Assessing circadian rhythms in propofol PK and PD during prolonged infusion in ICU patients

This study evaluates possible circadian rhythms during prolonged propofol infusion in patients in the intensive care unit. Eleven patients were sedated with a constant propofol infusion. The blood samples for the propofol assay were collected every hour during the second day, the third day, and after the termination of the propofol infusion. Values of electroencephalographic bispectral index (BIS), arterial blood pressure, heart rate, blood oxygen saturation and body temperature were recorded every hour at the blood collection time points. A two-compartment model was used to describe propofol pharmacokinetics. Typical values of the central and peripheral volume of distribution and inter-compartmental clearance were V _C  = 27.7 l, V _T  = 801 l, and CL _D  = 2.73 l/min. The systolic blood pressure (SBP) was found to influence the propofol metabolic clearance according to Cl (l/min) = 2.65·(1 − 0.00714·(SBP − 135)). There was no significant circadian rhythm detected with respect to propofol pharmacokinetics. The BIS score was assessed as a direct effect model with EC ₅₀ equal 1.98 mg/l. There was no significant circadian rhythm detected within the BIS scores. We concluded that the light–dark cycle did not influence propofol pharmacokinetics and pharmacodynamics in intensive care units patients. The lack of night–day differences was also noted for systolic blood pressure, diastolic blood pressure and blood oxygenation. Circadian rhythms were detected for heart rate and body temperature, however they were severely disturbed from the pattern of healthy patients.     

Pharmacokinetics and pharmacodynamics of propofol in children undergoing different types of surgeries

BackgroundPropofol is a commonly used agent in total intravenous anesthesia (TIVA). However, the link between its pharmacokinetics and pharmacodynamics has not been fully characterized in children yet. Our aim was to determine the quantitative relationship between the venous plasma concentration and bispectral index (BIS) effect in a heterogeneous group of pediatric patients undergoing various surgical procedures (ASA status I–III).MethodsNine male and nine female patients were anesthetized with propofol–fentanyl TIVA. Sparse venous samples for propofol concentrations assay and dense BIS measurements were collected during and after the end of infusion. Nonlinear mixed-effect modeling in NONMEM was used for data analysis.ResultsA three-compartment model was linked with a classical E_max model through a biophase compartment to describe the available data. All clearance and volume terms were allometrically scaled to account for the body mass difference among the patients under study. A typical patient had their PK parameters observed within the range of literature values for children. The pharmacodynamic parameters were highly variable. The EC₅₀ of 2.80 mg/L and the biophase distribution rate constant of 3.33 min⁻¹ were found for a typical patient.ConclusionsThe BIS values in children are highly correlated with the propofol effect compartment concentrations according to the classical E_max concentration–response relationship. Children had slightly lower sensitivity to propofol and slightly higher clearance, as compared with the adult data available in literature. The intra-patient variations in the BIS require the anesthesiologist's attention in using BIS values alone to evaluate the depth of anesthesia in children.     

Pharmacokinetics and pharmacodynamics of propofol and fentanyl in patients undergoing abdominal aortic surgery – a study of pharmacodynamic drug–drug interactions

Propofol is routinely combined with opioid analgesics to ensure adequate anesthesia during surgery. The aim of the study was to assess the effect of fentanyl on the hypnotic effect of propofol and the possible clinical implications of this interaction. The pharmacokinetic/pharmacodynamic (PK/PD) data were obtained from 11 patients undergoing abdominal aortic surgery, classified as ASA III. Propofol was administered by a target‐controlled infusion system. Fentanyl 2–3 µg/kg was given whenever insufficient analgesia occurred. The bispectral index (BIS) was used to monitor the depth of anesthesia. A population PK/PD analysis with a non‐linear mixed‐effect model (NONMEM 7.2 software) was conducted. Two‐compartment models satisfactorily described the PK of propofol and fentanyl. The delay of the anesthetic effect in relation to PK was described by the effect compartment. The BIS was linked to propofol and fentanyl effect‐site concentrations through an additive E_max model. Context‐sensitive decrement times (CSDT) determined from the final model were used to assess the influence of fentanyl on the recovery after anesthesia. The population PK/PD model was successfully developed to describe simultaneously the time course and variability of propofol and fentanyl concentrations and BIS. Additive propofol–fentanyl interactions were observed and quantitated. The duration of the fentanyl infusion had minimal effect on CSDT when it was shorter than the duration of the propofol infusion. If the fentanyl infusion was longer than the propofol infusion, an almost two‐fold increase in CSDT occurred. Additional doses of fentanyl administered after the cessation of the propofol infusion result in lower BIS values, and can prolong the time of recovery from anesthesia. Copyright © 2016 John Wiley & Sons, Ltd.     

Pharmacokinetics and pharmacodynamics of propofol in patients undergoing abdominal aortic surgery

Available propofol pharmacokinetic protocols for target-controlled infusion (TCI) were obtained from healthy individuals. However, the disposition as well as the response to a given drug may be altered in clinical conditions. The aim of the study was to examine population pharmacokinetics (PK) and pharmacodynamics (PD) of propofol during total intravenous anesthesia (propofol/fentanyl) monitored by bispectral index (BIS) in patients scheduled for abdominal aortic surgery. Population nonlinear mixed-effect modeling was done with Nonmem. Data were obtained from ten male patients. The TCI system (Diprifusor) was used to administer propofol. The BIS index served to monitor the depth of anesthesia. The propofol dosing was adjusted to keep BIS level between 40 and 60. A two-compartment model was used to describe propofol PK. The typical values of the central and peripheral volume of distribution, and the metabolic and inter-compartmental clearance were V(C) = 24.7 l, V(T) = 112 l, Cl = 2.64 l/min and Q = 0.989 l/min. Delay of the anesthetic effect, with respect to plasma concentrations, was described by the effect compartment with the rate constant for the distribution to the effector compartment equal to 0.240 min(-1). The BIS index was linked to the effect site concentrations through a sigmoidal E(max) model with EC(50) = 2.19 mg/l. The body weight, age, blood pressure and gender were not identified as statistically significant covariates for all PK/PD parameters. The population PK/PD model was successfully developed to describe the time course and variability of propofol concentration and BIS index in patients undergoing surgery.     

Feedback modeling of non-esterified fatty acids in rats after nicotinic acid infusions

A feedback model was developed to describe the tolerance and oscillatory rebound seen in non-esterified fatty acid (NEFA) plasma concentrations following intravenous infusions of nicotinic acid (NiAc) to male Sprague-Dawley rats. NiAc was administered as an intravenous infusion over 30 min (0, 1, 5 or 20 μmol kg⁻¹ of body weight) or over 300 min (0, 5, 10 or 51 μmol kg⁻¹ of body weight), to healthy rats (n = 63), and serial arterial blood samples were taken for measurement of NiAc and NEFA plasma concentrations. Data were analyzed using nonlinear mixed effects modeling (NONMEM). The disposition of NiAc was described by a two-compartment model with endogenous turnover rate and two parallel capacity-limited elimination processes. The plasma concentration of NiAc was driving NEFA (R) turnover via an inhibitory drug-mechanism function acting on the formation of NEFA. The NEFA turnover was described by a feedback model with a moderator distributed over a series of transit compartments, where the first compartment (M ₁) inhibited the formation of R and the last compartment (M _N ) stimulated the loss of R. All processes regulating plasma NEFA concentrations were assumed to be captured by the moderator function. The potency, IC ₅₀, of NiAc was 45 nmol L⁻¹, the fractional turnover rate k _out was 0.41 L mmol⁻¹ min⁻¹ and the turnover rate of moderator k _tol was 0.027 min⁻¹. A lower physiological limit of NEFA was modeled as a NiAc-independent release (k _cap ) of NEFA into plasma and was estimated to 0.032 mmol L⁻¹ min⁻¹. This model can be used to provide information about factors that determine the time-course of NEFA response following different modes, rates and routes of administration of NiAc. The proposed model may also serve as a preclinical tool for analyzing and simulating drug-induced changes in plasma NEFA concentrations after treatment with NiAc or NiAc analogues.     

Influence of Different Fat Emulsion-Based Intravenous Formulations on the Pharmacokinetics and Pharmacodynamics of Propofol

Purpose. The influence of different intravenous formulations on the pharmacokinetics and pharmacodynamics of propofol was investigated using the effect on the EEG (11.5-30 Hz) as pharmacodynamic endpoint. Methods. Propofol was administered as an intravenous bolus infusion (30 mg/kg in 5 min) or as a continuous infusion (150 mg/kg in 5 hours) in chronically instrumented male rats. Propofol was formulated as a 1% emulsion in an Intralipid 10%^®-like fat emulsion (Diprivan-10^®, D) or as a 1%- or 6% emulsion in Lipofundin^® MCT/LCT-10% (Pl% and P6%, respectively). EEG was recorded continuously and arterial blood samples were collected serially for the determination of propofol concentrations using HPLC. Results. Following bolus infusion, the pharmacokinetics of the various propofol emulsions could adequately be described by a two-compart-mental pharmacokinetic model. The average values for clearance (Cl), volume of distribution at steady-state (V_d,ss) and terminal half-life (t_{1/2, 2}) were 107 ± 4 ml/min/kg, 1.38 ± 0.06 l/kg and 16 ± 1 min, respectively (mean ± S.E., n = 22). No significant differences were observed between the three propofol formulations. After continuous infusion these values were 112 ± 11 ml/min/kg, 5.19 ± 0.41 l/kg and 45 ± 3 min, respectively (mean±S.E., n = 20) with again no statistically significant differences between the three propofol formulations. Comparison between the bolus- and the continuous infusion revealed a statistically significant difference for both V_d,ss and t_{1/2, 2} (p < 0.05), whereas Cl remained unchanged. In all treatment groups infusion of propofol resulted in a burst-suppression type of EEG. A profound hysteresis loop was observed between blood concentrations and EEG effect for all formulations. The hysteresis was minimized by a semi-parametric method and resulted in a biphasic concentration-effect relationship of propofol that was described non-parametrically. For P6% a larger rate constant onset of drug effect (t,_{1/2, keo}) was observed compared to the other propofol formulations (p<0.05). Conclusions. The pharmacokinetics and pharmacodynamics of propofol are not affected by to a large extent the type of emulsion nor by the concentration of propofol in the intravenous formulation.     

Influence of demographic factors, basic blood test parameters and opioid type on propofol pharmacokinetics and pharmacodynamics in ASA I-III patients

The aim of the study was to examine population pharmacokinetics (PK) and pharmacodynamics (PD) of propofol (CAS 2078-54-8) during total intravenous anesthesia monitored by spectral frequency index (SFx). Twenty-eight patients of ASA physical status I-III (ASA: American Society of Anesthesiologists) scheduled for laparoscopic cholecystectomy were included. In group I an anesthesia was induced with a bolus of propofol (2 mg/kg) and remifentanil (CAS 132875-61-7) (1.0 microg/kg), followed by a continuous infusion of remifentanil. In group II, an alfentanil (CAS 71195-58-9) (10 microg/kg) bolus dose was followed by a continuous infusion of alfentanil. The general anesthetic technique included propofol, opioid and muscle relaxant. During anesthesia, the propofol infusion rate (3-8 mg/kg/h) was adjusted to the SFx value. Venous blood samples were collected from the patients during 240 min after termination of the infusion. A two compartment model was used to describe propofol PK. A standard effect compartment model was used to describe the delay between the effect and the concentration of propofol. The SFx index was linked to the effect site concentrations through a sigmoidal Emax model. The influence of continuous (body weight, age, blood pressure, heart rate and blood oxygenation, serum protein, the erythrocyte count, hemoglobin and hematocrit, serum creatinine and creatinine clearance) and categorical (gender and the type of opioid) covariates on the pharmacokinetic and pharmacodynamic parameters was investigated. PK/PD analysis was performed using NONMEM. All the screened covariates did not influence propofol PK and PD, except of the opioid type. The central compartment volume of propofol was larger in the presence of remifentanil than in the presence of alfentanil.     

Population Pharmacokinetics Analysis and Dosing Simulations Of Meropenem in Critically Ill Patients with Pulmonary Infection

PurposeThis study aimed to develop a population pharmacokinetic (PPK) model for meropenem to optimize dosing regimens for critically ill patients with pulmonary infection.Patients and methodsThis prospective PPK study of meropenem was conducted on a pooled dataset of 236 blood samples obtained from 48 patients with pulmonary infection in the intensive care unit. Meropenem plasma concentrations were measured by a validated high-performance liquid chromatography-tandem mass spectrometry method, and the data were analyzed using NONMEM. The effect of covariates on meropenem pharmacokinetics was investigated. The probability of target attainment (PTA) to achieve the target of 100% fT_>MIC at the proposed dosage regimens were investigated by Monte Carlo simulations.ResultsA two-compartment model adequately described the data with estimated glomerular filtration rate (eGFR) as a covariate significantly associated with the clearance (CL) from the central compartment. The typical value of CL was 7.48 L/h, with an eGFR adjustment factor of 0.0103 mL?1.73 m²/min, and the typical values of volume of the central compartment (V₁), peripheral compartmental clearance (Q), and volume of the peripheral compartment (V₂) were 15.9 L, 15.8 L/h, and 14.8 L, respectively. The goodness-of-fit plots, normalized prediction distribution error, and visual predictive checks showed good fitting and predictability of the final PPK model. When eGFR was >90 mL/min/1.73 m^2, and there was a short duration of infusion (<60min), it was difficult for the probability target attainment (PTA) to reach >90% for MIC ≥ 2. Continuous infusion and frequent administration were necessary to achieve the target of 100% fT_>MIC for critically ill patients with pulmonary infection.ConclusionTo achieve the optimal PTA, meropenem must be administered by frequent administration or continuously by an intravenous infusion. Our findings provide important information to optimize the meropenem regime in critically ill patients with pulmonary infection depending on eGFR values.     

Kinetics of drug action in disease states. XXI. Relationship between drug infusion rate and dose required to produce a pharmacologic effect

Computer simulations were performed to determine if the threshold dose of an infused drug (rather than the drug concentration in the biophase at onset of action) can be a suitable index for pharmacodynamic investigations as proposed by others. A two-compartment pharmacokinetic model with drug elimination from the central compartment was used for the simulations. Drug was administered into the central compartment by a constant-rate infusion, and concentrations in the central and peripheral compartments were calculated as a function of time. The pharmacologic effect was assumed to be reversible and to occur at a defined concentration (the effective concentration) in one or the other compartment. The dose required to produce an effective concentration (threshold dose) was determined as a function of infusion rate. The relationship between infusion rate and the dose required to produce an effective concentration in the peripheral compartment was found to be affected by drug distribution and elimination kinetics and by the effective concentration. The infusion rate-dose relationship showed a dose minimum at an infusion rate which others have designated as the "optimal dose rate" and have used for pharmacodynamic studies. No such minimum occurred for pharmacologic effects associated directly with drug concentrations in the central compartment. Since optimum dose rate and threshold dose are affected by both pharmacokinetic and pharmacodynamic alterations, it is concluded that this method (which avoids determination of drug concentrations) is not generally suitable for quantitative pharmacodynamic investigations.     

A pharmacokinetic-pharmacodynamic model for quantal responses with thiopental

The pharmacokinetic-pharmacodynamic model developed here characterizes the relationship between simulated plasma concentrations of thiopental and two dichotomous endpoints determined at induction of anesthesia: loss of voluntary motor power (clinical endpoint), and burst suppression of the electroencephalogram (EEG endpoint). The model incorporated data from two separate thiopental patient studies: a pharmacokinetic study with 21 males, and a pharmacodynamic study with 30 males. In the pharmacodynamic study, cumulative quantal dose-response curves for the clinical and EEG endpoints were developed from observations made during a constant-rate infusion of thiopental. Population mean parameters, derived from the bolus pharmacokinetic thiopental study, were used to simulate concentration-time data for the 150 mg·min¹ thiopental infusion rate used in the dose-response study. A single biophase model incorporating the two endpoints was generated, combining the pharmacokinetic and pharmacodynamic data from the two groups. Estimates of the mean effective thiopental concentrations affecting 50% of the population (EC₅₀s) for the clinical and EEG endpoints were 11.3 and 33.9g·ml^–1, respectively. The half-time for equilibration between arterial thiopental and the effect compartment was 2.6 min. These results are in reasonable agreement with previously described quantal concentration-response data, and with pharmacodynamic models developed for graded EEG responses. Simulation of bolus doses of thiopental with the new model provided ED₅₀s for the clinical and EEG endpoints of 265 mg and 796 mg, respectively; the dose predicted to produce loss of voluntary motor power in 90% of an adult male population was 403 mg. A model combining population pharmacokinetics with cumulative dose-response relationships could prove useful in predicting dosage regimens for those drugs with responses that are categorical.     

Pharmacokinetics and pharmacodynamics of clevidipine in healthy volunteers after intravenous infusion

Objective: To determine the pharmacokinetics and pharmacodynamics of clevidipine, a new ultrashort-acting calcium antagonist, in healthy male volunteers following a constant rate infusion. Methods: Eight healthy male volunteers received 1030 nmol · min⁻¹ of clevidipine together with a tracer dose of ³[H]-clevidipine for 1 h as an i.v. infusion. Frequent venous blood samples and effect recordings were obtained during ongoing infusion and up to 32 h following termination of the infusion. The excretion of radioactivity in urine and faeces was followed for 7 days. Results: A two-compartment model gave the best fit to the individual clevidipine blood levels, resulting in a mean blood clearance of 0.14 (0.03) l · min⁻¹ · kg⁻¹ and a mean volume of distribution at steady state of 0.6 (0.1) l · kg⁻¹. The initial half-life was 1.6 (0.3) min, and the terminal half-life was 15 (5) min. The maximum concentration of the metabolite H 152/81 was reached 2.2 (1.3) min following termination of the infusion. The mean terminal half-life of the inactive primary metabolite was 9.5 (0.8) h and the mean recovery of the radioactive dose reached 83 (3)%. Following termination of the 1 h infusion, the effect on blood pressure (BP) and heart rate was back to pre-dose values within 15 min. Conclusion: Clevidipine is a high clearance drug, which is rapidly metabolized to the corresponding inactive acid. The t_max value of the primary metabolite, and a virtually identical value of the initial half-life and the half-life for elimination from the central compartment, indicate that the initial rapid decline of the post-infusion blood levels is mainly due to elimination rather than distribution. The duration of action of clevidipine is short. Received: 23 September 1998 / Accepted in revised form: 20 November 1998     

The pharmacokinetics of single high doses of dexamethasone in cancer patients

Summary We have given single high doses of dexamethasone phosphate by intravenous infusion as an antiemetic to 15 cancer patients receiving regimens containing cisplatin and/or doxorubicin. The patients received graded doses of dexamethasone phosphate, in the range 40–200 mg, dependent upon nausea and vomiting scores, during up to three consecutive cycles of cancer chemotherapy. Plasma and urine concentrations of dexamethasone (dexamethasone alcohol) were measured by HPLC. The plasma concentration-time data were described by an open two-compartment model. The pharmacokinetic variables were independent of the dose of dexamethasone over the range studied. The terminal half-time was 4.0±0.4 h and the total body clearance was 3.5±0.4 ml·min⁻¹·kg⁻¹. The volume of the central compartment and the total apparent volume of distribution were 0.23±0.03 and 1.0±0.1 l·kg⁻¹ respectively. Approximately 8% of the dose was excreted into the urine as dexamethasone.     

Pharmacokinetic Modeling of Non-Linear Brain Distribution of Fluvoxamine in the Rat

Introduction A pharmacokinetic (PK) model is proposed for estimation of total and free brain concentrations of fluvoxamine. Materials and methods Rats with arterial and venous cannulas and a microdialysis probe in the frontal cortex received intravenous infusions of 1, 3.7 or 7.3 mg.kg⁻¹ of fluvoxamine. Analysis With increasing dose a disproportional increase in brain concentrations was observed. The kinetics of brain distribution was estimated by simultaneous analysis of plasma, free brain ECF and total brain tissue concentrations. The PK model consists of three compartments for fluvoxamine concentrations in plasma in combination with a catenary two compartment model for distribution into the brain. In this catenary model, the mass exchange between a shallow perfusion-limited and a deep brain compartment is described by a passive diffusion term and a saturable active efflux term. Results The model resulted in precise estimates of the parameters describing passive influx into (k _in) of 0.16 min⁻¹ and efflux from the shallow brain compartment (k _out) of 0.019 min⁻¹ and the fluvoxamine concentration at which 50% of the maximum active efflux (C ₅₀) is reached of 710 ng.ml⁻¹. The proposed brain distribution model constitutes a basis for precise characterization of the PK–PD correlation of fluvoxamine by taking into account the non-linearity in brain distribution.     

Influence of biophase distribution and P-glycoprotein interaction on pharmacokinetic-pharmacodynamic modelling of the effects of morphine on the EEG

BACKGROUND AND PURPOSE: The aim was to investigate the influence of biophase distribution including P-glycoprotein (Pgp) function on the pharmacokinetic-pharmacodynamic correlations of morphine's actions in rat brain. EXPERIMENTAL APPROACH: Male rats received a 10-min infusion of morphine as 4 mg kg(-1), combined with a continuous infusion of the Pgp inhibitor GF120918 or vehicle, 10 or 40 mg kg(-1). EEG signals were recorded continuously and blood samples were collected. KEY RESULTS: Profound hysteresis was observed between morphine blood concentrations and effects on the EEG. Only the termination of the EEG effect was influenced by GF120918. Biophase distribution was best described with an extended catenary biophase distribution model, with a sequential transfer and effect compartment. The rate constant for transport through the transfer compartment (k(1e)) was 0.038 min(-1), being unaffected by GF120918. In contrast, the rate constant for the loss from the effect compartment (k(eo)) decreased 60% after GF120918. The EEG effect was directly related to concentrations in the effect compartment using the sigmoidal E(max) model. The values of the pharmacodynamic parameters E(0), E(max), EC(50) and Hill factor were 45.0 microV, 44.5 microV, 451 ng ml(-1) and 2.3, respectively. CONCLUSIONS AND IMPLICATIONS: The effects of GF120918 on the distribution kinetics of morphine in the effect compartment were consistent with the distribution in brain extracellular fluid (ECF) as estimated by intracerebral microdialysis. However, the time-course of morphine concentrations at the site of action in the brain, as deduced from the biophase model, is distinctly different from the brain ECF concentrations.     

The peak bispectral index time cannot predict early phase propofol pharmacodynamics with effect site-controlled infusion algorithm

Objectives:

The plasma-effect site equilibration rate constant (ke0) of propofol was determined with peak bispectral index (BIS) time (T_PEAK) in our previous study. The present study has been conducted to evaluate the ke0''s performance with effect site-controlled infusion algorithm.

Materials and Methods:

Forty unpremedicated patients were randomized to group TE1 (Schnider''s pharmacokinetic model with ke0 adapted to T_PEAK = 74s) and TE2 (T_PEAK = 96s). In stage 1, all patients received propofol with effect-site concentration (Ce) controlled infusion. Once the pump had injected the mass of propofol necessary to achieve pre-set Ce and while the infusion was stopped, target was reset at 0 μg/ml. When BIS returned to 80 or above, then, in stage 2, the patients received plasma concentration controlled infusion for 10 min. The time of loss of responsiveness (LOR) and BIS were recorded. The differences of Ce at the time of LOR, lowest BIS between stages 1 and 2, hysteresis loop were used to evaluate the performance of ke0.

Results:

In both groups, the calculated propofol Ce at the time of LOR in stages 1 and 2 differed significantly (P<0.01); the mean lowest BIS in stage 1 were significantly higher than those in stage 2 (P < 0.05).The relations of propofol Ce versus BIS revealed the apparent hysteresis loop.

Conclusions:

The study cannot clinically validate the accuracy of application of ke0 derived from the T_PEAK = 74 s of BIS with Schnider propofol pharmacokinetic model.KEY WORDS: Bispectral index, propofol, the plasma effect site equilibration rate constant     

Pharmacokinetics and pharmacodynamics of a new reformulated microemulsion and the long-chain triglyceride emulsion of propofol in beagle dogs

Background and purpose:

Microemulsion propofol was developed to eliminate lipid solvent-related adverse events of long-chain triglyceride emulsion (LCT) propofol. We compared dose proportionality, pharmacokinetic and pharmacodynamic characteristics of both formulations.

Experimental approach:

The study was a randomized, two-period and crossover design with 7-day wash-out period. Microemulsion and LCT propofol were administered by zero-order infusion (0.75, 1.00 and 1.25 mg·kg⁻¹·min⁻¹) for 20 min in 30 beagle dogs (male/female = 5/5 for each rate). Arterial samples were collected at preset intervals. The electroencephalographic approximate entropy (ApEn) was used as a measure of propofol effect. Dose proportionality, pharmacokinetic and pharmacodynamic bioequivalence were evaluated by non-compartmental analyses. Population analysis was performed using nonlinear mixed effects modelling.

Key results:

Both formulations showed dose proportionality at the applied dose range. The ratios of geometric means of AUC_last and AUC_inf between both formulations were acceptable for bioequivalence, whereas that of C_max was not. The pharmacodynamic bioequivalence was indicated by the arithmetic means of AAC (areas above the ApEn time curves) and E₀ (baseline ApEn)–E_max (maximally decreased ApEn) between both formulations. The pharmacokinetics of both formulations were best described by three compartment models. Body weight was a significant covariate for V₁ of both formulations and sex for k₂₁ of microemulsion propofol. The blood-brain equilibration rate constants (k_e0, min⁻¹) were 0.476 and 0.696 for microemulsion and LCT propofol respectively.

Conclusions and implications:

Microemulsion propofol was pharmacodynamically bioequivalent to LCT propofol although pharmacokinetic bioequivalence was incomplete, and demonstrated linear pharmacokinetics at the applied dose ranges.     

Pharmacokinetic–pharmacodynamic modeling of the effect of propofol on α1-adrenoceptor-mediated positive inotropy in rat heart

Since it is unclear whether and how propofol affects the α₁-mediated inotropic response, we used a pharmacokinetic–pharmacodynamic modeling approach in isolated rat hearts to analyze the effect of propofol on receptor binding and signal transduction. In Langendorff rat hearts perfused with buffer containing 12.3 μM phenylephrine, 1.27 nmol doses of [³H]-prazosin were infused (over 1 min), in the absence and presence of propofol (28 μM). Simultaneous analysis of prazosin outflow concentration and inotropic response (left ventricular developed pressure) using an agonist–antagonist interaction model allowed to estimate receptor affinity, as well as the parameters of the operational model of agonism. Propofol significantly (P < 0.05) increased the negative inotropic effect of prazosin. Modeling suggested that propofol increased the Hill coefficient, which determines the steepness of the stimulus–response curve for the positive inotropic effect of phenylephrine, from 1 to 2.6 ± 0.1 and decreased the maximum achievable inotropic effect from 121.2 ± 12 to 91.8 ± 6 mmHg. Thus, propofol may attenuate the positive inotropic effect of α₁-agonists by decreasing the transduction efficiency of α₁-adrenergic receptor signaling primarily at lower receptor occupancy.     

Pharmacokinetics of ornidazole in neonates and infants after a single intravenous infusion

Summary The single dose pharmacokinetics of ornidazole has been evaluated in 12 neonates or infants (aged 1 to 42 weeks) after the infusion of 20 mg/kg over 20 min. Plasma disposition was described by a two-compartment open model. The distribution phase was short (T_1/2 (1)=0.31 h) and was followed by an elimination phase (t_1/2 (2)=14.67 h). The mean apparent volume of distribution was 0.96 l/kg^–1. These results did not differ from data previous by reported in adults. Total plasma clearance was between 0.4 and 1.4 ml·min^–1·kg^–1. The plasma concentration 24 h after the infusion was 7.32 mg·l^–1, which was above the minimum inhibitory concentration for clinically significant anaerobic bacteria. Based on the pharmacokinetic results and residual concentrations at 24 h, a single daily infusion of ornidazole 20 mg·kg^–1 appears adequate for therapy in neonates and infants.     

First-dose and steady-state population pharmacokinetics and pharmacodynamics of piperacillin by continuous or intermittent dosing in critically ill patients with sepsis

The objectives of this study were (i) to compare the plasma concentration–time profiles for first-dose and steady-state piperacillin administered by intermittent or continuous dosing to critically ill patients with sepsis and (ii) to use population pharmacokinetics to perform Monte Carlo dosing simulations in order to assess the probability of target attainment (PTA) by minimum inhibitory concentration (MIC) for different piperacillin dosing regimens against bacterial pathogens commonly encountered in critical care units. Plasma samples were collected on Days 1 and 2 of therapy in 16 critically ill patients, with 8 patients receiving intermittent bolus dosing and 8 patients receiving continuous infusion of piperacillin (administered with tazobactam). A population pharmacokinetic model was developed using NONMEM^®, which found that a two-compartment population pharmacokinetic model best described the data. Total body weight was found to be correlated with drug clearance and was included in the final model. In addition, 2000 critically ill patients were simulated for pharmacodynamic evaluation of PTA by MIC [free (unbound) concentration maintained above the MIC for 50% of the dosing interval (50% f_T>MIC)] and it was found that continuous infusion maintained superior free piperacillin concentrations compared with bolus administration across the dosing interval. Dosing simulations showed that administration of 16 g/day by continuous infusion vs. bolus dosing (4 g every 6 h) provided superior achievement of the pharmacodynamic endpoint (PTA by MIC) at 93% and 53%, respectively. These data suggest that administration of piperacillin by continuous infusion, with a loading dose, both for first dose and for subsequent dosing achieves superior pharmacodynamic targets compared with conventional bolus dosing.     

Distribution in female rats of an anaesthetic intravenous dose of 14C-propofol

1. Bolus i.v. doses of ¹⁴C-propofol (9?mg/kg) were administered to female rats for measurement of tissue levels of total ¹⁴C and propofol from 2?min to 24?h post-dose; whole-body autoradiography was studied at 6?min, 2h and 24?h post-dose, and also involved 15-day pregnant rats.

2. The blood propofol concentration-time profile was fitted by a tri-exponential function corresponding to a three-compartment open model. Data show rapid distribution during the mixing period into highly perfused tissues and muscle, comprising the central compartment, and slower uptake into less well-perfused skin and adipose tissues comprising the deeper compartments.

3. The initial decline in blood propofol concentration was associated with redistribution (t_1/2 4?min), the second decline (15–240?min post-dose) was associated with metabolism (t_1/2 33?min) and the third decline reflected slow depletion of drug from deep tissue compartments (t_1/2 6.4h).

4. Blood and brain propofol concentrations on waking (at 7?min post-dose) were 4 μg/ml and 9 μg/g respectively; the model shows that, at this time, 30% of the dose was lost from the central compartment by redistribution and a similar amount by metabolism.

5. Tissue profiles of total ¹⁴C and propofol diverged for highly perfused tissues (other than brain) because of slow clearance of metabolites, accentuated by enterohepatic recirculation.