Safety, tolerability, and pharmacokinetics of the HV integrase inhibitor dolutegravir given twice daily with rifampin or once daily with rifabutin: Results of a phase 1 study among healthy subjects.
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Study Design
This was a phase 1, open-label, fixed-sequence study conducted in healthy adults. Participants received 50mg dolutegravir (DTG) once daily for 7 days, followed by 50mg DTG BID for 7 days, followed by 50mg DTG BID plus 600mg rifampin (RIF) once daily for 14 days. Plasma samples were collected for DTG at the end of each dosing period.
In part 2: Participants received 50mg dolutegravir (DTG) QD for 7 days, followed by 50mg DTG QD plus 300mg rifabutin (RBT) QD for 14 days. Plasma samples were collected for DTG at the end of each dosing period.
Study Results
Reduced DTG concentrations were observed with addition of RIF 600mg QD to DTG 50mg BID. The geometric mean ratio (90% confidence interval) for AUC, Cmax and Cmin were 0.46 (90%CI, 0.38-0.55), 0.57 (90%CI, 0.49-0.65) and 0.28 (90%CI, 0.23-0.34) respectively, compared to DTG 50mg BID alone. However, plasma concentrations of DTG 50mg BID plus RIF 600mg QD were similar to or higher than those achieved when DTG 50mg was given once daily alone (AUC0-24, 1.33 (90%CI 1.15-1.53), Cmax, 1.18 (90%CI 1.03-1.37) and Ct, 1.22 (90% CI 1.01-1.48)).
Plasma concentrations were similar when DTG 50mg QD was administered with and without RBT 300mg QD. The geometric mean ratio (90% confidence interval) for AUC was 0.95 (90%CI, 0.82-1.10), Cmax 1.16 (90%CI, 0.98-1.37) and Cmin 0.70 (90%CI, 0.57-0.87). While the trough concentrations for DTG were reduced by approximately 30%, they were still higher than the protein-adjusted IC50 of 0.016 mcg/ml against HIV-1.
Study Conclusions
A dose adjustment of TIVICAY (dolutegravir) to 50 mg twice daily is recommended in treatment-naïve or treatment experienced, INSTI-naïve patients.
Alternatives to rifampin should be used where possible for INSTI-experienced patients with certain INSTI-associated resistance substitutions or clinically suspected INSTI resistance.
Based on virologic responses observed in DTG doses ranging from 10-50 mg QD in the SPRING-1 trial, the 30% reduction in DTG trough concentrations when co-administered with RBT is unlikely to lower clinical efficacy of DTG. No dose adjustments are required.
References
Dooley KE, Sayre P, Borland J. Safety, tolerability, and pharmacokinetics of the hv integrase inhibitor dolutegravir given twice daily with rifampin or once daily with rifabutin: results of a phase 1 study among healthy subjects. Jaids: Journal Of Acquired Immunodeficiency Syndrome. 2013; 1: 21-26.
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