Drug Interactions

Drug Interactions

Didanosine Methadone: It is known that co-administration of the original buffered tablet formulation of didanosine (ddI) with methadone results in up to a 52% reduction in the ddI AUC without effecting methadone pharmacokinetics. One question that has been frequently asked is whether methadone would have a similar effect on the pharmacokinetics of the new enteric coated (EC) formulation of ddI. Gerry Friedland and colleagues presented results of an open-label randomized two-way crossover study in which HIV negative subjects on chronic methadone mainten-ance were randomized to receive ddI EC or the buffered formulation (400 mg PO qd) [Abstract 4548]. Each formulation was given for two days and then followed by pharmacokinetic sampling over 24 hours. At the end of the study, 15 subjects had completed both treatments. The authors reported a mean Cmax that was 12% lower and an AUC that was 22% higher for the EC formulation compared with the buffered tablets. The relative bioavailability of the EC formulation was 122% higher than that of buffered tablets, possibly explaining this result. Subjects receiving the buffered tablets had a decreased ddI AUC (2633 ng-hr/mL) and Cmax (1554 ng/mL) when compared to historical data obtained from patients treated with ddI who were not receiving methadone (AUC 3136-3489 ng-hr/mL and Cmax 1838-2321 ng/mL), confirming previous results. On the other hand, the pharmacokinetic parameters for study participants treated with the EC formulation (AUC 3062 ng-hr/mL and Cmax 1196 ng/mL) were comparable to historical data in patients not taking methadone (AUC 2562-3578 ng-hr/mL and Cmax 794-1427 ng/mL). Based on these results, the authors recommended that HIV infected patients on chronic methadone should be treated with the EC formulation of ddI.

Triple PIs: Lopinavir/Ritonavir Plus Saquinavir: Stephan and colleagues assessed pharmacokinetic interactions at steady state between LPV/r (400/100 mg bid) combined with SQVsgc (1000 mg bid) compared with SQV/RTV (1000/100 mg bid) [Abstract 4561]. The median Cmin for LPV (5500 ng/mL) and SQV (181-216 ng/mL) was 2-fold greater than the IC95 for susceptible HIV in all cases. The median RTV concentration was lower in subjects treated with LPV/r/SQV. However, the boosting effect of RTV was comparable in the two groups. LPV plasma concentrations were not affected by SQV. The authors concluded that LPV/r effectively boosts SQV concentrations, and that it is unnecessary to add RTV to this regimen.

Indinavir and Ritonavir: Comparison of Two Regimens: Gerber and colleagues from the AIDS Clinical Trials Group presented results from a pharmacokinetic study comparing two indinavir/ritonavir (IDV/RTV) combination regimens [Abstract 4552]. Forty-four HIV infected subjects who had failed their first PI-containing regimen (amprenavir, nelfinavir, saquinavir, or saquinavir/nelfinavir), were randomized to receive IDV/RTV at a dose of either 800/200 mg bid or 400/400 mg bid. Twelve hour pharmacokinetic sampling was obtained at steady-state (2 weeks). Two subjects were excluded from the final analysis due to incorrect dosing and undetectable IDV levels. The authors found that the AUC0-12h) and Cmax of IDV was higher in the 800/200 mg arm (AUC0-12h) 38.2 µg/h/mL and Cmax 6309.1 ng/mL) compared with the 400/400 mg arm (AUC0-12h) 23.0 µg/h/mL and Cmax 3633.0 ng/mL). On the other hand, trough (C12h)) was comparable in both groups. The authors conclude that if the trough concentration is the important pharmacokinetic parameter in suppressing HIV, then these two regimens should have comparable anti-HIV effect, but the risk of nephrolithiasis may be greater with the the 800/200 dosing regimen. The authors also observed that the concentrations of IDV and RTV were lower on average in the HIV infected subjects when compared with historical data from healthy volunteers. One possible explanation was a difference in medication adherence monitoring in the two populations. The healthy volunteer group received medications under direct super-vision during the entire study, while in the current study observed doses only occurred during pharmacokinetic sampling.

http://www.hopkins-aids.edu/publications/report/sept02_3.html#drug