Generic Workflow to Predict Medicine Concentrations in Human Milk Using Physiologically-Based Pharmacokinetic (PBPK) Modelling-A Contribution from the ConcePTION Project.

Women commonly take medication during lactation. Currently, there is little information about the exposure-related safety of maternal medicines for breastfed infants. The aim was to explore the performance of a generic physiologically-based pharmacokinetic (PBPK) model to predict concentrations in human milk for ten physiochemically diverse medicines. First, PBPK models were developed for "non-lactating" adult individuals in PK-Sim/MoBi v9.1 (Open Systems Pharmacology). The PBPK models predicted the area-under-the-curve (AUC) and maximum concentrations (Cmax) in plasma within a two-fold error. Next, the PBPK models were extended to include lactation physiology. Plasma and human milk concentrations were simulated for a three-months postpartum population, and the corresponding AUC-based milk-to-plasma (M/P) ratios and relative infant doses were calculated. The lactation PBPK models resulted in reasonable predictions for eight medicines, while an overprediction of human milk concentrations and M/P ratios (>2-fold) was observed for two medicines. From a safety perspective, none of the models resulted in underpredictions of observed human milk concentrations. The present effort resulted in a generic workflow to predict medicine concentrations in human milk. This generic PBPK model represents an important step towards an evidence-based safety assessment of maternal medication during lactation, applicable in an early drug development stage.

Predicting model-informed precision dosing: A test-case in tacrolimus dose adaptation for kidney transplant recipients.

Before investing resources into the development of a precision dosing (model-informed precision dosing [MIPD]) tool for tacrolimus, the performance of the tool was evaluated in silico. A retrospective dataset of 315 de novo kidney transplant recipients was first used to identify a one-compartment pharmacokinetic (PK) model with time-dependent clearance. MIPD performance was subsequently evaluated by calculating errors to predict future concentrations, which is directly related to dosing precision and probability of target attainment (PTA). Based on the identified model residual error, the theoretical upper limit was 45% PTA for a target of 13.5 ng/ml and an acceptable range of 12-15 ng/ml. Using empirical Bayesian estimation, this limit was reached on day 5 post-transplant and beyond. By incorporating correlated within-patient variability when predicting future individual concentrations, PTA improved beyond the theoretical upper limit. This yielded a Bayesian feedback dosing algorithm accurately predicting future trough concentrations and adapting each dose to reach a target concentration. Simulated concentration-time profiles were then used to quantify MIPD-based improvement on three end points: average PTA increased from 28% to 39%, median time to three concentrations in target decreased from 10 to 7 days, and mean log-squared distance to target decreased from 0.080 to 0.055. A study of 200 patients was predicted to have sufficient power to demonstrate these nuanced PK end points reliably. These simulations supported our decision to develop a precision dosing tool for tacrolimus and test it in a prospective trial.

Model-Informed Precision Dosing during Infliximab Induction Therapy Reduces Variability in Exposure and Endoscopic Improvement between Patients with Ulcerative Colitis.

Model-informed precision dosing (MIPD) may be a solution to therapeutic failure of infliximab for patients with ulcerative colitis (UC), as underexposure could be avoided, and the probability of endoscopic improvement (pEI; Mayo endoscopic subscore ≤ 1) could be optimized. To investigate in silico whether this claim has merit, four induction dosing regimens were simulated: 5 mg/kg (label dosing), 10 mg/kg, covariate-based MIPD (fat-free mass, corticosteroid use, and presence of extensive colitis at baseline), and concentration-based MIPD (based on the trough concentration at day 14). Covariate- and concentration-based MIPD were chosen to target the same median area under the infliximab concentration-time curve up to endoscopy at day 84 (AUCd84), as was predicted from 10 mg/kg dosing. Dosing at 5 mg/kg resulted in a mean ± standard deviation pEI of 55.7 ± 9.0%. Increasing the dose to 10 mg/kg was predicted to improve pEI to 65.1 ± 6.1%. Covariate-based MIPD reduced variability in exposure and pEI (65.1 ± 5.5%). Concentration-based MIPD decreased variability further (66.0 ± 3.9%) but did so at an increased average dose of 2293 mg per patient, as compared to 2168 mg for 10 mg/kg dosing. Mean pEI remained unchanged between 10 mg/kg dosing and MIPD, since the same median AUCd84 was targeted. In conclusion, quantitative simulations predict MIPD will reduce variability in exposure and pEI between patients with UC during infliximab induction therapy.

Apixaban in patients on haemodialysis: a single-dose pharmacokinetics study.

BACKGROUND: Apixaban, a direct oral anticoagulant inhibiting factor Xa, has been proven to reduce the risk of atrial fibrillation-related stroke and thromboembolism in patients with mild to moderate renal insufficiency. Patients on renal replacement therapy, however, were excluded from randomized controlled trials. Therefore, uncertainty remains concerning benefits, dosing and timing of intake in haemodialysis population. METHODS: We conducted a Phase II pharmacokinetics study in which 24 patients on maintenance haemodialysis were given a single dose (2.5 mg or 5 mg) of apixaban, either 30 min before or immediately after dialysis on the mid-week dialysis day. RESULTS: Apixaban 5 mg resulted in higher area under the curve (AUC0-48) in comparison with 2.5 mg, although significance could only be reached for dosing pre-dialysis (2.5 mg versus 5 mg, P = 0.008). In line, peak concentrations (Cmax) after dosing pre-dialysis were significantly higher in the 5 mg than in the 2.5 mg groups (P = 0.02). In addition, dialysis resulted in significant reduction of drug exposure. AUC0-48 pre-dialysis were on average 48% (2.5 mg) and 26% (5 mg) lower than the AUC0-48 post-dialysis, in line with Cmax. As a result, a dose of 2.5 mg post-dialysis and a dose of 5 mg pre-dialysis resulted in similar AUC0-48. In contrast, significant differences were found between the 5 mg group post-dialysis and the 2.5 mg group pre-dialysis (P = 0.02). CONCLUSIONS: Our data suggest that exposure to apixaban in patients on maintenance haemodialysis is dependent not only on drug dose but also on timing of intake relative to the haemodialysis procedure.

Population pharmacokinetics of propofol in neonates and infants: Gestational and postnatal age to determine clearance maturation.

AIMS: Develop a population pharmacokinetic model describing propofol pharmacokinetics in (pre)term neonates and infants, that can be used for precision dosing (e.g. during target-controlled infusion) of propofol in this population. METHODS: A nonlinear mixed effects pharmacokinetic analysis (Monolix 2018R2) was performed, based on a pooled study population in 107 (pre)term neonates and infants. RESULTS: In total, 836 blood samples were collected from 66 (pre)term neonates and 41 infants originating from 3 studies. Body weight (BW) of the pooled study population was 3.050 (0.580-11.440) kg, postmenstrual age (PMA) was 36.56 (27.00-43.00) weeks and postnatal age (PNA) was 1.14 (0-104.00) weeks (median and min-max range). A 3-compartment structural model was identified and the effect of BW was modelled using fixed allometric exponents. Elimination clearance maturation was modelled accounting for the maturational effect on elimination clearance until birth (by gestational age [GA]) and postpartum (by PNA and GA). The extrapolated adult (70 kg) population propofol elimination clearance (1.64 L min-1 , estimated relative standard error = 6.02%) is in line with estimates from previous population pharmacokinetic studies. Empirical scaling of BW on the central distribution volume in function of PNA improved the model fit. CONCLUSIONS: It is recommended to describe elimination clearance maturation by GA and PNA instead of PMA on top of size effects when analyzing propofol pharmacokinetics in populations including preterm neonates. Changes in body composition in addition to weight changes or other physio-anatomical changes may explain the changes in central distribution volume. The developed model may serve as a prior for propofol dose finding and target-controlled infusion in (preterm) neonates.

A Population Pharmacokinetic and Exposure-Response Model of Golimumab for Targeting Endoscopic Remission in Patients With Ulcerative Colitis.

BACKGROUND: Unlike other anti-tumor necrosis factor alpha antibodies, golimumab does not deliver on its promise of effectiveness for treating patients with ulcerative colitis. We investigated the value of therapeutic drug monitoring for optimizing golimumab therapy. METHODS: We analyzed the golimumab pharmacokinetics data of 56 patients with moderate to severe ulcerative colitis. Induction and maintenance golimumab concentrations (296 venipuncture, 414 serum) were used to develop a population pharmacokinetic model. Exposure-response relationships were analyzed using the data of 40/56 patients with available endoscopy data. Receiver operating characteristic curve analysis was performed, and an exposure-response Markov model was developed, linking golimumab exposure to probabilities of transitioning between Mayo endoscopic subscore (MES) states from baseline to week (w)14. RESULTS: Golimumab pharmacokinetics was best described by a 2-compartment model with linear absorption and elimination. Antibodies to golimumab and previous biological therapy reduced golimumab exposure. Still, interindividual pharmacokinetic variability (IIVPK) remained largely unexplained. Endoscopic remission (ER; MESw14 ≤ 1) was achieved in 14/40 (35%) patients. Golimumab serum trough concentration thresholds of 7.4 mg/L (w6) and 3.2 mg/L (w14) predicted ER at w14 (positive predictive values [pv+] 83% and 91%, pv- 82% and 67%, respectively). The 3.2-mg/L target predicted 38% and 44% chances of achieving ER in patients with MESbaseline of 3 and 2, respectively. CONCLUSIONS: Personalized, model-based induction dosing aiming at here-established target concentrations may account for IIVPK and thus provide patients with more equal chances of achieving ER. As <50% of patients attained the exposure targets, higher golimumab induction dosing requires investigation to secure its future in clinical practice.

Current insights in the complexities underlying drug-induced cholestasis.

Drug-induced cholestasis (DIC) poses a major challenge to the pharmaceutical industry and regulatory agencies. It causes both drug attrition and post-approval withdrawal of drugs. DIC represents itself as an impaired secretion and flow of bile, leading to the pathological hepatic and/or systemic accumulation of bile acids (BAs) and their conjugate bile salts. Due to the high number of mechanisms underlying DIC, predicting a compound's cholestatic potential during early stages of drug development remains elusive. A profound understanding of the different molecular mechanisms of DIC is, therefore, of utmost importance. Although many knowledge gaps and caveats still exist, it is generally accepted that alterations of certain hepatobiliary membrane transporters and changes in hepatocellular morphology may cause DIC. Consequently, liver models, which represent most of these mechanisms, are valuable tools to predict human DIC. Some of these models, such as membrane-based in vitro models, are exceptionally well-suited to investigate specific mechanisms (i.e. transporter inhibition) of DIC, while others, such as liver slices, encompass all relevant biological processes and, therefore, offer a better representation of the in vivo situation. In the current review, we highlight the principal molecular mechanisms associated with DIC and offer an overview and critical appraisal of the different liver models that are currently being used to predict the cholestatic potential of drugs.

Detection of Drug-Induced Cholestasis Potential in Sandwich-Cultured Human Hepatocytes.

Drug-induced cholestasis poses a major hurdle for the pharmaceutical industry as it is one the primary mechanisms of drug-induced liver injury. Hence, detection of drug-induced cholestasis during the early stages of drug development is of utmost importance. The most commonly used in vitro models rely on the extent of inhibition of bile salt export pump-mediated taurocholic acid transport, thereby assuming that drug-induced cholestasis mechanisms are merely restricted to the interaction with this sole hepatic transporter. Sandwich-cultured human hepatocytes represent a more holistic in vitro tool to investigate drug-induced cholestasis as they preserve all relevant disposition pathways and cellular functions involved in bile acid homeostasis. We developed and validated a sandwich-cultured human hepatocytes-based in vitro assay which is able to identify compounds causing cholestasis by altering bile acid disposition. The in vitro cholestatic potential is expressed by calculating a drug-induced cholestasis index value, which reflects the relative residual urea formation of sandwich-cultured human hepatocytes co-incubated with bile acids and test compound as compared to sandwich-cultured human hepatocytes treated with test compound alone. In addition, a safety margin can be calculated to determine the in vivo risk for cholestasis based on the determination of the drug-induced cholestasis index at various concentrations and the peak plasma concentration of the drug candidate. This chapter outlines the various steps involved in performing our sandwich-cultured human hepatocytes-based in vitro assay.

Optimising infliximab induction dosing for patients with ulcerative colitis.

AIMS: The therapeutic failure of infliximab therapy in patients with ulcerative colitis remains a challenge even 2 decades after its approval. Therapeutic drug monitoring (TDM) has shown value during maintenance therapy, but induction therapy has still not been explored. Patients may be primary nonresponders or underexposed with the standard dosing regimen. We aimed to: (i) develop a population pharmacokinetic-pharmacodynamic model; (ii) identify the best exposure metric that predicts mucosal healing; and (iii) build an exposure-response (ER) model to demonstrate model-based dose finding during induction therapy with infliximab. METHODS: Data were retrospectively collected from a clinical database. A total of 583 samples, from 204 patients, was used to develop a population pharmacokinetic model to generate exposure metrics for subsequent ER modelling. A subset of 159 patients was used to develop a logistic regression ER model, describing the relationship between infliximab exposure and ordered transitions between Mayo endoscopic subscore (MES) 3, 2 and ≤1 (baseline to post-induction). RESULTS: A 1-compartment population pharmacokinetic model with interindividual and interoccasion variability was found to fit the data best. Covariates influencing exposure were C-reactive protein, albumin, baseline MES, fat-free mass, concomitant corticosteroid use and pancolitis. The cumulative area under the infliximab concentration-time curve until endoscopy (CAUCendoscopy ) was found to be the best exposure metric for predicting mucosal healing (baseline MES >1 and post-induction MES ≤1). The model predicted that 70% of patients will attain mucosal healing with infliximab administered at days 0, 14 and 42 and a target CAUCendoscopy of 3752 mg/L*day at day 84. CONCLUSIONS: TDM-based dose individualisation targeting CAUCendoscopy has the potential to improve the effectiveness of infliximab during induction therapy.

Effect of Cryopreservation on Enzyme and Transporter Activities in Suspended and Sandwich Cultured Rat Hepatocytes.

Freshly-isolated rat hepatocytes are commonly used as tools for hepatic drug disposition. From an ethical point of view, it is important to maximize the use of isolated hepatocytes by cryopreservation. The present study compared overall hepatocyte functionality as well as activity of the organic anion transporting polypeptide (Oatp), multidrug resistance-associated protein 2 (Mrp2), and UDP-glucuronosyltransferase 1 (Ugt1), in in vitro models established with cryopreserved and freshly-isolated hepatocytes. A similar culture time-dependent decline in cellular functionality, as assessed by urea production, was observed in sandwich-cultured hepatocytes (SCH) obtained from freshly-isolated and cryopreserved cells. Concentration-dependent uptake kinetics of the Oatp substrate sodium fluorescein in suspended hepatocytes (SH) or SCH were not significantly affected by cryopreservation. Mrp2-mediated biliary excretion of 5 (and 6)-carboxy-2',7'-dichlorofluorescein by SCH was assessed with semi-quantitative fluorescence imaging: biliary excretion index values increased between day 3 and day 4, but did not differ significantly between cryopreserved and freshly-isolated hepatocytes. Finally, telmisartan disposition was evaluated in SCH to simultaneously explore Oatp, Ugt1, and Mrp2 activity. In order to distinguish between the susceptibilities of the individual disposition pathways to cryopreservation, a mechanistic cellular disposition model was developed. Basolateral and canalicular efflux as well as glucuronidation of telmisartan were affected by cryopreservation. In contrast, the disposition parameters of telmisartan-glucuronide were not impacted by cryopreservation. Overall, the relative contribution of the rate-determining processes (uptake, metabolism, efflux) remained unaltered between cryopreserved and freshly-isolated hepatocytes, indicating that cryopreserved hepatocytes are a suitable alternative for freshly-isolated hepatocytes when studying these cellular disposition pathways.

Optimizing dose regimens and fixed dose combination ratios in clinical trials.

Successful treatment of many diseases depends on the level of drug concentration in blood and its maintenance over a period of time around a value considered as therapeutic. The dose regimen that minimizes the underexposure and overexposure around the target concentration maximizes efficacy and safety, resulting in increased chances of a successful patient recovery. We present a method of computer-assisted dose finding by explicit optimization of a target criterion. We develop a general theory for such dose regimens and propose criteria for their computation. This approach is likely to supersede "brute force" techniques exclusively based on simulation. In case of a combination of two drugs in a single dosing unit, it is crucial that the optimal combination ratio is identified during the developmental process and is taken forward to further trials or approval. The algorithm computes the optimal ratio along with the optimal dose regimen. If the interest is in restricting the concentration profile of the drug to a therapeutic range, we adapt the algorithm to determine the optimal dose regimen. In future, this work is intended to aid the development of fixed dose combinations, especially antimalarials and other anti-infectives. The methodology also has potential applications in randomized concentration-controlled trials where adherence to the target concentration is a fundamental requirement.

Population pharmacokinetic analysis for 10-monohydroxy derivative of oxcarbazepine in pediatric epileptic patients shows no difference between Japanese and other ethnicities.

Oxcarbazepine is an anti-epileptic drug, which is almost completely metabolized by cytosolic enzymes in the liver to the active 10-monohyroxy metabolite (MHD) following oral administration. The pharmacokinetic (PK) profiles of MHD were evaluated in pediatric epileptic patients and a possible ethnic difference in PK of MHD between Japanese and non-Japanese pediatric patients was assessed. A non-linear mixed effect modeling approach was used to determine the PK of MHD. A one-compartment population model with first-order absorption appropriately described the PK of MHD. No clinically relevant differences were found for using body surface area or weight to explain between-patient variability, therefore the final model included the effects of body weight on apparent clearance (CL/F) and apparent volume of distribution (V/F) of MHD, and in addition, the effect of 3 concomitant anti-epileptic drugs (carbamazepine, phenobarbital and phenytoin) on CL/F of MHD. Inclusion of ethnicity as a covariate in the final model, concluded no ethnic difference with respect to CL/F of MHD between Japanese and non-Japanese patients. Hence, oxcarbazepine can be generally applied using the same dosage and administration for the treatment of partial onset seizures in pediatric patients, regardless of ethnicity.

Pharmacokinetic interactions among imatinib, bosentan and sildenafil, and their clinical implications in severe pulmonary arterial hypertension.

AIMS: This study characterized the population pharmacokinetics (PK) of imatinib in patients with severe pulmonary arterial hypertension (PAH), investigated drug-drug interactions (DDI) among imatinib, sildenafil and bosentan, and evaluated their clinical implications. METHODS: Plasma concentrations of imatinib, bosentan and sildenafil were collected in a phase III study and were used to characterize the PK of imatinib in this population. DDIs among the three drugs were quantified using a linear mixed model and log-transformed drug concentrations. RESULTS: The population mean estimates of apparent clearance (CL/F) and volume (V/F) were 10.8 l h(-1) (95% CI 9.2, 12.4 l h(-1) ) and 267 l (95% CI 208, 326 l), respectively. It was estimated that sildenafil concentrations increased, on average, by 64% (95% CI 32%, 103%) and bosentan concentrations by 51% (95% CI 12%, 104%), in the presence of imatinib. Despite increased concentrations of co-medications, treatment differences between imatinib and placebo for change in 6 min walk distance and pulmonary vascular resistance were relatively constant across the entire concentration range for sildenafil and bosentan. Overall, higher concentrations of imatinib and bosentan were not associated with increasing liver enzymes (serum glutamic oxaloacetic transaminases [SGOT]/serum glutamic-pyruvic transaminase [SGPT]). CONCLUSIONS: Population PKs of imatinib in patients with severe PAH were found comparable with those of patients with chronic myeloid leukemia. Imatinib was found effective regardless of the co-medications and showed intrinsic efficacy beyond merely elevating the concentrations of the co-medications due to DDIs. There was no evidence of increased risk of liver toxicity upon co-administration with bosentan.

Sevoflurane remifentanil interaction: comparison of different response surface models.

BACKGROUND: Various pharmacodynamic response surface models have been developed to quantitatively describe the relationship between two or more drug concentrations with their combined clinical effect. We examined the interaction of remifentanil and sevoflurane on the probability of tolerance to shake and shout, tetanic stimulation, laryngeal mask airway insertion, and laryngoscopy in patients to compare the performance of five different response surface models. METHODS: Forty patients preoperatively received different combined concentrations of remifentanil (0-12 ng/ml) and sevoflurane (0.5-3.5 vol.%) according to a criss-cross design (160 concentration pairs, four per patient). After having reached pseudosteady state, the response to shake and shout, tetanic stimulation, laryngeal mask airway insertion, and laryngoscopy was recorded. For the analysis of the probability of tolerance, five different interaction models were tested: Greco, Reduced Greco, Minto, Scaled C50(O) Hierarchical, and Fixed C50(O) Hierarchical model. All calculations were performed with NONMEM VI (Icon Development Solutions, Ellicott City, MD). RESULTS: The pharmacodynamic interaction between sevoflurane and remifentanil was strongly synergistic for both the hypnotic and the analgesic components of anesthesia. The Greco model did not result in plausible parameter estimates. The Fixed C50(O) Hierarchical model performed slightly better than the Scaled C50(O) Hierarchical and Reduced Greco models, whereas the Minto model fitted less well. CONCLUSION: We showed the importance of exploring various surface model approaches when studying drug interactions. The Fixed C50(O) Hierarchical model fits our data on sevoflurane remifentanil interaction best and appears to be an appropriate model for use in hypnotic-opioid drug interaction.

Noxious stimulation response index: a novel anesthetic state index based on hypnotic-opioid interaction.

BACKGROUND: The noxious stimulation response index (NSRI) is a novel anesthetic depth index ranging between 100 and 0, computed from hypnotic and opioid effect-site concentrations using a hierarchical interaction model. The authors validated the NSRI on previously published data. METHODS: The data encompassed 44 women, American Society of Anesthesiology class I, randomly allocated to three groups receiving remifentanil infusions targeting 0, 2, and 4 ng/ml. Propofol was given at stepwise increasing effect-site target concentrations. At each concentration, the observer assessment of alertness and sedation score, the response to eyelash and tetanic stimulation of the forearm, the bispectral index (BIS), and the acoustic evoked potential index (AAI) were recorded. The authors computed the NSRI for each stimulation and calculated the prediction probabilities (PKs) using a bootstrap technique. The PKs of the different predictors were compared with multiple pairwise comparisons with Bonferroni correction. RESULTS: The median (95% CI) PK of the NSRI, BIS, and AAI for loss of response to tetanic stimulation was 0.87 (0.75-0.96), 0.73 (0.58-0.85), and 0.70 (0.54-0.84), respectively. The PK of effect-site propofol concentration, BIS, and AAI for observer assessment of alertness and sedation score and loss of eyelash reflex were between 0.86 (0.80-0.92) and 0.92 (0.83-0.99), whereas the PKs of NSRI were 0.77 (0.68-0.85) and 0.82 (0.68-0.92). The PK of the NSRI for BIS and AAI was 0.66 (0.58-0.73) and 0.63 (0.55-0.70), respectively. CONCLUSION: The NSRI conveys information that better predicts the analgesic component of anesthesia than AAI, BIS, or predicted propofol or remifentanil concentrations. Prospective validation studies in the clinical setting are needed.

Response surface modeling of the interaction between propofol and sevoflurane.

BACKGROUND: Propofol and sevoflurane display additivity for gamma-aminobutyric acid receptor activation, loss of consciousness, and tolerance of skin incision. Information about their interaction regarding electroencephalographic suppression is unavailable. This study examined this interaction as well as the interaction on the probability of tolerance of shake and shout and three noxious stimulations by using a response surface methodology. METHODS: Sixty patients preoperatively received different combined concentrations of propofol (0-12 microg/ml) and sevoflurane (0-3.5 vol.%) according to a crisscross design (274 concentration pairs, 3 to 6 per patient). After having reached pseudo-steady state, the authors recorded bispectral index, state and response entropy and the response to shake and shout, tetanic stimulation, laryngeal mask airway insertion, and laryngoscopy. For the analysis of the probability of tolerance by logistic regression, a Greco interaction model was used. For the separate analysis of bispectral index, state and response entropy suppression, a fractional Emax Greco model was used. All calculations were performed with NONMEM V (GloboMax LLC, Hanover, MD). RESULTS: Additivity was found for all endpoints, the Ce(50, PROP)/Ce(50, SEVO) for bispectral index suppression was 3.68 microg. ml(-1)/ 1.53 vol.%, for tolerance of shake and shout 2.34 microg . ml(-1)/ 1.03 vol.%, tetanic stimulation 5.34 microg . ml(-1)/ 2.11 vol.%, laryngeal mask airway insertion 5.92 microg. ml(-1) / 2.55 vol.%, and laryngoscopy 6.55 microg. ml(-1)/2.83 vol.%. CONCLUSION: For both electroencephalographic suppression and tolerance to stimulation, the interaction of propofol and sevoflurane was identified as additive. The response surface data can be used for more rational dose finding in case of sequential and coadministration of propofol and sevoflurane.

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.

Drug-induced respiratory depression: an integrated model of drug effects on the hypercapnic and hypoxic drive.

Drug-induced respiratory depression is a common side effect of the agents used in anesthesia practice to provide analgesia and sedation. Depression of the ventilatory drive in the spontaneously breathing patient can lead to severe cardiorespiratory events and it is considered a primary cause of morbidity. Reliable predictions of respiratory inhibition in the clinical setting would therefore provide a valuable means to improve the safety of drug delivery. Although multiple studies investigated the regulation of breathing in man both in the presence and absence of ventilatory depressant drugs, a unified description of respiratory pharmacodynamics is not available. This study proposes a mathematical model of human metabolism and cardiorespiratory regulation integrating several isolated physiological and pharmacological aspects of acute drug-induced ventilatory depression into a single theoretical framework. The description of respiratory regulation has a parsimonious yet comprehensive structure with substantial predictive capability. Simulations relative to the synergistic interaction of the hypercarbic and hypoxic respiratory drive and the global effect of drugs on the control of breathing are in good agreement with published experimental data. Besides providing clinically relevant predictions of respiratory depression, the model can also serve as a test bed to investigate issues of drug tolerability and dose finding/control under non-steady-state conditions.

The well-being model: a new drug interaction model for positive and negative effects.

BACKGROUND: Drugs are routinely combined in anesthesia and pain management to obtain an enhancement of the desired effects. However, a parallel enhancement of the undesired effects might take place as well, resulting in a limited therapeutic usefulness. Therefore, when addressing the question of optimal drug combinations, side effects must be taken into account. METHODS: By extension of a previously published interaction model, the authors propose a method to study drug interactions considering also their side effects. A general outcome parameter identified as patient's well-being is defined by superposition of positive and negative effects. Well-being response surfaces are computed and analyzed for varying drugs pharmacodynamics and interaction types. In particular, the existence of multiple maxima and of optimal drug combinations is investigated for the combination of two drugs. RESULTS: Both drug pharmacodynamics and interaction type affect the well-being surface and the deriving optimal combinations. The effect of the interaction parameters can be explained in terms of synergy and antagonism and remains unchanged for varying pharmacodynamics. For all simulations performed for the combination of two drugs, the presence of more than one maximum was never observed. CONCLUSIONS: The model is consistent with clinical knowledge and supports previously published experimental results on optimal drug combinations. This new framework improves understanding of the characteristics of drug combinations used in clinical practice and can be used in clinical research to identify optimal drug dosing.

Control of muscle relaxation during anesthesia: a novel approach for clinical routine.

During general anesthesia drugs are administered to provide hypnosis, ensure analgesia, and skeletal muscle relaxation. In this paper, the main components of a newly developed controller for skeletal muscle relaxation are described. Muscle relaxation is controlled by administration of neuromuscular blocking agents. The degree of relaxation is assessed by supramaximal train-of-four stimulation of the ulnar nerve and measuring the electromyogram response of the adductor pollicis muscle. For closed-loop control purposes, a physiologically based pharmacokinetic and pharmacodynamic model of the neuromuscular blocking agent mivacurium is derived. The model is used to design an observer-based state feedback controller. Contrary to similar automatic systems described in the literature this controller makes use of two different measures obtained in the train-of-four measurement to maintain the desired level of relaxation. The controller is validated in a clinical study comparing the performance of the controller to the performance of the anesthesiologist. As presented, the controller was able to maintain a preselected degree of muscle relaxation with excellent precision while minimizing drug administration. The controller performed at least equally well as the anesthesiologist.