Pharmacokinetics and Safety of Posaconazole Administered by Intravenous Solution and Oral Tablet in Healthy Chinese Subjects and Effect of Food on Tablet Bioavailability
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Background and Objectives
New intravenous and solid oral formulations of the antifungal agent posaconazole have been developed. This randomized, open-label, crossover study in 18 healthy adult Chinese male and female subjects evaluated the pharmacokinetics of single-dose posaconazole (oral 300-mg posaconazole tablet fasted, intravenous 300-mg posaconazole solution fasted, and oral 300-mg posaconazole tablet with standard high-fat breakfast). Primary objectives were to determine the single-dose pharmacokinetics of posaconazole in healthy Chinese subjects when administered as an intravenous solution and as an oral tablet under fasted conditions and the effect of food on the absorption of posaconazole.
The three treatments consisted of the following: a single oral dose of posaconazole 300 mg (fasted), a single oral dose of posaconazole 300 mg (high-fat breakfast), and a single intravenous dose of posaconazole 300 mg (fasted). Blood samples for pharmacokinetic analysis were collected before dosing and at regular intervals after dosing. Adverse events were monitored throughout. The pharmacokinetic population included the per-protocol population. The safety population included all subjects who received one or more doses of the study drug.
Time to maximum plasma concentration of intravenous posaconazole coincided with the end of infusion; the half-life (t½) was 25.76 h. Geometric mean (% coefficient of variation) values of area under the plasma concentration–time curve from time 0 extrapolated to infinity (AUC0–∞) and maximum plasma concentration (Cmax) were 59,925 (36.2%) h·ng/mL and 3999 (28.5%) ng/mL, respectively. The posaconazole tablet had a time to maximum plasma concentration of 4 h and a t½ of 25.21 h after fasting. Geometric mean (coefficient of variation) values of AUC0–∞ and Cmax were 25,263 (39.9%) h·ng/mL and 674.5 (29.6%) ng/mL, respectively. Standard high-fat breakfast increased the exposure of posaconazole approximately twofold with geometric mean ratios (high-fat breakfast/fasted) for AUC0–∞ and Cmax of 2.06 (90% confidence interval 1.86–2.30) and 1.95 (90% confidence interval 1.65–2.31), respectively. The geometric mean absolute bioavailability of the tablet formulation was 42.2% in the fasted state and 87.1% under high-fat breakfast conditions. The most commonly reported adverse events were nausea, vomiting, dizziness, and first-degree atrioventricular block for intravenous posaconazole 300 mg and nausea for oral posaconazole 300 mg (high-fat breakfast). All adverse events were mild and resolved without sequelae.
Posaconazole was generally well tolerated in healthy Chinese male and female subjects. The safety and the high-fat breakfast and fasted pharmacokinetics of posaconazole in healthy Chinese subjects are within exposures demonstrated to be generally well tolerated and efficacious and compare reasonably well with the overall posaconazole data across Western countries.
The design, study conduct, and financial support for this research were provided by Merck & Co., Inc., Kenilworth, NJ, USA. Medical writing assistance, supported by Merck & Co., Inc., Kenilworth, NJ, USA, was provided by Jennifer M. Kulak, PhD, of ApotheCom (Yardley, PA, USA) during the preparation of this article. The authors gratefully acknowledge the staff of the phase 1 unit at Peking University Third Hospital in Beijing, China.
HL was involved in the study design, acquisition and analysis of the data, and interpretation of the results and wrote the manuscript. YW, SZ, LX, and SX were involved in the acquisition of the data. JJ and XMZ were involved in the interpretation of the data. YQ was involved in the analysis of the data and interpretation of the data. EM was involved in the acquisition and analysis of the data. All authors critically reviewed and revised the manuscript and approved the final draft for submission.
Compliance with Ethical Standards
This study was funded by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, MSD China, Beijing.
Conflict of interest
Haiyan Li, Yudong Wei, Shuang Zhang, and Lin Xu have no conflicts that are directly relevant to the content of this article. Jun Jiang, Yanping Qiu, Shuang Xie, and Xu Min Zhao are employees of Merck Sharp & Dohme, Beijing, China. Eric Mangin is an employee of Merck & Co., Inc., Kenilworth, NJ, USA.
The Independent Ethics Committee of Peking University Third Hospital reviewed and approved the protocol and applicable amendments. This trial was conducted in conformance with Good Clinical Practice standards and applicable country and/or local statutes and regulations regarding ethics committee review, informed consent, and the protection of human subjects participating in biomedical research. All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.
All subjects provided written informed consent.
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