Optimizing First-Time-In-Human Trial Design for Studying Dose Proportionality
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Drug lnformarion Journal, Vol. 35, pp. 1065-1078, 2001 Printed in h e USA. All rights reserved.
OPTIMIZING FIRST-TIME-INHUMAN TRIAL DESIGN FOR STUDYING DOSE PROPORTIONALITY YIN YIN, PHD Statistical and Data Sciences Leader, Metabolic, Musculoskeletal and Viral Diseases Center of Excellence for Drug Discovery
CHAOCHEN,PHD Senior Clinical Pharmacokineticist,Clinical Pharmacology & Experimental Medicine GlaxoSmithKline, Research Triangle Park, North Carolina
Mixed effect models are becoming common in analyzing data from clinical trials involving several measurements for each subject. However; designs using mixed effect models have not received as much attention. Data collected from first-time-in-human studies are frequently usedfor studying dose proportionality. Two design types were evaluated theoretically for a hypothetical study conducted at six doses evenly spaced on a log scale for a drug whose AUC-dose relationship can be described by a mixed effect power model. In sequential panel design, subjects receive consecutive doses and in alternute panel design, subjects receive nonconsecutive doses. Sample sizes required to characterize the AUC-dose relationship to the same level of precision by both designs were calculated at given inter- and intra-subject variabilities. The conclusion is that an alternute panel design always requires fewer subjects than a sequential panel design. In many common cases, less than half as many subjects are required. Key Words: Dose proportionality; First-time-in-human (FTIH); Power model; Mixed effect model; Design
INTRODUCTION THE USUAL OBJECTIVES of a first-time-in-human (FTIH)study for an investigational drug are to assess the safetyholerability and the pharmacokinetics of the compound over a range of doses. Dose proportionality, one aspect of pharmacokinetics, characterizes whether a change in the dose results in a proportional change in the maximum circulating concentration (CmJ or the systemic exposure, which is usually represented by the area under the circulating concentration versus time curve (AUC). Early understanding of the dose proportionality is important for several reasons: 1. It helps guide dose selection for subsequent clinical trials, 2. It determines the regimen for dosage adjustment in clinical practice and the need for therapeutic concentration monitoring, and 3. It contributes to the evaluation of the ease of clinical use and, therefore, the commercial viability of a potential product. ~~~
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Reprint address: Yin Yin, GlaxoSmithKline, 5 Moore Drive, Research Triangle Park,NC 27709
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Yin Yin and Chao Chen
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Since in FTIH studies a wide range of doses are given in a controlled environment where the safety of the test subjects is closely monitored, these studies are ideal opportunities for investigating dose proportionality. Given the dose levels to be tested, among the key questions often asked about the design of a FTIH study are: 0 0
How many subjects should receive each dose? and How many and which doses each subject should receive?
Mixed ef
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