A phase I, open-label, single-dose, randomized, cross-over study of cenicriviroc (CVC) and tenofovir (TDF) in healthy volunteers

Background: CVC is a potent CCR5/CCR2 antagonist with potent antiretroviral activity in HIV-1-infected patients. In preparation for phase 2/3 studies, the pharmacokinetics, safety, and tolerability of CVC and TDF were studied.
Methods: In this open-label, random sequence, cross-over study, 21 healthy volunteers received a single dose each of CVC 150 mg, TDF 300 mg, and CVC 150 mg + TDF 300 mg, with a washout of 14 days between regimens. PK profiles were obtained over a 7-day period after each treatment. Safety was assessed by AE, laboratory, and vital sign assessments; ECGs; and physical examinations.
Results: Coadministration of CVC and TDF did not affect the PK of CVC nor the AUC0-t and AUC0-∞ of TDF. The Cmax of TDF was increased approximately 36%, with 90% CIs outside the equivalence range, suggesting that CVC may affect the rate of absorption of TDF. The t1/2 of TDF with and without CVC was 20.40 vs. 18.95 hours, respectively. Respective mean CL/F values of CVC alone and in combination with TDF were 17.0 L/h and 19.5 L/h and of TDF alone and in combination with CVC were 102 L/h and 78.2 L/h. . CVC+TDF was well tolerated. There were no deaths, no study discontinuations, and no SAEs; all AEs were of mild intensity. Fewer AEs were reported with combination therapy than with either drug alone (2, 1, and 0 subjects with drug-related AEs on CVC, TDF, and CVC+TDF, respectively).
Conclusion: Coadministration of CVC and TDF did not affect the PK of CVC nor the AUC0-t and AUC0-∞ of TDF. Coadministration increased the Cmax of TDF, suggesting that CVC may affect the rate of absorption of TDF. Overall, drug-drug interactions under steady-state conditions should be similar to those observed after single dose administration. There was no safety contraindication to the coadministration of CVC and TDF.

D. Martin1, C.H. Ballow2, C. Jomphe3, M. Beliveau3, J.F. Marier3, R. Driz1, S.M. Palleja1
1Tobira Therapeutics, Inc., Manalapan, United States, 2Buffalo Clinical Research Center, Buffalo, United States, 3Pharsight - A Certara? Company, Reporting and Analysis Services, Montreal, Canada