3 Clinical trials have proven the efficacy of posaconazole in preventing invasive fungal infections and improving overall survival rates versus comparator triazole antifungal agents in patients with acute myeloid leukemia (AML).4–6 The efficacy of posaconazole prophylaxis for patients with AML requires a steady-state serum concentration at least 0.7 mcg/mL, with no known toxicity threshold or upper limit of serum concentration.7 However, poor and highly variable absorption of posaconazole suspension and therapeutic drug monitoring may be necessary to attain maximal efficacy.8,9 However, the role of dose adjustment in response to subtherapeutic serum concentrations has not been evaluated in humans. Currently, a dose-adjustment algorithm based on plasma concentrations using a computer simulation model has been posited.7 The primary outcome for this study was posaconazole serum concentrations after dose adjustment in adult patients with AML receiving intensive remission induction chemotherapy. Secondary outcomes included treatmentemergent adverse effects and clinical outcomes at day 100 after first dose of posaconazole.
METHODS A retrospective chart review study was conducted at a single academic medical center after institutional review board approval. Eligibility included patients aged 18 years or older, with primary or secondary AML treated with intensive remission induction chemotherapy, received posaconazole oral suspension 200 mg orally 3 times daily as prophylaxis for $14 days (defined as $7 days predose adjustment and $7 postdose adjustment), and required at least 1 dose adjustment secondary to a subtherapeutic steady-state posaconazole serum concentration. Exclusion criteria included concurrent pharmacotherapy that is known to decrease serum posaconazole concentrations during the first 14 days of posaconazole administration, alternate indications for posaconazole, and nonadherence with posaconazole or “posaconazole bundle,” which consists of strategies to optimize absorption of posaconazole oral suspension.10 Both in predose and Ther Drug Monit Volume 37, Number 4, August 2015
Copyright © 2015 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
Ther Drug Monit Volume 37, Number 4, August 2015
Dose Adjustment of Posaconazole
postdose adjustment, all patients were carefully screened for adherence to posaconazole administration and “posaconazole bundle”; nonadherence was defined as #95% adherence with any element of “posaconazole bundle” at any time during the dosing interval. All posaconazole serum concentrations were drawn 7–10 days after posaconazole initiation or adjustment and were analyzed at The Fungus Testing Laboratory, University of Texas Health Science Center at San Antonio (San Antonio, TX). The steady-state posaconazole serum concentration was considered subtherapeutic if ,0.7 mcg/mL.8,9 Patients were stratified into 4 groups based on posaconazole dose adjustment schema chosen at the discretion of the oncologist and/or infectious diseases physician. The 4 groups consisted of group A = 200 mg 4 times daily, group B = 300 mg 3 times daily, group C = 400 mg 3 times daily, and group D = 400 mg 4 times daily (Table 1). Posaconazole was continued until absolute neutrophil count exceeded 500 cells per cubic millimeter for 2 consecutive days or breakthrough fungal infection necessitating alternate antifungal treatment.5 Patients were followed for 100 days after the first dose of posaconazole. All statistical analyses used 2-sided P values, with statistical significance set at ,0.05. Chi-squared test was used to compare gender demographic comparisons between all 4 groups, whereas analysis of variance (ANOVA) was used for age and body mass index. Baseline posaconazole serum concentrations were compared with posaconazole serum concentrations after dose adjustment in each group using paired t test and Pearson r correlation. ANOVA was used to compare posaconazole serum concentrations and the percent increase in posaconazole serum concentrations after dose adjustment between the groups. Renal and hepatic toxicities were evaluated using ANOVA and x2 test, respectively.
RESULTS Eighty-three patients were screened over a 51-month period from October 2008 to December 2012. Twenty-nine patients were included in the final analysis. Each dose adjustment was treated as a separate event with a total of 32 dose adjustments occurring in 29 adults. The causes for ineligibility were lack of need for dose adjustment because of attainment of therapeutic posaconazole serum concentration with 200 mg orally 3 times daily dosing (45 patients; 54%) and nonadherence with posaconazole and/or “posaconazole bundle” (9 patients; 11%). Patients were categorized into 4 groups (A, B, C, and D) based on posaconazole dosing and administration after dose adjustment. All 4 groups were similar at baseline (Table 1).
After $7 days of posaconazole oral suspension 200 mg 3 times daily along with a bundle shown to optimize absorption of posaconazole, 29 of 83 patients (35%) required dose increase because of subtherapeutic steady-state posaconazole serum concentration. The median baseline steady-state posaconazole serum concentration using posaconazole 200 mg orally 3 times daily was 0.41 mcg/mL (SD, 60.134; range, 0.5). Patients in groups A, B, and D displayed an increase in posaconazole serum concentrations, with median increases ranging from 124% to 212% (Table 2). The median posaconazole serum concentration achieved in these 3 groups was 0.87 mcg/mL (group A), 0.76 mcg/mL (group B), and 0.8 mcg/mL (group D), respectively (Table 2). Group C displayed an increase in posaconazole serum concentration of only 122% above baseline with a median posaconazole serum concentration that continued to be subtherapeutic (0.51 mcg/ mL). Of note, Group C follows the schema recommended by Food and Drug Administration in response to subtherapeutic serum concentration.7 After dose adjustment, posaconazole serum concentrations achieved therapeutic range in a greater percentage of patients in group A (87%) than any other group (B = 47%, C = 9%, and D = 33%) (Table 2), but this did not reach statistical significance (P = 0.35). Three of the 4 groups (A, B, and D) achieved goal median posaconazole serum concentrations, whereas group C failed to increase medial serum posaconazole concentration .0.7 mcg/mL. This did not reach statistical significance with any group compared with baseline posaconazole serum concentration (P = 0.245). All patients in this study who required more than 1 posaconazole dose adjustment were initially administered posaconazole oral suspension 400 mg 3 times daily after subtherapeutic serum concentration with posaconazole 200 mg orally 3 times daily. No clinically relevant drug– drug interactions were identified as pertinent for this analysis. All indices of hepatic and renal function did not alter significantly after modification of posaconazole administration irrespective of dose and schedule used (Table 3). All patients included in this analysis remained adherent with posaconazole and “posaconazole bundle” until recovery absolute neutrophil count exceeded 500 cells per cubic millimeter for 2 consecutive days. No patient in any group demonstrated a documented breakthrough yeast or mold infection. Favoring a preemptive antifungal strategy, routine serologic or radiographic screenings for fungal infections were not used. One patient in group C displayed symptoms and radiographic evidence of fungal pneumonia on posaconazole at day 24 with negative serum galactomannan results for which he was alive at day 100. No positive fungal culture was obtained.
TABLE 1. Baseline Patient Characteristics Demographic Category Posaconazole oral suspension dose, postdose adjustment Age, yrs BMI 6 SD, kg/m2 Female gender, %
A (N = 3) 200 mg orally 4 times daily 32 6 5 20.0 6 3.13 100
B (N = 15) 300 mg orally 3 times daily 55 6 17 32.3 6 15.6 53
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C (N = 11) 400 mg orally 3 times daily 50 6 10 30.2 6 7.14 36
D (N = 3) 400 mg orally 4 times daily 42 6 5 27.2 6 5.5 0
P — 0.056 0.468 0.405
509
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Ther Drug Monit Volume 37, Number 4, August 2015
Hummert and Green
TABLE 2. Results of Posaconazole Dose Adjustment Parameter
A (N = 3)
Posaconazole dose, postdose adjustment Observed posaconazole serum concentrations (baseline,* followed by serum concentration obtained $7 days after dose)†
200 mg orally 4 times daily 0.6, 0.5
0.6, 1.1 0.7, 1.0
Posaconazole serum concentration (median 6 SD), ng/mL Median increase in serum posaconazole concentration, % Achieved therapeutic range, postdose adjustment,‡ % Pearson r effect size (P, compared with baseline)
B (N = 15) 300 mg orally 3 times daily 0.2, 1.7
C (N = 11) 400 mg orally 3 times daily 0.26, 0.37
0.3, 0.3, 0.37, 0.4, 0.4, 0.4, 0.4, 0.5, 0.5, 0.6,
0.3 0.3 0.32 0.2 0.5 0.6 0.6 0.8 1.0 0.6
D (N = 3) 400 mg orally 4 times daily 0.3, 1.5
P — —
0.87 6 0.32
0.22, 0.42 0.3, 0.3 0.32, 0.7 0.36, 0.79 0.4, 0.67 0.41, 0.25 0.44, 0.68 0.46, 0.63 0.5, 0.8 0.5, 1.19 0.58, 0.83 0.59, 0.5 0.61, 1.2 0.64, 0.67 0.76 6 0.38
0.2, 0.3 0.5, 0.6
0.51 6 0.24
0.80 6 0.62
0.245
212
185
124
195
—
87
47
9
33
0.35
1.34 (,0.001)
0.85 (,0.001)
0.29 (0.24)
0.58 (0.007)
—
*Baseline serum level obtained after 7 days of administration of posaconazole 200 mg orally 3 times daily. †Results in bold type indicate serum posaconazole concentration after second dose adjustment in same subject. ‡Therapeutic range defined as $0.7 mcg/mL at steady state (eg, $7 days of posaconazole administration).
DISCUSSION
demonstrated subtherapeutic posaconazole serum concentration necessitating dose increase. Posaconazole dose modifications in this study ranged from 800 mg per day divided in 4 doses to 1600 mg per day divided into 4 doses. No dose modification schema emerged superior as measured by attainment of goal posaconazole serum concentrations or toxicity. Groups A, B, and D all yielded an increase in posaconazole
This is the first study analyzing therapeutic drug monitoring and dose adjustment of posaconazole oral suspension in human subjects. Although the utility of therapeutic drug monitoring is not universally recognized when using posaconazole for prophylaxis, recent data suggest clinical benefit.7–9 Greater than 1 in 3 patients included in this study TABLE 3. Postadjustment Treatment-Emergent Adverse Effects Parameter Posaconazole dose, postdose adjustment Median serum creatinine 6 SD, mg/dL AST WNL, % ALT WNL, % Total bilirubin WNL, % Gastrointestinal adverse effects (including diarrhea, constipation, nausea, vomiting)
A (N = 3) 200 mg orally 4 times daily 0.5 6 0.1 100 100 33 0
B (N = 15) 300 mg orally 3 times daily 0.8 6 0.3 87 87 93 0
C (N = 11) 400 mg orally 3 times daily 0.7 6 0.2 100 100 100 0
D (N = 3) 400 mg orally 4 times daily 0.8 6 0.1 100 67 100 0
P — 0.35 0.676 0.877 0.097 0.894
ALT, alanine aminotransferase; AST, aspartate aminotransferase; WNL, within normal limits.
510
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Ther Drug Monit Volume 37, Number 4, August 2015
serum concentration of 185% or greater. However, patients in group C (400 mg orally 3 times daily) demonstrated only a modest increase in posaconazole serum concentrations with a median posaconazole concentration of 0.51 mcg/mL, remaining below goal serum concentration. This puzzling lack of improvement in serum posaconazole concentrations for group C was explored for other factors to explain this lack of benefit, such as formulation differences, timing of procedures, and drug–drug or drug–nutrient interactions. Nothing significant was found to explain this finding, and the authors cannot provide a plausible explanation for the lack of benefit despite significant increase in posaconazole dosing. All other groups (ie, groups A, B, and D) yielded a similar median posaconazole serum concentration of 0.76–0.87 mcg/mL. These results obtained in human patients stand in contrast with the dose adjustment algorithm proposed using a computer simulation of a subset of patients with pharmacokinetic data collected from registration trials.7 This algorithm proposes an increase in dose posaconazole suspension to 400 mg orally 3 times daily when 200 mg orally 3 times daily dosing fails to produce a steady-state posaconazole serum concentration $0.7 mcg/mL. In this study, 11 of 32 dose adjustments (34%) used followed this algorithm, yet only 1 of 11 (9%) yielded a steady-state posaconazole serum concentration within goal. Although this study includes a small number of patients, it challenges the current dogma.7 No statistical difference was identified in organ function among all of the posaconazole dosing and administration groups. Patients receiving higher doses of posaconazole did not demonstrate greater rates of toxicity, including hepatic toxicity, or difficulty tolerating the increased dose and/or schedule of posaconazole oral suspension (Table 3). Because of retrospective design and limited sample number within the posaconazole dose groups, further research is required to expand on these findings. Future research should also include the use of posaconazole delayed-release tablets and/or intravenous posaconazole in patients with subtherapeutic serum concentrations achieved with standard prophylactic dosing of posaconazole oral suspension. In conclusion, it seems that there is no singular dosing schema that yields the greatest likelihood of attaining therapeutic posaconazole serum concentrations. The schema
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Dose Adjustment of Posaconazole
proposed by computerized simulation was the schema that proved the least useful in human subjects in this study.7 From cost-minimization perspective, administration of posaconazole oral suspension 200 mg 4 times daily uses the lowest daily dose of posaconazole at the expense of reduced adherence versus 3 times daily administration. Depending on patient-specific parameters, including financial and adherence to medication administration, it would be logical to choose either posaconazole suspension 200 mg orally 4 times daily or posaconazole suspension 300 mg orally 3 times daily in patients exhibiting subtherapeutic posaconazole serum concentrations while receiving 200 mg orally 3 times daily. REFERENCES 1. Cannas G, Pautas C, Raffoux E, et al. Infectious complications in adult acute myeloid leukemia: an analysis of the Acute Leukemia French Association-9802 prospective multicenter clinical trial. Leuk Lymphoma. 2012;53:1068–1076. 2. Lewis RE, Cahyame-Zuniga L, Leventakos K, et al. Epidemiology and sites of involvement of invasive fungal infections in patients with haematological malignancies: a 20-year autopsy study. Mycoses. 2013;56: 638–645. 3. Frampton JE, Scott LJ. Posaconazole: a review of its use in the prophylaxis of invasive fungal infections. Drugs. 2008;68:993–1016. 4. Cornely OA, Maertens J, Winston DJ, et al. Posaconazole vs. fluconazole or itraconazole prophylaxis in patients with neutropenia. N Engl J Med. 2007;356:348–359. 5. Vehreschild JJ, Ruping MJGT, Wisplinghoff H, et al. Clinical effectiveness of posaconazole prophylaxis in patients with acute myelogenous leukaemia (AML): a 6 year experience of the Cologne AML cohort. J Antimicrob Chemother. 2010;65:1466–1471. 6. Pechlivanoglou P, Le HH, Daenen S, et al. Mixed treatment comparison of prophylaxis against invasive fungal infections in neutropenic patients receiving therapy for haematological malignancies: a systematic review. J Antimicrob Chemother. 2014;69:1–11. 7. Jang SH, Colangelo PM, Gobburu JVS. Exposure-response of posaconazole used for prophylaxis against invasive fungal infections: evaluating the need to adjust doses based on drug concentrations in plasma. Clin Pharmacol Ther. 2010;88:115–119. 8. Dolton MJ, Ray JE, Marriott D, et al. Posaconazole exposure-response relationship: evaluating the utility of therapeutic drug monitoring. Antimicrob Agents Chemother. 2012;56:2806–2813. 9. Hoenigl M, Raggam RB, Salzer HJF, et al. Posaconazole plasma concentrations and invasive mould infections in patients with haematological malignancies. Int J Antimicrob Agents. 2012;39:510–513. 10. Green MR, Woolery JE. Optimising absorption of posaconazole. Mycoses. 2011;54:e775–e779.
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