David J. Hermann

Influence of age and gender on the pharmacokinetics and pharmacodynamics of remifentanil I. Model development

BackgroundPrevious studies have reported conflicting results concerning the influence of age and gender on the pharmacokinetics and pharmacodynamics of fentanyl, alfentanil, and sufentanil. The aim of this study was to determine the influence of age and gender on the pharmacokinetics and pharmacodyn

The Pharmacokinetics of the New Short-acting Opioid Remifentanil (gi87084b) in Healthy Adult Male Volunteers

BackgroundRemifentanil (GI87084B) is a new short-acting opioid with a unique ester structure. Metabolism of remifentanil by ester hydrolysis results in very rapid elimination. The aim of this study was to characterize in detail the pharmacokinetic profile of remifentanil in healthy male volunteers. MethodsTen healthy adult male volunteers received a zero-order infusion of remifentanil at doses ranging from 1 to 8 μg · kg-1 · min-1 for 20 min. Frequent arterial blood samples were drawn and analyzed by gas chromatographic mass spectroscopy to determine the remifentanil blood concentrations. The raw pharmacokinetic data were analyzed using three different parametric compartmental modeling methods (traditional two-stage, naive pooled data, and NONMEM). The raw pharmacokinetic data also were analyzed using numeric deconvolution and a nonparametric moment technique. A computer simulation using the pharmacokinetic parameters of the NONMEM compartmental model was performed to provide a more intuitively meaningful and clinically relevant description of the pharmacokinetics. The simulation estimated the time necessary to achieve a 50% decrease in remifentanil concentration after a variable-length infusion. ResultsFor each parametric method, a three-compartment mamillary model that accurately describes remifentanils concentration decay curve was constructed. The NONMEM analysis population pharmacokinetic parameters included a central clearance of 2.8 1/min, a volume of distribution at steady state of 32.8 1, and a terminal half-life of 48 min. The mean results of the nonparametric moment analysis included a clearance of 2.9 1/min, a volume of distribution at steady state of 31.8 1, and a mean residence time of 10.9 min. The computer simulation revealed the strikingly unique pharmacokinetic profile of remifentanil compared to that of the currently available fentanyl family of opioids. ConclusionsRemifentanil is a new, short-acting opioid with promising clinical potential in anesthesiology.

Remifentanil versus alfentanil : Comparative pharmacokinetics and pharmacodynamics in healthy adult male volunteers

Background Remifentanil is an esterase-metabolized opioid with a rapid clearance. The aim of this study was to contrast the pharmacokinetics and pharmacodynamics of remifentanil and alfentanil in healthy, adult male volunteers. Methods Ten volunteers received infusions of remifentanil and alfentanil on separate study sessions using a randomized, open-label crossover design. Arterial blood samples were analyzed to determine drug blood concentrations. The electroencephalogram was employed as the measure of drug effect. The pharmacokinetics were characterized using a moment analysis, a nonlinear mixed effects model (NONMEM) population analysis, and context-sensitive half-time computer simulations. After processing the raw electroencephalogram to obtain the spectral edge parameter, the pharmacodynamics were characterized using an effect compartment, inhibitory maximum effect model. Results Pharmacokinetically, the two drugs are similar in terms of steady-state distribution volume (VDss), but remifentanils central clearance (CLc) is substantially greater. The NONMEM analysis population pharmacokinetic parameters for remifentanil include a CLc of 2.9 l *symbol* min sup -1, a VDss of 21.81, and a terminal half-life of 35.1 min. Corresponding NONMEM parameters for alfentanil are 0.36 l *symbol* min sup -1, 34.11, and 94.5 min. Pharmacodynamically, the drugs are similar in terms of the time required for equilibration between blood and the effect-site concentrations, as evidenced by a T12 Ke0 for remifentanil of 1.6 min and 0.96 min for alfentanil. However, remifentanil is 19 times more potent than alfentanil, with an effective concentration for 50% maximal effect of 19.9 ng *symbol* ml sup -1 versus 375.9 ng *symbol* ml sup -1 for alfentanil. Conclusions Compared to alfentanil, the high clearance of remifentanil, combined with its small steady-state distribution volume, results in a rapid decline in blood concentration after termination of an infusion. With the exception of remifentanils nearly 20-times greater potency (30-times if alfentanil partitioning between whole blood and plasma is considered), the drugs are pharmacodynamically similar.

Measured Context-sensitive Half-times of Remifentanil and Alfentanil

BackgroundThe context-sensitive half-time, rather than the terminal elimination half-life, has been proposed as a more clinically relevant measure of decreasing drug concentration after a constant infusion of a given duration. The context-sensitive half-time is derived from computer modelling using

Influence of arteriovenous sampling on remifentanil pharmacokinetics and pharmacodynamics

Remifentanil is a new, short‐acting, rapidly metabolized opioid. Because remifentanil is metabolized in blood and tissues by nonspecific esterases, there is a substantial difference between arterial and venous remifentanil concentrations. This difference may greatly affect the estimation of pharmacokinetic and pharmacodynamic parameters.

The electroencephalogram (EEG)and clinical measures of opioid potency: defining the EEG-clinical potency relationship (‘fingerprint’) with application to remifentanil

SummaryBackgroundThe processed electroencephalogram (EEG) is a useful surrogate effect measure in estimating opioid potency and latency to peak effect. However, the relationship between EEG determined potency and clinical measures of potency is unclear. The aim of this study was to characterize the relationship between EEG potency and clinical therapeutic windows for fentanyl, alfentanil and sufentanil and then apply this relationship to the new opioid remifentanil.MethodsThe fentanyl congener literature published since 1980 was reviewed in detail. Articles reporting EEG or clinically based concentration-effect relationships were analyzed. The relationship between the EEG potency and clinical measures of potency was examined for consistency and proportionality for all the fentanyl congeners. A generalized ‘fingerprint’ of this relationship was established. This fingerprint was then used to predict clinical therapeutic windows for the new opioid remifentanil. These predicted concentrations were compared to those actually measured in clinical trials.ResultsThe processed EEG is a reproducible measure of profound opioid effect. Therapeutic windows of the fentanyl congeners estimated in clinical studies relate to the EEG measure of potency in a reproducible, proportional way; that is, clinically determined therapeutic concentration ranges for specific surgical stimuli or drug synergism are a relatively constant fraction of the plasma concentration required to produce 50% of the maximal EEG effect (EC50) for all the fentanyl congeners. The generalized model of this relationship between EEG potency and clinical measures of potency based on data for alfentanil accurately predicted the remifentanil therapeutic windows estimated in clinical studies.ConclusionsThe processed EEG is a useful surrogate measure of opioid effect. In addition to estimating potency and latency to peak effect, the EEG surrogate can also be used to estimate the therapeutic concentrations required for a variety of surgical endpoints. Thus, a single combined pharmacokinetic-pharmacodynamic EEG modeling study can yield not only information about potency and latency to peak effect but can also be used to predict the clinical pharmacodynamics of a novel opioid (as was the case in the remifentanil development program). This information can be useful in guiding a novel opioid development program, improving the efficiency of the overall development process.

Influence of Age and Gender on the Pharmacokinetics and Pharmacodynamics of Remifentanil: I. Model Development

Background Previous studies have reported conflicting results concerning the influence of age and gender on the pharmacokinetics and pharmacodynamics of fentanyl, alfentanil, and sufentanil. The aim of this study was to determine the influence of age and gender on the pharmacokinetics and pharmacodynamics of the new short‐acting opioid remifentanil. Methods Sixty‐five healthy adults (38 men and 27 women) ages 20 to 85 y received remifentanil by constant‐rate infusion of 1 to 8 micro gram [centered dot] kg sup ‐1 [centered dot] min sup ‐1 for 4 to 20 min. Frequent arterial blood samples were drawn and assayed for remifentanil concentration. The electroencephalogram was used as a measure of drug effect. Population pharmacokinetic and pharmacodynamic modeling was performed using the software package NONMEM. The influence of volunteer covariates were analyzed using a generalized additive model. The performances of the simple (without covariates) and complex (with covariates) models were evaluated prospectively in an additional 15 healthy participants ages 41 to 84 y. Results The parameters for the simple three‐compartment pharmacokinetic model were V1 = 4.98 l, V2 = 9.01 l, V3 = 6.54 l, Cl1 = 2.46 l/min, Cl2 = 1.69 l/min, and Cl3 = 0.065 l/min. Age and lean body mass were significant covariates. From the ages of 20 to 85 y, V1 and Cl1 decreased by approximately 25% and 33%, respectively. The parameters for the simple sigmoid Emax pharmacodynamic model were ke0 = 0.516 min sup ‐1, E0 = 20 Hz, Emax = 5.62 Hz, EC50 = 11.2 ng/ml, and gamma = 2.51. Age was a significant covariate of EC50 and ke0, with both decreasing by approximately 50% for the age range studied. The complex pharmacokinetic‐pharmacodynamic model performed better than did the simple model when applied prospectively. Conclusions This study identified (1) an effect of age on the pharmacokinetics and pharmacodynamics of remifentanil; (2) an effect of lean body mass on the pharmacokinetic parameters; and (3) no influence of gender on any pharmacokinetic or pharmacodynamic parameter.

Measured Context-Sensitive Half-Times of Remifentanil and Alfentanil

Background The context‐sensitive half‐time, rather than the terminal elimination half‐life, has been proposed as a more clinically relevant measure of decreasing drug concentration after a constant infusion of a given duration. The context‐sensitive half‐time is derived from computer modelling using known pharmacokinetic parameters. The modelled context‐sensitive half‐time for a 3‐h infusion of alfentanil is 50–55 min and is 3 min for remifentanil. The terminal elimination half‐life is 111 min for alfentanil and 12–30 min for remifentanil. It has not been tested whether the modelled context‐sensitive half‐time reflects the true time for a 50% decrease in drug concentration or drug effect.