D J Kempf

The metabolism and disposition of [14C]ritonavir (ABT-538, NOR-VIR), a potent, orally active HIV-1 protease inhibitor, were investigated in male and female Sprague-Dawley rats, beagle dogs, and HIV-negative male human volunteers. Rats and dogs received a 5 mg/kg iv, 20 mg/kg oral or 20 mg/kg intraduodenal dose, whereas humans received a single 600-mg liquid oral dose. Ritonavir was cleared primarily via hepatobiliary elimination in all three species. After iv or oral dosing in either rats or dogs, > 92% of the dose was recovered in rat and dog feces and < or = 4% was recovered in the urine. Humans excreted 86.3% of the oral dose in feces and 11.3% in urine over 6 days. Bile-exteriorized rats and dogs excreted 85.5% and 39.8%, respectively, of the iv dose in bile, with < 3% recovered in urine. Radio-HPLC analysis of bile, feces, and urine from all three species indicated extensive metabolism of ritonavir to a number of oxidative metabolites, some being species-specific, and all involving metabolism at the terminal functional groups of the molecule. Glucuronide metabolites were observed in dog only. Plasma radioactivity consisted predominantly of unchanged parent drug in all three species. M-2, the product of hydroxylation at the methine carbon of the terminal isopropyl moiety of ritonavir, was the only metabolite present in human plasma and made up 30.4% of the total dose recovered in human excreta over 6 days. Tissue distribution of ritonavir in rat was widespread, with good distribution into lymphatic tissue but low CNS penetration. Plasma protein binding of ritonavir was high (96-99.5%) in all species and was nonsaturable in humans at concentrations up to 30 micrograms/ml. Partitioning into the formed elements of whole blood was minimal.

Coadministration with the human immunodeficiency virus (HIV) protease inhibitor ritonavir was investigated as a method for enhancing the levels of other peptidomimetic HIV protease inhibitors in plasma. In rat and human liver microsomes, ritonavir potently inhibited the cytochrome P450 (CYP)-mediated metabolism of saquinavir, indinavir, nelfinavir, and VX-478. The structural features of ritonavir responsible for CYP binding and inhibition were examined. Coadministration of other protease inhibitors with ritonavir in rats and dogs produced elevated and sustained plasma drug levels 8 to 12 h after a single dose. Drug exposure in rats was elevated by 8- to 46-fold. A > 50-fold enhancement of the concentrations of saquinavir in plasma was observed in humans following a single codose of ritonavir (600 mg) and saquinavir (200 mg). These results indicate that ritonavir can favorably alter the pharmacokinetic profiles of other protease inhibitors. Combination regimens of ritonavir and other protease inhibitors may thus play a role in the treatment of HIV infection. Because of potentially substantial drug level increases, however, such combinations require further investigation to establish safe regimens for clinical use.