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Pharmacokinetic/Pharmacodynamic Modelling and Simulation of Lusutrombopag, a Novel Thrombopoietin Receptor Agonist, for the Treatment of Thrombocytopenia in Patients with Chronic Liver Disease Undergoing Invasive Procedures
- Source :
- Clinical Pharmacokinetics
- Publication Year :
- 2019
- Publisher :
- Springer Science and Business Media LLC, 2019.
-
Abstract
- Background Patients with thrombocytopenia associated with chronic liver disease (CLD) are at greater risk of bleeding during invasive procedures. This study characterized the pharmacokinetic/pharmacodynamic (PK/PD) profile of lusutrombopag, a novel thrombopoietin-receptor agonist, using modelling and simulation, and evaluated the appropriate dose regimen for treatment of thrombocytopenia in CLD patients undergoing invasive procedures. Methods A population PK/PD model was developed using plasma lusutrombopag concentrations from 78 healthy subjects and 349 CLD patients, as well as platelet counts from 347 of these 349 patients. Covariates were explored from subject characteristics. Monte-Carlo simulations were performed to assess a dose response for efficacy (platelet counts ≥ 50,000/μL) and a risk for platelet overshooting (platelet counts > 200,000/μL). Results Visual predictive checks indicated the developed models described the PK/PD profile of lusutrombopag well. In the simulations, without stopping criteria, lusutrombopag 3 mg once daily for 7 days before scheduled invasive procedures provided effective platelet response (85.2% probability for efficacy). The probability of platelet overshooting was 1.2%, indicating that platelet monitoring is not necessary. Although body weight was an influential covariate on the pharmacokinetics of lusutrombopag, individually estimated peak platelet counts overlapped among the body weight groups, suggesting no clinically significant effect on body weight. Conclusion The modelling and simulation support lusutrombopag 3 mg once daily for 7 days without platelet monitoring. Electronic supplementary material The online version of this article (10.1007/s40262-019-00770-4) contains supplementary material, which is available to authorized users.
- Subjects :
- Adult
Blood Platelets
Male
Agonist
medicine.medical_specialty
medicine.drug_class
Population
Chronic liver disease
Models, Biological
Gastroenterology
Young Adult
03 medical and health sciences
0302 clinical medicine
Pharmacokinetics
Internal medicine
Humans
Medicine
Pharmacology (medical)
Platelet
Original Research Article
education
Aged
Aged, 80 and over
Pharmacology
Thrombopoietin receptor
education.field_of_study
Platelet Count
business.industry
Liver Diseases
Middle Aged
medicine.disease
Thrombocytopenia
Thiazoles
Regimen
Cinnamates
030220 oncology & carcinogenesis
Pharmacodynamics
Chronic Disease
Female
030211 gastroenterology & hepatology
business
Receptors, Thrombopoietin
Subjects
Details
- ISSN :
- 11791926 and 03125963
- Volume :
- 58
- Database :
- OpenAIRE
- Journal :
- Clinical Pharmacokinetics
- Accession number :
- edsair.doi.dedup.....e41c4f8ae3a5d8f35483dabf731a67b2