title: Bayesian methods for pharmacokinetic/pharmacodynamic modeling of pazopanib-induced increases in blood pressure and transaminases.
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 (Cτ ) 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 Cτ 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) Cτ at which the probability of a clinically significant increase in blood pressure was 50% (EC50 ) was 12.3 μg/mL (6.12, 18.4). The median (95% CrI) EC50 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.
authors: Clinical Pharmacology Modeling and Simulation, GlaxoSmithKline, Research Triangle Park, NC 27709, USA. ben.b.suttle@gsk.com
authors: A Benjamin
authors: AB
authors: Suttle
authors: Paul
authors: P
authors: de Souza
authors: Thangam
authors: T
authors: Arumugham
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000410:Alanine Transaminase / Q000097:blood*; D000469:Alkaline Phosphatase / Q000097:blood; D020533:Angiogenesis Inhibitors / Q000097:blood / Q000494:pharmacology*; D001219:Aspartate Aminotransferases / Q000097:blood; D001499:Bayes Theorem; D001794:Blood Pressure / Q000187:drug effects*; D006801:Humans; D007191:Indazoles; D016015:Logistic Models; D008875:Middle Aged; D008954:Models, Biological; D009369:Neoplasms / Q000097:blood / Q000188:drug therapy / Q000503:physiopathology; D011743:Pyrimidines / Q000097:blood / Q000494:pharmacology*; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors; D013449:Sulfonamides / Q000097:blood / Q000494:pharmacology*; D055815:Young Adult
chemical_list: D020533:Angiogenesis Inhibitors; D007191:Indazoles; D011743:Pyrimidines; D013449:Sulfonamides; C516667:pazopanib; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D040262:Receptors, Vascular Endothelial Growth Factor; D000469:Alkaline Phosphatase