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.

• Authors: Ashraf Yassen, Erik Olofsen, Jingmin Kan, Albert Dahan, Meindert Danhof
• Journal: Pharmaceutical research (Pharm Res) Vol. 25 Issue 1 Pg. 183-93 (Jan 2008) ISSN: 0724-8741 [Print] United States
• PMID: 17914664 (Publication Type: Journal Article)

Chemical References

• Narcotic Antagonists
• Buprenorphine
• Fentanyl

Topics

• Algorithms
• Animals
• Buprenorphine (adverse effects, pharmacokinetics, pharmacology)
• Depression, Chemical
• Fentanyl (adverse effects, pharmacokinetics, pharmacology)
• Linear Models
• Logistic Models
• Male
• Models, Statistical
• Narcotic Antagonists (adverse effects, pharmacokinetics, pharmacology)
• Odds Ratio
• Pain Measurement (drug effects)
• Plethysmography, Whole Body
• Rats
• Rats, Wistar
• Regression Analysis
• Respiratory Function Tests
• Respiratory Mechanics (drug effects)