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Safety, Tolerability and Pharmacokinetic and Pharmacodynamic Learnings from a Double-Blind, Randomized, Placebo-Controlled, Sequential Group First-in-Human Study of the TRPV1 Antagonist, JNJ-38893777, in Healthy Men

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Abstract

Background and Objective

Nociceptive and neuropathic pain, one of common reasons of disability and loss of quality life, are often undertreated due to safety concerns with current therapies. This study assessed the safety, tolerability, pharmacokinetics and pharmacodynamics of JNJ-38893777, a potent and selective transient receptor potential vanilloid 1 (TRPV1) channel antagonist in healthy men.

Methods

In a single-center, double-blind, placebo-controlled, sequential group, single-ascending-dose phase 1 study, 80 healthy men (18–45 years old; body mass index 18.5 to <30 kg/m2), randomized to two groups, received either JNJ-38893777 (n = 6) or placebo (n = 2) in a dose-escalation manner. The study was designed in two parts: Part 1, an early tablet formulation was administered under fasting conditions at 5, 15, 45, 125, 250, or 500 mg; Part 2, a new tablet formulation was administered in a fasting state (250 mg) and a high-fat fed state (250 mg, 375 mg, or 500 mg). Serial plasma and urine samples (collected over 120 h post-dose) were analyzed using LC–MS/MS for pharmacokinetic evaluations.

Results

JNJ-38893777 concentrations peaked from 3.0 to 5.5 h (median) post-administration, and then declined multi-exponentially with a prolonged terminal phase. Renal clearance was negligible. Maximum concentration (C max) and area under the concentration–time curve from time zero to infinity (AUC∞) of the early formulation increased with increasing doses but less than dose-proportionally over 5–500 mg (fasted) doses. The new tablet formulation showed no improvements in the fasting state but showed an 11- to 22-fold increase in JNJ-38893777 exposure; interindividual variability reduced from 73–85 % to 23–24 %, and a significant increase (P < 0.05) in heat pain detection threshold (~3 °C) was observed in the fed state. Mild to moderate adverse events were observed, with no evidence of exposure dependence up to 500 mg (fed). Concentration-related increases in body temperature or changes in Fridericia-corrected QT interval (QTcF) were not observed.

Conclusion

JNJ-38893777 was tolerated at single doses up to 500 mg (fed) and is suitable for further clinical development.

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Acknowledgments

The authors thank Dr. Mary Ellen Frustaci for statistical analysis, Dr. Shruti Shah (SIRO Clinpharm Pvt. Ltd.) for writing assistance, and Dr. Wendy Battisti (Janssen Research & Development, LLC) for additional editorial assistance. The authors also thank the study participants, without whom this study would not have been accomplished, as well as the investigators for their participation in this study. This study was funded by Janssen Research & Development. The sponsor also provided support for manuscript development.

Conflict of interest

PM, AM, KS, MDM, GR, CJ and JAM are employees of Janssen Research & Development. All authors meet ICMJE criteria and all those who fulfilled those criteria are listed as authors. All authors hold stock in the company. All authors had access to the study data and made the final decision about where to publish these data.

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Authors and Affiliations

  1. Janssen Research & Development, LLC, 920 Rt 202, Raritan, 08869, NJ, USA

    Prasarn Manitpisitkul, Arthur Mayorga, Kevin Shalayda, Gary Romano, Chen Jun & John A. Moyer

  2. Janssen Research & Development, Beerse, Belgium

    Marc De Meulder

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  1. Prasarn Manitpisitkul
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  2. Arthur Mayorga
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  3. Kevin Shalayda
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  4. Marc De Meulder
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  5. Gary Romano
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  6. Chen Jun
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  7. John A. Moyer
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Corresponding author

Correspondence to Prasarn Manitpisitkul.

Additional information

Registration: EudraCT Number: 2008-000206-37.

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Manitpisitkul, P., Mayorga, A., Shalayda, K. et al. Safety, Tolerability and Pharmacokinetic and Pharmacodynamic Learnings from a Double-Blind, Randomized, Placebo-Controlled, Sequential Group First-in-Human Study of the TRPV1 Antagonist, JNJ-38893777, in Healthy Men. Clin Drug Investig 35, 353–363 (2015). https://doi.org/10.1007/s40261-015-0285-7

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  • DOI: https://doi.org/10.1007/s40261-015-0285-7

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