The objective of this study was to characterize the pharmacokinetic/pharmacodynamic (PK/PD) relationship of buprenorphine and fentanyl for the respiratory depressant effect in healthy volunteers. Data on the time course of the ventilatory response at a fixed P_ETCO₂ of 50 mm Hg and P_ETO₂ of 110 mm Hg following intravenous administration of buprenorphine and fentanyl were obtained from two phase I studies (50 volunteers received buprenorphine: 0.05–0.6 mg/70 kg and 24 volunteers received fentanyl: 0.075–0.5 mg/70 kg). The PK/PD correlations were analyzed using nonlinear mixed effects modeling. A two‐ and three‐compartment pharmacokinetic model characterized the time course of fentanyl and buprenorphine concentration, respectively. Three structurally different PK/PD models were evaluated for their appropriateness to describe the time course of respiratory depression: (1) a biophase distribution model with a fractional sigmoid E_max pharmacodynamic model, (2) a receptor association/dissociation model with a linear transduction function, and (3) a combined biophase distribution‐receptor association/dissociation model with a linear transduction function. The results show that for fentanyl hysteresis is entirely determined by the biophase distribution kinetics, whereas for buprenorphine hysteresis is caused by a combination of biophase distribution kinetics and receptor association/dissociation kinetics. The half‐time values of biophase equilibration were 16.4 and 75.3 min for fentanyl and buprenorphine, respectively. In addition, for buprenorphine, the value of k_on was 0.246 ml/ng/min and the value of k_off was 0.0102 min⁻¹. The concentration–effect relationship of buprenorphine was characterized by a ceiling effect at higher concentrations (intrinsic activity α=0.56, 95% confidence interval (CI): 0.50–0.62), whereas fentanyl displayed full respiratory depressant effect (α=0.91, 95% CI: 0.19–1.62).

Clinical Pharmacology & Therapeutics (2007) 81, 50–58. doi:10.1038/sj.clpt.6100025