Individualized Dosing for Multiple Ordered Groups of Patients
In this article, the problem of dose finding in Phase I clinical trials for a heterogeneous patient population is considered. A new interval-based nonparametric design is proposed that stratifies the patients into multiple groups of varying sizes according to their susceptibility to toxicity and finds the maximum tolerable dose (MTD) in each group. The proposed design allows for sharing of patient information between groups, thus increasing the efficiency in identifying the group MTDs correctly, especially in patient groups with low prevalence. The convergence results for the proposed algorithm are presented. Various simulation studies are performed to illustrate the new methodology.
KeywordsInterval-based design nonparametric Phase I polymorphism warfarin
AMS Subject Classification62P10
Unable to display preview. Download preview PDF.
- Millican, E. A., P. A. Lenzini, P. E. Milligan, L. Grosso, C. Eby, E. Deych, G. Grice, J. C. Clohisy, R. L. Barrack, R. Stephen, J. Burnett, D. Voora, S. Gatchel, A. Tiemeier, and B. F. Gage. 2007. Genetic-based dosing in orthopedic patients beginning warfarin therapy. Am. Soc. Hematol., 110, 1511–1515.Google Scholar
- Sconce, E. A., T. I. Khan, H. A. Wynne, P. Avery, L. Monkhouse, B. P. King, P. Wood, P. Kesteven, A. K. Daly, and F. Kamali. 2005. The impact of CYP2C9 and VKORC1 genetic polymorphism and patient characteristics upon warfarin dose requirements: Proposal for a new dosing regimen. Blood, 106, 2329–2333.CrossRefGoogle Scholar
- Stroke Prevention in Atrial Fibrillation Investigators. 1996. Adjusted-dose warfarin versus low-intensity, fixed-dose warfarin plus aspirin for high-risk patients with atrial fibrillation: Stroke prevention in atrial fibrillation III randomised clinical trial. Lancet, 348, 633–638.CrossRefGoogle Scholar