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Pharmacokinetics, Safety, and Tolerability of the
HIV Integrase Inhibitor Dolutegravir Co-Administered with Rifabutin in Healthy Subjects
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Reported by jules Levin
13th HIV Clinical Pharmacology Intl Workshop
Barcelona Spain April-16-18 2012
Kelly E Dooley1; Patrick Sayre1; Julie Borland2; Elizabeth Purdy1; Shuguang Chen2; Ivy Song2; Amanda Peppercorn2; Stephanie Everts1; Stephen Piscitelli2; and Charles Flexner1 1Johns Hopkins University School of Medicine, Baltimore, MD; 2GlaxoSmithKline, Research Triangle Park, NC
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EXCERPT from - Clinical Pharmacology at the 13th Workshop on Clinical
Pharmacology of HIV Therapy - Courtney V. Fletcher, Pharm.D. - (05/14/12)
Dolutegravir and Rifabutin: Co-administration Looks to be OK.
Poster P_11 described the PK of dolutegravir, 50 mg, when given alone and with rifabutin, 300 mg once daily, for 14 days to healthy volunteers. The geometric mean ratios for the PK parameters of DTG (DTG + RBT to DTG) were: AUC, 0.95; Cmax, 1.15; and Ctrough, 0.70. These data indicate no effect of RBT on the AUC and Cmax of DTG, but a 30% reduction in the trough concentrations of DTG. The authors concluded that based on the PKPD relationships that have been described for DTG, this reduction is unlikely to be clinically significant. I agree. The published PKPD relationship (see http://www.ncbi.nlm.nih.gov/pubmed/21716073 ) and the most recent 96-week results from the SPRING clinical study (see http://www.retroconference.org/2012b/Abstracts/45432.htm) provide support for this conclusion. This is actually a very good example of the importance of a well-described clinical PKPD relationship - because it provides a scientific basis to predict whether a given reduction in concentrations is likely to be associated with a loss of response. I think it is warranted to confirm that adequate DTG concentrations are achieved in HIV and TB co-infected persons, and to obtain information on RBT concentrations as well.
As a reminder, a related drug interactions study between DTG and rifampin (RIF) was presented at CROI 2012 (see http://www.natap.org/2012/CROI/croi_46.htm ). This study found that a double dose of DTG, 50 mg twice daily, when given with RIF achieved DTG concentrations similar to 50 mg once daily without RIF.
For DTG with either RIF or RBT, clinical validation of safety and efficacy is necessary. That said, these results look promising as much-needed therapeutic options for treatment of HIV and TB coinfection.
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