On the Relationship Between Plasma Concentrations of Drugs and Outcome of
Stroke Studies in Laboratory Animals
Stephen H. Curry, Astra-Zeneca R&D Boston, 3 Biotech, One Innovation Drive, Worcester, MA 01605-4307
Data from experimental stroke models often show confusing discrepancies, which may, in part, relate to pharmacokinetic factors in drug response. Plasma sampling for pharmacokinetic analysis in stroke models is related to: (i) proof of exposure, (ii) design of experiments which optimize pharmacodynamic assessment in relation to bioavailability and half-life of drugs, and (iii) facilitation of comparisons across species including extrapolation from animals to humans. However, plasma sampling is often complicated by difficulty of access caused by multiple sampling lines, volume of blood removable from an already traumatized animal, and legal constraints when using primates. This presentation will focus on pharmacokinetic differences between stroked and non-stroked animals, design of dosing regimens for animals inducing target concentrations determined in human safety studies, comparison of concentrations during the first one to two hours after an infarct and at more accessible times such as seven days, and problem solving when responses fail to agree with expectations. An optimum design will be presented involving: (i) study of the pharmacokinetics in non-stroked animals, (ii) prediction of a dosing regimen intended to incude target concentrations during the time window of opportunity, and (iii) post-hoc confirmation in a parallel group of stroked animals after neurological testing and after the beneficial effect has been established, but before the return of termination for histology.
Proc. NY Acad. Sci., 939, 297 - 308, 2001
Fifth International Conference on Neuroprotective Agents, Lake Tahoe, California, September 17-20, 2000
Pharmacokinetics in Stroke Studies