Exploratory and Population Pharmacodynamic Analysis of Pilot Dose-Response Data in the Bioequivalence Testing of Topical
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EXPLORATORY AND POPULATION PHARMACODYNAMIC ANALYSIS OF PILOT DOSE-RESPONSE DATA IN THE BIOEQUIVALENCE TESTING OF TOPICAL CORTICOSTEROID PREPARATIONS LASZLOENDRENYI, PHD Department of Pharmacology, and Department of Preventive Medicine and Biostatistics, University of Toronto, Toronto, Canada
MIN GAO,PHD Scian Clinical, Etobicoke, Canada
YONGHAO, PHD Department of Biostatistics, Ontario Cancer lnstitute/Princess Margaret Hospital, Toronto, Canada
A guidance of the Food and Drug Administration (FDA)recommends that the pharmacodynamic (PD) equivalence of topical corticosteroid preparations be demonstrated by a twostep procedure. A pilot study would establish the ED50 of a PD relationship between dose duration and a vasoconstrictor response. The relevance of the assumed hyperbolic Michaelis-Menten response model is evaluated by both graphical exploratory andpopulation PD analyses of the data presented in the guidance. It is shown that the observations are far removed from their asymptotic plateau, and that they can be characterized well by a simplified Hill equation with a Hill coefficient of 0.4. Consequently, it is suggested that pilot studies are not needed when the dose range for sensitive responses is known. Nonresponding subjects should be removed from the analyses of both stages of an investigation. PD equivalence should be assessed with dose durations distanced as far as possible from each other. Finally, the study demonstrates the usefulness of graphical, exploratory analyses without which modeling b y regression, including population kinetic and PD computations, can be misinterpreted. Key Words: Bioequivalence; Topical corticosteroids; Exploratory data analyiis; Population dynamic analysis; Hill model
THE FOOD AND DRUG Administration has recently issued a guidance for assessing the equivalence of topical corticosteroid formulations (1). Two phases of evaluation were recommended. The first, a pilot study, deter-
Reprint address: Laszlo Endrenyi, PhD. Department of Pharmacology, University of Toronto, Toronto, Ontario M5S 1A8, Canada. E-mail: [email protected].
mines the relationship between the response and dose durations for the reference drug product. The estimated ED50 is used as a reference point for conducting the second phase of the investigation. In this, the test and reference formulations are to be compared at two dose durations which are to be set at one-half and twice the ED50. The rationale for the suggested procedure is that the region around ED50 is assumed to be the most sensi-
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Laszlo Endrenyi, Min Gao, and Yong Ha0
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When n = 1, the equation is reduced to tive portion of the curve contrasting the rethe Michaelis-Menten equation: sponse with dose durations. The equivalence of topical corticosteroid D formulations has been the subject of numerE = Em, (2) ous studies. The guidance (1) recommends ED50 + D
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