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

10 Background: Evidence suggests higher RIF doses (>10 mg/kg) maybe more effective for TB treatment. It is unclear if incremental RIF doses will increase risk of drug interactions through more potent induction of metabolic enzymes and transporters. Some data suggest that maximum induction is already achieved with standard dose (10 mg/kg). We characterized the impact of incremental RIF (10, 20, 35 mg/kg) on the pharmacokinetics (PK) of DTG, MDZ and DIG as probe drugs for UGT1A1, CYP3A4 and the transporter P-gp, respectively. Materials and methods: DoRIS was an open-label, fixed-sequence, 4-phase study in TB-infected adults living without HIV, nearing the end of the continuation phase of standard anti-TB therapy (ATT). DTG (50 mg BID for 1 week) exposure from intensive sampling was compared when dosed with RIF at 10 mg/kg (D14), 20 mg/kg (D28) and 35 mg/kg (D42) and ≥4 weeks post-ATT (at 50 mg OD). Single dose MDZ (0.025 mg/kg) and DIG (0.25 mg) were given on PK sampling days; RIF was administered 1 h prior to other study medications under fasting conditions. PK parameters were calculated (WinNonlin Phoenix, v.8.5) using drug concentrations and actual time post-dose. Changes in parameters were evaluated by linear mixed effects determining geometric mean ratio (GMR) and associated 90% CI; changes were considered statistically significant if the CI did not include 1.0. Results: Of the 36 participants enrolled from South Africa and Uganda (11% female at birth, median [range] age 35 years [18–62], weight 61 kg [50–93]), drug PK were available from a maximum of 33 individuals. Geometric mean DTG Ctau were 602, 610 and 561 ng/mL on D14, D28 and D42 vs. 643 ng/mL post-ATT and not significantly impacted by incremental RIF (GMR, 90% CI: 0.93 [0.73–1.17]; 1.00 [0.79–1.25]; 0.93 [0.73–1.17], respectively). DTG AUC0–12 and Cmax were significantly lower with RIF on D14: 0.55 [0.49–0.63] and 0.70 [0.63–0.78], D28: 0.59 [0.52–0.67] and 0.71 [0.64–0.80] and D42: 0.57 [0.51–0.65] and 0.72 [0.64–0.80]. Twice daily DTG exposures were not significantly reduced further beyond that observed with standard RIF (D28/D14: 1.08 [0.94–1.23], D42/D14: 1.04 [0.91–1.19]). Proportion of Ctau above DTG EC90 (342 ng/mL) was 76%, 85%, 92% and 86% on D14, D28, D42 and post-ATT, respectively. Single dose MDZ PK parameters exhibited marked variability (CV% > 100%) and were significantly reduced in the presence of RIF (35%–65%) but not incrementally with higher RIF doses (D28, D42/D14 AUC0–12: 1.39 [0.96–2.01], 0.84 [0.58–1.21]). Conversely, statistically significant increases in single dose DIG AUC0-12 were observed in the presence of RIF (7–21%) and for Cmax with higher RIF doses (20 mg/kg: 1.21 [1.09–1.34]; 35 mg/kg: 1.17 [1.06–1.30]). DIG AUC0-12 was significantly increased to a similar extent with increasing RIF doses beyond 10 mg/kg (D28/D14: 1.12 [1.06–1.18], D42/D14: 1.13 [1.07–1.19]). RIF increased supraproportionally with dose (D28, D42/D14 AUC0-last: 3.70 [2.97–4.62], [20 mg/kg] and 5.88 [4.68–7.40] [35 mg/kg]). Conclusions: DTG exposure was reduced to a similar extent following higher RIF doses, with little impact on Ctau. MDZ exposures were not reduced further with incremental RIF, whereas small but statistically significant increases in DIG were observed, potentially associated with net inhibition of P-gp upon simultaneous drug administration. These data suggest maximum impact of RIF on UGT1A1/CYP3A4/P-pg at the standard 10 mg/kg dose.