Abstract
PurposeDrug-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.MethodsThe 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.ResultsIn 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.ConclusionsIn 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.
Highlights
Lusutrombopag (S-888711) is a small-molecule thrombopoietin (TPO) receptor agonist developed by Shionogi & Co., Ltd. (Osaka, Japan)
The following pharmacokinetic parameters were calculated based on the plasma concentrations of substrates using noncompartmental analysis: maximum plasma concentration (Cmax), time to maximum plasma concentration (Tmax), area under the plasma concentration-time curve from time zero to the time of last quantifiable concentration after dosing (AUC0– last), area under the plasma concentration-time curve extrapolated from time zero to infinity (AUC0–inf), and terminal elimination half-life (t1/2,z)
Mean plasma concentration profiles of midazolam following the single dose of midazolam were similar between midazolam alone and coadministration with lusutrombopag (Fig. 1)
Summary
Lusutrombopag (S-888711) is a small-molecule thrombopoietin (TPO) receptor agonist developed by Shionogi & Co., Ltd. (Osaka, Japan). Lusutrombopag (S-888711) is a small-molecule thrombopoietin (TPO) receptor agonist developed by Shionogi & Co., Ltd. Lusutrombopag promotes thrombocytopoiesis in the same fashion as endogenous TPO. Thrombocytopenia commonly develops in patients with chronic liver disease (CLD) [1]. Lusutrombopag is approved for treatment of thrombocytopenia in adult CLD patients undergoing elective invasive procedures in Japan, the USA, and the EU [2,3,4]. The pharmacokinetics of lusutrombopag is linear from 0.25 to 50 mg in single- or multiple-dose studies [3, 4]. The accumulation ratios of Cmax and AUC were approximately 2 with once-daily multiple-dose administration, and steady-state plasma lusutrombopag concentrations were achieved after
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