|Pharmacokinetic Interactions between Cenicriviroc and Dolutegravir|| |
|E. Lefebvre1, J. Enejosa1, W. Chang1, H. Jenkins1, A. Martinez2, M. Willett3, S. Griffith4|
|1Tobira Therapeutics, Inc., San Francisco, United States, 2SeaView Research, Inc., Miami, United States, 3Ready Clinical, LLC, Princeton, United States, 4ClinPharma Resources, San Diego, United States|
|Objectives: Cenicriviroc (CVC), a novel, once-daily, potent, CCR5/CCR2 antagonist, is metabolised via CYP3A4 and CYP2C8. CVC is under evaluation for the treatment of HIV infection (NCT01338883). Dolutegravir (DTG), an investigational integrase inhibitor, is metabolised primarily by UGT1A1. Phase 1 study evaluated the effect of DTG on CVC pharmacokinetics (PK) and CVC on DTG PK (NCT01827540).|
Methods: Multiple-dose, open-label, crossover study in 2 groups of healthy subjects (n=20/group). In Group 1, single-tablet CVC 150 mg once-daily (qd) was administered alone on Days 1‑10 (Period 1) and with DTG 50 mg qd on Days 11‑20 (Period 2). In Group 2, DTG 50 mg qd was administered alone on Days 1‑10 (Period 1) and with CVC 150 mg qd on Days 11‑20 (Period 2). Dosing was immediately after breakfast. Plasma CVC (Group 1) and DTG (Group 2) profiles were evaluated on Days 10 and 20 for calculation of AUC0‑τ, Cmax and Cmin. To assess drug interactions, ratios of geometric means (Period 2/Period 1) and 90% confidence intervals (CIs) were calculated. Safety and tolerability were also assessed.
Results: All 40 subjects completed and were evaluable. PK analyses are summarised below.
|Analyte [Group]||Least-squares geometric means||Ratio (90% confidence intervals [CIs])|
| ||Period 1 (n=20)||Period 2 (n=20)||Period 2/Period 1|
|CVC [Group 1]|| || || |
(ng∙h/mL)||7805||5580||0.71 (0.63, 0.81)|
|Cmax (ng/mL)||574||410||0.72 (0.62, 0.82)|
|Cmin (ng/mL)||154||119||0.77 (0.69, 0.87)|
|DTG [Group 2]|| || || |
(ng∙h/mL)||58.31||66.54||1.14 (1.09, 1.20)|
|Cmax (µg/mL)||4.39||4.81||1.10 (1.03, 1.16)|
|Cmin (µg/mL||1.27||1.45||1.14 (1.08, 1.20)|
[PK analysis of CVC and DTG]
Treatment-related adverse events (AEs) were reported in 11 (27.5%) subjects. AE incidence during co-administration was comparable to that of the study drugs alone. Most common (≥2 subjects) treatment-related AEs were: headache (n=3), abdominal distension, flatulence, constipation and diarrhoea (each n=2). All AEs were mild to moderate in severity. No discontinuations due to AEs and no serious AEs.Conclusions:
Ratios (90% CIs) for DTG were within “no-effect” limits (80‑125%), suggesting no dose adjustment will be required when co-administered with CVC. A 23‑29% reduction in CVC exposure was observed with DTG, which will be further investigated. The combination was generally well tolerated. Phase 3 CVC studies are planned.
Eric Lefebvre , Tobira Therapeutics, Inc. , San Francisco , United States
Assigned in sessions:
17.10.2013, 12:00-14:00, Poster Session, Poster Session 1, Exhibition
18.10.2013, 12:00-14:00, Poster Session, Poster Session 2, Exhibition