Results of a study published in Open Forum Infectious Diseases indicate that rifampicin induction among HIV-positive patients with obesity may further reduce the peak concentration (Cmax) and exposure of dolutegravir (DTG), but not the trough concentration at the end of the dosing interval (Cτ).
Researchers performed virtual drug-drug interaction studies via physiologically-based pharmacokinetic modeling to assess the effect of obesity on drug-drug interactions between DTG and rifampicin induction among HIV-positive patients. Drug-drug interactions were compared among patients without obesity (BMI, 18.5-30 kg/m2), those with obesity (BMI, 30-40 kg/m2), and those with morbid obesity (BMI, 40-50 kg/m2). Each cohort consisted of an equal number of men and women (each 50%) aged between 20 and 50 years. The researchers verified the drug schedule for dolutegravir and rifampicin using pharmacokinetic and physicochemical properties sourced from published clinical trials, a literature review, and the Swiss HIV Cohort Study. Patients were administered a 600-mg steady-state dose of rifampicin and DTG 50 mg twice daily.
The researchers evaluated the magnitude of the drug-drug interaction among all 3 patient cohorts, accounting for induction by rifampicin and the effect of obesity. Results showed that the Cmax of DTG was reduced by 53% in patients without obesity, 63% in those with obesity, and 71% in those with morbid obesity. Interactions were also more pronounced among patients in all 3 cohorts for the area under the plasma-concentration time curve for dosing interval (AUCτ;reduced by 72%, 77%, and 68%, respectively), but Cτ was mostly unchanged (83%, 85%, and 85%, respectively).
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Simulated geometric mean values for Cτ were above the protein-adjusted 90% inhibitory concentration for DTG (64 ng/mL) in all 3 cohorts. The simulated geometric mean DTG concentrations were 397 and 448 ng/mL among patients with obesity and those with morbid obesity, respectively, and 387 ng/mL among those without obesity.
Rifampicin concentrations differed between the cohorts. Patients with obesity had 23% lower Cmax and 15% lower AUCτ, compared with those without obesity; whereas, those with morbid obesity had 35% lower Cmax and 21% lower AUCτ, compared with those without obesity.
Administration of dolutegravir twice daily with rifampicin induction was associated with trough concentrations above the predicted maximum tolerated dose for patients in all 3 cohorts.
This study is limited as only data from White patients were considered in the development of the model. In addition, the researchers did not consider the potential effect of tuberculosis drugs used in combination with rifampicin.
According to the researchers, “[T]hese data suggest that the recommendation to administer dolutegravir twice daily with rifampicin can be adopted also in obese and morbidly obese individuals.”
Disclosure: One study author declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures.
Reference
Berton M, Bettonte S, Stader F, Battegay M, Marzolini C. Impact of obesity on the drug-drug interaction between dolutegravir and rifampicin or any other strong inducers. Open Forum Infect Dis. Published online July 10, 2023. doi:10.1093/ofid/ofad361
This article originally appeared on Infectious Disease Advisor
