Pharmacokinetic-pharmacodynamic modeling of the effectiveness and safety of buprenorphine and fentanyl in rats.

ABSTRACT: 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. CONCLUSION: 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.

SUBMITTER: Yassen A 

PROVIDER: S-EPMC2190336 | biostudies-other | 2008 Jan

REPOSITORIES: biostudies-other