High dose rifampicin is being investigated for shortening TB therapy as well as in other indications such as leprosy. Strategies to manage the risk of drug-drug interactions (DDIs) with co-administered antiretroviral drugs may therefore be needed. The current study used physiologically-based pharmacokinetic (PBPK) modelling to predict the magnitude of DDI between once monthly (QMT) high dose rifampicin (RIF) and multiple dolutegravir (DTG) regimens for the treatment of leprosy in HIV coinfected patients.
A whole-body PBPK model was designed in Simbiology v. 9.4.0 (MATLAB R2018a) and used to simulate 100 adult individuals. The DTG model was qualified against reported clinical data for DTG 50mg once daily (QD) and twice daily (BID). The RIF model describing the induction of DTG’s major metabolic pathways, UGT1A1 and CYP3A4, was qualified using in vitro and oral clinical data for midazolam, nifedipine, raltegravir, DTG and RIF. As per convention, PBPK models were assumed to be qualified if the simulated values were within 2-fold of the mean reported clinical values and if the absolute average-fold error (AAFE) was below 2. The verified DTG and RIF models were used to simulate the magnitude of DDI between RIF 600mg QMT co-administered with DTG 50mg BID as well as RIF 1200mg QMT co-administered with DTG 50mg BID, DTG 50mg three times daily (TID) and DTG 100mg BID.
The PBPK models were successfully qualified according to the criteria. There was a tendency to overpredict the magnitude of RIF induction for DTG 50mg BID, with simulated versus observed area under the curve (AUC), maximum plasma concentration (Cmax) and minimum plasma concentration (Cmin) ratios of 0.63, 0.58 and 0.74, respectively. The simulated Cmin of DTG after the administration of RIF are summarised in the table. For DTG 50mg BID co-administered with RIF 1200mg QMT, the Cmin minus one standard deviation (SD) fell below DTG’s protein adjusted (PA)-IC90 1 day post RIF dose and recovered within 24 hours.
The PBPK model predicted marked reductions in the Cmin of several DTG dosing regimens when co-administered with 600mg and 1200mg RIF QMT. Importantly, the return of DTG plasma concentrations to steady state Cmin was predicted to be considerably delayed after coadministration of both 600mg and 1200mg RIF QMT. These simulations could inform development of effective high-dose RIF strategies for special HIV populations with comorbidities such as Leprosy.