Remifentanil by bolus injection: a safety, pharmacokinetic, pharmacodynamic, and age effect investigation in human volunteers.

BACKGROUND: Although remifentanil's short-acting pharmacokinetic profile makes it well suited for procedures during which a brief period of intense analgesia is required, setting up an infusion pump for brief procedures is inconvenient. The clinical pharmacology of remifentanil administered by bolus injection, a more convenient alternative, has not been explored in detail. The primary aim of this study was to examine the safety of single bolus doses of remifentanil in conscious, healthy, adult volunteers breathing room air. Secondary aims included the evaluation of remifentanil pharmacokinetics and analgesic effects after bolus injection and a comparison of these issues in younger vs older adults. METHODS: Using a randomized, double-blind, placebo-controlled, dose-escalation, crossover study design, 64 subjects (16 over 60 years old) received remifentanil or placebo by bolus injection in a fixed unit dose separated by a 1 h washout period. Respiratory effects were assessed using a respiratory intervention scale. Analgesic effects were assessed using pressure algometry. A population pharmacokinetic model was constructed using non-linear, mixed-effects modelling techniques based on arterial blood samples. Computer simulations were performed to illustrate the clinical application of the pharmacokinetic model. RESULTS: Dose-related increases in both respiratory and analgesic effects were observed. In general, the respiratory depression observed was mild and easily treated with requests to breathe or the administration of oxygen, although the older cohort (and some younger subjects) experienced more substantial respiratory depression at lower doses. The pharmacokinetics of bolus-dose remifentanil were adequately described by a two-compartment model. The pharmacokinetic simulations illustrated the potential utility of bolus-dose remifentanil. CONCLUSIONS: Bolus injection could potentially be a safe and effective means of administering remifentanil in clinical situations requiring a brief period of intense analgesia. Because some subjects, both old and young, experienced significant respiratory depression even at low doses, careful monitoring of respiratory function is essential.

Pharmacokinetics of remifentanil in anesthetized pediatric patients undergoing elective surgery or diagnostic procedures.

UNLABELLED: Remifentanil hydrochloride is an ultra-short-acting opioid that undergoes rapid metabolism by tissue and plasma esterases. We aimed to characterize the pharmacokinetics and determine the hemodynamic profile of remifentanil after a single-bolus dose in children aged 0 to 18 yr. Forty-two children undergoing elective surgical procedures received remifentanil 5 microg/kg infused over 1 min. Patients were divided into age groups as follows: young infants (< or =2 mo), older infants (> 2 mo to < 2 yr), young children (2 to < 7 yr), older children (7 to < 13 yr), adolescents (13 to < 16 yr), and young adults (16 to < 18 yr). Arterial blood samples were collected and analyzed by mass spectroscopy to determine remifentanil pharmacokinetic profiles. Hemodynamic measurements for remifentanil's effect were made after the infusion. Methods of statistical analysis included analysis of variance and linear regression, with significance at P < or = 0.05. Complete remifentanil pharmacokinetic data were obtained from 34 patients. The volume of distribution was largest in the infants < 2 mo (mean, 452 mL/kg) and decreased to means of 223 to 308 mL/kg in the older patients. There was a more rapid clearance in the infants < 2 mo of age (90 mL. kg(-1). min(-1)) and infants 2 mo to 2 yr (92 mL. kg(-1). min(-1)) than in the other groups (means, 46 to 76 mL. kg(-1). min(-1)). The half-life was similar in all age groups, with means of 3.4 to 5.7 min. Seven subjects (17%) developed hypotension related to the remifentanil bolus. Remifentanil showed an extremely rapid elimination similar to that in adults. The fast clearance rates observed in neonates and infants, as well as the lack of age-related changes in half-life, are in sharp contrast to the pharmacokinetic profile of other opioids. Remifentanil in a bolus dose of 5 microg/kg may cause hypotension in anesthetized children. IMPLICATIONS: The pharmacokinetics of remifentanil were studied in children from birth to 18 yr. Remifentanil was found to have age-related changes in clearance and volume of distribution, but not half-life. The increased clearance observed in young infants is in contrast to other opioids.

Care management in three practices--scope for improvement?

OBJECTIVE: The process of assessment of older people for residential/nursing home care may take place by hospital based social workers, or by care managers working in the community. We sought to compare the assessment process in each setting. The standards for the audit were that the data collection for both groups was equivalent, that both groups had a multi-disciplinary assessment, and that outcomes in both settings were appropriate. DESIGN: Identification of all older people assessed as requiring residential/nursing home care from 1/7/97-31/12/97, who were registered with the three general practices in Aberdeen participating in this study. Social Work case files and care plans were reviewed. All individuals were visited and dependency scores obtained--Abbreviated Mental Test, Barthel Index, and CAPE (Clifton Assessment Procedures for the elderly--Behaviour Rating Scale component) score. SETTING: Review of hospital social work case files, and community based case files. Interviewing of the older person in their own home, hospital, residential or nursing home to obtain dependency scores. SUBJECTS: Thirty three people were referred-17 from the community, and 16 from hospital. RESULTS: Case files in both groups were well maintained. There were differences in procedures between the assessment processes, but outcomes appeared to be similar. There was no statistical difference in mean dependency scores between each group. However, information on levels of support in the files was limited, particularly for the community group. Dependency scores correlated with residential/nursing home care being appropriate for the 33 individuals, but only 50% of people were identified as wanting such arrangements. Evidence of a recorded medical assessment was absent in 47% of the community referred population. CONCLUSION: Evidence of a multi-disciplinary assessment was not always available, especially for the community referred individuals. A greater emphasis on a multi-disciplinary assessment could highlight a need for rehabilitation, which might allow for the improvement and maintenance of some frail older people in the community, this often being in accordance with their wishes.

Influence of arteriovenous sampling on remifentanil pharmacokinetics and pharmacodynamics.

INTRODUCTION: 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. OBJECTIVES: To assess the effects of sampling site on the pharmacokinetic and pharmacodynamic characteristics of remifentanil. METHODS: Ten healthy female subjects received intravenous remifentanil at an infusion rate of 3 microg/kg/min for 10 minutes. Serial blood samples were collected during and after drug administration from the radial artery and antecubital vein. A spectral edge measure was derived from the processed electroencephalographic and used as a measure of opioid effect. RESULTS: Venous concentrations were lower than arterial concentrations during the infusion of remifentanil. Pharmacokinetic parameters estimated from venous and arterial data differed significantly. When arterial concentrations were plotted against electroencephalographic effect, a classic counterclockwise hysteresis loop was observed, indicating a time-lag between changes in concentration and changes in effect. However, concentrations from venous blood produced a clockwise hysteresis loop that would classically suggest the development of acute tolerance. CONCLUSIONS: If this study had been conducted with venous samples alone, inappropriate conclusions such as acute tolerance could have been inferred. When designing studies to measure the acute time course (ie, non-steady state) of concentration and effect, the potential effects of sampling site on pharmacokinetic and pharmacodynamic characteristics must be carefully considered, particularly when the arteriovenous drug concentration difference is large.

The comparative pharmacodynamics of remifentanil and its metabolite, GR90291, in a rat electroencephalographic model.

BACKGROUND: The purpose of this study was to investigate the in vivo pharmacodynamics and the pharmacodynamic interactions of remifentanil and its major metabolite, GR90291, in a rat electroencephalographic model. METHODS: Remifentanil and GR90291 were administered according to a stepwise infusion scheme. The time course of the electroencephalographic effect (0.5-4.5 Hz) was determined in conjunction with concentrations of the parent drug and the metabolite in blood. RESULTS: Administration of remifentanil resulted in concentrations of remifentanil and GR90291 in the ranges 0-120 ng/ml and 0-850 ng/ml, respectively. When the metabolite was administered, concentrations of the metabolite in the range 0-220 microg/ml and no measurable concentrations of remifentanil were observed. The mean +/- SE values of the pharmacokinetic parameters clearance and volume of distribution at steady state were 920+/-110 ml x min(-1) x kg(-1) and 1.00+/-0.93 l/kg for remifentanil and 15+/-2 ml x min(-1) x kg(-1) and 0.56+/-0.08 l/kg for GR90291. The relative free concentrations in the brain, as determined on the basis of the cerebrospinal fluid/total blood concentration ratio at steady state, were 25+/-5% and 0.30+/-0.11% for remifentanil and GR90291, respectively. Concentration-electroencephalographic effect relations were characterized on the basis of the sigmoidal Emax pharmacodynamic model. The mean +/- SE values for the maximal effect (Emax), the concentration at which 50% of the maximal effect is obtained (EC50), and Hill factor for remifentanil were 109+/-12 microV, 9.4+/-0.9 ng/ml, and 2.2+/-0.3, respectively (n = 8). For GR90291, the mean +/- SE values for EC50 and the Hill factor were 103,000+/-9,000 microg/ml and 2.5+/-0.4, respectively (n = 6). CONCLUSIONS: Analysis of the data on the basis of a previously postulated, mechanism-based pharmacokinetic-pharmacodynamic model for synthetic opioids revealed that the low in vivo potency of GR90291 can be explained by a low affinity to the mu-opioid receptor in combination with a poor brain penetration.

Remifentanil pharmacokinetics in obese versus lean patients.

BACKGROUND: Remifentanil is a short-acting opioid whose pharmacokinetics have been characterized in detail. However, the impact of obesity on remifentanil pharmacokinetics has not been specifically examined. The goal of this study was to investigate the influence of body weight on remifentanil pharmacokinetics. METHODS: Twelve obese and 12 matched lean subjects undergoing elective surgery received a 1-min remifentanil infusion after induction of anesthesia. Arterial blood samples were collected for determination of remifentanil blood concentrations. Each subject's pharmacokinetic parameters were estimated by fitting a two-compartment model to the concentration versus time curves. Nonlinear mixed-effects population models examining the influence of lean body mass (LBM) and total body weight (TBW) were also constructed. Clinical simulations using the final population model were performed. RESULTS: The obese patient cohort reached substantially higher remifentanil concentrations. The individual pharmacokinetic parameters of a two-compartment model were not significantly different between the obese versus lean cohorts (unless normalized to TBW). The final population model scaled central clearance and the central and peripheral distribution volumes to LBM. The simulations illustrated that remifentanil pharmacokinetics are not grossly different in obese versus lean subjects and that TBW based dosing in obese patients can result in excessively high remifentanil concentrations. CONCLUSIONS: The essential findings of the study are that remifentanil's pharmacokinetics are not appreciably different in obese versus lean subjects and that remifentanil pharmacokinetic parameters are therefore more closely related to LBM than to TBW. Clinically this means that remifentanil dosing regimens should be based on ideal body weight (or LBM) and not TBW.

Metabolism of remifentanil during liver transplantation.

We have investigated the pharmacokinetics of remifentanil and its less potent metabolite, GR90291, in six adult patients undergoing orthotopic liver transplantation (OLT). A single bolus infusion of remifentanil 10 micrograms kg-1 min-1 was given at the beginning of the dissection and anhepatic phases of OLT. Remifentanil and GR90291 concentrations were measured in subsequent serial arterial and mixed venous blood samples. Mean arterial clearance of remifentanil was significantly greater (P = 0.02) in the dissection phase (79.54 ml min-1 kg-1) than in the anhepatic phase (39.57 ml min-1 kg-1). Steady state volumes of distribution were not significantly different. Clearance of remifentanil during the anhepatic phase was similar to that of healthy adult patients. Mean maximum concentration (Cpmax) of GR90291 was lower in the dissection phase than in the anhepatic phase (P = 0.026). There was no significant pulmonary metabolism of remifentanil.

Evaluating a possible pharmacokinetic interaction between remifentanil and esmolol in the rat.

Remifentanil (Ultiva) is a novel, ultra-short-acting opioid which has recently been approved for use as an analgesic during induction and maintenance of general anesthesia. Esmolol is a short-acting beta-blocker used during surgical procedures to reduce heart rate and blood pressure. Both drugs are metabolized by nonspecific esterases in the blood and other tissues and may be administered concomitantly during surgery. The goal of this study was to determine if coadministration of esmolol significantly alters the pharmacokinetics of remifentanil in the rat. Two groups of rats were dosed with remifentanil [25 micrograms/kg/min (n = 8)] and remifentanil plus esmolol [25 and 200 mg/kg/min (n = 7)] for 20 min. Cardiovascular measurements were collected continuously over the course of the study. Serial blood samples (12) were collected over 25 min into test tubes containing 0.5 mL of acetonitrile. Blood samples were extracted (liquid-liquid) with methylene chloride and then analyzed by a validated GC-MS assay. Compartmental data analysis was performed using PCNONLIN. The mean(+/- SD) for Cl and t1/2 observed in treatment I were 390(+/- 98) mL/min/kg and 0.69(+/- 0.27) min and in treatment II were 421(+/- 164) mL/min/kg and 0.56(+/- 0.22) min, respectively. Comparison of clearance, volume of distribution, and terminal half-life between the two groups showed that coadministration of esmolol had no significant (p < 0.05) effect on the pharmacokinetics of remifentanil in the rat.

Pharmacokinetics and pharmacodynamics of remifentanil in persons with renal failure compared with healthy volunteers.

BACKGROUND: Remifentanil is an opioid analgesic for use in anesthesia. An ester linkage renders it susceptible to rapid metabolism by blood and tissue esterases. Thus it was hypothesized that remifentanil elimination would be independent of renal function. Because its principal metabolite (GR90291) is eliminated renally, it would depend on renal function. This study was designed to evaluate the pharmacokinetics and pharmacodynamics of remifentanil and its metabolite in persons with and without renal failure. METHODS: Two groups of volunteers received two-stage infusions of remifentanil: low dose with 0.0125 microg x kg(-1) x min(-1) for 1 h followed by 0.025 microg x kg(-1) x min(-1) for 3 h; and high dose with 0.025 microg x kg(-1) x min(-1) for 1 h followed by 0.05 microg x kg(-1) x min(-1) for 3 h. Blood samples were collected for analysis of remifentanil and GR90291 concentrations. The pharmacokinetics of remifentanil were fit using a one-compartment pharmacokinetic model. Remifentanil's effect was determined intermittently using minute ventilation during a hypercapnic (7.5% CO2) challenge. RESULTS: Fifteen patients with renal failure and eight control participants were enrolled. The clearance and volume of distribution of remifentanil were not different between those with renal failure and the controls. Patients with renal failure showed a marked reduction in the elimination of GR90291; the half-life of the metabolite increased from 1.5 h in the controls to more than 26 h in patients with renal failure. The steady-state concentration of GR90291 is likely to be more than 25 times higher in persons with renal failure. There were no obvious differences in opioid effects on minute ventilation in the controls and in patients with renal failure. CONCLUSIONS: The pharmacokinetics and pharmacodynamics of remifentanil were not altered in patients with renal disease, but the elimination of its principal metabolite, GR90291, was markedly reduced. Based on simulations, the concentration of GR90291 at the end of a 12-h remifentanil infusion of 2 microg x kg(-1) x min(-1) is not likely to produce significant opioid effects.

Remifentanil and pulmonary extraction during and after cardiac anesthesia.

We measured the apparent blood clearance and pulmonary extraction ratio of remifentanil in 10 adult patients undergoing elective myocardial revascularization for the first time with hypothermic cardiopulmonary bypass (CPB). Patients received continuous infusions of remifentanil 1.0, 1.5 or 2.0 microg x kg(-1) x min(-1). After surgery, remifentanil was infused at 1.0 microg x kg(-1) x min(-1) in all patients. Remifentanil concentrations were measured in pulmonary and radial artery blood by gas chromatography with high resolution mass spectrometry before and after CPB and 165 min (60 SD) after surgery. Cardiac output was measured by thermodilution at the time of blood sampling. The mean pulmonary extraction ratio of remifentanil was 5.7% (13.1% SD), which was not significantly different from zero. However, pulmonary extraction ratio was related inversely to the pulmonary artery hydrogen ion concentration and directly to the percent of nonionized form of the base in the pulmonary artery. Remifentanil concentrations in pulmonary and radial artery blood were related directly to infusion rate, but not to duration of infusion. There was no evidence of accumulation or sequestration. Mean apparent blood remifentanil clearance was 2.03 L/min (0.35 SD) and, in contrast to remifentanil pulmonary extraction ratio, was related directly to cardiac index and oxygen delivery. Increased tissue perfusion increased blood remifentanil clearance. We found predictable blood remifentanil levels with no evidence of accumulation or pulmonary extraction.

Comparative pharmacokinetics and pharmacodynamics of remifentanil, its principle metabolite (GR90291) and alfentanil in dogs.

Remifentanil is an esterase-metabolized opioid developed for use in anesthesia. The principal metabolite of remifentanil, GR90291, is considered to be less potent. This study determined the relative potency of GR90291 and alfentanil, compared with remifentanil, in anesthetized dogs. Male dogs received thiamylal sodium, and anesthesia was maintained using isoflurane and N2O in oxygen. Each dog received a 5-min infusion of 0.5 microg/kg/min remifentanil, 500 microg/kg/min GR90291 and 1.6 mg/kg/min alfentanil in random order, separated by 1 week. Serial blood samples were collected during and after the infusion. The electroencephalogram was evaluated using aperiodic analysis. The pharmacokinetics and pharmacodynamics of remifentanil, GR90291 and alfentanil were determined using nonlinear least-squares regression analysis. Remifentanil was rapidly eliminated, with a terminal half-life of 6 min, compared with 19 min for GR90291 and alfentanil. Using the estimated concentration that elicits 50% of the maximum response (EC50) for delta EEG activity and spectral edge95, remifentanil was 4213 to 4637 times more potent than GR90291 and 7.7 to 8.5 times more potent than alfentanil. The blood-brain equilibration half-life was 2.3 to 5.2 min for remifentanil, 0.39 to 0.41 min for GR90291 and 3.1 to 3.7 min for alfentanil.

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 micrograms.kg-1.min-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-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.

The pharmacokinetics and electroencephalogram response of remifentanil alone and in combination with esmolol in the rat.

PURPOSE: The goal of this study was to determine if the co-administration of esmolol (ES), a short acting cardioselective beta-blocker, significantly alters the pharmacokinetics and/or pharmacodynamics of remifentanil (REMI), an ultra short-acting opioid, in the rat. METHODS: Sprague-Dawley rats (N = 8, Wt. = 325 +/- 15 g) were surgically implanted with stainless steel cerebrocortical EEG electrodes three days before the study. Each rat was dosed with REMI (15 micrograms/kg/min), and REMI & ES (15 micrograms/kg/min and 600 micrograms/kg/min) for 21 minutes in a random crossover design. Six serial blood samples were collected over 25 minutes into test-tubes containing 0.5 ml acetonitrile. Blood samples were extracted with methylene chloride and analyzed by a validated GC-MS assay. EEG was captured and subjected to power spectral analysis (0.1-50 Hz) for spectral edge (97%). RESULTS: No significant differences (p < 0.05) were found in clearance (REMI = 287 + 73 ml/min/leg vs. REMI & ES = 289 +/- 148 ml/min kg) or Vd (REMI = 286 +/- 49 ml/kg vs REMI & ES = 248 + 40 ml/kg). A linked sigmoid Emax PK-PD model was used and the pharmacodynamic parameters were not statistically different. Mean Emax and EC50 after REMI were 18.0 +/- 6.0 Hz and 32 +/- 12 ng/ml; and after REMI + ES were 19 + 4.8 Hz and 26 + 8.6 ng/ml. CONCLUSIONS: At the doses tested, there is no pharmacokinetic or pharmacodynamic interaction between remifentanil and esmolol in the rat.

Ethanol Pharmacodynamics at Low Blood Concentrations.

Ranitidine has been shown to produce increases in blood alcohol concentration (BAC) after low doses of alcohol. The objective of this study was to reproduce, in a controlled setting, the BACs seen after low oral doses of ethanol in the presence and absence of ranitidine and to assess the effect of these concentrations on cognitive performance. An active control group (0.45 g per kg alcohol) was included as a validation of the methodology used. A randomized, double-blind, placebo-controlled, four-way crossover study was performed in eight healthy males. Subjects received a 20-min intravenous infusion of 0.10, 0.15, or 0.45 g per kg alcohol or placebo. Blood samples were obtained to measure BAC and psychometric effects were assessed over 8 h. A pharmacokinetic model was used to fit simultaneously the BAC--time profiles of all three doses for each subject. Cognitive improvement was assessed using digit symbol substitution, continuous tracking, and divided attention tests. Analysis of variance was conducted in order to compare peak blood alcohol impairment (E(max)) and area under the alcohol impairment--time curve (AUEC) across treatments. Observed median peak BAC (C(max)) for 0.10- and 0.15-g/kg dose groups (median BACs 15.2 and 27 mg/dl, respectively) were very similar to the target C(max) (13 and 26 mg/dl). Analysis of variance of AUEC and E(max) showed difference in impairment measures after the 0.10- and 0.15-g/kg doses. A significant difference in impairment measures between placebo and the active control, 0.45 g/kg (median BAC of 110 mg/dl) was observed, indicating that the methodology was capable of detecting significant psychomotor effects at the legal limit of BAC. Results indicated that the BAC increments from 15 to 27 mg/dl are not associated with significantly impaired performance and, hence, it is unlikely that increases in BAC of this magnitude, such as those caused by ranitidine therapy, are of any clinical relevance.

Pharmacokinetics and pharmacodynamics of remifentanil in volunteer subjects with severe liver disease.

BACKGROUND: Remifentanil, a new mu-opioid agonist with an extremely short duration of action, is metabolized by circulating and tissue esterases; therefore, its clearance should be relatively unaffected by changes in hepatic or renal function. This study was designed to determine whether severe hepatic disease affects the pharmacokinetics or pharmacodynamics of remifentanil. METHODS: Ten volunteers with chronic, stable, severe hepatic disease and awaiting liver transplantation and ten matched controls were enrolled. Each subject was given a 4-h infusion of remifentanil. The first five pairs received 0.0125 microgram x kg(-1) x min(-1) for 1 h followed by 0.025 microgram x kg(-1) x min(-1) for 3 h; the second five pairs received double these infusion rates. During and after the infusion, arterial blood was obtained for pharmacokinetic analyses, and the ventilatory response to a hypercarbic challenge was assessed. Simultaneous pharmacokinetic and pharmacodynamic analyses were performed. The pharmacokinetics were described using a one-compartment intravenous infusion model, and ventilatory depression was modelled using the inhibitory E(max) model. The pharmacokinetics of the metabolite GR90291 were determined using noncompartmental methods. RESULTS: There were no differences in any of the pharmacokinetic parameters for remifentanil or GR90291 between the two groups. The subjects with liver disease were more sensitive to the ventilatory depressant effects of remifentanil. The EC(50) values (the remifentanil concentrations determined from simultaneous pharmacokinetic/pharmacodynamic analyses to depress carbon dioxide-stimulated minute ventilation by 50%) in the control and hepatic disease groups were 2.52 ng/ml (95% confidence interval 2.07-2.97 ng/ml) and 1.56 ng/ml (95% confidence interval 1.37-1.76 ng/ml), respectively. CONCLUSIONS: The pharmacokinetics of remifentanil and GR90291 are unchanged in persons with severe, chronic liver disease. Such patients may be more sensitive to the ventilatory depressant effects of remifentanil, a finding of uncertain clinical significance, considering the extremely short duration of action of the drug.

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 (VD(SS)), but remifentanil's central clearance (CLc)) is substantially greater. The NONMEM analysis population pharmacokinetic parameters for remifentanil include a CLc of 2.9 l x min(-1), a VDss of 21.81, and a terminal half-life of 35.1 min. Corresponding NONMEM parameters for alfentanil are 0.36 l x min(-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 T(12)k(e0) for remifentanil of 0.75 min [corrected] 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 x ml(-1) versus 375.9 ng x ml(-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 remifentanil's 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.

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. METHODS: Thirty volunteers received a 3-h infusion of remifentanil or alfentanil at equieffective concentrations. Depression of minute ventilation to 7.5% ETCO2 was used as a measure of drug effect. Minute ventilation response was measured, and blood samples for drug concentration were taken during and after drug infusion. The recovery of minute ventilation (drug effect) and decrease in blood drug concentration was plotted, and the time for a 50% change was determined. RESULTS: The measured pharmacokinetic context-sensitive half-time for remifentanil after a 3-h infusion was 3.2 +/- 0.9 min, and its pharmacodynamic offset was 5.4 +/- 1.8 min. Alfentanil's measured pharmacokinetic context-sensitive half-time was 47.3 +/- 12 min, and its pharmacodynamic offset was 54.0 +/- 48 min. The terminal elimination half-life modelled from the volunteers was 11.8 +/- 5.1 min for remifentanil and 76.5 +/- 12.6 min for alfentanil. CONCLUSIONS: The measured context-sensitive half-times were in close agreement with the context-sensitive half-times previously modelled for these drugs. The results of this study confirm the value of the context-sensitive half-time in describing drug offset compared to the terminal elimination half-life.

Histamine concentrations and hemodynamic responses after remifentanil.

Remifentanil is a new potent opioid analgesic that undergoes rapid esterase metabolism. The purpose of this study was to investigate hemodynamic responses to 2-30 micrograms/kg remifentanil (escalating doses) injected as a bolus over 1 min during general anesthesia. After general anesthesia with endotracheal intubation, placement of a radial artery catheter, and pretreatment with glycopyrrolate, remifentanil 2, 5, 15, or 30 micrograms/kg (six patients, three male and three female per group) was administered over 1 min. Arterial blood pressure and heart rate were measured noninvasively before drug administration, after drug administration, and then every minute for 5 min. Arterial blood was taken for histamine determinations before drug administration and then at 1, 3, and 5 min after drug administration. Administration of remifentanil was associated with a reduction in systolic blood pressure from 134 +/- 18 to 91 +/- 16 mm Hg and heart rate from 99 +/- 20 to 69 +/- 21 bpm and was not associated with alterations in histamine concentration.

The pharmacokinetics of the new short-acting opioid remifentanil (GI87084B) in healthy adult male volunteers.

BACKGROUND: Remifentanil (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. METHODS: Ten healthy adult male volunteers received a zero-order infusion of remifentanil at doses ranging from 1 to 8 micrograms.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 hte 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. RESULTS: For each parametric method, a three-compartment mamillary model that accurately describes remifentanil's concentration decay curve was constructed. The NONMEM analysis population pharmacokinetic parameters included a central clearance of 2.8 l/min, a volume of distribution at steady state of 32.8 l, and a terminal half-life of 48 min. The mean results of the nonparametric moment analysis included a clearance of 2.9 l/min, a volume of distribution at steady state of 31.8 l, 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. CONCLUSIONS: Remifentanil is a new, short-acting opioid with promising clinical potential in anesthesiology.