Talmage D. Egan

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.

Remifentanil pharmacokinetics and pharmacodynamics : a preliminary appraisal

SummaryRemifentanil is a novel, short-acting μ-receptor opioid agonist currently in the late stages of development. A member of the 4-anilidopiperidine class, it is unique among the currently marketed agents because of its ester structure. Remifentanil undergoes widespread extrahepatic metabolism by blood and tissue nonspecific esterases, resulting in an extremely rapid clearance of approximately 3 L/min (180 L/h). Like the other members of this class of drugs, remifentanil is lipophilic and is widely distributed in body tissues with a steady-state volume of distribution of approximately 30L.Because of its unique metabolic pathway (among this group of drugs) and rapid clearance, remifentanil represents a new pharmacokinetic class of opioid. Unlike the other fentanyl congeners, termination of the therapeutic effect of remifentanil mostly depends on metabolic clearance rather than on redistribution. The context-sensitive half-time [defined as the time necessary to achieve a 50% decrease in blood (or plasma) concentration after termination of a variable-length, continuous infusion targeted to maintain a steady-state concentration, where the ‘context’ is the duration of the infusion] is strikingly short for remifentanil, and this is perhaps the most compelling evidence of the pharmacokinetic singularity of the drug. Determined by computer simulation, the context-sensitive half-time of remifentanil is approximately 3 minutes, and is independent of infusion duration.Pharmacodynamically, remifentanil is similar to the other fentanyl congeners. The drug produces physiological changes consistent with potent γ-receptor agonist activity, including analgesia and sedation. Its adverse effect profile (like that of the other drugs of this class) includes ventilatory depression, nausea, vomiting, muscular rigidity, bradycardia and pruritus. Because it does not release histamine upon injection, remifentanil has fewer haemodynamic adverse effects than morphine. The therapeutic potency of remifentanil is somewhat less than that of fentanyl, with an effective concentration (producing 50% of maximal effect, as measured by electroencephalography) of approximately 15 to 20 µg/L. Speed of onset of effect is very rapid and is similar to that of alfentanil, which is reflected in a t1/2 ke0(a parameter used to characterise the delay between peak blood drug concentration and peak pharmacodynamic effect utilising a theoretical effect compartment) of approximately 1 to 2 minutes.Remifentanil is likely to be a welcome addition to the anaesthesia drug formulary. Anaesthetists have long recognised the need for a short-acting opioid with a predictable pharmacokinetic profile. Because the length of surgical procedures is often unpredictable, and because the level of surgical stimulation against which the depth of anaesthesia must be balanced is highly variable and dynamic, the advantages of predictably short-acting agents are obvious.

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 subjects 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 remifentanils 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.

A Response Surface Analysis of Propofol–Remifentanil Pharmacodynamic Interaction in Volunteers

Background: Characterizing drug interactions using a response surface allows for the determination of the interaction over a complete range of clinically relevant concentrations. Gathering the data necessary to create this surface is difficult to do in a clinical setting and requires the use of volunteer experiments with surrogate noxious stimuli to adequately control the process for data collection. The pharmacodynamic synergy of opioids and hypnotics was investigated using a volunteer study paradigm. Methods: Twenty-four volunteer subjects (12 male, 12 female) were studied using computer-controlled infusions of propofol and remifentanil to create an increasing staircase drug concentration profile in each subject. Three different drug delivery profiles were administered to subjects, one with a single agent and two with combinations of propofol and remifentanil. At each plateau of the staircase profile, drug effect was assessed using four surrogate measures: Observer Assessment of Alertness/Sedation score, tibial pressure algometry, electrical tetany, and response to laryngoscopy. Response surfaces were developed that mapped the interaction of propofol and remifentanil to these surrogate effect measures in all subjects. An interaction parameter was used to assess whether these two drugs behave synergistically to blunt response to noxious stimuli. Results: The response surfaces showed considerable synergy between remifentanil and propofol for blunting response to the noxious stimuli. The interaction index, a measure of synergy, was 8.2 and 14.7 for response to algometry and tetany, respectively (P < 0.001), and 5.1 and 33.2 for sedation and laryngoscopy, respectively (P < 0.001), using the Greco interaction model. The surrogate stimuli mapped to clinically relevant concentrations for these agents in combination. Conclusions: The response surface models reveal the tremendous synergy between remifentanil and propofol. The surface morphologic features give some indication of the relative contribution of sedation and analgesia to blunting subject response. Further, the results of this investigation validate the volunteer study paradigm and use of surrogate effect measures for its clinical relevance.

Propofol Dosing Regimens for ICU Sedation Based upon an Integrated Pharmacokinetic- Pharmacodynamic Model

Background The pharmacology of propofol infusions administered for long-term sedation of intensive care unit (ICU) patients has not been fully characterized. The aim of the study was to develop propofol dosing guidelines for ICU sedation based on an integrated pharmacokinetic–pharmacodynamic model of propofol infusions in ICU patients. Methods With Institutional Review Board approval, 30 adult male medical and surgical ICU patients were given target-controlled infusions of propofol for sedation, adjusted to maintain a Ramsay sedation scale score of 2–5. Propofol administration in the first 20 subjects was based on a previously derived pharmacokinetic model for propofol. The last 10 subjects were given propofol based on a pharmacokinetic model derived from the first 20 subjects. Plasma propofol concentrations were measured, together with sedation score. Population pharmacokinetic and pharmacodynamic parameters were estimated by means of nonlinear regression analysis in the first 20 subjects, then prospectively tested in the last 10 subjects. An integrated pharmacokinetic–pharmacodynamic model was used to construct dosing regimens for light and deep sedation with propofol in ICU patients. Results The pharmacokinetics of propofol were described by a three-compartment model with lean body mass and fat body mass as covariates. The pharmacodynamics of propofol were described by a sigmoid model, relating the probability of sedation to plasma propofol concentration. The pharmacodynamic model for propofol predicted light and deep levels of sedation with 73% accuracy. Plasma propofol concentrations corresponding to the probability modes for sedation scores of 2, 3, 4, and 5 were 0.25, 0.6, 1.0, and 2.0 &mgr;g/ml. Predicted emergence times in a typical subject after 24 h, 72 h, 7 days, and 14 days of light sedation (sedation score = 3 → 2) with propofol were 13, 34, 198, and 203 min, respectively. Corresponding emergence times from deep sedation (sedation score = 5 → 2) with propofol were 25, 59, 71, and 74 h. Conclusions Emergence time from sedation with propofol in ICU patients varies with the depth of sedation, the duration of sedation, and the patient’s body habitus. Maintaining a light level of sedation ensures a rapid emergence from sedation with long-term propofol administration.

Attentional effects of noradrenaline vary with arousal level: selective activation of thalamic pulvinar in humans

Subjects sedated by noradrenergic alpha2 agonists can switch rapidly from a state of extremely low to almost full consciousness following phasic increases in arousal or cognitive demand. Such flexibility is not displayed by traditional sedatives, such as the benzodiazepine diazepam. Experimentally, the phasic modulation of alpha2 effect by arousing or distracting stimuli can counteract the deleterious cognitive effects of alpha2 agonists. We used behavioural and fMRI indices of brain function to investigate the phasic modulatory effect that presentation of loud white noise would have on attentional dysfunction induced by administration of dexmedotomidine, an alpha2 agonist. Dexmedotomidine and midazolam were compared to placebo during performance of a target detection task, which was presented in the presence or absence of white noise. Compared to placebo, both dexmedotomidine and midazolam impaired task performance. This impairment was significantly attenuated by presentation of white noise in the dexmedotomidine condition only. This functional improvement corresponded to selective increase in activity of left medial pulvinar nucleus of the thalamus. This regional increase is suggested to index increases in phasic arousal, which counteract dexmedotomidines detrimental attentional effects. Finally, despite sedating subjects to equivalent degrees, dexmedotomidine and midazolam had strikingly different regional effects on task-induced brain activity. Therefore, for the same level of sedation, the behavioural and anatomical attributes identifying the quality of sedation can vary.

Opioid-volatile anesthetic synergy : A response surface model with remifentanil and sevoflurane as prototypes

Background:Combining a hypnotic and an analgesic to produce sedation, analgesia, and surgical immobility required for clinical anesthesia is more common than administration of a volatile anesthetic alone. The aim of this study was to apply response surface methods to characterize the interactions between remifentanil and sevoflurane. Methods:Sixteen adult volunteers received a target-controlled infusion of remifentanil (0–15 ng/ml) and inhaled sevoflurane (0–6 vol%) at various target concentration pairs. After reaching pseudo–steady state drug levels, the Observers Assessment of Alertness/Sedation score and response to a series of randomly applied experimental pain stimuli (pressure algometry, electrical tetany, and thermal stimulation) were observed for each target concentration pair. Response surface pharmacodynamic interaction models were built using the pooled data for sedation and analgesic endpoints. Using computer simulation, the pharmacodynamic interaction models were combined with previously reported pharmacokinetic models to identify the combination of remifentanil and sevoflurane that yielded the fastest recovery (Observers Assessment of Alertness/Sedation score ≥ 4) for anesthetics lasting 30–900 min. Results:Remifentanil synergistically decreased the amount of sevoflurane necessary to produce sedation and analgesia. Simulations revealed that as the duration of the procedure increased, faster recovery was produced by concentration target pairs containing higher amounts of remifentanil. This trend plateaued at a combination of 0.75 vol% sevoflurane and 6.2 ng/ml remifentanil. Conclusion:Response surface analyses demonstrate a synergistic interaction between remifentanil and sevoflurane for sedation and all analgesic endpoints.

The pharmacokinetics and pharmacodynamics of propofol in a modified cyclodextrin formulation (Captisol) versus propofol in a lipid formulation (Diprivan): an electroencephalographic and hemodynamic study in a porcine model.

The currently marketed propofol formulation has a number of undesirable properties that are in part a function of the lipid emulsion formulation, including pain on injection, serious allergic reactions, and the support of microbial growth. A modified cyclodextrin-based formulation of propofol (sulfobutyl ether-&bgr;-cyclodextrin) has been developed that may mitigate some of these formulation-dependent problems. However, reformulation may alter propofol’s pharmacologic behavior. Our aim in this study was to compare the pharmacokinetics and pharmacodynamics of propofol in the currently marketed lipid-based formulation with those of the novel cyclodextrin formulation. We hypothesized that the pharmacokinetics and pharmacodynamics of the propofol in cyclodextrin would be substantially similar to those of the propofol in lipid. Thirty-two isoflurane-anesthetized animals were instrumented with pulmonary artery, arterial, and IV catheters and were randomly assigned to receive either propofol in lipid or propofol in cyclodextrin by continuous infusion. Arterial blood samples for propofol assay were collected. The processed electroencephalogram, heart rate, mean arterial blood pressure, and cardiac output were measured continuously. The propofol formulations were compared by using model-independent analysis techniques. Combined kinetic/dynamic models were also constructed for simulation purposes. There were no significant differences in the pharmacokinetics or pharmacodynamics of the two propofol formulations. The simulations based on the combined pharmacokinetic/pharmacodynamic models confirmed the substantial similarity of the two formulations. The hypothesis that the propofol-in-cyclodextrin formulation would exhibit pharmacokinetic and pharmacodynamic behavior that was substantially similar to the propofol-in-lipid formulation was confirmed.