| Model-based treatment optimization of a novel VEGFR inhibitor. | |
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MedLine Citation:
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PMID: 22295876 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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AIM: To evaluate dosing and intervention strategies for the phase II programme of a VEGF receptor inhibitor using PK-PD modelling and simulation, with the aim of maximizing (i) the number of patients on treatment and (ii) the average dose level during treatment. METHODS: A previously developed PK-PD model for lenvatinib (E7080) was updated and parameters were re-estimated (141 patients, once daily and twice daily regimens). Treatment of lenvatinib was simulated for 16 weeks, initiated at 25 mg once daily. Outcome measures included the number of patients on treatment and overall drug exposure. A hypertension intervention design proposed for phase II studies was evaluated, including antihypertensive treatment and dose de-escalation. Additionally, a within-patient dose escalation was investigated, titrating up to 50 mg once daily unless unacceptable toxicity occurred. RESULTS: Using the proposed antihypertension intervention design, 82% of patients could remain on treatment, and the mean dose administered was 21.5 mg day⁻¹. The adverse event (AE) guided dose titration increased the average dose by 4.6 mg day⁻¹, while only marginally increasing the percentage of patients dropping out due to toxicity (from 18% to 20.8%). CONCLUSIONS: The proposed hypertension intervention design is expected to be effective in maintaining patients on treatment with lenvatinib. The AE-guided dose titration with blood pressure as a biomarker yielded a higher overall dose level, without relevant increases in toxicity. Since increased exposure to lenvatinib seems correlated with increased treatment efficacy, the adaptive treatment design may thus be a valid approach to improve treatment outcome. |
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Authors:
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Ron J Keizer; Anubha Gupta; Robert Shumaker; Jos H Beijnen; Jan H M Schellens; Alwin D R Huitema |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't |
Journal Detail:
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Title: British journal of clinical pharmacology Volume: 74 ISSN: 1365-2125 ISO Abbreviation: Br J Clin Pharmacol Publication Date: 2012 Aug |
Date Detail:
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Created Date: 2012-07-11 Completed Date: 2012-11-13 Revised Date: 2013-04-23 |
Medline Journal Info:
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Nlm Unique ID: 7503323 Medline TA: Br J Clin Pharmacol Country: England |
Other Details:
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Languages: eng Pagination: 315-26 Citation Subset: IM |
Copyright Information:
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© 2012 The Authors. British Journal of Clinical Pharmacology © 2012 The British Pharmacological Society. |
Affiliation:
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Department of Pharmacy & Pharmacology, Slotervaart Hospital/The Netherlands Cancer Institute, Louwesweg 6, 1066 EC Amsterdam, the Netherlands. ron.keizer@farmbio.uu.se |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Adult Aged Aged, 80 and over Angiogenesis Inhibitors / administration & dosage*, adverse effects, pharmacokinetics Antihypertensive Agents / therapeutic use Blood Pressure / drug effects Clinical Trials, Phase I as Topic Clinical Trials, Phase II as Topic Computer Simulation Drug Administration Schedule Female Humans Hypertension / chemically induced, drug therapy, physiopathology Male Markov Chains Middle Aged Models, Biological* Neoplasms / drug therapy*, enzymology Phenylurea Compounds / administration & dosage*, adverse effects, pharmacokinetics Protein Kinase Inhibitors / administration & dosage*, adverse effects, pharmacokinetics Proteinuria / chemically induced Quinolines / administration & dosage*, adverse effects, pharmacokinetics Receptors, Vascular Endothelial Growth Factor / antagonists & inhibitors*, metabolism Research Design Treatment Outcome |
| Chemical | |
Reg. No./Substance:
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0/4-(3-chloro-4-(N'-cyclopropylureido)phenoxy)-7-methoxyquinoline-6-carboxamide; 0/Angiogenesis Inhibitors; 0/Antihypertensive Agents; 0/Phenylurea Compounds; 0/Protein Kinase Inhibitors; 0/Quinolines; EC 2.7.10.1/Receptors, Vascular Endothelial Growth Factor |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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