Ritonavir/saquinavir combination: effect of ritonavir dosage
Ritonavir increases plasma levels of coadministered PIs by inhibition of metabolism via the CYP3A4 pathway. This may occur during first-pass metabolism (intestinal wall and liver) leading to an increase in PI Cmax. Alternatively inhibition of CYP3A4 during subsequent metabolism and elimination in the liver may lead to increases in the PI half-life.
Both mechanisms would be expected to increase trough levels which are thought to be the major pharmacokinetic determinant of PI activity. The effects of ritonavir on first pass metabolism and metabolism/elimination may differ for different PIs and require different doses of ritonavir.
Saquinavir pharmacokinetic data from two dose ranging trials of saquinavir-sgc (FortovaseTM) in combination with ritonavir was analysed to determine the enhancement effects of varying dose combinations of either PI . The results from a total of 120 healthy volunteers was presented by Michael Kilby of the University of Alabama. Multivariate regression analysis of the plasma concentrations of saquinavir revealed that ritonavir had a strong effect on Cmax and Cmin of saquinavir, but there was no greater effect of higher versus lower ritonavir dosages on either parameter. There was also a linear correlation between higher saquinavir dosage and higher Cmax and Cmin. The presenters concluded that ritonavir increases saquinavir concentrations mainly by inhibition of first pass metabolism to increase the Cmax. This boosting effect appears to be similar for ritonavir dosages of 100-200 mg BID. This is in contrast to the effect of ritonavir on indinavir, nelfinavir or amprenavir which boosts the plasma half-life and may require higher ritonavir dosages.
It is becoming increasingly clear that response to PIs is a complex relationship of genotype/phenotype and trough levels attainable in vivo. The relationship between in vitro EC50 or IC95’s and in vivo trough levels is also complex and poorly defined.
It is difficult to compare across agents and across studies as there is no standard method for compensating for plasma protein binding. It is also unclear if maintaining therapeutic levels of both PIs in a dual combination (as with 400/400 mg) dosing, a true dual PI combination, has any added value over ritonavir boosted single PIs (obtained with 100 or 200 mg of ritonavir).
It also remains to be seen if boosted levels of saquinavir might be at a level expected to be active against PI resistant HIV as has been shown for indinavir and ABT-378.
- Kilby M, Hill A and Buss N. The effect of ritonavir on increases in saquinavir plasma concentration is independent of ritonavir dosage: combined analysis of 120 subjects. 4th International Workshop on HIV Drug Resistance & Treatment Strategies. 12-16 June 2000, Sitges, Spain. Abstract 151.