Pharmacokinetic-pharmacodynamic modeling in drug development: application to the investigational opioid trefentanil.
OBJECTIVE
We determined the possible benefits of a new opioid, trefentanil, relative to fentanyl and alfentanil using high-resolution pharmacokinetic-pharmacodynamic modeling and computer simulations of clinical 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 crossover fashion in five volunteers, we compared the pharmacokinetics and EEG pharmacodynamics of trefentanil with fentanyl and alfentanil. Finally, we used computer simulations to predict offset of opioid effects of trefentanil, fentanyl, and alfentanil when given in different dosing schemes.


RESULTS
The pharmacokinetic-pharmacodynamic profile of trefentanil was similar to alfentanil, except for a higher elimination clearance. Trefentanil versus alfentanil pharmacokinetic parameters were 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 equilibration half-time between EEG effect and arterial drug concentration, 1.2 +/- 0.5 versus 0.6 +/- 0.4 minutes; and the concentration resulting in 50% of maximal EEG effect, 429 +/- 313 versus 577 +/- 273 ng/ml. The pharmacokinetic-pharmacodynamic profile of fentanyl was significantly different from trefentanil and alfentanil. Simulation of effect compartment concentration decay curves after variable-length infusions predicted more rapid recovery from trefentanil than from alfentanil or fentanyl.


CONCLUSIONS
We suggest that high-resolution pharmacokinetic-pharmacodynamic studies and computer simulations of clinical dosing scenarios may have significant usefulness in appreciating differences between new and established drugs in early phase I studies.
Lemmens
H J
HJ
Department of Anesthesia, Stanford University School of Medicine, CA.
Dyck
J B
JB
Shafer
S L
SL
Stanski
D R
DR
D000328:Adult; D015760:Alfentanil / Q000493:pharmacokinetics; D000700:Analgesics / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D003198:Computer Simulation; D015507:Drugs, Investigational / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D004569:Electroencephalography / Q000187:drug effects; D005283:Fentanyl / Q000493:pharmacokinetics; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D010880:Piperidines / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D012016:Reference Values; D013777:Tetrazoles / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology
D000700:Analgesics; D015507:Drugs, Investigational; D010880:Piperidines; D013777:Tetrazoles; D015760:Alfentanil; C080498:trefentanil; D005283:Fentanyl