title: A model of hypertension and proteinuria in cancer patients treated with the anti-angiogenic drug E7080.
abstract: 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.
authors.affiliation: Department of Pharmacy & Pharmacology, The Netherlands Cancer Institute, Slotervaart Hospital, Amsterdam, The Netherlands. ron.keizer@slz.nl
authors.forename: Ron J
authors.initials: RJ
authors.lastname: Keizer
authors.forename: Anubha
authors.initials: A
authors.lastname: Gupta
authors.forename: Melvin R
authors.initials: MR
authors.lastname: Mac Gillavry
authors.forename: Mendel
authors.initials: M
authors.lastname: Jansen
authors.forename: Jantien
authors.initials: J
authors.lastname: Wanders
authors.forename: Jos H
authors.initials: JH
authors.lastname: Beijnen
authors.forename: Jan H M
authors.initials: JH
authors.lastname: Schellens
authors.forename: Mats O
authors.initials: MO
authors.lastname: Karlsson
authors.forename: Alwin D R
authors.initials: AD
authors.lastname: Huitema
mesh_terms: D020533:Angiogenesis Inhibitors / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D000959:Antihypertensive Agents / Q000008:administration & dosage / Q000627:therapeutic use; D001794:Blood Pressure / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D006801:Humans; D006973:Hypertension / Q000139:chemically induced* / Q000188:drug therapy; D008954:Models, Biological; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000652:urine; D010671:Phenylurea Compounds / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D011507:Proteinuria / Q000139:chemically induced* / Q000517:prevention & control; D011804:Quinolines / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D016482:Urinalysis
chemical_list: D020533:Angiogenesis Inhibitors; D000959:Antihypertensive Agents; D010671:Phenylurea Compounds; D011804:Quinolines; C531958:lenvatinib