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Physiologically Based Pharmacokinetic Approach to Determine Dosing on Extracorporeal Life Support: Fluconazole in Children on ECMO.

ABSTRACT: Extracorporeal life support (e.g., dialysis, extracorporeal membrane oxygenation (ECMO)) can affect drug disposition, placing patients at risk for therapeutic failure. In this population, dose selection to achieve safe and effective drug exposure is difficult. We developed a novel and flexible approach that uses physiologically based pharmacokinetic (PBPK) modeling to translate results from ECMO ex vivo experiments into bedside dosing recommendations. To determine fluconazole dosing in children on ECMO, we developed a PBPK model, which was validated using fluconazole pharmacokinetic (PK) data in adults and critically ill infants. Next, an ECMO compartment was added to the PBPK model and parameterized using data from a previously published ex vivo study. Simulations using the final ECMO PBPK model reasonably characterized observed PK data in infants on ECMO, and the model was used to derive dosing in children on ECMO across the pediatric age spectrum. This approach can be generalized to other forms of extracorporeal life support (ECLS), such as dialysis.

SUBMITTER: Watt KM

PROVIDER: S-EPMC6202466 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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Physiologically Based Pharmacokinetic Approach to Determine Dosing on Extracorporeal Life Support: Fluconazole in Children on ECMO.

Watt Kevin M KM Cohen-Wolkowiez Michael M Barrett Jeffrey S JS Sevestre Michael M Zhao Ping P Brouwer Kim L R KLR Edginton Andrea N AN

CPT: pharmacometrics & systems pharmacology 20180813 10

Extracorporeal life support (e.g., dialysis, extracorporeal membrane oxygenation (ECMO)) can affect drug disposition, placing patients at risk for therapeutic failure. In this population, dose selection to achieve safe and effective drug exposure is difficult. We developed a novel and flexible approach that uses physiologically based pharmacokinetic (PBPK) modeling to translate results from ECMO ex vivo experiments into bedside dosing recommendations. To determine fluconazole dosing in children ...[more]

PMID: 30033691

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Project description:Background: Atezolizumab has been studied in multiple indications for both pediatric and adult patient populations. Generally, clinical studies enrolling pediatric patients may not collect sufficient pharmacokinetic data to characterize the drug exposure and disposition because of operational, ethical, and logistical challenges including burden to children and blood sample volume limitations. Therefore, mechanistic modeling and simulation may serve as a tool to predict and understand the drug exposure in pediatric patients. Objective: To use mechanistic physiologically-based pharmacokinetic (PBPK) modeling to predict atezolizumab exposure at a dose of 15 mg/kg (max 1,200 mg) in pediatric patients to support dose rationalization and label recommendations. Methods: A minimal mechanistic PBPK model was used which incorporated age-dependent changes in physiology and biochemistry that are related to atezolizumab disposition such as endogenous IgG concentration and lymph flow. The PBPK model was developed using both in vitro data and clinically observed data in adults and was verified across dose levels obtained from a phase I and multiple phase III studies in both pediatric patients and adults. The verified model was then used to generate PK predictions for pediatric and adult subjects ranging from 2- to 29-year-old. Results: Individualized verification in children and in adults showed that the simulated concentrations of atezolizumab were comparable (76% within two-fold and 90% within three-fold, respectively) to the observed data with no bias for either over- or under-prediction. Applying the verified model, the predicted exposure metrics including Cmin, Cmax, and AUCtau were consistent between pediatric and adult patients with a geometric mean of pediatric exposure metrics between 0.8- to 1.25-fold of the values in adults. Conclusion: The results show that a 15 mg/kg (max 1,200 mg) atezolizumab dose administered intravenously in pediatric patients provides comparable atezolizumab exposure to a dose of 1,200 mg in adults. This suggests that a dose of 15 mg/kg will provide adequate and effective atezolizumab exposure in pediatric patients from 2- to 18-year-old.

Project description:Long-term use of imatinib is effective and well-tolerated in children with chronic myeloid leukaemia (CML) yet defining an optimal dosing regimen for imatinib in younger patients is a challenge. The potential interactions between imatinib and coadministered drugs in this "special" population also remains largely unexplored. This study implements a physiologically based pharmacokinetic (PBPK) modeling approach to investigate optimal dosing regimens and potential drug interactions with imatinib in the paediatric population. A PBPK model for imatinib was developed in the Simcyp Simulator (version 17) utilizing in silico, in vitro drug metabolism, and in vivo pharmacokinetic data and verified using an independent set of published clinical pharmacokinetic data. The model was then extrapolated to children and adolescents (aged 2-18 years) by incorporating developmental changes in organ size and maturation of drug-metabolising enzymes and plasma protein responsible for imatinib disposition. The PBPK model described imatinib pharmacokinetics in adult and paediatric populations and predicted drug interaction with carbamazepine, a cytochrome P450 (CYP)3A4 and 2C8 inducer, with a good accuracy (evaluated by visual inspections of the simulation results and predicted pharmacokinetic parameters that were within 1.25-fold of the clinically observed values). The PBPK simulation suggests that the optimal dosing regimen range for imatinib is 230-340 mg/m2/d in paediatrics, which is supported by the recommended initial dose for treatment of childhood CML. The simulations also highlighted that children and adults being treated with imatinib have similar vulnerability to CYP modulations. A PBPK model for imatinib was successfully developed with an excellent performance in predicting imatinib pharmacokinetics across age groups. This PBPK model is beneficial to guide optimal dosing regimens for imatinib and predict drug interactions with CYP modulators in the paediatric population.

Project description:BackgroundExtracorporeal membrane oxygenation (ECMO) is an important rescue therapy for patients with refractory respiratory or circulatory failure. High cost and associated complications warrant careful case selection. The aim of this study was to investigate the outcomes and factors associated with mortality in acute hypoxemic respiratory failure patients who received ECMO support, and to externally validate preexisting ECMO survival prediction scoring systems.MethodsThis retrospective study enrolled acute hypoxemic respiratory failure patients who received veno-venous (VV) or veno-arterial (VA) ECMO support at Siriraj Hospital (Bangkok, Thailand) from 2010 to 2020. All relevant baseline patient characteristics including ECMO survival prediction scores were recorded. The primary outcome was in-hospital mortality. Multivariate logistic regression analysis was employed to identify independent predictors of in-hospital mortality.ResultsOf a total of 65 patients, 34 (52%) were male, the median (IQR) age was 61 years (49-70 years), the median body mass index (BMI) was 22.6 kg/m2 (20.6-28 kg/m2), and the median Sequential Organ Failure Assessment (SOFA) score was 13 [11-16]. Forty-three patients (66%) received VV-ECMO, and 22 (34%) received VA-ECMO support. In-hospital mortality was 69%. Multivariate analysis identified a SOFA score >14, hospitalized >72 hours before ECMO initiation, PaO2/FiO2 ratio <60, and pH <7.2 as independent predictors of in-hospital mortality. These four parameters were combined to create the SHOP (S: SOFA >14, H: hospitalize >72 hours, O: PF ratio <60, and P: pH <7.2) score. Compared with three different preexisting ECMO survival prediction scoring systems, the SHOP score had the highest area under the curve (AUC) for predicting in-hospital mortality (overall: 0.873, VV-EMCO: 0.866, and VA-EMCO: 0.891).ConclusionsIn-hospital mortality among ECMO-supported patients was high at 69%. SOFA score >14, hospitalized >72 hours, PaO2/FiO2 ratio <60, and pH <7.2 were found to be independent predictors of in-hospital mortality. A SHOP score of 2 or higher significantly predicts in-hospital mortality in EMCO-supported patients.Trial registrationwww.clinicaltrials.gov (reg. No. NCT04031794).

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Physiologically Based Pharmacokinetic Approach to Determine Dosing on Extracorporeal Life Support: Fluconazole in Children on ECMO.

Publications

Physiologically Based Pharmacokinetic Approach to Determine Dosing on Extracorporeal Life Support: Fluconazole in Children on ECMO.

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