A model of hypertension and proteinuria in cancer patients treated with the anti-angiogenic drug E7080

作者：Ron J. Keizer, Anubha Gupta, Melvin R. Mac Gillavry, Mendel Jansen, Jantien Wanders, Jos H. Beijnen, Jan H.M. Schellens, Mats O. Karlsson, Alwin D. R. Huitema · 发表于：Journal of Pharmacokinetics and Pharmacodynamics · 年份：2010 · DOI：10.1007/s10928-010-9164-2 · 被引用次数：64 · 研究领域：Angiogenesis and VEGF in Cancer、Cancer Treatment and Pharmacology、Chemotherapy-induced cardiotoxicity and mitigation

Hypertension and proteinuria are commonly observed side-effects for anti-angiogenic drugs targeting the VEGF pathway. In most cases, hypertension can be controlled by prescription of anti-hypertensive (AH) therapy, while proteinuria often requires dose reductions or dose delays. We aimed to construct a pharmacokinetic-pharmacodynamic (PK-PD) model for hypertension and proteinuria following treatment with the experimental VEGF-inhibitor E7080, which would allow optimization of treatment, by assessing the influence of anti-hypertensive medication and dose reduction or dose delays in treating and avoiding toxicity. Data was collected from a phase I study of E7080 (n = 67), an inhibitor of multiple tyrosine kinases, among which VEGF. Blood pressure and urinalysis data were recorded weekly. Modeling was performed in NONMEM, and direct and indirect response PK-PD models were evaluated. A previously developed PK model was used. An indirect response PK-PD model described the increase in BP best, while the probability of developing proteinuria toxicity in response to exposure to E7080, was best described by a Markov transition model. This model may guide clinical interventions and provide treatment recommendations for E7080, and may serve as a template model for other drugs in this class.