Population pharmacokinetic/pharmacodynamic modelling of eltrombopag in healthy volunteers and subjects with chronic liver disease

Abstract

AIMSTo characterize the pharmacokinetics (PK)/pharmacodynamics (PD) of eltrombopag in chronic liver disease (CLD). METHODSThe PK/PD model was developed using data from 79 CLD patients using nonlinear mixed-effects modelling. RESULTSThe PK of eltrombopag were described by a two-compartment model with dual sequential first-order absorption. Gender, race and severity of CLD were predictors of the apparent clearance of eltrombopag. The PD of eltrombopag in CLD were adequately described by a four-compartment lifespan model, in which eltrombopag stimulated platelet precursor production rate. East Asian CLD patients were less sensitive to the stimulatory effect of eltrombopag. Following a daily dose regimen of 50 mg eltrombopag, the time to achieve peak platelet counts was longer for the CLD population compared with patients who had immune thrombocytopenic purpura, but was comparable to patients with hepatitis C. Likewise, it took a longer time for platelet counts to rebound back to baseline once eltrombopag treatment was discontinued. CONCLUSIONSThe time course of the platelet response in CLD was different from that in immune thrombocytopenic purpura but comparable to that in hepatitis C.

Multicentre, randomised phaseIIIstudy of the efficacy and safety of eltrombopag in Chinese patients with chronic immune thrombocytopenia

“…The total duration and the maximum period of time a patient had a platelet count ≥50 9 10 9 /l during Stage I were analysed by the van Elteren stratified rank test, with stratification factors as stated previously. PK and PK/PD analyses were conducted using a population approach with non-linear mixed effects modelling methods (Farrell et al, 2014). The following covariates were explored in PK analysis: body weight, gender, estimated creatinine clearance (based on the Cockcroft-Gault equation), age, body mass index, albumin, alanine transaminase (ALT), aspartate transaminase (AST), total bilirubin, alkaline phosphatase and concomitant use of corticosteroids.…”

Eltrombopag dose predictors in thrombocytopenic subjects with hepatitis C virus infection

“…10 This explains females having decreased odds of receiving a large eltrombopag dose. Eltrombopag is predominantly metabolized in the liver through oxidation (CYP1A2 and CYP2C8) and glucuronidation (UGT1A1 and UGT1A3).…”

“…13 It has been reported that age does not seem to affect eltrombopag pharmacokinetics. 10,13 However, eltromboapag pharmacodynamics do seem to be affected by age. 13 Increased lymphocyte count is a predictive of lower eltrombopag dose.…”

“…This is possibly attributed to a previous finding that East Asian race patients are less sensitive to eltrombopag. 10 Less eltrombopag sensitivity might balance out the higher exposure of eltrombopag in East Asian patients. Concurrent corticosteroids administration has been previously reported to decrease eltrombopag clearance (normalized to bioavailability).…”

Impact of target‐mediated drug disposition on hetrombopag pharmacokinetics and pharmacodynamics in Chinese healthy subjects and patients with chronic idiopathic thrombocytopenic purpura

“…The final PK model and parameter estimates were fixed and used to produce individual concentration-time curves in the PD model. A semiphysiological model as described previously [15][16][17][18][19][20] incorporating the platelet production process in bone marrow and the degradation process in circulating blood was used as the PD structural model. Initially, three-to five-transit compartments were tested and compared based on the OFVs, the precision of parameter estimates and goodness-of-fit plots.…”