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This double-blind, randomized, placebo-controlled, sequential group, phase 1 study was designed to assess in healthy men, the safety, tolerability, pharmacokinetics, and translational pharmacodynamics of JNJ-39439335 (mavatrep), a transient receptor potential vanilloid subtype 1 antagonist; it was preceded by a translational preclinical study which assessed the ability of JNJ-39439335 to block capsaicin-induced flare in rats, providing predictive pharmacokinetic and pharmacodynamic data that informed the subsequent phase 1 clinical study. The clinical study consisted of 2 parts: part 1 assessed pharmacokinetics and pharmacodynamics, including heat pain detection threshold and heat pain tolerance, of JNJ-39439335, and part 2 assessed pharmacodynamic effect of JNJ-39439335 on capsaicin-induced flare and sensory testing on naïve and UVB-sensitized skin in humans. Plasma concentrations of JNJ-39439335 peaked at approximately 2 to 4 hours postdose, then declined multiexponentially, with a prolonged terminal phase (half-life: 30-86 hours). Renal clearance of JNJ-39439335 was negligible. JNJ-39439335 treatment resulted in clear, consistent dose-related increases in heat pain detection threshold, heat pain tolerance, and heat pain latency. JNJ-39439335 reduced the capsaicin-induced flare area and flare intensity, with complete blocking observed in the 50-mg dose group at 144 hours postdose. This was consistent with the capsaicin flare results observed with JNJ-39439335 in rats. The most common adverse events observed in the clinical study were related to increases in body temperature after JNJ-39439335 treatment; these were predominately mild to moderate in severity with no evidence of exposure dependence up to 225 mg. JNJ-39439335 was well tolerated at single doses up to 225 mg, recommending its suitability for further clinical development., Competing Interests: Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article.

Purpose: To characterize the pharmacokinetics of adjunctive topiramate in infants (1-24 months) with refractory partial-onset seizures (POS); also to evaluate safety and tolerability of topiramate in the dose range of 3-25 mg/kg/day., Methods: In this open-label phase 1 study, infants (N = 55) with refractory POS receiving at least one concurrent antiepileptic drug (AED) were enrolled. Infants were stratified by age and randomly assigned to one of four topiramate target dose groups (3-, 5-, 15-, or 25 mg/kg/day). Treatment was initiated at 3 mg/kg/day with titration to the target dose by weekly dose escalation. Topiramate was administered daily in two divided doses as oral liquid (5 mg/ml for infants <9 kg or those who could not tolerate solid foods) or sprinkle capsule (25 mg) formulations. Following seven consecutive days of topiramate administration at the target dose, four blood samples were collected from each infant for pharmacokinetic assessments (predose, 1-3, 4-6, and 8-10 h postdose)., Key Findings: Fifty-five infants (mean [SD] age in months: 11.4 [5.79]) with POS were enrolled, of whom 33% had seizures with or without secondary generalization. Complete pharmacokinetic profiles were obtained in 35 infants in whom mean plasma topiramate concentration-time profiles demonstrated linear pharmacokinetics (predose topiramate concentrations [C(trough) ] and area under the plasma concentration-time curve from time 0 through 12 h [AUC(12 h)]) of topiramate over the dose range studied). Apparent steady state oral clearance (CL(ss) /F) remained similar across all topiramate target dose groups and was independent of creatinine clearance, age, and weight. Mean values for CL(ss) /F were approximately twofold greater in infants receiving concomitant enzyme-inducing AEDs versus enzyme-inhibiting AEDs. Topiramate was well tolerated and safety findings were consistent with previous reports in children and adults. Most common treatment emergent adverse events (≥10%) were upper respiratory tract infection, fever, vomiting, somnolence, and anorexia., Significance: In infants (1-24 months), topiramate exhibited linear steady state pharmacokinetics over the dose range 3-25 mg/kg/day, and CL(ss) /F of topiramate was independent of dose. Moreover, the concomitant enzyme-inducing AEDs doubled the clearance of topiramate. Topiramate was generally well tolerated as adjunctive therapy at doses up to 25 mg/kg/day., (Wiley Periodicals, Inc. © 2012 International League Against Epilepsy.)