Donald R. Stanski

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.

Absorption characteristics of transdermally administered fentanyl.

Fentanyl was administered intravenously and transdermally to eight surgical patients to determine the systemic bioavailability and rate of absorption of the transdermally administered drug. Serum fentanyl concentrations reached a plateau approximately 14 h after placement of the transdermal fentanyl delivery system. This plateau was maintained until removal of the system at 24 h. The decline in serum fentanyl concentrations after removal of the transdermal system had a terminal half-life of 17.0 +/- 2.3 h (mean +/- SD), considerably longer than the terminal elimination half-life seen after intravenous administration of fentanyl in the same patients (6.1 +/- 2.0 h). The rate of fentanyl absorption, predicted to be 100 micrograms/h from in vitro data, appeared to be relatively constant during a period starting 4-8 h after placement of the transdermal system until removal of the system at 24 h. The rate of absorption during this period was 91.7 +/- 25.7 micrograms/h. After removal of the transdermal fentanyl delivery system, absorption continued at a declining rate. This indicates that the long terminal half-life of serum fentanyl concentrations after transdermal system removal is due to continued slow absorption of fentanyl, probably from a cutaneous depot of drug at the site of prior transdermal system placement. At the time of removal of the transdermal fentanyl system, 1.07 +/- 0.43 mg of drug remained in this depot. Systemic fentanyl bioavailability was found to be 0.92 +/- 0.33, with no evidence of significant cutaneous metabolism or degradation by the skins bacterial flora. The transdermal administration of fentanyl produces relatively constant serum fentanyl concentrations for significant periods of time in the postsurgical patient requiring analgesic therapy.

Electroencephalographic quantitation of opioid effect: comparative pharmacodynamics of fentanyl and sufentanil.

The authors compared the pharmacodynamics of sufentanil with those of fentanyl using the electroencephalogram (EEG) as a measure of opioid drug effect. Sixteen patients were given a rapid infusion of sufentanil (18.75 micrograms/min) during EEG recording. To quantitate the opioid-induced slowing of the EEG, the authors analyzed its power spectrum and calculated the spectral edge. An inhibitory sigmoid Emax model of the maximal decrease in spectral edge produced by the opioid related spectral edge values to serum concentrations of sufentanil. The resulting data for the pharmacodynamic parameters of sufentanil were compared with fentanyl parameters that were obtained by reanalysis from an identically conducted, previously published study. The half-time of blood-brain equilibration (T1/2Keo) was not statistically different between sufentanil and fentanyl (6.2 +/- 2.8 vs. 6.6 +/- 1.7 min, mean +/- SD, respectively). The intrinsic potency of sufentanil, as measured by the serum concentration needed to cause half the maximal EEG slowing (IC50), was 12-fold greater (0.68 +/- 0.31 ng/ml) than that of fentanyl (8.1 +/- 2.2 ng/ml). The second part of the study verified the hypothesis that administration of equipotent bolus doses would produce equal onset times. Bolus injections of either 125 micrograms of sufentanil or 1,250 micrograms of fentanyl were given during EEG recording. The time from injection to 50% maximal EEG slowing (T50) was calculated for each patient. The values for T50 for the two groups did not differ. The authors conclude that fentanyl and sufentanil have similar pharmacodynamic profiles, the former being 12 times more potent than the latter.

A comparison of spectral edge, delta power, and bispectral index as EEG measures of alfentanil, propofol, and midazolam drug effect

The effects of anesthetic drugs on electroencephalograms (EEG) have been studied to develop the EEG as a measure of anesthetic depth. Bispectral analysis is a new quantitative technique that measures the consistency of the phase and power relationships and returns a single measure, the bispectral index. The purpose of this study was to compare the performance of the bispectral index, version 1.1, with other spectral analysis EEG measures of drug effect for three commonly used anesthetic drugs.

Plasma Concentrations of Alfentanil Required to Supplement Nitrous Oxide Anesthesia for General Surgery

To design an efficient infusion regimen from pharmacokinetic data, it is necessary to know the alfentanil plasma concentrations required for satisfactory anesthesia. In 37 patients about to undergo lower abdominal gynecologic, upper abdominal, or breast surgery, anesthesia was induced with alfentanil 150 μg/kg iv and 66% N2O in oxygen. Thereafter, N2O anesthesia was supplemented with a continuous infusion of alfentanil that was varied between 25 and 150 μg · kg-1 · h-1, as indicated by the patients responses to surgical stimulation. Small bolus doses of alfentanil 7 or 14 μg/kg were administered and the infusion rate increased to suppress precisely defined somatic, autonomic, and hemodynamic responses. Arterial plasma concentrations of alfentanil were measured during the operation when the patient did and did not respond to noxious stimulation. Logistic regression was used to determine plasma concentration–effect curves for different stimuli. Plasma alfentanil concentrations required along with 66% N2O to obtund responses to single episodes of stimulation in 50% of the 37 patients (Cp50 ± SE) were: 475 ± 28 ng/ml for tracheal intubation, 279 ± 20 ng/ml for skin incision, and 150 ± 23 ng/ml for skin closure. Between skin incision and closure, multiple determinations of response/no response were made for each patient and an individual Cp50 was estimated. The Cp50 (mean ± SD) for the three surgical procedures were: breast, 270 ± 63 ng/ml (n = 12); lower abdominal, 309 ± 44 ng/ml (n = 14); and upper abdominal, 412 ± 135 ng/ml (n = 11). The Cp50 for satisfactory spontaneous ventilation after the discontinuation of N2O was 223 ± 13 ng/ml. These data demonstrate that different perioperative stimuli require different alfentanil concentrations to suppress undesirable responses. Thus, the alfentanil infusion rate should be varied according to the patients responsiveness to stimulation in order to maintain satisfactory anesthetic and operative conditions and to provide rapid recovery of consciousness and spontaneous ventilation.

Absorption and Bioavailability of Oral Transmucosal Fentanyl Citrate

Oral transmucosal fentanyl citrate (OTFC) is a novel, noninvasive dosage form of fentanyl used to provide children and adults with sedation, anxiolysis, and analgesia. In order to determine the bioavailability and absorption of fentanyl from OTFC, 12 volunteers were given intravenous fentanyl citrate or OTFC 15 micrograms/kg on each of two occasions. On a third occasion, the authors assessed oral administration (gastrointestinal absorption) by giving eight of the same volunteers the same dose of a solution of fentanyl citrate to swallow. In each study, arterial blood samples were taken over 24 h for analysis of plasma fentanyl. After intravenous (iv) administration of fentanyl, clearance (mean +/- standard deviation) was 0.67 +/- 0.15 l/min; volume of distribution at steady state was 287 +/- 79 l; and the terminal elimination half-life was 425 +/- 102 min. Peak plasma concentrations of fentanyl were higher (3.0 +/- 1.0 vs. 1.6 +/- 0.6 ng/ml, P = 0.01) and occurred sooner (22 +/- 2.5 vs. 101 +/- 48.8 min, P = 0.003) after OTFC than after oral solution administration. Plasma concentrations of fentanyl after OTFC decreased rapidly, to less than 1.0 ng/ml within 75-135 min after the beginning of administration. Peak absorption rate was greater (11.1 +/- 4.3 vs. 3.6 +/- 2.1 micrograms/min, P = 0.004) and occurred much sooner after OTFC than after oral solution administration (19 +/- 2.6 vs. 87.5 +/- 38.1 min, P = 0.001). Systemic bioavailability was greater after OTFC administration than after the oral solution (0.52 +/- 0.1 vs. 0.32 +/- 0.1, P = 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Population pharmacokinetics of alfentanil: the average dose-plasma concentration relationship and interindividual variability in patients

The population pharmacokinetic parameters describing the plasma concentration versus time profile of alfentanil in patients undergoing general anesthesia were determined from 614 plasma concentration measurements collected in four previously reported studies with a total of 45 patients. A nonlinear regression analysis evaluating the effect of six concomitant variables revealed a significant influence of body weight on the volume of the central compartment (Vc), and a decrease with age of total body clearance (CL) and of redistribution rate from the deep compartment (k31). A small but significant effect of sex on the Vc was also observed. The duration of anesthesia and the concomitant administration of inhalational anesthetics had no effect on alfentanil pharmacokinetic parameters. The mean CL and Vc for alfentanil in a 70-kg male, aged less than 40 yr, were estimated as 0.356 l/min and 7.77 l, respectively. After correction for age, body weight, and sex, the remaining interindividual variability of alfentanil kinetics (expressed as coefficient of variation) was 48% for CL and 33% for Vc. These population pharmacokinetic parameter estimates should increase the accuracy of predicting concentration-time profiles for intravenous alfentanil infusions. A computer program is presented that allows prediction of the alfentanil plasma concentration and the 68% interval limits of the prediction from the study data analysis.

Kinetics of intravenous and intramuscular morphine.

The disposition of parenteral morphine was assessed in two pharmacokinetic studies. In Study 1, 10 mg of morphine sulfate was administered by intravenous (IV) infusion, intramuscular (1M) injection, or both, to 8 healthy young adult male volunteers. Plasma morphine concentrations were determined by radioimmunoassay in multiple blood samples drawn after each dose. Mean (±SE) kinetic parameters following IV morphine were: volume of distribution (Vd), 3.2 (±0.3) Llkg; elimination half‐life (t½β), 2.9 (±0.5) hr; clearance, 14.7 (±0.9) ml/min/kg; extraction ratio, 0.70 (±0.04). After IM morphine, peak plasma levels ranged from 51 to 62 ng/ml and were reached within 20 min of injection. The absorption half‐life averaged 7.7 (±1.6) min. Systemic availability was 100% complete. In study 2, 4 elderly male patients (61 to 80 yr of age) received 45 to 80 mg of morphine sulfate IV prior to operative repair of an abdominal aortic aneurysm. Morphine pharmacokinetics were determined as described above. Kinetic variables were: Vd, 4.7 (±0.2) L/kg; t½β 4.5 (±0.3) hr; clearance, 12.4 (±1.2) ml/min/kg; extraction ratio, 0.59 (±0.05). Both studies demonstrate that morphine distribution is rapid and extensive and its t½β relatively short. IM morphine is rapidly and completely absorbed.

A three-step approach combining bayesian regression and NONMEM population analysis: Application to midazolam

NONMEM, the only available supported program for population pharmacokinetic analysis, does not provide the analyst with individual subject parameter estimates. As a result, the relationship between pharmacokinetic parameters and demographic factors such as age, gender, and body weight cannot be sought by plotting demographic factors vs. kinetic parameters. To overcome this problem, we devised a three-step approach. In step 1, an initial NONMEM analysis provides the population pharmacokinetic parameters without taking into account the demographic factors. Step 2 consists of individual bayesian regressions using the measured drug concentrations for each subject and the population pharmacokinetic parameters obtained in step 1. The bayesian parameter estimates of the individual subject can be plotted against the demographic factors of interest. From the scatter plots, it can be seen which are the demographic factors that appear to affect the pharmacokinetic parameters. In step 3, the NONMEM analysis is resumed, and the demographic factors found in step 2 are entered into the NONMEM regression model in a stepwise manner. This method was used to analyze the pharmacokinetics of midazolam in 64 subjects from 714 plasma concentrations and 11 demographic factors. CL (elimination clearance) and V1were found to be a function of body weight. Age and liver disease were found to decrease CL. Of the 11 demographic factors recorded for each patient, none was found to influence Vssor intercompartmental clearance.

Linearity of Pharmacokinetics and Model Estimation of Sufentanil

Background The pharmacokinetic profiles of sufentanil available in the literature are conflicting because of methodologic differences. Length of sampling and assay sensitivity are key factors involved in accurately estimating the volumes of distribution, clearances, and elimination phase. The unit disposition function of increasing doses of sufentanil were investigated and the influence of dose administered on the linearity of pharmacokinetics was assessed.