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 threeand 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.

The objective of this investigation was to characterize the pharmacokinetic-pharmacodynamic (PK-PD) correlation of buprenorphine's active metabolite norbuprenorphine for the effect on respiration in rats. Following i.v. administration in rats (dose range 0.32-1.848 mg), the time course of the concentration in plasma was determined in conjunction with the effect in ventilation as determined with a novel whole-body plethysmography technique. 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. No saturation of the effect at high concentrations was observed, indicating that norbuprenorphine acts as a full agonist with regard to respiratory depression. Moreover, analysis of the hysteresis based on the combined receptor association-dissociation biophase distribution model yielded high values of the rate constants for receptor association and dissociation, indicating that these processes are not rate-limiting. In a separate analysis, the time course of the plasma concentrations of buprenorphine and norbuprenorphine following administration of both the parent drug and the metabolite were simultaneously analyzed based on a six-compartment PK model with nonlinear elimination of norbuprenorphine. This analysis showed that following i.v. administration, 10% of the administered dose of buprenorphine is converted into norbuprenorphine. By simulation it is shown that following i.v. administration of buprenorphine, the concentrations of norbuprenorphine reach values that are well below the values causing an effect on respiration.Recently, the pharmacokinetic-pharmacodynamic (PK-PD) relationship of buprenorphine for the effect on the respiratory response has been studied in rats and humans (Yassen et al., 2007). In these investigations, buprenorphine has been shown to display ceiling of the respiratory depressant effect, indicating that buprenorphine acts functionally as a partial agonist at the -opioid receptor. The in vivo behavior correlates well with data obtained from in vitro receptor binding assays (Martin et al., 1976;Lee et al., 1999;Lutfy et al., 2003). Clearly, partial agonistic activity for respiratory depression contributes to the safety profile on buprenorphine administration even at high doses .In the previous investigations, the observed hysteresis between plasma concentration and effect has in part been explained by slow receptor association and dissociation kinetics at the -opioid receptor. This pharmacological characteristic is unique for buprenorphine and is not shared by other opiates like morphine and fentanyl (Cowan et al., 1977;Boas and Villiger, 1985). The slow receptor association-dissociation kinetics may be a complicating factor in the reversal of buprenorphine-induced respiratory depression with naloxone. Furthermore, buprenorphine was shown to bind with high affinity to the -opioid receptor. Specifically, the estimate of the equilibrium d...

The purpose of this investigation was to develop a mechanismbased pharmacokinetic/pharmacodynamic (PK/PD) model to predict the time course of respiratory depression following administration of opioids in rats. The proposed model is based on receptor theory and aims at the separate characterization of biophase distribution and receptor association/dissociation kinetics as determinants of hysteresis between plasma concentration and effect. Individual concentration time courses of buprenorphine and fentanyl were determined in conjunction with continuous monitoring of respiratory depression. Buprenorphine and fentanyl were administered intravenously in various doses. For buprenorphine hysteresis was best described by a combined biophase distribution-receptor association/dissociation model with a linear transducer function. The values of the parameter estimates of the rate constants for biophase distribution (k eo ), receptor association (k on ), and dissociation (k off ) were 0.0348 min Ϫ1 [95% confidence interval (CI), 0.0193-0.0503 min Ϫ1 ], 0.57 ml/ng/min (95% CI, 0.38 -0.76 ml/ng/min), and 0.0903 min Ϫ1 (95% CI, 0.035-0.196 min Ϫ1 ), respectively. The values of the equilibrium dissociation constant and intrinsic activity were 0.16 ng/ml and 0.48 (95% CI, 0.45-0.51), respectively. The value of the K d is close to reported estimates of receptor affinity in vitro confirming the validity of the mechanism-based PK/PD model. For fentanyl, unrealistically high estimates of the rate constants for receptor association and dissociation were obtained, indicating that hysteresis is caused solely by biophase distribution kinetics. This is consistent with fentanyl's fast receptor association/ dissociation kinetics in vitro. As a result, the mechanism-based PK/PD model of fentanyl could be reduced to a biophase distribution model with fractional sigmoid E max pharmacodynamic model.

The different values of the drug-specific pharmacodynamic parameters are consistent with the different opioid mu receptor subtypes involved in the antinociceptive and respiratory depressant effects.

The development of rapid and sensitive bioanalytical methods in a short time frame with acceptable levels of precision and accuracy is imperative for successful drug discovery. We previously reported that the use of a mobile phase containing an extremely low concentration of ammonium formate or formic acid increased analyte electrospray ionization (ESI) response and controlled against matrix effects. We designated these favorable effects 'LC-electrolyte effects'. In order to support rapid pharmacokinetic (PK) studies for drug discovery, we applied LC-electrolyte effects to the development of generic procedures that can be used to quickly generate reliable PK data for compound candidates. We herein demonstrate our approach using four model tested compounds (Compd-A, -B, -C, and -D). The analytical methods involve generic protein precipitation for sample clean-up, followed by application of fast liquid chromatographic (LC) gradients and the subsequent use of electrospray ionization tandem mass spectrometry (ESI-MS/MS) for individual measurement of the tested compounds in 20-microL plasma samples. Good linearity over the concentration range of 1.6 or 8-25000 ng/mL (r(2) > 0.99), precision (RSD, 0.45-13.1%), and accuracy (91-112%) were achieved through the use of a low dose of formic acid (0.4 mM or 0.015 per thousand) in the methanol/water-based LC mobile phase. The analytical method was quite sensitive, providing a lower limit of quantification of 1.6 pg on-column except for Compd-C (8 pg), and showed negligible ion suppression caused by matrix components. Finally, the assay suitability was demonstrated in simulated discovery PK studies of the tested compounds with i.v./p.o. dosing of rats. This new assay approach has been adopted with good results in our laboratory for many recent discovery PK studies.