A new solid oral tablet formulation of posaconazole: a randomized clinical trial to investigate rising single- and multiple-dose pharmacokinetics and safety in healthy volunteers
G Krishna, L Ma, M Martinho, R A Preston, E O'Mara, G Krishna, L Ma, M Martinho, R A Preston, E O'Mara
Abstract
Objectives: Posaconazole is an extended-spectrum triazole with proven efficacy as antifungal treatment and prophylaxis. The marketed oral suspension should be taken with food to maximize systemic absorption. A new solid oral tablet has been developed with improved bioavailability that can be administered without regard to food. The aim of this study was to evaluate rising single- and multiple-dose pharmacokinetics, safety and tolerability of the new tablet.
Methods: This was a single-centre, randomized, placebo-controlled, Phase I, rising single- and multiple-dose study of healthy subjects aged 18-65 years who received a posaconazole tablet as 200 mg once daily, 200 mg twice daily or 400 mg once daily. The 24 subjects were studied in two cohorts of 12 subjects each (9 active and 3 placebo).
Results: After single or multiple oral dose administration of posaconazole tablets (200 and 400 mg), exposure increased in a dose-related manner. Peak posaconazole concentrations were attained at a median T(max) of 4-5 h. Mean half-life was similar for 200 and 400 mg posaconazole doses (25 and 26 h). The accumulation ratio upon multiple doses over 8 days was ∼3 for 200 and 400 mg once daily and ∼5 for 200 mg twice daily. C(avg) values exceeded 1300 ng/mL. The posaconazole oral tablet was safe and well tolerated, although mild, transient elevations in liver function were reported in some patients.
Conclusions: Posaconazole exposure increased in a dose-related manner. The pharmacokinetics of this new solid oral tablet of posaconazole supports the clinical evaluation of once-daily dosing regimens for fungal infections.
Figures
References
- Cornely OA, Maertens J, Winston DJ, et al. Posaconazole vs. fluconazole or itraconazole prophylaxis in patients with neutropenia. N Engl J Med. 2007;356:348–59.
- Ullmann AJ, Lipton JH, Vesole DH, et al. Posaconazole or fluconazole for prophylaxis in severe graft-versus-host disease. N Engl J Med. 2007;356:335–47.
- Walsh TJ, Raad I, Patterson TF, et al. Treatment of invasive aspergillosis with posaconazole in patients who are refractory to or intolerant of conventional therapy: an externally controlled trial. Clin Infect Dis. 2007;44:2–12.
- Raad II, Hachem RY, Herbrecht R, et al. Posaconazole as salvage treatment of invasive fusariosis in patients with underlying hematologic malignancy and other conditions. Clin Infect Dis. 2006;42:1398–403.
- Courtney R, Wexler D, Radwanski E, et al. Effect of food on the relative bioavailability of two oral formulations of posaconazole in healthy adults. Br J Clin Pharmacol. 2003;57:218–22.
- Krishna G, Moton A, Ma L, et al. The pharmacokinetics and absorption of posaconazole oral suspension under various gastric conditions in healthy volunteers. Antimicrob Agents Chemother. 2009;53:958–66.
- Schering Corporation. 2010. NOXAFIL® (Posaconazole) Oral Suspension 40 mg/mL.
- Krishna G, Ma L, Vickery D, et al. Effect of varying amounts of a liquid nutritional supplement on the pharmacokinetics of posaconazole in healthy volunteers. Antimicrob Agents Chemother. 2009;53:4749–52.
- Krishna G, Ma L, Martinho M, et al. A single dose phase I study to evaluate the pharmacokinetics of posaconazole new tablet and capsule formulations relative to oral suspension. Antimicrob Agents Chemother. 2012 .
- Shen JX, Krishna G, Hayes RN. A sensitive liquid chromatography and mass spectrometry method for the determination of posaconazole in human plasma. J Pharm Biomed Anal. 2007;43:228–36.
- Moton A, Krishna G, Wang Z. Tolerability and safety profile of posaconazole: evaluation of 18 controlled studies in healthy volunteers. J Clin Pharm Ther. 2009;34:301–11.
Source: PubMed