APPLICATION OF PHYSIOLOGICAL MODELS TO PREDICT THE INFLUENCE OF CHANGES IN BODY-COMPOSITION AND BLOOD FLOWS ON THE PHARMACOKINETICS OF FENTANYL AND ALFENTANIL IN PATIENTS

Background: The influence of changes in the physiologic state of a pat ient on the disposition of fentanyl and alfentanil is poorly understoo d. The aims of this study were to determine whether physiologic pharma cokinetic models for fentanyl and alfentanil, based on data from rats, could predict plasma concentrations of these opioids in humans and to determine how changes in physiology would influence the predictions o f their disposition. Methods: The predictions of the models were teste d against plasma concentration data from published pharmacokinetic stu dies. The influences of changes in body composition, cardiac output, a nd regional blood flows on the disposition of the opioids were simulat ed. Results: The models could predict independently measured plasma co ncentrations of the opioids after short infusions in humans, Simulatio ns then predicted that differences in body composition between men and women would have little influence on the pharmacokinetics of the opio ids. Changes in cardiac output would affect drug redistribution, and c onsequently the early decay of the plasma concentrations, but not mark edly influence rates of elimination. Further, the clearance of the opi oids would decrease and their volumes of distribution increase with th e age of the patient, but this would only marginally affect the early disposition of the drugs. Even large fluctuations in peripheral or hep atic blood flows would have modest effects on arterial plasma concentr ations of the opioids, and sudden ''postoperative'' increases in perip heral blood flows mould cause minor secondary plasma concentration pea ks. Conclusions: The ability of the physiologic models to predict plas ma concentrations of fentanyl and alfentanil in humans was confirmed. When changes in physiologic condition were simulated, effects on the p harmacokinetics of the opioids with possible implications for dosing w ere obtained only if cardiac output was varied over a wide range.