Background: TPV is the first of a new class of non-peptidic PIs, and has potent activity against multiple PI-resistant HIV. To enhance TPV PK, it is combined with low-dose ritonavir. This abstract reports the results of nonlinear mixed effects modeling to characterize the PK of TPV and to elucidate the effects of demographic parameters on the population pharmacokinetic parameters of TPV.
Methods: The steady-state PK of TPV was assessed in 187 individuals derived from 4 healthy volunteer studies and 2 patient studies (64.2% HIV+ patients, 35.8% HIV- subjects; 79.1% male, 20.9% female; 85% white, 11% black, 4%; 18-73 years; 47-123 Kg;); a total of 1866 TPV concentrations from PK profiles and troughs were available for PK analysis. Nonlinear mixed effects modeling was performed using the computer program NONMEM. TPV concentration-time data were fit to a 1-compartment model with first order absorption parameterized in terms of absorption rate constant (Ka), apparent oral clearance (CL), and volume of distribution (V).
Results: Population PK analysis demonstrated that TPV CL can be significantly affected by body weight and HIV status. 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%) and in males (32.3%). Since HIV+ patients exhibited not only higher CL, but also a larger V, they tended to have lower tipranavir concentrations compared HIV- subjects. The covariates 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 interindividual variability was relatively low for CL and V with a coefficient of variation (CV) of 32.4% and 14.2%, respectively, and moderately high for Ka with a CV of 53.3%.
Conclusions: The steady-state population PK of TPV 500 mg bid coadministered with low-dose ritonavir 200 mg bid can be adequately characterized by a 1-compartment model with first order absorption. Body weight, HIV status and gender were identified as covariates that may affect steady-state TPV PK. However, no dosage adjustment for TPV is recommended based on population pharmacokinetic results.
Note: The poster was originally presented at the CROI 2005 Conference, Boston, U.S.A.