title: Mechanism-based PK/PD modeling of the respiratory depressant effect of buprenorphine and fentanyl in healthy volunteers.
abstract: 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(ET)CO(2) of 50 mm Hg and P(ET)O(2) 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 (t(1/2, k(eo))) 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 alpha=0.56, 95% confidence interval (CI): 0.50-0.62), whereas fentanyl displayed full respiratory depressant effect (alpha=0.91, 95% CI: 0.19-1.62).
authors.affiliation: Department of Pharmacology, Leiden/Amsterdam Center for Drug Research, Leiden, The Netherlands.
authors.forename: A
authors.initials: A
authors.lastname: Yassen
authors.forename: E
authors.initials: E
authors.lastname: Olofsen
authors.forename: R
authors.initials: R
authors.lastname: Romberg
authors.forename: E
authors.initials: E
authors.lastname: Sarton
authors.forename: L
authors.initials: L
authors.lastname: Teppema
authors.forename: M
authors.initials: M
authors.lastname: Danhof
authors.forename: A
authors.initials: A
authors.lastname: Dahan
mesh_terms: D000328:Adult; D000701:Analgesics, Opioid / Q000009:adverse effects* / Q000493:pharmacokinetics*; D002047:Buprenorphine / Q000009:adverse effects* / Q000493:pharmacokinetics*; D004311:Double-Blind Method; D005260:Female; D005283:Fentanyl / Q000009:adverse effects* / Q000493:pharmacokinetics*; D006207:Half-Life; D006801:Humans; D008297:Male; D008657:Metabolic Clearance Rate; D008954:Models, Biological; D012131:Respiratory Insufficiency / Q000139:chemically induced*
chemical_list: D000701:Analgesics, Opioid; D002047:Buprenorphine; D005283:Fentanyl