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- Title
Effects of enzyme inducers efavirenz and tipranavir/ritonavir on the pharmacokinetics of the HIV integrase inhibitor dolutegravir.
- Authors
Song, Ivy; Borland, Julie; Chen, Shuguang; Guta, Phyllis; Lou, Yu; Wilfret, David; Wajima, Toshihiro; Savina, Paul; Peppercorn, Amanda; Castellino, Stephen; Wagner, David; Hosking, Louise; Mosteller, Michael; Rubio, Justin; Piscitelli, Stephen
- 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, C and C, respectively. Co-administration with TPV/r resulted in decreases of 59, 46 and 76 % in DTG AUC, C and C, 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.
- Subjects
ANTIVIRAL agents; CLINICAL trials; CONFIDENCE intervals; DRUG interactions; DRUG side effects; HIV infections; MATHEMATICAL statistics; RESEARCH funding; PARAMETERS (Statistics); DATA analysis software; TIPRANAVIR (Drug); EFAVIRENZ; RITONAVIR
- Publication
European Journal of Clinical Pharmacology, 2014, Vol 70, Issue 10, p1173
- ISSN
0031-6970
- Publication type
Article
- DOI
10.1007/s00228-014-1732-8