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

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, 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

Abstract

Purpose: 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.

Methods: 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.

Results: 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.

Conclusions: 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.

Figures

Fig. 1
Fig. 1
Mean concentration-time profiles of DTG with and without concomitant a EFV or b TPV/r. DTG, dolutegravir; EFV, efavirenz; PA-IC90, protein-adjusted 90 % inhibitory concentration; TPV/r, tipranavir/ritonavir

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