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A model of hypertension and proteinuria in cancer patients treated with the anti-angiogenic drug E7080
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. (Farmakometri)
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2010 (English)In: Journal of Pharmacokinetics and Pharmacodynamics, ISSN 1567-567X, E-ISSN 1573-8744, Vol. 37, no 4, 347-363 p.Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
2010. Vol. 37, no 4, 347-363 p.
Keyword [en]
Hypertension, Proteinuria, VEGF, Pharmacodynamics, Model
National Category
Medical and Health Sciences
URN: urn:nbn:se:uu:diva-134969DOI: 10.1007/s10928-010-9164-2ISI: 000280919400003OAI: oai:DiVA.org:uu-134969DiVA: diva2:375068
Available from: 2010-12-07 Created: 2010-12-03 Last updated: 2011-10-07Bibliographically approved

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Karlsson, Mats O.
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