Evaluation of clinical drug interaction potential of clofazimine using static and dynamic modeling approaches

The 2016 World Health Organization treatment recommendations for drug-resistant tuberculosis (DR-TB) positioned clofazimine as a core second-line drug. Being identified as a cytochrome P450 (CYP) inhibitor in vitro, a CYP-mediated drug interaction may be likely when clofazimine is co-administered with substrates of these enzymes. The CYP-mediated drug interaction potential of clofazimine was evaluated using both static (estimation of “R1” and area under the plasma concentration-time curve ratio [AUCR] values) and dynamic (physiologically based pharmacokinetic [PBPK]) modeling approaches. For static and dynamic predictions, midazolam, repaglinide, and desipramine were used as probe substrates for CYP3A4/5, CYP2C8, and CYP2D6, respectively. The AUCR static model estimations for clofazimine with the substrates midazolam, repaglinide, and desipramine were 5.59, 1.34, and 1.69, respectively. The fold increase in AUC predicted for midazolam, repaglinide, and desipramine with clofazimine based upon PBPK modeling was 2.66, 1.70, and 1.48, respectively. Clofazimine was predicted to be a moderate to strong CYP3A4/5 inhibitor and weak CYP2C8 and CYP2D6 inhibitor based on the calculated AUCR by static and PBPK modeling. Additionally, for selected antiretroviral, antitubercular, antihypertensive, antidiabetic, and antihyperlipidemic CYP3A4/5 substrate drugs, approximately 2- to 6-fold increases in the AUC were predicted with static modeling when co-administered with 100 mg of clofazimine. Therefore, the possibility of an increase in the AUC of CYP3A4/5 substrates when co-administered with clofazimine cannot be ignored