Bioavailability and Pharmacokinetics of TRPV1 Antagonist Mavatrep (JNJ-39439335) Tablet and Capsule Formulations in Healthy Men: Two Open-Label, Crossover, Single-Dose Phase 1 Studies.

ABSTRACT

To improve room temperature stability and oral bioavailability of mavatrep (JNJ-39439335, a transient receptor potential vanilloid subtype-1 antagonist), various formulations were initially developed and evaluated in 2 phase 1 open-label, randomized, 3-way crossover studies in healthy participants. Study 1 evaluated 2 new overencapsulated tablet formulations (formulations B and C) relative to an overencapsulated early tablet formulation (formulation A), using mavatrep HCl salt form. Because these tablets were still not room-temperature stable, in study 2 two free-base solid dispersion amorphous formulations (formulations D and E) were evaluated relative to the best encapsulated formulation from study 1 (formulation C) and also food effect. Both studies had screening (∼4 weeks), treatment (study 1 n = 18, 6-sequenced; formulations B and C [2 × 25 mg] versus A [2 × 25 mg]; study 2, part 1 n = 24, formulations D and E [2 × 12.5 mg] versus C [1 × 25 mg]; study 2, part 2 n = 16, best formulation from part 1 fed versus fasted, 2 × 12.5 mg) with a 21-day washout period and a follow-up. Mavatrep exhibited consistent pharmacokinetics across formulations. Following rapid absorption (median tmax , 1.5-6.5 hours), plasma concentrations declined multiexponentially (mean t1/2 , 67-104 hours). The new encapsulated tablet formulation (formulation C, capsule filler poloxamer 407) was the best formulation (Cmax and AUC values 2-3-fold > than the other 2) from study 1. Using this as a reference in study 2, part 1, only small (<20%) differences in mean Cmax and AUC were observed between the 3 formulations (C, D, and E). Formulation E (gelatin capsule with amorphous solid dispersion [12.5 mg free base], hydroxypropyl methylcellulose, vitamin E polyethylene glycol succinate, silicified microcrystalline cellulose, magnesium stearate, colloidal silicon dioxide) showed improved room-temperature stability and provided the best overall bioavailability with small variability. Small effects of a high-fat meal on oral bioavailability were observed for formulation E, but were not clinically meaningful. Mavatrep safety profiles were similar across formulations and under fasted and fed conditions. No new safety concerns were reported.