Physiologically Based Pharmacokinetic Modeling of the Drug Drug Interaction Between Rifampin and SGLT2 Inhibitors: The Contribution of CYP Induction to the Observed Interaction

Purpose- Rifampin is a known inducer of cytochrome P450 (CYP) enzymes and transporters while the impact on induction of uridine diphosphate-glucuronosyltransferase (UGT) enzymes is an ongoing area of research. To estimate the induction by rifampin, three drug-drug interaction (DDI) studies have been conducted with sodium glucose co-transporter 2 (SGLT2) inhibitors, dapagliflozin, ertugliflozin and canagliflozin, with observed AUC ratios of 0.78, 0.61 and 0.49, respectively, in the presence vs. absence of rifampin. As a class, the SGLT2 inhibitors are metabolized predominantly by UGT enzymes (UGT1A9/UGT2B4/UGT2B7) with minor contributions from CYP enzymes (11-12% of overall clearance). The objectives of the current study were to: 1) develop and verify mechanistic PBPK models for ertugliflozin, dapagliflozin and canagliflozin and 2) simulate the DDI due to induction of CYP3A4/3A5 by rifampin.

Methods- Mechanistic PBPK models for ertugliflozin, dapagliflozin and canagliflozin were developed using clinical intravenous and ADME data and in vitro CYP reaction phenotyping results with commercially available software (Simcyp V15, Certara). The modeling assumptions and parameters were verified using clinical data in healthy volunteers. The Simcyp rifampin PBPK compound file, which only incorporates CYP3A4/5 induction, was used without further modification in the simulated DDI studies.

Results- A 29% reduction in AUC of ertugliflozin with rifampin coadministration was predicted using PBPK modeling while a 39% reduction was observed in the ertugliflozin-rifampin clinical study. Since the rifampin PBPK compound file only incorporated CYP3A4/3A5 induction, these results suggest that the induction of the minor CYP3A4/3A5 pathways (~11% of overall clearance) by rifampin contributes to a majority of the observed DDI while induction of the major UGT1A9 pathway (~70% of overall clearance) by rifampin is relatively minor. Similar results were obtained by PBPK modeling of the DDI between rifampin and dapagliflozin and rifampin and canagliflozin.

Conclusion- PBPK modeling suggests that induction of the minor CYP pathway is a key contributor to the observed DDI between rifampin and SGLT2 inhibitors, which are predominantly metabolized by UGT enzymes.