Effects of enzyme inducers efavirenz and tipranavir/ritonavir on the pharmacokinetics of the HIV integrase inhibitor dolutegravir.

European journal of clinical pharmacology 2014 Oct

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Dolutegravir (DTG) is an unboosted, integrase inhibitor for the treatment of HIV infection. Two studies evaluated the effects of efavirenz (EFV) and tipranavir/ritonavir (TPV/r) on DTG pharmacokinetics (PK) in healthy subjects. The first study was an open-label crossover where 12 subjects received DTG 50 mg every 24 hours (q24h) for 5 days, followed by DTG 50 mg and EFV 600 mg q24h for 14 days. The second study was an open-label crossover where 18 subjects received DTG 50 mg q24h for 5 days followed by TPV/r 500/200 mg every 12 hours (q12h) for 7 days and then DTG 50 mg q24h and TPV/r 500/200 mg q12h for a further 5 days. Safety assessments and serial PK samples were collected. Non-compartmental PK analysis and geometric mean ratios and 90% confidence intervals were generated. The combination of DTG with EFV or TPV/r was generally well tolerated. Four subjects discontinued the TPV/r study due to increases in alanine aminotransferase that were considered related to TPV/r. Co-administration with EFV resulted in decreases of 57, 39 and 75% in DTG AUC(0-τ), Cmax and Cτ, respectively. Co-administration with TPV/r resulted in decreases of 59, 46 and 76% in DTG AUC(0-τ), Cmax and Cτ, respectively. Given the reductions in exposure and PK/pharmacodynamic relationships in phase II/III trials, DTG should be given at an increased dose of 50 mg twice daily when co-administered with EFV or TPV/r, and alternative regimens without inducers should be considered in integrase inhibitor-resistant patients.

Citation

Ivy Song, Julie Borland, Shuguang Chen, Phyllis Guta, Yu Lou, David Wilfret, Toshihiro Wajima, Paul Savina, Amanda Peppercorn, Stephen Castellino, David Wagner, Louise Hosking, Michael Mosteller, Justin P Rubio, Stephen C Piscitelli. Effects of enzyme inducers efavirenz and tipranavir/ritonavir on the pharmacokinetics of the HIV integrase inhibitor dolutegravir. European journal of clinical pharmacology. 2014 Oct;70(10):1173-9