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Safety and Pharmacokinetics of the HIV-1 Protease Inhibitor TMC310911 Coadministered With Ritonavir in Healthy Participants: Results From 2 Phase 1 Studies

Hoetelmans, Richard M.W. PhD*; Dierynck, Inge PhD*; Smyej, Ilham MD*; Meyvisch, Paul PhD*; Jacquemyn, Bert MSc*; Marien, Kris MSc*; Simmen, Kenneth PhD; Verloes, Rene MD*

JAIDS Journal of Acquired Immune Deficiency Syndromes: March 1st, 2014 - Volume 65 - Issue 3 - p 299–305
doi: 10.1097/QAI.0000000000000011
Clinical Science

Objectives: To evaluate safety, tolerability, and pharmacokinetics of TMC310911, a novel human immunodeficiency virus type-1 protease inhibitor.

Methods: Healthy participants aged 18–55 years with body mass index 18–30 kg/m2 were enrolled in 2 phase 1 studies. In the first-in-human, single-dose study, 18 participants received placebo or TMC310911 (75–2000 mg) in the double-blind phase and 8 participants received 300 or 600 mg of TMC310911 [administered alone or with 100 mg ritonavir twice daily (bid)] in the subsequent open-label phase. The multiple-dose double-blind study included 5 successive treatment sessions wherein healthy participants received placebo or TMC310911 [300 mg bid, 600 mg once daily or 150 mg bid (plus 100 mg ritonavir bid), 900 mg bid (alone) or 300 mg bid (plus ritonavir 50 mg bid)]; in all sessions, TMC310911 and ritonavir were administered for 6 and 9 days, respectively.

Results: In the single-dose study, no dose-limiting toxicity was observed up to 2000 mg of TMC310911. Systemic exposure to TMC310911 generally increased in a dose-proportional manner after the single- or multiple-dose administrations. Coadministration of ritonavir increased the systemic exposure to TMC310911. The mean Cmax and area under plasma concentration–time curve values (single-dose: 1200 mg TMC310911) were higher under fasted conditions than in fed condition. In both studies, most treatment-emergent adverse events were related to gastrointestinal system.

Conclusions: TMC310911 exhibited a linear pharmacokinetic profile after the single- (up to 2000 mg) and multiple-dose (up to 900 mg) administrations; ritonavir improved the pharmacokinetic profile of TMC310911. TMC310911 was generally safe and tolerable when administered with or without ritonavir.

*Department of Research and Early Development, Janssen Infectious Diseases-Diagnostics BVBA, Beerse, Belgium; and

Department of Infectious Diseases, Janssen Research & Development, High Wycombe, United Kingdom.

Correspondence to: Rene Verloes, MD, Janssen Infectious Diseases, Turnhoutseweg 30, Beerse B2340, Belgium (e-mail: rverloes@its.jnj.com).

Supported by Janssen Research & Development, Ireland (previously known as Tibotec Pharmaceuticals Ltd., Ireland). Sponsor also provided the formal review of manuscript.

All authors are employees of Janssen Research & Development. I.D., R.M.W.H., I.S., K.S., and R.V. were involved in study design; R.M.W.H. was also involved in interpretation of data; K.M. was involved in the study conduct; B.J. was the project leader; and P.M. was involved in analysis and interpretation of the data. All authors met ICMJE criteria and all those who fulfilled those criteria are listed as authors. All authors critically review the manuscript and approved submission to the journal.

The authors have no funding or conflicts of interest to disclose.

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Received June 19, 2013

Accepted September 11, 2013

© 2014 by Lippincott Williams & Wilkins