Case Study 1 Preclinical Pharmacokinetic Pharmacodynamic Modeling of the Respiratory Depressant Effect of Norbuprenorphine in Rats

The objective of this investigation was to characterize the PK/PD correlation of buprenorphine's active metabolite norbuprenorphine for the effect on respiration in rats - 25] . Following intravenous administration, the time course of plasma concentrations of buprenorphine and norbuprenorphine were determined in conjunction with the effect on ventilation as determined using plethysmography, a test used to measure changes in air volume. The PK of norbuprenorphine was best described by a three-compartment PK model with nonlinear elimination. A saturable biophase distribution model with a power PD model described the PK/PD relationship best as presented in Figure 4.

No saturation of the effect at high concentrations was observed, indicating that norbuprenorphine acted as a full agonist with regard to respiratory depression. By simulation, it was shown that following intravenous administration of buprenorphine, the concentrations of norbuprenorphine reached values that were well below the values causing an effect on respiration. In

Dose

Dose

Figure 4 PK/PD model for respiratory depressant effect of norbuprenorphine and norbuprenorphine. (From ref. 25, by permission of the American Society for Pharmacology and Experimental Therapeutics.)

conclusion, the PD of the metabolite norbuprenorphine was determined to be markedly different from the PD of the parent compound buprenorphine with regard to the receptor association-dissociation kinetics, the in vivo potency, and the intrinsic efficacy for the respiratory depressant effect. The values of these norbuprenorphine concentrations are well below values causing an effect on respiration. Therefore, it was concluded norbuprenorphine does not contribute to the overall respiratory depressant effect of buprenorphine. These results were consistent with the experience from clinical use of buprenor-phine in patients.

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Project Management Made Easy

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