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Bayesian Methods for Pharmacokinetic/Pharmacodynamic Modeling of Pazopanib‐Induced Increases in Blood Pressure and Transaminases
Author(s) -
Suttle A. Benjamin,
de Souza Paul,
Arumugham Thangam
Publication year - 2013
Publication title -
the journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.92
H-Index - 116
eISSN - 1552-4604
pISSN - 0091-2700
DOI - 10.1002/jcph.16
Subject(s) - pazopanib , medicine , confidence interval , logistic regression , pharmacokinetics , pharmacodynamics , blood pressure , oncology , urology , cancer , sunitinib
Abstract Relationships between plasma pazopanib concentrations and the probability of elevations in blood pressure, a marker of vascular endothelial growth factor receptor inhibition, and alanine aminotransferase (ALT) were investigated with logistic regression models. Data from a Phase I dose‐escalation study in cancer patients (n = 57) were examined to determine the relationship between steady‐state trough plasma pazopanib concentrations (C τ ) and a clinically significant blood pressure increase, using a Bayesian logistic regression model. Data from 5 monotherapy studies in cancer patients (n = 344) were pooled to investigate the relationship between C τ and maximum ALT ≥ 3× the upper limit of normal (ULN), using a Bayesian logistic regression model incorporating an asymptote. Both models were fit using WinBUGS. The median (95% credible interval, CrI) C τ at which the probability of a clinically significant increase in blood pressure was 50% (EC 50 ) was 12.3 μg/mL (6.12, 18.4). The median (95% CrI) EC 50 for the maximum probability of ALT ≥ 3 × ULN was 15.4 μg/mL (3.8, 41.2) and the median (95% CrI) maximum probability of ALT ≥ 3 × ULN was 21% (14.5, 43.1). Results suggest that dose adjustments could be useful in managing the potential for hepatotoxicity.