Abstract PE10/9
 
Pharmacokinetic Interactions between Cenicriviroc and Darunavir/Ritonavir Print
 
E. Lefebvre1, J. Enejosa1, W. Chang1, H. Jenkins1, C. Ballow2, A. Martinez3, M. Willett4, S. Griffith5
1Tobira Therapeutics, Inc., San Francisco, United States, 2Buffalo Clinical Research Center, Buffalo, United States, 3SeaView Research, Inc., Miami, United States, 4Ready Clinical, LLC, Princeton, United States, 5ClinPharma Resources, San Diego, United States
 
Objectives: Cenicriviroc (CVC), a novel, once-daily, potent, dual CCR5/CCR2 antagonist, is metabolised via CYP3A4 and CYP2C8. CVC is under evaluation for the treatment of HIV infection (NCT01338883). Two Phase 1 studies were conducted to assess the effects of darunavir/ritonavir (DRV/RTV) on CVC pharmacokinetics (PK) (Study 652-1-107) and of CVC on DRV/RTV PK (Study 652-1-113).
Methods: Both studies utilised a multiple-dose, open-label, crossover design. In Study 107, 20 subjects received CVC 50 mg once daily (qd) on Days 1‑10 (Period 1) and CVC 50 mg with DRV/RTV 800/100 mg qd on Days 11‑20 (Period 2). In Study 113, 20 subjects received DRV/RTV 800/100 mg qd on Days 1‑10 (Period 1) and DRV/RTV 800/100 mg with CVC 50 mg qd on Days 11‑20 (Period 2). In both studies, dosing was immediately after breakfast. Plasma CVC (Study 107) and DRV/RTV (Study 113) 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 were calculated. Safety and tolerability were also assessed.
Results: In both studies, all 20 subjects completed and were evaluable. PK analyses are summarised below.
Analyte [Study]Least-squares geometric meansRatio (90% confidence intervals)
 Period 1 (n=20)Period 2 (n=20)Period 2/Period 1
CVC [Study 107]
AUC0-τ (ng∙h/mL)
Cmax (ng/mL)
Cmin (ng/mL)

1264
105
24.7

3956
229
103.0

3.13 (2.88, 3.40)
2.17 (2.03, 2.32)
4.17 (3.74, 4.66)
DRV [Study 113]
AUC0-τ (ng∙h/mL)
Cmax (ng/mL)
Cmin (ng/mL)

102 847
7627
2280

100 912
7805
2140

0.98 (0.94, 1.02)
1.02 (0.98, 1.07)
0.94 (0.87, 1.02)
RTV [Study 113]
AUC0-τ (ng∙h/mL)
Cmax (ng/mL)
Cmin (ng/mL)

4142
489
31.7

4487
560
34.8

1.08 (1.00, 1.18)
1.14 (1.02, 1.29)
1.10 (0.98, 1.23)
[PK analysis of CVC, DRV and RTV]

Adverse events (AEs) were reported in a total of 12 subjects in both studies. The most common treatment-related AEs, reported in ≥2 subjects, were pruritus and rash in Study 107 and headache in Study 113. All AEs were mild. No subject discontinued due to AEs and no serious AEs were reported in either study.
Conclusions: When co-administered, CVC had no effect on plasma DRV/RTV exposure, while DRV/RTV significantly increased plasma CVC exposure (consistent with inhibition of CYP3A4 by RTV). The combination was well tolerated. Phase 3 studies are being planned.


Assigned speakers:
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