A multiple-dose double-blind randomized study to evaluate the safety, pharmacokinetics, pharmacodynamics and analgesic efficacy of the TRPV1 antagonist JNJ-39439335 (mavatrep)

Abstract

<jats:title>Abstract</jats:title> <jats:sec id="j_sjpain-2017-0184_s_999"> <jats:title id="d1724619e35643">Background and aims:</jats:title> <jats:p>This double-blind (DB), randomized, placebo-controlled, sequential-group, multiple-ascending dose, phase 1 study evaluated safety, pharmacokinetics and pharmacodynamics of JNJ-39439335 in healthy men (part 1), and in participants with knee osteoarthritis (part 2).</jats:p></jats:sec> <jats:sec id="j_sjpain-2017-0184_s_998"> <jats:title id="d1724619e35651">Methods:</jats:title> <jats:p>Both parts 1 and 2 consisted of screening (upto 21 days), 21-day DB treatment phase [eight participants/group: JNJ-39439335 (part 1: 2–50 mg; part 2: 10–50 mg): <jats:italic>n</jats:italic>=6; placebo: <jats:italic>n</jats:italic>=2] and follow-up (total study duration ~10 weeks).</jats:p></jats:sec> <jats:sec id="j_sjpain-2017-0184_s_997"> <jats:title id="d1724619e35665">Results:</jats:title> <jats:p>Plasma concentrations and systemic exposure of JNJ-39439335 increased in slightly higher than dose-proportional fashion (steady-state reached by day 14). Renal excretion of JNJ-39439335 was negligible. Marked dose-related increases in pharmacodynamic heat pain assessments were observed in JNJ-39439335-treated participants, which persisted throughout the treatment with no signs of tolerance with repeated dosing. No effect on pharmacodynamic cold pain or mechanical pain assessments were seen. Effects on pharmacodynamic capsaicin-induced flare assessments in JNJ-39439335-treated participants versus placebo were consistent with effects observed with single-dose, and did not demonstrate tolerance with multiple dosing. In participants with knee osteoarthritis, significant improvements versus placebo were observed in a stair-climbing-induced pain model. All JNJ-39439335-treated participants reported ≥1 treatment-emergent adverse events (TEAE); most common (≥50% incidence) TEAEs in part 1 were feeling hot (79%), thermohypoesthesia (71%), paresthesia (58%) and feeling cold (50%), and in part 2, were minor thermal burns (50%).</jats:p></jats:sec> <jats:sec id="j_sjpain-2017-0184_s_996"> <jats:title id="d1724619e35673">Conclusions:</jats:title> <jats:p>JNJ-39439335 (doses 2–50 mg) was well-tolerated, and associated with acceptable multiple-dose pharmacokinetic profile. JNJ-39439335 demonstrated sustained pharmacodynamic effects (heat pain perception, heat pain latency, capsaicin-induced flare), and an efficacy signal in participants with osteoarthritis pain.</jats:p></jats:sec> <jats:sec id="j_sjpain-2017-0184_s_995"> <jats:title id="d1724619e35682">Implications:</jats:title> <jats:p>Given the efficacy signal observed and the unique safety profile, larger phase 2 studies are needed to better understand the potential of JNJ-39439335 in the treatment of chronic pain. Analgesic efficacy of lower doses administered over a longer period of time and improved patient counseling techniques to reduce the minor thermal burns can be explored to minimize the adverse events.</jats:p></jats:sec>

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

“…7,8 Tissue-binding studies revealed that mavatrep is highly bound to plasma proteins (98.7%). 7,8 Tissue-binding studies revealed that mavatrep is highly bound to plasma proteins (98.7%).…”

“…The reference formulation A contained a core tablet (consisting of mavatrep HCl salt, microcrystalline cellulose, sodium starch glycolate, magnesium stearate, hydroxypropyl methylcellulose, and poloxamer 407), which was the same as an early tablet used in the single and multiple ascending-dose studies, 7,8 and then the core tablet was encapsulated, backfilling with microcrystalline cellulose. It is well known that the in vivo dissolution of a drug plays a critical role for oral bioavailability.…”

“…7,8 In men and women with osteoarthritis, mavatrep doses of 10, 25, and 50 mg per day over 21 days were well tolerated and pharmacologically active. Single doses of mavatrep up to 225 mg and multiple doses up to 50 mg daily for 21 days were well tolerated.…”

Pharmacokinetics and Safety of Mavatrep (JNJ‐39439335), a TRPV1 Antagonist in Healthy Japanese and Caucasian Men: A Double‐Blind, Randomized, Placebo‐Controlled, Sequential‐Group Phase 1 Study

“…Blood samples were also collected predose on days 3-13, days [16][17][18][19][20], and at the follow-up visits. For part 1, blood samples (4 mL each) were collected in tubes containing K 2ethylenediaminetetraacetic acid on day 1 at 30 minutes prior to dose, 0 to 120 hours postdose.…”

“…15,16 Mavatrep is eliminated mainly via nonrenal clearance (possible cytochrome P450 [CYP] metabolism and/or biliary excretion). 15,16 Mavatrep is eliminated mainly via nonrenal clearance (possible cytochrome P450 [CYP] metabolism and/or biliary excretion).…”