PHARMACOKINETIC-PHARMACODYNAMIC MODELING IN DRUG DEVELOPMENT - APPLICATION TO THE INVESTIGATIONAL OPIOID TREFENTANIL

Objective: We determined the possible benefits of a new opioid, trefen tanil, relative to fentanyl and alfentanil using high-resolution pharm acokinetic-pharmacodynamic modeling and computer simulations of clinic al dosing scenarios. Methods: First, we determined in nine volunteers the electroencephalographic (EEG) effects and the trefentanil infusion rate that gave maximal EEG changes in 3 to 10 minutes. Then, in a cro ssover fashion in five volunteers, we compared the pharmacokinetics an d EEG pharmacodynamics of trefentanil with fentanyl and alfentanil. Fi nally, we used computer simulations to predict offset of opioid effect s of trefentanil, fentanyl, and alfentanil when given in different dos ing schemes. Results: The pharmacokinetic-pharmacodynamic profile of t refentanil was similar to alfentanil, except for a higher elimination clearance. Trefentanil versus alfentanil pharmacokinetic parameters we re as follows: Elimination clearance, 0.444 +/- 0.073 versus 0.184 +/- 0.031 L/min; steady-state distribution volume, 37 +/- 7 versus 23 +/- 3 L; and elimination half-life, 127 +/- 24 versus 114 +/- 19 minutes, Trefentanil versus alfentanil pharmacodynamics were as follows: the e quilibration half-time between EEG effect and arterial drug concentrat ion, 1.2 +/- 0.5 versus 0.6 +/- 0.4 minutes; and the concentration res ulting in 50% of maximal EEG effect, 429 +/- 313 versus 577 +/- 273 ng /ml. The pharmacokinetic-pharmacodynamic profile of fentanyl was signi ficantly different from trefentanil and alfentanil. Simulation of effe ct compartment concentration decay curves after variable-length infusi ons predicted more rapid recovery ti om trefentanil than from alfentan il or fentanyl. Conclusion: We suggest that high-resolution pharmacoki netic-pharmacodynamic studies and computer simulations of clinical dos ing scenarios may have significant usefulness in appreciating differen ces between new and established drugs in early phase I studies.