Effect of moderate liver impairment on the multiple dose pharmacokinetics of ritonavir-boosted saquinavir in HIV patients
L. Chang1, C. Kreuzer2, R. Farha3, M. Abt2, L. Baher1, P. Tebas4, C. Cooper5, M. Rodriguez-Torres6, L. Donatacci3, I. Patel3
1Roche, South San Francisco, United States, 2Roche, Basel, Switzerland, 3Roche, Nutley, United States, 4Hospital of the University of Pennsylvania, Philadelphia, United States, 5University of Ottawa, Ottawa, Canada, 6Fundacion de Investigacion de Diego, Santurce, Puerto Rico
Background: Saquinavir (SQV) is extensively metabolized in the liver by CYP3A4. Hepatic impairment is likely to affect SQV clearance by reducing liver blood flow and possibly by influencing CYP3A4 activity. The impact of moderate hepatic impairment on the steady-state pharmacokinetics (PK) of ritonavir (RTV)-boosted SQV was investigated.
Methods: This open-label, multicenter, nonrandomized study enrolled treatment-experienced HIV-infected patients with moderate liver impairment (Group 2; Child-Pugh Grade B) and age, gender, weight, and tobacco-use matched controls (Group 1). Patients received SQV/RTV 1000/100 mg twice daily for 14 days combined with 2 or 3 NRTIs. Predose and serial postdose SQV and RTV plasma concentrations were measured on Day 14. Cmax, Cmin, Tmax, and AUC0-τ, t½ were estimated using standard non-compartmental methods. Geometric mean ratios (GMR) were used to compare AUC0-12 (ug?hr/mL) and Cmax (ug/mL) between treatment groups.
Results: Seven patients with moderate liver impairment (Child‑Pugh score range, 7-9), all hepatitis C virus-infected, and seven controls were evaluable. SQV and RTV AUC0-12 was reduced approximately 35% and 25%, respectively, in patients with liver impairment. Unbound plasma protein fractions were similar between groups.
[Mean (%CV) and GMR (90% CI) SQV RTV PK Parameters]
| ||Group 1 (n=7)|
|Group 2 (n=7)|
|GMR (90% CI)|
|SQV, mean (% CV)||28.5 (70.7)||4.30 (68.2)||24.3 (101.5)||3.61 (83.3)||0.7 (0.3-1.6)||0.7 (0.3-1.6)|
|RTV, mean (% CV)||11.0 (15.7)||1.5 (19.7)||9.93 (52.8)||1.46 (47.3)||0.8 (0.5-1.2)||0.8 (0.6-1.3)|
Sixteen patients (7 in Group 1 and 9 in Group 2) who received at least one dose of study medication were included in the safety analysis. No special safety concerns were indicated in HIV-infected patients with moderate liver disease.
Conclusion: SQV and RTV exposure were modestly reduced in patients with moderate liver impairment suggesting that dose adjustments are not indicated for SQV therapy in HIV-infected patients with moderate liver disease.
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