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

Abstract

BackgroundPatients 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.MethodsA 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).ResultsVisual 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.ConclusionThe modelling and simulation support lusutrombopag 3 mg once daily for 7 days without platelet monitoring.Electronic supplementary materialThe online version of this article (10.1007/s40262-019-00770-4) contains supplementary material, which is available to authorized users.

Is platelet monitoring during 7‐day lusutrombopag treatment necessary in chronic liver disease patients with thrombocytopenia undergoing planned invasive procedures? A phase IIIb open‐label study

“…There is currently insufficient information to determine whether platelet monitoring using these discontinuation criteria during a 7-day lusutrombopag treatment period is necessary for all patients, or if platelet monitoring could be reduced or omitted in suitable patients without negatively impacting safety or efficacy outcomes. 18 Furthermore, only a few reports describe the effect of lusutrombopag in patients being retreated with lusutrombopag. 19,20 This open-label study aimed to determine whether platelet monitoring and the discontinuation criteria could be applied at a reduced frequency without affecting clinical outcomes.…”

“…However, strict application of these criteria can be burdensome and unpleasant for patients, as platelet monitoring requires repeated hospital visits and blood sampling. There is currently insufficient information to determine whether platelet monitoring using these discontinuation criteria during a 7‐day lusutrombopag treatment period is necessary for all patients, or if platelet monitoring could be reduced or omitted in suitable patients without negatively impacting safety or efficacy outcomes 18 . Furthermore, only a few reports describe the effect of lusutrombopag in patients being retreated with lusutrombopag 19,20 .…”

Quantitative systems pharmacology model of thrombopoiesis and platelet life‐cycle, and its application to thrombocytopenia based on chronic liver disease

“…Because actual data for cell counts in humans, such as precursor cells and megakaryocytes in bone marrow, were not available, they were assumed based on the observed platelet count data from clinical studies. 13,14 The platelet model was constructed assuming that cell division of progenitor cells occurs once a day (k out = 1/day), on average, based on the typical cell proliferation time (24 h) 19 and the typical doubling time of megakaryoblastic leukemia cell lines (24 h), 20 and that cells do not die in the process of megakaryocyte formation from progenitor cells. For megakaryocyte maturation, k out was used to describe the daily maturation process.…”

“…Some models have been reported for describing platelet count profiles, which address the slow onset. As one major approach, semimechanistic pharmacokinetic-pharmacodynamic (PK-PD) models [11][12][13][14] have been reported to describe and understand the PKs and the change of platelet count profiles after drug administration. Harker et al developed a mathematical model, which included biology of megakaryocyte for describing platelet counts after administration of pegylated recombinant megakaryocyte growth and development factor (PEG-rHuMGDF) 15 for healthy volunteers.…”

“…Although all of these models are useful for describing platelet count profiles, the model structures involved in the underlying thrombopoiesis were different among the reports. [11][12][13][14][15][16] Therefore, it is valuable to construct a comprehensive systems pharmacology model for the platelet life-cycle based on physiological, pathological, and mechanistic information also by utilizing reported model structures and assumptions for understanding the complex processes of thrombopoiesis and platelet life-cycle.…”