Pharmacology of Protease Inhibitors
Wednesday, 1:30 - 3:30 pm
Background: Tipranavir (TPV) is the first of a new class of non-peptidic protease inhibitors (PI), and has potent activity against multiple PI-resistant HIV. To enhance TPV pharmacokinetics, it is combined with low-dose (200 mg) ritonavir (RTV) and administered twice a day. Nonlinear mixed effects modeling was conducted to characterize the pharmacokinetics of TPV and to elucidate the effects of demographic parameters on systemic TPV steady state concentrations.
Methods: The steady-state pharmacokinetics of TPV was assessed in 187 individuals using 1866 TPV concentrations derived from 4 healthy volunteer studies (n = 67 subjects; serial sampling) and 2 clinical studies (n = 120 HIV+ patients; serial, sparse, and trough sampling). The final nonlinear mixed effects modeling (NONMEM) database consisted of 79% male, 21% female; 85% white, 11% black, 4% other; ranging from18 to 73 years, and 47 to 123 kg weight. TPV concentration-time data were fit to a 1‑compartment model with first order absorption described in terms of absorption rate (Ka), apparent oral clearance (CL), and volume of distribution (V) parameters.
Results: TPV CL can be significantly affected by body weight (p < 0.001) and HIV status (p < 0.005). Body weight caused the more prominent linear increase (75.7%) in CL, whereas HIV+ patients exhibited a mild increase (18.8%) in CL when compared to HIV– subjects. V was moderately increased in HIV+ patients (44.5%, p < 0.001) and in males (32.3%, p < 0.001). Since HIV+ patients exhibited not only higher CL, but also a larger V, they tended to have lower steady state TPV concentrations compared to HIV– subjects (13% lower for males and 22% lower for females). The co-variates age, gender, or race were shown to have no or little effect on CL and no effects of age or body weight were shown on V. The individual variability was relatively low for CL (CV = 32%) and V (14%), but higher for Ka (53%).
Conclusions: Body weight, HIV status, and gender were identified as co-variates that may affect steady-state TPV concentrations. However, no dosage adjustment for TPV is recommended based on population pharmacokinetic results.
Keywords: population pharmacokinetics; NONMEM; tipranavir