Background: Enfuvirtide (T-20, ENF) is the most clinically advanced in a new class of drugs, the HIV-1 fusion inhibitors. It is administered subcutaneously (SC) at a dose of 90 mg BID. As a synthetic peptide, it is not expected to be subject to drug-drug interactions experienced by many of the conventional antiretrovirals (ARVs). Following IV dosing, ENF has a steady state volume of distribution of 5.5 ±1.1 L and is 92% bound to plasma proteins. Following a 90 mg SC dose of ENF the mean ±SD elimination half-life is 3.8 ±0.6 h and the mean ± SD clearance is 1.7 ±0.4 L/h. Three (3) PK interaction studies were performed to investigate potential drug-drug interactions. Ritonavir (RTV) boosted saquinavir (SQV), RTV alone, and rifampicin were selected being a commonly boosted protease inhibitor regimen and a potent enzyme inhibitor and inducer respectively.

Methods: Each study included 12 HIV-1 infected patients (pts) who had received up to 3 NRTIs. The studies investigated the co-administration of ENF (90 mg BID) with either SQV-SGC 1000 mg BID + RTV 100 mg BID (SQV/r) or RTV 200 mg BID or rifampicin 600 mg QD. In studies 1 and 2 pts were dosed with ENF for 7 days, and SQV/r (study 1) or RTV (study 2) was administered BID on days 4–7. Blood samples were collected for PK on days 3 and 7. In study 3, pts received ENF for 3 days on 2 occasions (days 1–3 and 11–13). Rifampicin 600 mg was administered QD for 10 days from days 4–13. Blood samples were collected for PK on days 3 and 13.

Results: ENF was well tolerated in each study with generally mild to moderate adverse events (AEs) and no serious AE, deaths, or withdrawals due to AEs. The table describes the effect of concomitantly administered drugs on the steady state PK exposure parameters of ENF.

Conclusion: Co-administration of ENF with SQV/r, RTV, or rifampicin did not lead to a clinically relevant interaction and was well tolerated over the duration of the studies. Consistent with the expectations of a peptide drug, low potential for drug-drug interaction is confirmed for ENF by these investigations.

 

Co-administered Drug	Dose of Co-administered Drug	Ratio of Least Squares Mean and (90% CI)
		Cmax	AUC	Ctrough
SQV/r	1000/100 mg BID, 4 days	1.07 (0.94–1.21)	1.14 (1.05–1.24)	1.26 (1.17–1.35)
RTV	200 mg BID, 4 days	1.24 (1.09–1.41)	1.22 (1.08–1.37)	1.14 (1.02–1.28)
Rifampicin	600 mg QD, 10 days	1.03 (0.93–1.14)	0.98 (0.89–1.06)	0.85 (0.78–0.93)