Steven L. Shafer

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 influence of method of administration and covariates on the pharmacokinetics of propofol in adult volunteers.

Background Unresolved issues with propofol include whether the pharmacokinetics are linear with dose, are influenced by method of administration (bolus vs. infusion), or are influenced by age. Recently, a new formulation of propofol emulsion, containing disodium edetate (EDTA), was introduced in the United States. Addition of EDTA was found by the manufacturer to significantly reduce bacterial growth. This study investigated the influences of method of administration, infusion rate, patient covariates, and EDTA on the pharmacokinetics of propofol. Methods Twenty‐four healthy volunteers aged 26–81 yr were given a bolus dose of propofol, followed 1 h later by a 60‐min infusion. Each volunteer was randomly assigned to an infusion rate of 25, 50, 100, or 200 micro gram [center dot] kg‐1 [center dot] min‐1. Each volunteer was studied twice under otherwise identical circumstances: once receiving propofol without EDTA and once receiving propofol with EDTA. The influence of the method of administration and of the volunteer covariates was explored by fitting a three‐compartment mamillary model to the data. The influence of EDTA was investigated by direct comparison of the measured concentrations in both sessions. Results The concentrations of propofol with and without EDTA were not significantly different. The concentration measurements after the bolus dose were significantly underpredicted by the parameters obtained just from the infusion data. The kinetics of propofol were linear within the infusion range of 25–200 micro gram [center dot] kg‐1 [center dot] min‐1. Age was a significant covariate for Volume2 and Clearance2, as were weight, height, and lean body mass for the metabolic clearance. Conclusions These results demonstrate that method of administration (bolus vs. infusion), but not EDTA, influences the pharmacokinetics of propofol. Within the clinically relevant range, the kinetics of propofol during infusions are linear regarding infusion rate.

The Influence of Age on Propofol Pharmacodynamics

BACKGROUND The authors studied the influence of age on the pharmacodynamics of propofol, including characterization of the relation between plasma concentration and the time course of drug effect. METHODS The authors evaluated healthy volunteers aged 25-81 yr. A bolus dose (2 mg/kg or 1 mg/kg in persons older than 65 yr) and an infusion (25, 50, 100, or 200 microg x kg(-1) x min(-1)) of the older or the new (containing EDTA) formulation of propofol were given on each of two different study days. The propofol concentration was determined in frequent arterial samples. The electroencephalogram (EEG) was used to measure drug effect. A statistical technique called semilinear canonical correlation was used to select components of the EEG power spectrum that correlated optimally with the effect-site concentration. The effect-site concentration was related to drug effect with a biphasic pharmacodynamic model. The plasma effect-site equilibration rate constant was estimated parametrically. Estimates of this rate constant were validated by comparing the predicted time of peak effect with the time of peak EEG effect. The probability of being asleep, as a function of age, was determined from steady state concentrations after 60 min of propofol infusion. RESULTS Twenty-four volunteers completed the study. Three parameters of the biphasic pharmacodynamic model were correlated linearly with age. The plasma effect-site equilibration rate constant was 0.456 min(-1). The predicted time to peak effect after bolus injection ranging was 1.7 min. The time to peak effect assessed visually was 1.6 min (range, 1-2.4 min). The steady state observations showed increasing sensitivity to propofol in elderly patients, with C50 values for loss of consciousness of 2.35, 1.8, and 1.25 microg/ml in volunteers who were 25, 50, and 75 yr old, respectively. CONCLUSIONS Semilinear canonical correlation defined a new measure of propofol effect on the EEG, the canonical univariate parameter for propofol. Using this parameter, propofol plasma effect-site equilibration is faster than previously reported. This fast onset was confirmed by inspection of the EEG data. Elderly patients are more sensitive to the hypnotic and EEG effects of propofol than are younger persons.

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.

Pharmacokinetics, Pharmacodynamics, and Rational Opioid Selection

Fentanyl, alfentanil, and sufentanil have important pharmacokinetic and pharmacodynamic differences. Selecting one of these opioid analgesics as an adjunct to general anesthesia requires appreciation of the relationship between the pharmacokinetic and pharmacodynamic characteristics of these drugs and the onset of and recovery from drug effect. Using a pharmacokinetic-pharmacodynamic model, the authors simulated the decrease in plasma fentanyl, alfentanil, and sufentanil concentration after intravenous administration by either bolus injection, brief infusion, or prolonged infusion. The percentage change in concentration, rather than absolute concentration, was simulated to permit comparison of the relative opioid concentration independently of drug potency. These computer simulations quantified the relationship between infusion duration and the time required for recovery after termination of the infusion. The analysis suggests that alfentanil is best used for operations longer than 6-8 h when a rapid decrease in effect site (i.e., biophase) opioid concentration is desired after discontinuation of the infusion. Alfentanil may also be the most appropriate drug to provide a transient peak effect after a single bolus. Although sufentanil has longer distribution and elimination half-lives than alfentanil, recovery from sufentanil infusions may be more rapid than recovery from alfentanil infusions for operations shorter than 6-8 h. These computer simulations demonstrate that simply comparing pharmacokinetic parameters (e.g., half-lives) of different drugs will not predict the relative rates of decrease in effect site concentrations after either an intravenous bolus or a continuous infusion.

Pharmacokinetics and Pharmacodynamics of Remifentanil: Ii. Model Application

Background The pharmacokinetics and pharmacodynamics of remifentanil were studied in 65 healthy volunteers using the electroencephalogram (EEG) to measure the opioid effect. [1] In a companion article, the authors developed complex population pharmacokinetic and pharmacodynamic models that incorporated age and lean body mass (LBM) as significant covariates and characterized intersubject pharmacokinetic and pharmacodynamic variability. In the present article, the authors determined whether remifentanil dosing should be adjusted according to age and LBM, or whether these covariate effects were overshadowed by the interindividual variability present in the pharmacokinetics and pharmacodynamics. Methods Based on the typical pharmacokinetic and pharmacodynamic parameters, nomograms for bolus dose and infusion rates at each age and LBM were derived. Three populations of 500 individuals each, ages 20, 50, and 80 yr, were simulated base on the interindividual variances in model parameters as estimated by the NONMEM software package. The peak EEG effect in response to a bolus, the steady‐state EEG effect in response to an infusion, and the time course of drug effect were examined in each of the three populations. Simulations were performed to examine the time necessary to achieve a 20%, 50%, and 80% decrease in remifentanil effect site concentration after a variable‐length infusion. The variability in the time for a 50% decrease in effect site concentrations was examined in each of the three simulated populations. Titratability using a constant‐rate infusion was also examined. Results After a bolus dose, the age‐related changes in V1 and ke0 nearly offset each other. The peak effect site concentration reached after a bolus dose does not depend on age. However, the peak effect site concentration occurs later in elderly individuals. Because the EEG shows increased brain sensitivity to opioids with increasing age, an 80‐yr‐old person required approximately one half the bolus dose of a 20‐yr old of similar LBM to reach the same peak EEG effect. Failure to adjust the bolus dose for age resulted in a more rapid onset of EEG effect and prolonged duration of EEG effect in the simulated elderly population. The infusion rate required to maintain 50% EEG effect in a typical 80‐yr‐old is approximately one third that required in a typical 20‐yr‐old. Failure to adjust the infusion rate for age resulted in a more rapid onset of EEG effect and more profound steady‐state EEG effect in the simulated elderly population. The typical times required for remifentanil effect site concentrations to decrease by 20%, 50%, and 80% after prolonged administration are rapid and little affected by age or duration of infusion. These simulations suggest that the time required for a decrease in effect site concentrations will be more variable in the elderly. As a result, elderly patients may occasionally have a slower emergence from anesthesia than expected. A step change in the remifentanil infusion rate resulted in a rapid and predictable change of EEG effect in both the young and the elderly. Conclusions Based on the EEG model, age and LBM are significant demographic factors that must be considered when determining a dosage regimen for remifentanil. This remains true even when interindividual pharmacokinetic and pharmacodynamic variability are incorporated in the analysis.

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.

Pharmacokinetics and pharmacodynamics of propofol infusions during general anesthesia

The pharmacokinetic and pharmacodynamic properties of propofol were studied in 50 surgical patients. Propofol was administered as a bolus dose, 2 mg/kg iv, followed by a variable-rate infusion, 0–20 mg/min, and intermittent supplemental boluses, 10–20 mg iv, as part of a general anesthetic technique that included nitrous oxide, meperidine, and muscle relaxants. For a majority of the patients (n = 30), the pharmacokinetics of propofol were best described by a two-compartment model. The propofol mean total body clearance rate was 2.09 ± 0.65 1/min (mean · SD), the volume of distribution at steady state was 159 ± 57 I, and the elimination half-life was 116 ± 34 min. Elderly patients (patients older than 60 yr vs. those younger than 60 yr) had significantly decreased clearance rates (1.58 ± 0.42 vs. 2.19 ± 0.64 1/min), whereas women (vs. men) had greater clearance rates (33 ± 8 vs. 26 ± 7 1 · kg−1 · min−1) and volumes of distribution (2.50 ± 0.81 vs. 2.05 ± 0.65 1/kg). Patients undergoing major (intraabdominal) surgery had longer elimination half-life values (136 ± 40 vs. 108 ± 29 min). Patients required an average blood propofol concentration of 4.05 ± 1.01 μg/ml for major surgery and 2.97 ± 1.07 μg/ml for nonmajor surgery. Blood propofol concentrations at which 50% of patients (EC50) were awake and oriented after surgery were 1.07 and 0.95 μg/ml, respectively. Psychomotor performance returned to baseline at blood propofol concentrations of 0.38–0.43 μg/ml (EC50). This clinical study demonstrates the feasibility of performing pharmacokinetic and pharmacodynamic analyses when complex infusion and bolus regimens are used for administering iv anesthetics.

Measuring the predictive performance of computer-controlled infusion pumps

Current measures of the performance of computer-controlled infusion pumps (CCIPs) are poorly defined, of little use to the clinician using the CCIP, and pharmacostatistically incorrect. We propose four measures be used to quantitate the performance of CCIPs: median absolute performance error (MDAPE), median performance error (MDPE), divergence, and wobble. These measures offer several significant advantages over previous measures. First, their definitions are based on the performance error as a fraction of the predicted (rather than measured) drug concentration, making the measures much more useful to the clinician. Second, the measures are defined in a way that addresses the pharmacostatistical issue of appropriate estimation of population parameters. Finally, the measure of inaccuracy, MDAPE, is defined in a way that is consistent with iteratively reweighted least squares nonlinear regression, a commonly used method of estimating pharmacokinetic parameters. These measures make it possible to quantitate the overall performance of a CCIP or to compare the predictive performance of CCIPs which differ in either general approach (e.g., compartmental model driven vs. plasma efflux approach), pump mechanics, software algorithms, or pharmacokinetic parameter sets.

Response surface model for anesthetic drug interactions

Background Anesthetic drug interactions traditionally have been characterized using isobolographic analysis or multiple logistic regression. Both approaches have significant limitations. The authors propose a model based on response-surface methodology. This model can characterize the entire dose–response relation between combinations of anesthetic drugs and is mathematically consistent with models of the concentration–response relation of single drugs. Methods The authors defined a parameter, &thgr;, that describes the concentration ratio of two potentially interacting drugs. The classic sigmoid Emax model was extended by making the model parameters dependent on &thgr;. A computer program was used to estimate response surfaces for the hypnotic interaction between midazolam, propofol, and alfentanil, based on previously published data. The predicted time course of effect was simulated after maximally synergistic bolus dose combinations. Results The parameters of the response surface were identifiable. With the test data, each of the paired combinations showed significant synergy. Computer simulations based on interactions at the effect site predicted that the maximally synergistic three-drug combination tripled the duration of effect compared with propofol alone. Conclusions Response surfaces can describe anesthetic interactions, even those between agonists, partial agonists, competitive antagonists, and inverse agonists. Application of response-surface methodology permits characterization of the full concentration–response relation and therefore can be used to develop practical guidelines for optimal drug dosing.