Mechanism-based Pharmacokinetic–Pharmacodynamic Modeling of the Antinociceptive Effect of Buprenorphine in Healthy Volunteers

Background The objective of this investigation was to characterize the pharmacokinetic-pharmacodynamic relation of buprenorphine's antinociceptive effect in healthy volunteers. Methods Data on the time course of the antinociceptive effect after intravenous administration of 0.05-0.6 mg/70 kg buprenorphine in healthy volunteers was analyzed in conjunction with plasma concentrations by nonlinear mixed-effects analysis. Results A three-compartment pharmacokinetic model best described the concentration time course. Four structurally different pharmacokinetic-pharmacodynamic models were evaluated for their appropriateness to describe the time course of buprenorphine's antinociceptive effect: (1) E(max) model with an effect compartment model, (2) "power" model with an effect compartment model, (3) receptor association-dissociation model with a linear transduction function, and (4) combined biophase equilibration/receptor association-dissociation model with a linear transduction function. The latter pharmacokinetic-pharmacodynamic model described the time course of effect best and was used to explain time dependencies in buprenorphine's pharmacodynamics. The model converged, yielding precise estimation of the parameters characterizing hysteresis and the relation between relative receptor occupancy and antinociceptive effect. The rate constant describing biophase equilibration (k(eo)) was 0.00447 min(-1) (95% confidence interval, 0.00299-0.00595 min(-1)). The receptor dissociation rate constant (k(off)) was 0.0785 min(-1) (95% confidence interval, 0.0352-0.122 min(-1)), and k(on) was 0.0631 ml . ng(-1) . min(-1) (95% confidence interval, 0.0390-0.0872 ml . ng(-1) . min(-1)). Conclusion This is consistent with observations in rats, suggesting that the rate-limiting step in the onset and offset of the antinociceptive effect is biophase distribution rather than slow receptor association-dissociation. In the dose range studied, no saturation of receptor occupancy occurred explaining the lack of a ceiling effect for antinociception.

Pharmacokinetic-Pharmacodynamic Modeling of the Electroencephalogram Effect of Norfloxacin in Rats

ABSTRACT A previously developed pharmacokinetic-pharmacodynamic (PK-PD) modeling approach was used to investigate the epileptogenic activity of norfloxacin as a representative antibiotic with concentration-dependent antimicrobial activity. Rats received an intravenous infusion of norfloxacin at a rate of 5 mg kg of body weight−1 min−1 over 30 min. Blood samples were collected for drug assay, and an electroencephalogram (EEG) was recorded during infusion and postinfusion. An important delay was observed between concentrations of norfloxacin in plasma and the EEG effect. Indirect effect models failed to describe these data, which were successfully fitted by using an effect compartment model with a spline function to describe the relationship between effect and concentration at the effect site, as previously observed with imipenem. The robustness of the PK-PD model was then assessed by keeping the dose constant but increasing the duration of infusion to 120 and 240 min. Although this was accompanied by PK modifications, PD parameters did not vary significantly, and the PK-PD model still applied. In conclusion, the successful PK-PD modeling of the norfloxacin EEG effect in rats should be considered to predict and reduce the epileptogenic risk associated with this antibiotic as a representative fluoroquinolone (E. Fuseau and L. B. Sheiner, Clin. Pharmacol. Ther. 35:733-741, 1984).

Pharmacokinetic-Pharmacodynamic Modeling of the Electroencephalogram Effect of Imipenem in Healthy Rats

ABSTRACT A pharmacokinetic-pharmacodynamic (PK-PD) modeling approach was developed to investigate the epileptogenic activity of imipenem in rats. Initially, animals received an intravenous infusion of imipenem at a rate of 2.65 mg min−1 for 30 min. Blood samples were collected for drug assay, and an electroencephalogram (EEG) was recorded during infusion and postinfusion. A dramatic delay was observed between concentrations of imipenem in serum and the EEG effect; this effect was accompanied by tremors and partial seizures. Indirect-effect models failed to describe these data, which were successfully fitted using an effect compartment model. The relationship between effect and concentration at the effect site was best described by a spline function. The elimination rate constant from the effect compartment was severalfold lower than that from the central compartment. The robustness of the model was then confirmed after administering the imipenem dose over 60 and 90 min. In conclusion, the successful PK-PD modeling of the imipenem EEG effect in rats constitutes a major improvement for better prediction of the epileptogenic risk associated with this antibiotic.