In-Silico Prediction of Drug Properties in Man Using Preclinical Data and Computer-Assisted Drug Development
- PDF / 1,385,730 Bytes
- 17 Pages / 504 x 720 pts Page_size
- 95 Downloads / 202 Views
Drug Information Journal. Vol. 35. pp. 1047-1063. 2001
Copyright 0 2001 Drug Information Association Inc.
Printed in the USA. All rights reserved.
IN-SILICO PREDICTION OF DRUG PROPERTIES IN MAN USING PRECLINICAL DATA AND COMPUTERASSISTED DRUG DEVELOPMENT ROBERTOGOMENI,PHD, CHRISTINEFALCOZ,PHD, CARLAD'ANGELI,PHD, AND ALANBYE, PHD GIaxoSmithKline Group, GlaxoWellcome S.p.A., Verona, Italy
Computer-assisted drug development (CADD) is a knowledge-based process that integrates newly collected information in a drug/disease-specific knowledge frame and provides a rational basis for decision making during drug development. A mathematical model was developed to predict the dosage regimen appropriate to reach a desired human response for a new central nervous system compound from data collected in preclinical studies. The model incorporates uncertainty on the human pharmacokinetic/pharmacodynamic (PWPD) relationship scaled from animal data, including the afJinity adjustment derived from in-vitro receptor binding studies. Brain receptor occupancy, estimated using positron emission tomography imaging, was used as a surrogate marker of clinical efficacy. The CADD approach was used to design the first-time-in-man and the proofof-concept study. The expected minimal effective dose in man was estimated by simulating a dose-escalating trial, as the dose necessary to reach and maintain during chronic treatment is a target receptor occupancy of less than 70%, assuming that the therapeutic effect is associated with a receptor occupancy of less than 70%at a given probability level (Prob > 70%).Finally, the optimal in-vivo release characteristics from a pharmaceutical formulation were evaluated using a convolution-based model linking the in-vivo delivery rate to the PK/PD response, minimizing an appropriate cost function. Clinical trial simulation was used as a supportive tool for decision making by evaluating different scenarios accounting for the uncertainty in the predicted PK/PD relationship, intersubject variability, and drug potency. Key Words: Computer-assisted drug development; First-time-in-man; Proof-of-concept; Trial simulation; Minimal effective dose; Convolution-based model
INTRODUCTION THE lNCREASING PRESSURE to improve the operational efficiency of drug development drives pharmaceutical research toward the extensive use of new technologies. Clini-
Reprint address: Roberto Gomeni, GlaxoSmithKline Group, GlaxoWellcome, Via A. Fleming 4, 37135 Verona, Italy. E-mail: rog3 13900gsk.com.
cal trial simulation has been recently recognized as an effective tool for more effective drug development (1-4). This approach has been predominantly used in clinical development (Phase I to IV), and only occasionally used to optimize preclinical development or to ensure an optimal transition from preclinical to clinical development. On to continuThe ability from ously integrate any information collected
1047
Downloaded from dij.sagepub.com at Swinburne Univ of Technology on May 17, 2015
1048
Roberto Gomeni, Christine Falcoz, Carla
Data Loading...
