New article: BJCP - Drug interactions between probe drugs dolutegravir (DTG), midazolam (MDZ) and digoxin (DIG) with escalating doses of rifampicin (RIF): DORIS study

Background:
Higher doses of rifampicin (RIF >10 mg/kg) may improve tuberculosis treatment outcomes. However, it's unclear whether increasing RIF doses also increases the risk of drug interactions due to stronger induction of metabolic enzymes and transporters. Some evidence suggests that enzyme induction may already be maximized at the standard 10 mg/kg dose. This study investigated how incremental RIF doses (10, 20, 35 mg/kg) affect the pharmacokinetics (PK) of dolutegravir (DTG), midazolam (MDZ), and digoxin (DIG), which are probe drugs for UGT1A1, CYP3A4, and P-glycoprotein (P-gp), respectively.

Materials and Methods:
The DoRIS study was a 4-phase, open-label, fixed-sequence trial in HIV-negative adults with TB nearing the end of standard therapy. DTG was given at 50 mg twice daily for 1 week alongside RIF at increasing doses (10, 20, 35 mg/kg), and once daily post-TB treatment. MDZ and DIG were administered as single doses on PK sampling days. RIF was given 1 hour before other drugs under fasting conditions. PK parameters were calculated and analyzed using linear mixed effects models, with changes considered significant if the 90% confidence interval (CI) excluded 1.0.

Results:
Among 36 participants (mostly from South Africa and Uganda), DTG trough concentrations (Ctau) remained stable across RIF doses and post-treatment, with no significant impact from higher RIF doses. However, DTG AUC and Cmax were significantly reduced with RIF, but not further reduced with higher doses. The proportion of DTG Ctau above the EC90 threshold remained high (76–92%). MDZ showed high variability and reduced exposure with RIF, but no further reduction with higher doses. DIG exposure increased slightly but significantly with higher RIF doses, possibly due to net P-gp inhibition. RIF exposure increased disproportionately with dose escalation.

Conclusions:
DTG exposure was reduced similarly across all RIF doses, with minimal impact on trough levels. MDZ exposure was reduced by RIF but not further with higher doses. DIG exposure increased slightly with higher RIF doses, suggesting possible P-gp inhibition. Overall, the data support that RIF’s maximum induction effect on UGT1A1, CYP3A4, and P-gp occurs at the standard 10 mg/kg dose.A

Additional information to the following link: Drug interactions between probe drugs dolutegravir (DTG), midazolam (MDZ) and digoxin (DIG) with escalating doses of rifampicin (RIF): DORIS study - Dickinson - 2025 - British Journal of Clinical Pharmacology - Wiley Online Library