Phenylpiperidine opioid effects on isoflurane minimum alveolar concentration in cats.

Different structurally related phenylpiperidine opioids exhibit different isoflurane-sparing effects in cats. Because minimum alveolar concentration (MAC) in cats is affected only by very high plasma concentrations of some phenylpiperidine opioids, we hypothesized these effects are caused by actions on nonopioid receptors. Using a prospective, randomized, crossover design, six cats were anesthetized with isoflurane, intubated, ventilated, and instrumented. Isoflurane MAC was measured in triplicate using a tail-clamp and bracketing technique. A computer-controlled intravenous infusion using prior pharmacokinetic models targeted plasma concentrations of 60 ng/ml fentanyl, 10 ng/ml sufentanil, or 500 ng/ml alfentanil, and isoflurane MAC was measured in duplicate. Next, naltrexone 0.6 mg/kg was administered to cats hourly during the opioid infusion, and isoflurane MAC was measured in duplicate. Blood was collected during MAC determinations to measure opioid concentrations. Responses were analyzed using repeated measures ANOVA with significance at p < .05. Alfentanil and sufentanil decreased isoflurane MAC by 16.4% and 6.4%, respectively, and these effects were completely reversed by naltrexone. Fentanyl had no significant effect on isoflurane MAC. Alfentanil and sufentanil modestly reduce isoflurane MAC via agonist effects on opioid receptors. However, these effects are too small to justify clinical use of phenylpiperidine opioids as single agents to reduce MAC in cats.

Preterm Physiologically Based Pharmacokinetic Model. Part II: Applications of the Model to Predict Drug Pharmacokinetics in the Preterm Population.

BACKGROUND: Preterm neonates are usually not part of a traditional drug development programme, however they are frequently administered medicines. Developing modelling and simulation tools, such as physiologically based pharmacokinetic (PBPK) models that incorporate developmental physiology and maturation of drug metabolism, can be used to predict drug exposure in this group of patients, and may help to optimize drug dose adjustment. OBJECTIVE: The aim of this study was to assess and verify the predictability of a preterm PBPK model using compounds that undergo diverse renal and/or hepatic clearance based on the knowledge of their disposition in adults. METHODS: A PBPK model was developed in the Simcyp Simulator V17 to predict the pharmacokinetics (PK) of drugs in preterm neonates. Drug parameters for alfentanil, midazolam, caffeine, ibuprofen, gentamicin and vancomycin were collated from the literature. Predicted PK parameters and profiles were compared against the observed data. RESULTS: The preterm PBPK model predicted the PK changes of the six compounds using ontogeny functions for cytochrome P450 (CYP) 1A2, CYP2C9 and CYP3A4 after oral and intravenous administrations. For gentamicin and vancomycin, the maturation of renal function was able to predict the exposure of these two compounds after intravenous administration. All PK parameter predictions were within a twofold error criteria. CONCLUSION: While the developed preterm model for the prediction of PK behaviour in preterm patients is not intended to replace clinical studies, it can potentially help with deciding on first-time dosing in this population and study design in the absence of clinical data.

Plasma concentration based response surface model predict better than effect-site concentration based model for wake-up time during gastrointestinal endoscopy sedation.

BACKGROUND: Sedation for esophagogastroduodenoscopy (EGD) and colonoscopy is characterized by rapid patient induction and emergence. The drugs midazolam and alfentanil have long been used for procedural sedation; however, the relationship between plasma or effect-site concentrations (Cp or Ce, respectively) and emergence remains unclear. The aim of this study is to develop patient wake-up prediction models for both Cp and Ce using response surface modeling, a pharmacodynamics tool for assessing patients' responses. METHODS: The Observer's Alertness/Sedation (OAA/S) score was used to monitor sedation depth during the examinations. Concentration pairs of midazolam and alfentanil were calculated for each of Cp and Ce using pharmacokinetic simulation software. Response surface models were developed using the Greco construct. Temporal analysis was done by comparing model-predicted wake-up time with true patient wake-up time. RESULTS: Thirty-three patients with an average body mass index of 21.85 ± 2.3 kg/m2 were pooled for analysis. The average duration of examination were 2.9 ± 1.4 min for EGD and 6.6 ± 2.7 min for colonoscopy. Seventy-five concentration pairs of midazolam and alfentanil were obtained for each Cp and Ce. The Cp-based Greco response surface model showed significant synergy between midazolam and alfentanil and was a better predictor of patient wake-up time, with an average deviation of 1.0 ± 3.9 min, while the Ce model show time deviation greater than 20 min. CONCLUSION: The early phases of drug distribution are unique and complicated by nonsteady-state concentrations, and our study revealed that Ce-based wake-up time prediction is more difficult under these circumstances.

Adaptation of non-linear mixed amount with zero amount response surface model for analysis of concentration-dependent synergism and safety with midazolam, alfentanil, and propofol sedation.

BACKGROUND: The non-linear mixed amount with zero amounts response surface model can be used to describe drug interactions and predict loss of response to noxious stimuli and respiratory depression. We aimed to determine whether this response surface model could be used to model sedation with the triple drug combination of midazolam, alfentanil and propofol. METHODS: Sedation was monitored in 56 patients undergoing gastrointestinal endoscopy (modelling group) using modified alertness/sedation scores. A total of 227 combinations of effect-site concentrations were derived from pharmacokinetic models. Accuracy and the area under the receiver operating characteristic curve were calculated. Accuracy was defined as an absolute difference <0.5 between the binary patient responses and the predicted probability of loss of responsiveness. Validation was performed with a separate group (validation group) of 47 patients. RESULTS: Effect-site concentration ranged from 0 to 108 ng ml-1 for midazolam, 0-156 ng ml-1 for alfentanil, and 0-2.6 µg ml-1 for propofol in both groups. Synergy was strongest with midazolam and alfentanil (24.3% decrease in U50, concentration for half maximal drug effect). Adding propofol, a third drug, offered little additional synergy (25.8% decrease in U50). Two patients (3%) experienced respiratory depression. Model accuracy was 83% and 76%, area under the curve was 0.87 and 0.80 for the modelling and validation group, respectively. CONCLUSION: The non-linear mixed amount with zero amounts triple interaction response surface model predicts patient sedation responses during endoscopy with combinations of midazolam, alfentanil, or propofol that fall within clinical use. Our model also suggests a safety margin of alfentanil fraction <0.12 that avoids respiratory depression after loss of responsiveness.

Multistep Unified Models Using Prior Knowledge for the Prediction of Drug Clearance in Neonates and Infants.

Allometric approaches are widely used for interspecies scaling for the prediction of pharmacokinetic (PK) parameters during drug development. The concept of allometry can also be extended to predict PK parameters from adults to children. Three methods for extrapolating pediatric clearance were developed and evaluated using the clearance values of 4 drugs. The first method was established using a simple allometric (SA) model with estimated coefficient and exponent based on data ranging from children older than 2 years to adult. Then we developed a unified multistep single-exponent (MSE) and multistep body-weight-dependent exponent (MBDE) models. The major steps in these 2 new methods include generating pseudopredicted clearance for unobserved new populations such as preterm neonates, term neonates, and infants. Subsequent steps involve incorporating the pseudopredicted clearance with the actual PK data from older children and adults. All 3 models were then used to predict drug clearance in children ≤2 years old (N = 278). Drug clearance was predicted with mean absolute error of 29.6, 14.2, and 12.9 using SA, MSE, MBDE, respectively. The root mean square error was 65.9, 29.8, 24.7 for SA, MSE, MBDE, respectively. Approximately 41%, 72%, and 74% of the children's clearance data were within 0.5 to 1.5-fold of the observed values when drug clearance was extrapolated using SA, MSE, and MBDE models, respectively. The present multistep unified extrapolation approaches improved the prediction of clearance from preterm neonates to 2 years of age and may have practical use for first-in-pediatric dose selection.

Pharmacokinetics of Fentanyl and Its Derivatives in Children: A Comprehensive Review.

Fentanyl and its derivatives sufentanil, alfentanil, and remifentanil are potent opioids. A comprehensive review of the use of fentanyl and its derivatives in the pediatric population was performed using the National Library of Medicine PubMed. Studies were included if they contained original pharmacokinetic parameters or models using established routes of administration in patients younger than 18 years of age. Of 372 retrieved articles, 44 eligible pharmacokinetic studies contained data of 821 patients younger than 18 years of age, including more than 46 preterm infants, 64 full-term neonates, 115 infants/toddlers, 188 children, and 28 adolescents. Underlying diagnoses included congenital heart and pulmonary disease and abdominal disorders. Routes of drug administration were intravenous, epidural, oral-transmucosal, intranasal, and transdermal. Despite extensive use in daily clinical practice, few studies have been performed. Preterm and term infants have lower clearance and protein binding. Pharmacokinetics was not altered by chronic renal or hepatic disease. Analyses of the pooled individual patients' data revealed that clearance maturation relating to body weight could be best described by the Hill function for sufentanil (R 2 = 0.71, B max 876 mL/min, K 50 16.3 kg) and alfentanil (R 2 = 0.70, B max (fixed) 420 mL/min, K 50 28 kg). The allometric exponent for estimation of clearance of sufentanil was 0.99 and 0.75 for alfentanil clearance. Maturation of remifentanil clearance was described by linear regression to bodyweight (R 2 = 0.69). The allometric exponent for estimation of remifentanil clearance was 0.76. For fentanyl, linear regression showed only a weak correlation between clearance and bodyweight in preterm and term neonates (R 2 = 0.22) owing to a lack of data in older age groups. A large heterogeneity regarding study design, clinical setting, drug administration, laboratory assays, and pharmacokinetic estimation was observed between studies introducing bias into the analyses performed in this review. A limitation of this review is that pharmacokinetic data, based on different modes of administration, dosing schemes, and parameter estimation methods, were combined.

Doxapram-mediated Increase in Cardiac Output Reduces Opioid Plasma Concentrations: A Pharmacokinetic/Pharmacodynamic-Pharmacokinetic/Pharmacodynamic Modeling Study in Healthy Volunteers.

Doxapram is an analeptic that induces ventilatory stimulation and increases blood pressure and cardiac output (CO). Its mechanism of action is the blockade of background K+ -channels expressed on type 1 carotid body cells. In the randomized controlled trial, the authors explored the role of the increase in CO by doxapram (plasma concentration (Cp) 1,000-3,500 ng/mL) on the pharmacokinetics (PKs) and pharmacodynamics (PDs) of the potent opioid alfentanil (Cp 100-200 ng/mL). Population PK-PD analyses were performed on the doxapram PK-CO data and the alfentanil PK-antinociception data. The analyses showed that the doxapram-induced increase in CO explained the increase in alfentanil distribution and elimination clearances causing a significant reduction in plasma alfentanil Cp and antinociception. This novel approach in which one PK-PD model effectively drives another PK-PD model highlights the importance of physiological influences on PK and PD of a potent opioid with rapid onset of effect and low clinical margin of safety.

Predicting the Best Fit: A Comparison of Response Surface Models for Midazolam and Alfentanil Sedation in Procedures With Varying Stimulation.

BACKGROUND: Selecting an effective dose of sedative drugs in combined upper and lower gastrointestinal endoscopy is complicated by varying degrees of pain stimulation. We tested the ability of 5 response surface models to predict depth of sedation after administration of midazolam and alfentanil in this complex model. The procedure was divided into 3 phases: esophagogastroduodenoscopy (EGD), colonoscopy, and the time interval between the 2 (intersession). METHODS: The depth of sedation in 33 adult patients was monitored by Observer Assessment of Alertness/Scores. A total of 218 combinations of midazolam and alfentanil effect-site concentrations derived from pharmacokinetic models were used to test 5 response surface models in each of the 3 phases of endoscopy. Model fit was evaluated with objective function value, corrected Akaike Information Criterion (AICc), and Spearman ranked correlation. A model was arbitrarily defined as accurate if the predicted probability is <0.5 from the observed response. RESULTS: The effect-site concentrations tested ranged from 1 to 76 ng/mL and from 5 to 80 ng/mL for midazolam and alfentanil, respectively. Midazolam and alfentanil had synergistic effects in colonoscopy and EGD, but additivity was observed in the intersession group. Adequate prediction rates were 84% to 85% in the intersession group, 84% to 88% during colonoscopy, and 82% to 87% during EGD. The reduced Greco and Fixed alfentanil concentration required for 50% of the patients to achieve targeted response Hierarchy models performed better with comparable predictive strength. The reduced Greco model had the lowest AICc with strong correlation in all 3 phases of endoscopy. Dynamic, rather than fixed, γ and γalf in the Hierarchy model improved model fit. CONCLUSIONS: The reduced Greco model had the lowest objective function value and AICc and thus the best fit. This model was reliable with acceptable predictive ability based on adequate clinical correlation. We suggest that this model has practical clinical value for patients undergoing procedures with varying degrees of stimulation.

A re-evaluation and validation of ontogeny functions for cytochrome P450 1A2 and 3A4 based on in vivo data.

BACKGROUND AND OBJECTIVES: Current cytochrome P450 (CYP) 1A2 and 3A4 ontogeny profiles, which are derived mainly from in vitro studies and incorporated in paediatric physiologically based pharmacokinetic models, have been reported to under-predict the in vivo clearances of some model substrates in neonates and infants. METHOD: We report ontogeny functions for these enzymes as paediatric to adult relative intrinsic clearance per mg of hepatic microsomal protein, based on the deconvolution of in vivo pharmacokinetic data and by accounting for the impact of known clinical condition on hepatic unbound intrinsic clearance for caffeine and theophylline as markers of CYP1A2 activity and for midazolam as a marker of CYP3A4 activity. RESULTS: The function for CYP1A2 describes an increase in relative intrinsic metabolic clearance from birth to 3 years followed by a decrease to adult values. The function for CYP3A4 describes a continuous rise in relative intrinsic metabolic clearance, reaching the adult value at about 1.3 years of age. The new models were validated by showing improved predictions of the systemic clearances of ropivacaine (major CYP1A2 substrate; minor CYP3A4 substrate) and alfentanil (major CYP3A4 substrate) compared with those using a previous ontogeny function based on in vitro data (alfentanil: mean squared prediction error 3.0 vs. 6.8; ropivacaine: mean squared prediction error 2.3 vs.14.2). CONCLUSIONS: When implementing enzyme ontogeny functions, it is important to consider potential confounding factors (e.g. disease) that may affect the physiological conditions of the patient and, hence, the prediction of net in vivo clearance.

Physiologically based pharmacokinetic modeling of CYP3A4 induction by rifampicin in human: influence of time between substrate and inducer administration.

The induction of cytochrome P450 enzymes (CYPs) is an important source of drug-drug interaction (DDI) and can result in pronounced changes in pharmacokinetics (PK). Rifampicin (RIF) is a potent inducer of CYP3A4 and also acts as a competitive inhibitor which can partially mask the induction. The objective of this study was to determine a clinical DDI study design for RIF resulting in maximum CYP3A4 induction. A physiologically based pharmacokinetic (PBPK) model was developed to project the dynamics and magnitude of CYP3A4 induction in vivo from in vitro data generated with primary human hepatocytes. The interaction model included both inductive and inhibitory effects of RIF on CYP3A4 in gut and liver and accounting for the observed RIF auto-induction. The model has been verified for 4 CYP3A4 substrates: midazolam, triazolam, alfentanil and nifedipine using plasma concentration data from 20 clinical study designs with intravenous (n=7) and oral (n=13) administrations. Finally, the influence of the time between RIF and substrate administration was explored for the interaction between midazolam and RIF. The model integrating in vitro induction parameters correctly predicted intravenous induction but underestimated oral induction with 30% of simulated concentrations more than 2-fold higher than of observed data. The use of a 1.6-fold higher value for the maximum induction effect (Emax) improved significantly the accuracy and precision of oral induction with 82% of simulated concentrations and all predicted PK parameters within 2-fold of observed data. Our simulations suggested that a concomitant administration of RIF and midazolam resulted in significant competitive inhibition limited to intestinal enzyme. Accordingly, a maximum induction effect could be achieved with a RIF pretreatment of 600 mg/day during 5 days and a substrate administration at least 2 h after the last RIF dose. A period of 2 weeks after RIF removal was found sufficient to allow return to baseline levels of enzyme.

Pharmacokinetics of fentanyl, alfentanil, and sufentanil in isoflurane-anesthetized cats.

The aim of this study was to compare the pharmacokinetics of fentanyl, alfentanil, and sufentanil in isoflurane-anesthetized cats. Six adult cats were used. Anesthesia was induced and maintained with isoflurane in oxygen. End-tidal isoflurane concentration was set at 2% and adjusted as required due to spontaneous movement. Fentanyl (10 µg/kg), alfentanil (100 µg/kg), or sufentanil (1 µg/kg) was administered intravenously as a bolus, on separate days. Blood samples were collected immediately before and for 8 h following drug administration. Plasma drug concentration was determined using liquid chromatography/mass spectrometry. Compartment models were fitted to concentration-time data. A 3-compartment model best fitted the concentration-time data for all drugs, except for 1 cat in the sufentanil group (excluded from analysis). The volume of the central compartment and the volume of distribution at steady-state (L/kg) [mean ± SEM (range)], the clearance (mL/min/kg) [harmonic mean ± pseudo-SD (range)], and the terminal half-life (min) [median (range)] were 0.25 ± 0.04 (0.09-0.34), 2.18 ± 0.16 (1.79-2.83), 18.6 ± 5.0 (15-29.8), and 151 (115-211) for fentanyl; 0.10 ± 0.01 (0.07-0.14), 0.89 ± 0.16 (0.68-1.83), 11.6 ± 2.6 (9.2-15.8), and 144 (118-501) for alfentanil; and 0.06 ± 0.01 (0.04-0.10), 0.77 ± 0.07 (0.63-0.99), 17.6 ± 4.3 (13.9-24.3), and 54 (46-76) for sufentanil. Differences in clearance and volume of distribution result in similar terminal half-lives for fentanyl and alfentanil, longer than for sufentanil.

Pharmacokinetic parameter sets of alfentanil revisited: optimal parameters for use in target controlled infusion and anaesthesia display systems.

BACKGROUND: In open TCI and anaesthesia display systems, the choice of pharmacokinetic (PK) parameter sets of opioids is clinically relevant. Accuracy and bias of the PK models may be affected by administration mode and the co-administered hypnotic drug. We retrospectively evaluated the performance of eight PK parameter sets for alfentanil in two data sets (infusion and bolus application). METHODS: With the dosing history from two studies in orthopaedic patients anaesthetized with propofol or inhalation anaesthetics the alfentanil plasma concentration over time was calculated with eight PK parameter sets. Median absolute performance error (MDAPE), log accuracy, median performance error (MDPE), log bias, Wobble, and Divergence were computed. Mann-Whitney rank test with Bonferroni correction was used for comparison between bolus and infusion data, repeated measures analysis of variance on ranks was used for comparison among parameter sets. RESULTS: The parameters by Scott (original and weight adjusted) and Fragen had a MDAPE ≤30% and a median log accuracy <0.15 independent of the administration mode, while MDPE was within ±20% and log bias nearly within ±0.1, respectively. The sets by Maitre and Lemmens were within these limits only in the bolus data. All other parameter sets were outside these limits. CONCLUSIONS: In healthy orthopaedic patients, the PK parameters by Scott and by Maitre were equally valid when alfentanil was given as repeated boluses. When given as infusion, the Maitre parameters were less accurate and subject to a significant bias. We cannot exclude that the difference between bolus and infusion is partially because of the different hypnotics used.

Performance of alfentanil target-controlled infusion in normal and morbidly obese female patients.

BACKGROUND: Available alfentanil pharmacokinetic (PK) sets for target-controlled infusion (TCI) were derived from populations with normal BMI. The performance and accuracy of the models devised by Maitre and colleagues and Scott and colleagues were evaluated in a population including morbidly obese patients. METHODS: Alfentanil TCI using Maitre and colleagues' model was administered to 10 obese and six non-obese women (BMI 19.5-57.4 kg m(-2)) undergoing laparoscopic surgery. The initial effect-site target concentration was 100 ng ml(-1). Alfentanil arterial plasma concentrations were sampled from TCI onset to 220 min after its termination. Stanpump(®) software calculated predicted alfentanil concentrations. Data were analysed with a non-linear mixed-effect model (NONMEM, version 7.2), including calculations of the median performance error (MDPE) and the median absolute performance error (MDAPE). Scott and colleagues' model was evaluated retrospectively. RESULTS: Using Maitre and colleagues' model, MDPE and MDAPE (range) for the whole population were 13.3% and 23.9%, respectively. With Scott and colleagues' model, MDPE and MDAPE were -30.7% and 50.1%, respectively. We created a three-compartment model with BMI as the covariate (CL), yielding MDPE 1.1% and MDAPE 30.6%. CONCLUSIONS: Maitre and colleagues' PK set underestimated the predicted concentrations in our mixed-weighted population, but its bias and accuracy were acceptable for clinical application. Scott and colleagues' model was inaccurate. The NONMEM model seemed to be more accurate during the infusion and for high concentrations, but it needs to be validated in a larger population.

Simultaneous determination of alfentanil and midazolam in human plasma using liquid chromatography and tandem mass spectrometry.

A fast, sensitive and selective liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for the determination of alfentanil and midazolam in human plasma has been developed and validated. Alfentanil and midazolam were extracted from plasma using a mixed-mode cation exchange solid phase extraction method, with recoveries of both compounds greater than 80% at 3 different concentrations (1, 10 and 100ng/ml). Compounds were analyzed on a C(18) column with a water and methanol mobile phase gradient with acetic acid as an additive, at a flow rate of 0.3ml/min. The working assay range was linear from 0.25 to 100ng/ml for each compound. The signal to noise ratio was 80 and 40 for alfentanil and midazolam, respectively, at the lowest concentration calibration standard, with less than 10% matrix suppression by human plasma at this concentration. Alfentanil and midazolam were stable in human plasma during storage at -80°C, processing, and analysis. The procedure was validated and applied to the analysis of plasma samples from healthy human subjects administered oral and intravenous alfentanil and midazolam.

Concurrent assessment of hepatic and intestinal cytochrome P450 3A activities using deuterated alfentanil.

Alfentanil (ALF) is a validated probe for hepatic, first-pass, and intestinal cytochrome P450 (CYP) 3A activity, using plasma clearances, single-point concentrations, and noninvasive pupil diameter change (miosis). Assessing intravenous (i.v.) and oral drug disposition typically requires separate dosing. This investigation evaluated concurrent administration of oral deuterated and i.v. unlabeled ALF to assess both intestinal and hepatic CYP3A, and compare sequential and simultaneous dosing. ALF disposition was evaluated after strong hepatic and/or intestinal CYP3A induction and inhibition by rifampin, ketoconazole, and grapefruit juice. Using plasma ALF concentrations and area under the curve (AUC), clearance, or single-point concentrations, both simultaneous and sequential dosing provided equivalent results and detected hepatic and intestinal CYP3A induction and inhibition. Miosis better detected CYP3A modulation with sequential vs. simultaneous dosing. These results show that concurrent administration of oral deuterated and i.v. ALF, either sequentially or simultaneously, is an efficient and effective approach to assessing hepatic and intestinal CYP3A activity.

Opioid pharmacogenomics using a twin study paradigm: methods and procedures for determining familial aggregation and heritability.

Opioids are the cornerstone medication for the treatment of moderate to severe pain. However, analgesic opioid requirements and the propensity to suffer from aversive opioid effects, including fatal respiratory depression and addiction, vary widely among patients. The factors underlying the substantial response variance remain largely unknown and need clarification for using opioids more effectively in appropriately selected patients. This ongoing study takes advantage of the twin paradigm to estimate the genetic and environmental contributions to inter-individual differences in opioid responses. Evidence of significant heritability will justify more detailed and extensive genomic studies. The enrollment target is 80 monozygotic and 45 dizygotic twin pairs who undergo a target-controlled infusion of the opioid alfentanil and saline placebo in sequential but randomized order. In a laboratory-type setting, well-defined pharmacodynamic endpoints are measured to quantify pain sensitivity, analgesic opioid effects, and aversive opioid effects including respiratory depression, sedation and reinforcing affective responses. First results obtained in 159 participants provide evidence for the feasibility and utility of this interventional study paradigm to estimate familial aggregation and heritability components of relevant drug effects. Areas highlighted in this report include recruitment strategies, required infrastructure and personnel, selection of relevant outcome measures, drug infusion algorithm minimizing pharmacokinetic variability, and considerations for optimizing data quality and quantity without hampering feasibility. Applying the twin paradigm to complex and potentially harmful studies comprehensively characterizing pharmacological response profiles is without much precedent. Methods and first results including heritability estimates for heat and cold pain sensitivity should be of interest to investigators considering similar studies.

The potential for mu-opioid receptor agonists to be anti-emetic in humans: a review of clinical data.

In animal models of vomiting, mu-opioid (MOP, OP(3)) receptors mediate both emesis and anti-emesis. mu-receptors within the blood-brain barrier, mediating anti-emesis, are more rapidly accessible to lipid-soluble mu-opioid receptor agonists such as fentanyl than to morphine, and fentanyl has broad-spectrum anti-emetic effects in a number of species. Whether a similar situation exists in humans is not known. A search was performed for clinical studies comparing the emetic side effects of opioids administered peri-operatively in an attempt to identify differences between morphine and more lipid-soluble mu-receptor-selective agonists such as fentanyl. Overall, the evidence appears to suggest that fentanyl and other phenylpiperidines are associated with less nausea and vomiting than morphine, but not all studies support this, and fentanyl-like drugs are associated with nausea and vomiting per se. Good evidence, however, exists to show that fentanyl and alfentanil do not cause more nausea and vomiting than the ultra fast-acting remifentanil. Because remifentanil is cleared rapidly post-operatively, such trials suggest that the emetic side effects of fentanyl and alfentanil are minimal. The clinical evidence, although limited, is at least consistent with the possibility that central mu-opioid receptors may mediate anti-emesis in humans. It is possible that the role of mu-opioid agonists in anti-emesis may become clearer in the future as a result of the use of peripheral mu-opioid receptor antagonists.

Physiology-based simulations of a pathological condition: prediction of pharmacokinetics in patients with liver cirrhosis.

BACKGROUND: Liver cirrhosis is a progressive disease characterized by loss of functional hepatocytes with concomitant connective tissue and nodule formation in the liver. The morphological and physiological changes associated with the disease substantially affect drug pharmacokinetics. Whole-body physiologically based pharmacokinetic (WB-PBPK) modelling is a predictive technique that quantitatively relates the pharmacokinetic parameters of a drug to such (patho-)physiological conditions. OBJECTIVE: To extend an existing WB-PBPK model, based on the physiological changes associated with liver cirrhosis, which allows for prediction of drug pharmacokinetics in patients with liver cirrhosis. METHODS: The literature was searched for quantitative measures of the physiological changes associated with the presence of Child-Pugh class A through C liver cirrhosis. The parameters that were included were the organ blood flows, cardiac index, plasma binding protein concentrations, haematocrit, functional liver volume, hepatic enzymatic activity and glomerular filtration rate. Predictions of pharmacokinetic profiles and parameters were compared with literature data for the model compounds alfentanil, lidocaine (lignocaine), theophylline and levetiracetam. RESULTS: The predicted versus observed plasma concentration-time profiles for alfentanil and lidocaine were similar, such that the pharmacokinetic changes associated with Child-Pugh class A, B and C liver cirrhosis were adequately described. The theophylline elimination half-life was greatly increased in Child-Pugh class B and C patients compared with controls, as predicted by the model. Levetiracetam urinary excretion was consistently reduced with disease progression and very closely resembled observed values. CONCLUSION: Consideration of the physiological differences between healthy individuals and patients with liver cirrhosis was important for the simulation of drug pharmacokinetics in this compromised group. The WB-PBPK model was altered to incorporate these physiological differences with the result of adequate simulation of drug pharmacokinetics. The information provided in this study will allow other researchers to further validate this liver cirrhosis model within a WB-PBPK model.

Mechanism of ritonavir changes in methadone pharmacokinetics and pharmacodynamics: II. Ritonavir effects on CYP3A and P-glycoprotein activities.

Ritonavir diminishes methadone plasma concentrations, an effect attributed to CYP3A induction, but the actual mechanisms are unknown. We determined short-term (2-day) and steady-state (2-week) ritonavir effects on intestinal and hepatic CYP3A4/5 (probed with intravenous (IV) and oral alfentanil (ALF) and with miosis) and P-glycoprotein (P-gp) (fexofenadine), and on methadone pharmacokinetics and pharmacodynamics in healthy volunteers. Acute ritonavir increased the area under the concentration-time curve (AUC)(0-infinity)/dose ratio (ritonavir/control) for oral ALF 25-fold. Steady-state ritonavir increased the AUC(0-Infinity)/dose ratio for IV and oral ALF 4- and 10-fold, respectively; reduced hepatic extraction (from 0.26 to 0.07) and intestinal extraction (from 0.51 to 0); and increased bioavailability (from 37 to 95%). Acute ritonavir inhibits first-pass CYP3A > 96%. Chronic ritonavir inhibits hepatic CYP3A (> 70%) and first-pass CYP3A (> 90%). Acute and steady-state ritonavir increased the fexofenadine AUC(0-infinity) 2.8- and 1.4-fold, respectively, suggesting P-gp inhibition. Steady-state compared with acute ritonavir caused mild apparent induction of P-gp and hepatic CYP3A, but net inhibition still predominated. Ritonavir inhibited both intestinal and hepatic CYP3A and drug transport. ALF miosis noninvasively determined CYP3A inhibition by ritonavir.

On the modeling of drug induced respiratory depression in the non-steady-state.

The ability of anesthetic agents to provide adequate analgesia and sedation is limited by the ventilatory depression associated with overdosing in spontaneously breathing patients. Therefore, quantitation of drug induced ventilatory depression is a pharmacokinetic-pharmacodynamic problem relevant to the practice of anesthesia. Although several studies describe the effect of respiratory depressant drugs on isolated endpoints, an integrated description of drug induced respiratory depression with parameters identifiable from clinically available data is not available. This study proposes a physiological model of CO2 disposition, ventilatory regulation, and the effects of anesthetic agents on the control of breathing. The predictive performance of the model is evaluated through simulations aimed at reproducing experimental observations of drug induced hypercarbia and hypoventilation associated with intravenous administration of a fast-onset, highly potent anesthetic mu agonist (including previously unpublished experimental data determined after administration of 1 mg alfentanil bolus). The proposed model structure has substantial descriptive capability and can provide clinically relevant predictions of respiratory inhibition in the non-steady-state to enhance safety of drug delivery in the anesthetic practice.