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Evaluation of drug-drug interaction of lusutrombopag, a thrombopoietin receptor agonist, via metabolic enzymes and transporters
- Source :
- European Journal of Clinical Pharmacology
- Publication Year :
- 2020
- Publisher :
- Springer Berlin Heidelberg, 2020.
-
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.
- Subjects :
- Agonist
Adult
Male
Physiologically based pharmacokinetic modelling
ATP Binding Cassette Transporter, Subfamily B
medicine.drug_class
CYP3A
Drug interaction
Midazolam
Cmax
Administration, Oral
Pharmacology
Transporter
030226 pharmacology & pharmacy
Models, Biological
03 medical and health sciences
Young Adult
0302 clinical medicine
Pharmacokinetics
In vivo
medicine
Cytochrome P-450 CYP3A
Humans
Pharmacology (medical)
Drug Interactions
Cross-Over Studies
business.industry
General Medicine
Pharmacokinetics and Disposition
Middle Aged
Lusutrombopag
Healthy Volunteers
Thiazoles
Cinnamates
030220 oncology & carcinogenesis
Metabolic enzyme
Cyclosporine
Female
business
Receptors, Thrombopoietin
medicine.drug
Subjects
Details
- Language :
- English
- ISSN :
- 14321041 and 00316970
- Volume :
- 76
- Issue :
- 12
- Database :
- OpenAIRE
- Journal :
- European Journal of Clinical Pharmacology
- Accession number :
- edsair.doi.dedup.....e2fda71dd1ed11251dec1c29d8d8293d