Pharmacokinetic-pharmacodynamic modeling of the effectiveness and safety of buprenorphine and fentanyl in rats.
OBJECTIVE
Respiratory depression is a serious and potentially life-threatening side-effect of opioid therapy. The objective of this investigation was to characterize the relationship between buprenorphine or fentanyl exposure and the effectiveness and safety outcome in rats.


METHODS
Data on the time course of the antinociceptive and respiratory depressant effect were analyzed on the basis of population logistic regression PK-PD models using non-linear mixed effects modeling software (NONMEM). The pharmacokinetics of buprenorphine and fentanyl were described by a three- and two-compartment model, respectively. A logistic regression model (linear logit model) was used to characterize the relationship between drug exposure and the binary effectiveness and safety outcome.


RESULTS
For buprenorphine, the odds ratios (OR) were 28.5 (95% CI, 6.9-50.1) and 2.10 (95% CI, 0.71-3.49) for the antinociceptive and respiratory depressant effect, respectively. For fentanyl these odds ratios were 3.03 (95% CI, 1.87-4.21) and 2.54 (95% CI, 1.26-3.82), respectively.


CONCLUSIONS
The calculated safety index (OR(antinociception)/OR(respiratory depression)) for fentanyl of 1.20 suggests that fentanyl has a low safety margin, implicating that fentanyl needs to be titrated with caution. For buprenorphine the safety index is 13.54 suggesting that buprenorphine is a relatively safe opioid.
Yassen
Ashraf
A
Division of Pharmacology, Gorlaeus Laboratories, Leiden/Amsterdam Center for Drug Research, Leiden, The Netherlands.
Olofsen
Erik
E
Kan
Jingmin
J
Dahan
Albert
A
Danhof
Meindert
M
D000465:Algorithms; D000818:Animals; D002047:Buprenorphine / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology*; D003864:Depression, Chemical; D005283:Fentanyl / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology*; D016014:Linear Models; D016015:Logistic Models; D008297:Male; D015233:Models, Statistical; D009292:Narcotic Antagonists / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology*; D016017:Odds Ratio; D010147:Pain Measurement / Q000187:drug effects; D010993:Plethysmography, Whole Body; D051381:Rats; D017208:Rats, Wistar; D012044:Regression Analysis; D012129:Respiratory Function Tests; D015656:Respiratory Mechanics / Q000187:drug effects
D009292:Narcotic Antagonists; D002047:Buprenorphine; D005283:Fentanyl