Unexpectedly low drug exposures among Ugandan patients with TB and HIV receiving high-dose rifampicin.

We characterized the pharmacokinetics of standard- and high-dose rifampicin in Ugandan adults with tuberculosis and HIV taking dolutegravir- or efavirenz-based antiretroviral therapy. A liver model with saturable hepatic extraction adequately described the data, and the increase in exposure between high and standard doses was 4.7-fold. This was lower than what previous reports of dose-exposure nonlinearity would predict and was ascribed to 38% lower bioavailability of the rifampicin-only top-up formulation compared to the fixed-dose combination.

Dolutegravir pharmacokinetics in Ugandan patients with TB and HIV receiving standard- versus high-dose rifampicin.

Higher rifampicin doses may improve tuberculosis treatment outcomes. This could however exacerbate the existing drug interaction with dolutegravir. Moreover, the metabolism of dolutegravir may also be affected by polymorphism of UGT1A1, a gene that codes for uridine diphosphate glucuronosyltransferase. We used population pharmacokinetic modeling to compare the pharmacokinetics of dolutegravir when coadministered with standard- versus high-dose rifampicin in adults with tuberculosis and HIV, and investigated the effect of genetic polymorphisms. Data from the SAEFRIF trial, where participants were randomized to receive first-line tuberculosis treatment with either standard- 10 mg/kg or high-dose 35 mg/kg rifampicin alongside antiretroviral therapy, were used. The dolutegravir model was developed with 211 plasma concentrations from 44 participants. The median (interquartile range) rifampicin area under the curve (AUC) in the standard- and high-dose arms were 32.3 (28.7-36.7) and 153 (138-175) mg·h/L, respectively. A one-compartment model with first-order elimination and absorption through transit compartments best described dolutegravir pharmacokinetics. For a typical 56 kg participant, we estimated a clearance, absorption rate constant, and volume of distribution of 1.87 L/h, 1.42 h-1, and 12.4 L, respectively. Each 10 mg·h/L increase in the AUC of coadministered rifampicin from 32.3 mg·h/L led to a 2.3 (3.1-1.4) % decrease in dolutegravir bioavailability. Genetic polymorphism of UGT1A1 did not significantly affect dolutegravir pharmacokinetics. Simulations of trough dolutegravir concentrations show that the 50 mg twice-daily regimen attains both the primary and secondary therapeutic targets of 0.064 and 0.3 mg/L, respectively, regardless of the dose of coadministered rifampicin, unlike the once-daily regimen.