Effect Compartment Concentration Research Articles

Propofol context-sensitive decrement times in children.

Plasma drug concentration is the variable linking dose to effect. The decrement time required for plasma concentration of anesthetic agents to decrease by 50% (context-sensitive half-time) correlates with the time taken to regain consciousness. However, the decrement time to consciousness may not be 50%. An effect compartment concentration is associated more closely with return of consciousness than plasma concentration. An alternative decrement time, the time required for propofol to decrease to a predetermined effect compartment concentration associated with movement (eg, 2µg.ml-1 ), was used to simulate time for the concentration to decrease from steady state at a typical targeted effect compartment concentration 3.5µg.ml-1 in children. These times were short and reflected a decrement time to consciousness (CSTAWAKE ) increase that was small with longer infusion time. CSTAWAKE ranged from 7.5min in 1-year-old infant given propofol for 15min to 13.5min in a 15-year-old adolescent given a 2-hour infusion. Changes in decrement time with age reflect maturation of drug clearance. Neonates had prolonged increment times, 10min after 15min infusion and 18min after 120min infusion using a target concentration of 3.5µg.ml-1 . Decrement times to a targeted arousal concentration are context-sensitive. Use of a higher target concentration of 6µg.ml-1 doubled decrement times. Decrement times are associated with variability: delayed recovery beyond these simulated times is likely more attributable to the use of adjuvant drugs or the child's clinical status. An understanding of propofol decrement times can be used to guide recovery after anesthesia.

Empirical and semi-mechanistic modelling of double-peaked pharmacokinetic profile phenomenon due to gastric emptying.

Models have been developed to explain double-peaked plasma concentration-time profiles using mechanisms such as variable absorption and enterohepatic recirculation. Interruption of gastric emptying has also been shown to produce double-peaks, and this work proposes models for analysis of such data. In the presence of levodopa, gastric emptying is interrupted at times associated with double-peaks in pharmacokinetic profiles. Data from a simultaneous scintigraphy and paracetamol absorption study with levodopa was obtained, and models with compartments for stomach, intestine, central and peripheral tissue were developed to describe levodopa and paracetamol pharmacokinetics, including the double-peak phenomenon. The empirical model uses two gastric emptying parameter rates which are applied over separate time periods to describe the varying gastric emptying rate. The semi-mechanistic model uses a feedback mechanism acting via an effect compartment to link the plasma concentration of levodopa to the rate of gastric emptying, allowing levodopa pharmacokinetics to vary the rate of gastric emptying and give rise to a multiple-peaked plasma pharmacokinetic profile. The models were applied to plasma levodopa and paracetamol pharmacokinetic data with and without simultaneous analysis of scintigraphy data, in both cases giving a good fit and in the absence of scintigraphy data adequately predicting the stomach profile. For the semi-mechanistic model, the first-order constant governing gastric emptying was shown to switch between fast and slow values at a critical levodopa effect compartment concentration. New models have thus been proposed for analysis of plasma concentration profiles that exhibit double-peak phenomenon and applied successfully to levodopa data.

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 Emax 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 2.80mg/L and the biophase distribution rate constant of 3.33min−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 Emax 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.

A Subspace-based Wiener System Identification Method for the Individualized Anesthesia Care

Abstract This study focuses on the individual sedation model identification problem, and proposes a subspace-based Wiener system identification method. The traditional compartmental pharmacokinetics-pharmacodynamics hypnosis model is considered as a specific Wiener system with the Hill equation nonlinear term. To deal with the Hill nonlinear term, the proposed method employs a set of specific bases to turn the Wiener system into a linear one, and then the subspace orthogonal projection identification method has been implemented to identify the transformed linear model. Compared with the traditional anesthesia model identification methods, the proposed method can effectively overcome the shortage of measurement data, get rid of the estimation of the effect compartment concentration which is impossible to be measured, and improve the individualization performance of the identified model. A simulation study on 24 various virtual patients from the Wang's Simulator has been conducted and validates the efficiency and robustness of the proposed method, and a drug infusion instruction has been provided in order to get relatively accurate identification performance.

Paracetamol: a focus for the general pediatrician

Paracetamol (acetaminophen) is one of the most popular and widely used drugs for the treatment of pain and fever in children. This drug has multiple mechanisms of action, but its pharmacodynamic is still not well known. The central nervous system is the main site of action and it mirrors the paracetamol effect compartment. The recommended dosages and routes of administration should be different whether paracetamol is used for the treatment of pain or fever. For example, the rectal route, while being efficacious for the treatment of fever, should be avoided in pain management. Paracetamol is a safe drug, but some clinical conditions and concomitant drugs, which are frequent in clinical practice, may increase the risk of paracetamol toxicity. Therefore, it is important to optimize its administration to avoid overdoses and maximize its effect. The principal mediator of the paracetamol toxicity is the N-acetyl-p-benzo-quinone imine (NAPQI), a toxic product of the paracetamol metabolism, which could bind cysteine groups on proteins forming paracetamol-protein adduct in the liver. Although frequently prescribed, the concept of "effect compartment concentration" and the possible co-factors that could cause toxicity at recommended doses are not familiar to all pediatricians and general practitioners. We reviewed the literature concerning paracetamol mechanisms of action, we highlighted some relevant pharmacodynamic concepts for clinical practice, and we summarized the possible risk factors for toxicity at therapeutic dosages.

Abstract 3362: Miniaturized PBPK model improves pharmacodynamic characterization and physiological interpretability for compounds with profound hysteresis in tumor.

Abstract Background: Significant hysteresis between plasma concentration and target inhibition at the effect site (e.g., tumor) is a frequent observation, commonly described mathematically by connecting the central (i.e., plasma) compartment to an ‘effect compartment’ by a ‘link’ which causes the concentration in the latter to be delayed relative to the plasma. The result is a direct response between effect-compartment concentration and target inhibition. A significant drawback is that the effect compartment cannot be observed (making it impossible to validate) and has no physiological interpretation (rendering communication with other disciplines difficult). We develop a novel approach that is more physiologically meaningful, provides more-precise model parameter estimates, and gives insight into the physico-chemical factors limiting distribution into the tumor. Method: We orally administered single doses of several compounds (including Crizotinib, AZD3463, and others) targeting ALK to mice bearing tumors derived from the DEL and H3122 non-small-cell lung cancer line, at several dose levels. At 6, 24, and 48 hours post-dose, we measured the plasma and tumor concentrations of each compound and associated target inhibition (phosphorylated ALK, pALK) in the tumor. pALK inhibition shows a direct response not to plasma, but to tumor concentration, indicating that the delay is distributional in nature. We constructed a miniature physiologically-based pharmacokinetic (mPBPK) model consisting of a central compartment and a tumor of fixed physiological volume. pALK inhibition was modeled as a direct Emax response to tumor concentration. For each compound, we simultaneously fitted the mPBPK model to the naïve-pooled plasma and tumor concentrations, as well as pALK, using all available dose levels. Beyond the standard PK and PD parameters (Emax, E0, IC50) we also fitted the tumor partition constant Kp, and tumor blood flow rate Qt. For comparison, we fitted a standard effect-compartment (‘link’) model to the plasma concentrations and pALK levels to the same data. Results: For each compound, we computed unbound EC50 for both effect-compartment and mPBPK models. We found that while the point estimates largely agree, the mPBPK model delivers more-precise estimates (typically 50% lower CV%). We attribute this to its use of additional data (tumor concentration) to constrain the model, which more than compensates for the additional parameters in the mPBPK model. We find that there is broad consistency in estimates of tumor flow rate Qt across the compounds studied, indicating that distribution from plasma to site of action is limited by blood flow, rather than by permeability. Additionally, we found that the greater physiological interpretability of the mPBPK model enhances cross-functional communication within project teams. Citation Format: Francis D. Gibbons, Dan Widzowski, Minhui Shen, Jane Cheng, Lisa Drew, Jamal C. Saeh, Douglas Ferguson. Miniaturized PBPK model improves pharmacodynamic characterization and physiological interpretability for compounds with profound hysteresis in tumor. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3362. doi:10.1158/1538-7445.AM2013-3362

The Response of the Composite Variability Index to a Standardized Noxious Stimulus During Propofol-Remifentanil Anesthesia

Recently the Composite Variability Index (CVI) was developed to quantify nociception. This index is derived from the standard deviations (s) of the Bispectral Index (sBIS) and the electromyogram (sEMG). The primary aim of our study was to compare CVI before and after a noxious stimulus. As secondary end points, we investigated the influence of remifentanil on the CVI and tested the ability of the CVI to indicate patient movement after a noxious stimulus under changing remifentanil concentrations. Furthermore, we measured the increase in CVI after a noxious stimulus in comparison to other clinical variables (BIS, sBIS, sEMG, heart rate [HR], and systolic blood pressure [BP(sys)]). Twenty-four patients without a history of cardiac disease were investigated. Anesthesia was induced with propofol administered by target-controlled infusion. A standardized noxious electrical stimulus was applied (50 Hz, 70 mA, 30 seconds) to the ulnar nerve at increasing or decreasing remifentanil effect-compartment concentrations (Ce(remi)). Changes in baseline and poststimulus CVI, BIS, sBIS, sEMG, HR, and BP(sys) were investigated. Parameters' ability to indicate movement after a noxious stimulus was evaluated with the prediction probability (P(K)). All investigated parameters (except BP(sys)) increased significantly after a noxious stimulus at 0, 1, 2, or 3 ng·mL(-1) Ce(remi). The association between poststimulus maximal parameters and movement were P(K) = 0.81 for HR, P(K) = 0.78 for sEMG, and P(K) = 0.72 for CVI (pairwise difference to CVI statistically nonsignificant). The association between ΔsEMG or ΔCVI (poststimulus value minus baseline value) and movement was significantly higher (P(K) = 0.76 and 0.75, respectively) compared with ΔHR (P(K) = 0.53) (P = 0.008 and P = 0.01, respectively). Receiver operating characteristic analysis revealed a threshold value for movement for ΔCVI of >0.39 (sensitivity of 0.71, specificity of 0.74) and for ΔsEMG of >0.31 (sensitivity of 0.68, specificity of 0.78). In paralyzed patients, ΔsEMG and ΔCVI might help identify inadequately low levels of analgesia with an acceptable sensitivity and specificity. The impact of profound neuromuscular block on the CVI should be investigated in further studies.

The paracetamol concentration‐effect relation in neonates

We suggested a loading dose (20 mg · kg(-1) ) followed by 10 mg · kg(-1) q6h of intravenous (IV) paracetamol to achieve an effect compartment concentration of 11 mg · l(-1) in neonates. Since there are no pharmacodynamic data to support such an effect compartment concentration, pain scores collected in neonates treated with an IV paracetamol loading dose (20 mg · kg(-1) ) were used to validate this effect compartment concentration. Pain scores (Leuven Neonatal Pain Score, LNPS, 0-14) before and 0.5, 1, 2, 3, 4, 5, and 6 h after IV paracetamol loading dose administration in neonates to whom IV paracetamol was administered as single analgesic (PARANEO, www.clinicaltrials.gov, NCT00969176) were collected. Trends were analyzed using repeated measures anova. An E(max) model with a delayed response compartment was fitted to data using population modeling. Nineteen of 60 neonates included in the PARANEO study received monotherapy with IV paracetamol to treat mild to moderate pain (e.g., alprostadil administration, delivery related trauma). Using repeated measures anova, there was a trend (P = 0.02) for lower pain scores within 30 min after administration, with a slight increase in pain scores from 5 to 6 h. An E(max) model had a maximum effect of 4.15 pain units, an EC(50) of 2.07 mg · l(-1). Equilibration halftime (T(1/2) keo) was 1.58 h. Intravenous paracetamol is effective for moderate pain. An effect compartment concentration of 10 mg · l(-1) (loading dose of 20 mg · kg(-1) ) is associated with a pain score reduction of 3.4 LNPS units. This analysis suggests a similar paracetamol effect compartment concentration in neonates compared to children.

Utility of Nociceptive Flexion Reflex Threshold, Bispectral Index, Composite Variability Index and Noxious Stimulation Response Index as measures for nociception during general anaesthesia

Movement and haemodynamic responses to noxious stimuli during general anaesthesia are regarded as signs of nociception. We compared the Nociceptive Flexion Reflex Threshold (NFRT), Bispectral Index (BIS), Composite Variability Index (CVI), Noxious Stimulation Response Index (NSRI) and the calculated propofol/remifentanil effect-compartment concentrations (Ce) as predictors for such responses in 50 female subjects at laryngeal mask airway insertion and skin incision. The following prediction probabilities (PK-values) were obtained at laryngeal mask airway insertion and skin incision, respectively. For movement responses: NFRT = 0.77 and 0.72; p = 0.0001 and 0.004, respectively; BIS = 0.41 and 0.56, p = 0.29 and 0.5, respectively; CVI = 0.48 and 0.57, p = 0.76 and 0.88, respectively; NSRI = 0.49 and 0.76, p = 0.92 and 0.0001, respectively; propofol-Ce = 0.35 and 0.66, p = 0.04 and 0.03, respectively; remifentanil-Ce = 0.68 and 0.72, p = 0.01 and 0.003, respectively. For heart rate responses: NFRT = 0.68 and 0.75, p = 0.04 and 0.01, respectively; BIS = 0.37 and 0.59, p = 0.15 and 0.41, respectively; CVI = 0.41 and 0.44, p = 0.39 and 0.37, respectively; NSRI = 0.48 and 0.53, p = 0.84 and 0.78, respectively; propofol-Ce = 0.42 and 0.56, p = 0.39 and 0.53, respectively; remifentanil-Ce = 0.58 and 0.54, p = 0.35 and 0.73, respectively. We conclude that the NFRT best predicts movement and heart rate responses to noxious stimuli. Effect-compartment concentrations and NSRI also predict movement (but not heart rate) responses satisfactorily.

The pharmacokinetics and pharmacodynamics of cisatracurium in critically ill patients with severe sepsis

To characterize the pharmacokinetics (PK) and pharmacodynamics (PD) of cisatracurium in critically ill patients with severe sepsis. Blood samples were collected before and over 8 h after a single bolus dose of cisatracurium 0.1 mg kg(-1) . Neuromuscular block was assessed by accelerometric peripheral nerve stimulation (TOF Watch). Plasma concentration and neuromuscular block data were fitted using population analysis. Steady-state volume of distribution was determined to be 111 ± 71 ml kg(-1) and plasma clearance was 5.2 ± 1.8 ml min(-1) kg(-1) in these patients with greater inter-patient variability compared with other populations. The time to maximum block (8.3 ± 2.9 min) and delay time of transferring from central to effect compartment (17.2 min) was much longer, while the maximum block (95.0 ± 6.3%) was less compared with those in other patient populations. The effect compartment concentration resulting in 50% of maximum effect (128 ± 58 ng ml(-1)) was larger than previously described. This study suggests that standard dosing of cisatracurium in patients with severe sepsis results in a slower patient response with a reduced effect. Use of a larger dose may overcome this reduced delayed response.

Ocular Pharmacokinetics of a Novel Tetrahydroquinoline Analog in Rabbit: Compartmental Analysis and PK–PD Evaluation

The elimination kinetics of the pharmacologically active compound 1-ethyl-6-fluoro-1,2,3,4-tetrahydroquinoline (MC4) were characterized along with pharmacodynamic (PD) measurements. Four compartmental models based on ocular anatomy, physiology, and possible absorption and disposition pathways were proposed to model the pharmacokinetic (PK) data in WinNonlin and the best model was chosen based on statistical and goodness-of-fit criteria. A three-compartment physiologic-based PK model with a bidirectional transfer between cornea and aqueous humor and a unidirectional transfer between aqueous humor and iris-ciliary body best described the data. The ocular PD parameters, maximum effect attributed to drug (E(max)) and drug concentration which produces 50% of maximum effect (EC(50)), were estimated with change in intraocular pressure (ΔIOP) as the effect (PD response) in the effect compartment model (PK-PD link model) using aqueous humor concentration-time and ΔIOP-time profiles. The link model better described the effect compartment concentrations than a simple E(max) model that used iris-ciliary body concentration-time data, indicating that there is an apparent temporal displacement between aqueous humor concentration (plasma/central compartment equivalent) and pharmacological effect. A physiologically plausible value of 0.0159 min(-1) was obtained for the drug elimination rate constant (k(eo)) from the effect site to account for equilibration time in the biophase. Hysteresis was observed for the iris-ciliary body, aqueous humor drug concentrations, and effect data, further confirming the utility of the link model to describe the PD of MC4.

Effect of pediatric TCI system for propofol plus remifentanil in pediatric short-duration surgery with laryngeal mask airway anesthesia

To study the effect of a pediatric TCI patent system for propofol plus remifentanil in pediatric short-duration surgery with laryngeal mask airway (LMA) anesthesia. A total of 120 pediatric patients underwent short-duration elective surgery, aged 3 - 9 years old, weighted 13 - 26 kg, ASAI grade, were randomly divided into 3 groups (n = 40 each). The propofol concentrations of effect compartment were set at 2 µg/ml in Group A, 3 µg/ml in Group B and 4 µg/ml in Group C. The remifentanil initial concentration of plasma compartment was 2 ng/ml and increased stepwise by 0.5 ng/ml until a successful insertion of LMA. The remifentanil concentration was recorded when LMA was successfully inserted and the cases were numerated at the each remifentanil concentration. Heart rate (HR), mean arterial pressure (MAP), BIS (bispectral index) values and postoperative adverse events were also recorded at the time points of pre-induction (T0), 2 min post-remifentanil TCI (T1), LMA insertion (T2), skin incision (T3), 5 min post-skin incision (T4), 10 min post-skin incision, (T5) and beginning surgery (T6). The satisfactory ratios of a successful insertion of LMA were highest in remifentanil 3.0 ng/ml (AR subgroup), 2.5 ng/ml (BR subgroup) and 2.0 ng/ml (CR subgroup) respectively. The laryngeal mask satisfactory ratio was high in BR subgroup (P < 0.05). There were significantly differences of T1-T5 values of HR, MAP and BIS in AR and CR subgroups (P < 0.05), but not in BR subgroup. The above-mentioned monitoring indices at T2 in AR subgroup and T3 in CR subgroup were significantly higher than those in BR subgroup. There were more adverse reactions in CR and AR subgroups versus BR subgroup (P < 0.05). The patented system for propofol 3 µg/ml effect compartment concentration plus remifentanil 2.5 ng/ml plasma concentration TCI displays stable hemodynamics, less stress, fewer complications and better clinical outcomes in pediatric short-duration surgery with LMA anesthesia.

A pharmacokinetic–pharmacodynamic model for cardiovascular safety assessment of R1551

Introduction Pharmacokinetic–pharmacodynamic relationships are crucial in understanding a drug's arrhythmogenic potential. Models assist to quantitatively relate parent and metabolite concentrations to adverse electrocardiographic effects, including an apparent delay between effect and circulating parent species concentration. Here, we used an effect compartment model to investigate PR and QRS prolongation previously observed in preclinical studies with the NK1–NK3 antagonist R1551. Method Using a cross-over design, beagle dogs received a single oral dose of R1551 (0–100 mg/kg), and cynomolgus monkeys received oral doses of 0–30 mg/kg once daily for 5 days. PR and QRS intervals and heart rate were measured by telemetry, for ≥ 24 h after each dose in dogs, and on treatment days 1, 3, and 5 in monkeys. Pharmacokinetic parameters were estimated by fitting a two-compartment model to the data. For each species, a linear effect compartment model was used to relate PR and QRS intervals to effect compartment concentrations. Results The effect compartment model provided a good fit to the observed data for both ECG parameters in dogs, and for QRS interval in monkeys (PR 0 = 95.1 ms ± 2.74 and 64.9 ms ± 1.46, QRS 0 = 42.5 ms ± 1.24 and 46.5 ms ± 1.11 in dog and monkey, respectively). For PR interval in monkeys, the fit was improved by adding a placebo effect compartment to the linear model. R1551 effects on intervals in dogs suggested the presence of responder and non-responder sub-populations. In monkeys, only the highest R1551 dose prolonged PR intervals. Effect slope factors were similar between dog and monkey for both intervals (S PR = 0.00930 ms mg −1 kg −1 l −1 ± 0.00133 in dog and 0.00934 ms mg −1 kg −1 l −1 ± 0.00141 in monkey; S QRS = 0.00274 ms mg −1 kg −1 l −1 ± 0.00101 in dog and 0.00200 ms mg −1 kg −1 l −1 ± 0.000552 in monkey). Discussion Our results indicate a non-linear relationship between R1551 plasma kinetics and electrophysiological effects and suggest that the parent was not responsible for the observed ECG effects. In addition, the population based approach allows exploitation of sparse PK data in dog and monkey, analysis throughout the complete effect time course, and assessment of inter-individual variability, all in a single comprehensive model.

Population Pharmacokinetics and Pharmacodynamics of Cinaciguat, a Soluble Guanylate Cyclase Activator, in Patients with Acute Decompensated Heart Failure

Cinaciguat (BAY 58-2667) is a novel soluble guanylate cyclase activator in clinical development for the treatment of acute decompensated heart failure (ADHF). In patients with ADHF, intravenously administered cinaciguat results in potent unloading of the heart with arterial vasodilation. The aims of this study were to define the structural pharmacokinetic and pharmacodynamic models of cinaciguat in patients with ADHF, to characterize interindividual variability and to explore the effects of potential covariates. Modelling was performed using NONMEM version V software, based on data from 56 adult patients with ADHF (pulmonary capillary wedge pressure > or = 18 mmHg) participating in a phase II study. Cinaciguat pharmacokinetics were well described using an open, two-compartment model with an 'effect compartment' and elimination from the central compartment. The population mean estimates for the clearance and volume of distribution at steady state were 26.4 L/h and 18.4 L, respectively. The pharmacokinetics were linear, with no dose-dependent or time-dependent effects on the clearance or volume of distribution, and with moderate interindividual variability. Covariate analyses showed that cardiac output significantly affected clearance, whereas patient age, bodyweight and renal function did not. Time delays between plasma concentrations and effect compartment concentrations, as described by the dissipation rate constant from the effect compartment, ranged from 0.32 h(-1) to 0.86 h(-1) for the different haemodynamic parameters of the final pharmacokinetic/pharmacodynamic model. A 50% recovery to pharmacodynamic baseline values was estimated to occur within 1 hour and a complete return to baseline was estimated to occur within 3-4 hours after the end of infusion. Intravenously administered cinaciguat had predictable pharmacokinetic and haemodynamic effects in patients with ADHF.

Comparative pharmacodynamic modeling of desflurane, sevoflurane and isoflurane

We compared dose-response curves of the hypnotic effects of desflurane, sevoflurane and isoflurane. In addition, we analyzed the k(e0) values of the different anesthetics. The EEG parameters Bispectral index (BIS, Aspect Medical Systems, Natick, MA, version XP) and Narcotrend index (MonitorTechnik, Bad Bramstedt, Germany, version 4.0) were used as measures of the pharmacodynamic effect. With IRB approval and informed consent we analyzed the data of three studies including 61 adult patients scheduled for radical prostatectomies. At least 45 min after induction of general anesthesia, end-tidal concentrations of desflurane, sevoflurane or isoflurane were varied between 0.5 and 2 MAC. We transferred the end-tidal concentrations into age-related MAC values. The relationship between MAC effect compartment concentrations and EEG was modeled with a variation of the classical fractional sigmoid E(max) model with two linked sigmoidal curves. All parameters were calculated as a population fit by NONMEM V (GloboMax, Hanover, USA) by minimizing log likelihood. The k(e0) values of the population fit derived from BIS data were 0.54 min(-1) for desflurane, 0.24 min(-1) for sevoflurane and 0.16 min(-1) for isoflurane, from the Narcotrend index 0.43 min(-1) for desflurane, 0.26 min(-1) for sevoflurane and 0.18 min(-1) for isoflurane. The change between the first and the second sigmoidal curve was positioned at nearly the same Narcotrend- and BIS index values between 41 and 44. The first order rate constant (k(e0) value) determining the equilibration between age-related MAC values and MAC effect site concentration is substantially higher for desflurane than for sevoflurane or isoflurane.

Pharmacokinetics of sertindole and its metabolite dehydrosertindole in rats and characterization of their comparative pharmacodynamics based on in vivo D2 receptor occupancy and behavioural conditioned avoidance response

The objectives of this study were to characterize the pharmacokinetics of sertindole and its active metabolite dehydrosertindole in rats and to evaluate the central modulatory and behavioural pharmacodynamics including a competitive interaction model between the compounds. Following oral administration of sertindole or dehydrosertindole, the plasma concentration-time courses were determined in conjunction with striatal dopamine D(2) receptor binding. In addition, the behavioural effects were recorded in the conditioned avoidance response (CAR) paradigm. A one-compartment model with Michaelis-Menten elimination best described the pharmacokinetics of sertindole. Formation of dehydrosertindole was incorporated into the pharmacokinetic model and exhibited first-order elimination. PK/PD modelling after administration of dehydrosertindole resulted in potency estimates of 165 and 424 ng/ml for D(2)-occupancy (Kd) and CAR measurements (EC(50)), respectively. The pharmacokinetics of the parent-metabolite system was integrated into a competitive pharmacodynamic E(max) model in order to quantitate the potency of sertindole with the pharmacodynamic parameters of the metabolite taken into account. Based on this approach, effect compartment concentrations of sertindole needed to attain 50% occupancy and half-maximal effect in the CAR paradigm were 133 and 338 ng/ml, respectively. The corresponding potency-estimates obtained after conventional modelling of the sertindole data without accounting for the metabolite amounted to 102 and 345 ng/ml. Based on competitive PK/PD analysis of the parent-metabolite interaction, the relative contribution of dehydrosertindole to the overall pharmacological effect after sertindole administration in rats appeared to be of minor significance. This could mainly be ascribed to the relatively low extent of bioconversion of sertindole into dehydrosertindole in this species.

Intravenous neonatal paracetamol dosing: the magic of 10 days

Intravenous (i.v.) paracetamol (acetaminophen) is gaining increasing use in neonates (1–3), despite an off-label status in some countries. Product information for i.v. paracetamol does not consider the clearance maturation with age in neonates in its dosing recommendations. In Australasia the same dose of 15 mgAEkg 6 h is suggested for neonates over 10 days of age and for infants and children up to 33 kg. A reduced dose of 7.5 mgAEkg 6 h is proposed in term neonates <10 days of age. In Europe there is no labeled use for neonates <10 days of age. The registered dose is 7.5 mgAEkg 6 h for neonates after 10 days of age through to infants of 10 kg. A dose of 15 mgAEkg 6 h (max daily dose 60 mgAEkg) is recommended between 10 and 40 kg. These dosing regimens suggest something magic about 10 days. There are data concerning the pharmacokinetics of this formulation in neonates. Population pharmacokinetics of the i.v. prodrug (propacetamol) have been studied in neonates following single (4,5) and repeat dose administration (6). Parameter estimates from neonates given repeat doses of i.v. paracetamol over a median of 4 days duration are consistent with those estimated using propacetamol (7). Dosing regimens used in some institutions for neonates have been published in Pediatric Anesthesia (2,8), but there are few data validating the safety or effectiveness of these regimens. The idea that a target effect and associated target concentration can be used to make rational individual dose decisions has acceptance (9). A knowledge of neonatal pharmacokinetics assists with dose prediction to achieve the target concentration. There are, however, flaws and constraints of current knowledge that limit implementation of this approach to dosing.

Comparison of the nociceptive flexion reflex threshold and the bispectral index as monitors of movement responses to noxious stimuli under propofol mono-anaesthesia

Prediction of movement responses to noxious stimuli during anaesthesia is of clinical importance. Susceptibility of a parameter of immobility to both hypnotic and analgesic influences could pose an advantage. Here, nociceptive reflexes might be useful, but data regarding the suppression by hypnotic substances are scarce. Therefore, we compared the prediction of movement responses by the RIII reflex threshold and the bispectral index (BIS) during propofol mono-anaesthesia. Fifteen male volunteers were included. Propofol effect compartment concentration was increased every 15 min in steps of 1 microg ml(-1) (max 7 microg ml(-1)). Every 5 min, the reactions to trapezius squeezes and 30 s tetanic stimulations (80 mA) of the right ulnar nerve were tested. The RIII reflex threshold was estimated continuously using an automated threshold tracking system that analyses the nociceptive RIII response at the left biceps femoris muscle to stimulation of the left sural nerve. Twelve subjects completed the study. RIII threshold values were normalized by subtraction of the first threshold that was estimated after the subject's loss of consciousness. The population prediction probability P(K) amounted to 0.84 for the RIII threshold and to 0.86 for the BIS (difference not significant). Movement responses to noxious stimuli under propofol can be predicted by the RIII threshold with a comparable accuracy as the BIS. Therefore, the RIII threshold seems to be influenced by hypnotic effects. Since susceptibility of the RIII threshold to analgesic influences is well established, an advantage for the RIII threshold in the prediction of motor responses could be expected when analgesic substances are used in addition to propofol.

Variability Comparison of the Composite Auditory Evoked Potential Index and the Bispectral Index During Propofol-Fentanyl Anesthesia

Monitors of hypnotic depth help anesthesiologists to guide the anesthetic. The performance of different monitors depends on several factors, index variability at a steady state of hypnotic depth being one. We compared the recently introduced AAI1.6 with the established bispectral index (BIS), regarding index variability during stable values of propofol effect-site concentration. After ethics committee approval and written informed consent, anesthesia was performed in 40 patients with propofol as the target controlled infusion and fentanyl. Variability of BIS and AAI1.6 was calculated during periods of constant predicted propofol effect compartment concentration and constant levels of surgical stimulation as the median absolute deviation (MAD) from the median value. A variability index was calculated as 1.48*MAD/(threshold - median value), with threshold being the division line between awake and asleep. Threshold crossing time was used to evaluate the performance in predicting return of consciousness. Variability index, however, was significantly larger for the AAI1.6, despite similar absolute variability measured as MAD. Lightening of anesthesia before recovery could be noticed earlier using the BIS than the AAI1.6, although consciousness was detected with a significantly higher Pk-value by the AAI1.6. Variability in relation to the difference between the median index value during anesthesia and the threshold necessary to detect consciousness with high sensitivity is higher for the AAI1.6 than for the BIS. This, as well as the steeper concentration-response function found for AAI1.6, impairs the performance of the AAI1.6 in predicting imminent return of consciousness during decreasing propofol concentrations. However, it makes AAI1.6 well suited to detect consciousness when it has occurred.

Interaction between propofol and thiopental: Isobolographic analysis using dose, central compartment and effect compartment concentrations

Interaction between propofol and thiopental: Isobolographic analysis using dose, central compartment and effect compartment concentrations