Evaluation of drug-drug interaction of lusutrombopag, a thrombopoietin receptor agonist, via metabolic enzymes and transporters

Abstract

Purpose Drug-drug interaction (DDI) potentials of lusutrombopag, a thrombopoietin receptor agonist, on the activity of cytochrome P450 (CYP) 3A and of cyclosporine, which inhibits P-glycoprotein and breast cancer resistance protein, on lusutrombopag pharmacokinetics were assessed via clinical studies and physiologically based pharmacokinetic (PBPK) modeling. Methods The effect of lusutrombopag on midazolam (a CYP3A probe substrate) pharmacokinetics was assessed in 15 healthy subjects receiving a single midazolam 5-mg dose with or without coadministration of lusutrombopag 0.75 mg for 6 days (first dose: 1.5-mg dose). The effect of cyclosporine on lusutrombopag pharmacokinetics was assessed in 16 healthy subjects receiving a single lusutrombopag 3-mg dose with or without a single cyclosporine 400- to 600-mg dose. PBPK modeling was employed to extrapolate the effect of lusutrombopag at the clinical dose (3 mg once daily) on midazolam pharmacokinetics. Results In the clinical study, mean ratios (90% confidence intervals [CIs]) of with/without lusutrombopag for maximum plasma concentration (Cmax) and area under the plasma concentration-time curve (AUC) of midazolam were 1.01 (0.908–1.13) and 1.04 (0.967–1.11), respectively, indicating no effect of lusutrombopag on midazolam pharmacokinetics. PBPK modeling suggested no effect of lusutrombopag at the clinical dose on midazolam pharmacokinetics. Mean ratios (90% CIs) of with/without cyclosporine for lusutrombopag Cmax and AUC were 1.18 (1.11–1.24) and 1.19 (1.13–1.25), respectively, indicating a slight increase in lusutrombopag exposure. Conclusions In consideration with in vitro data, the in vivo and in silico results suggested no clinically significant DDI potential of lusutrombopag with other medical products via metabolic enzymes and transporters.

Human mass balance, metabolism, and cytochrome P450 phenotyping of lusutrombopag

“…When the contribution ratio to lusutrombopag metabolism for CYP4 is 37%, CYP4 inhibitor increases the AUC of lusutrombopag at most 1.6-fold (Rodrigues 2008). The clinical DDI study with cyclosporine, a CYP3A4 inhibitor, indicated the fold increase of lusutrombopag AUC was 1.19 (Katsube et al 2020), suggesting the contribution of CYP3A4 for this drug metabolism is low. Considering that lusutrombopag was found to be metabolized primarily by CYP4A with minor contributions of CYP3A4 in this study, it could be concluded that the pharmacokinetics of lusutrombopag would be minimally or modestly changed via inhibition or induction for metabolic enzymes.…”

Lusutrombopag for thrombocytopenia in Chinese patients with chronic liver disease undergoing invasive procedures

“…Studies L-PLUS 1 and PLUS 2 were two randomized, double-blind, phase 3 trials; they demonstrated that lusutrombopag could effectively raise PLT and lower the requirements for platelet transfusion [12,13]. Moreover, there is an absence of restrictions on food and clinically significant interactions between drugs [14,15]. Unfortunately, there is no evidence-based data for lusutrombopag in a Chinese cohort yet.…”