Dataset Information

A Population-Based Pharmacokinetic Model Approach to Pantoprazole Dosing for Obese Children and Adolescents.

ABSTRACT: BACKGROUND AND AIMS:Pharmacokinetic data for proton pump inhibitors (PPIs), acid-suppression drugs commonly prescribed to children, are lacking for obese children who are at greatest risk for acid-related disease. In a recent multi-center investigation, we demonstrated decreased, total body weight adjusted, apparent clearance (CL/F) of the PPI pantoprazole for obese children compared with their non-obese peers. Subsequently, we developed a population-based pharmacokinetic (PopPK) model to characterize pantoprazole disposition and evaluated appropriate pantoprazole dosing strategies for obese pediatric patients, using simulation. METHODS:Pharmacokinetic data from the only prospective study of PPIs in obese children (aged 6-17 years; n?=?40) included 273 pantoprazole and 256 pantoprazole-sulfone plasma concentrations, after single oral-dose administration, and were used for pantoprazole model development and covariate analysis (NONMEM®). Model evaluation was performed via bootstrapping and predictive checks, and the final model was applied to simulate systemic pantoprazole exposures for common dosing scenarios. RESULTS:A two-compartment PopPK model, which included CYP2C19 genotype and total body weight, provided the best fit. Resultant, typical, weight-normalized pantoprazole parameter estimates were different than previously reported for children or adults, with significantly reduced pantoprazole CL/F for obese children. Of the dosing scenarios evaluated, the weight-tiered approach, approved by the US Food and Drug Administration, achieved pantoprazole exposures [area under the curve (AUC0-?)] within ranges previously reported as therapeutic, without over- or under-prediction for obese children. CONCLUSIONS:Our data argue against empiric dose escalation of PPIs for obese children and support current FDA-approved pediatric weight-tiered dosing for pantoprazole; however, 3- to 5-fold inter-individual variability in pantoprazole AUC0-? remained using this dosing approach.

SUBMITTER: Shakhnovich V

PROVIDER: S-EPMC6178956 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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A Population-Based Pharmacokinetic Model Approach to Pantoprazole Dosing for Obese Children and Adolescents.

Shakhnovich Valentina V Brian Smith P P Guptill Jeffrey T JT James Laura P LP Collier David N DN Wu Huali H Livingston Chad E CE Zhao Jian J Kearns Gregory L GL Cohen-Wolkowiez Michael M

Paediatric drugs 20181001 5

<h4>Background and aims</h4>Pharmacokinetic data for proton pump inhibitors (PPIs), acid-suppression drugs commonly prescribed to children, are lacking for obese children who are at greatest risk for acid-related disease. In a recent multi-center investigation, we demonstrated decreased, total body weight adjusted, apparent clearance (CL/F) of the PPI pantoprazole for obese children compared with their non-obese peers. Subsequently, we developed a population-based pharmacokinetic (PopPK) model t ...[more]

PMID: 30097906

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Project description:BackgroundOptimal dosing of propofol to maintain appropriate anesthetic depth is challenging in severely obese (SO) adolescents. We previously reported that total body weight (TBW) is predictive of propofol clearance. This study was aimed at characterizing pharmacokinetics (PK) and pharmacodynamics (PD) of propofol in SO adolescents, using bispectral index (BIS), and toward developing PK/PD model-based dosing guidelines.MethodsA prospective PK/PD study was conducted in 26 SO children and adolescents aged 9-18 years (body mass index 31-69 kg·m(-2)), undergoing surgery with intravenous propofol anesthesia clinically titrated by providers blinded to BIS. BIS data and propofol infusion schemes were recorded. Venous blood samples collected during and after propofol infusion were assayed for propofol concentrations. A propofol PK/PD model was developed using NONMEM and model-based simulations were performed to determine propofol dosing regimens targeting BIS of 50 ± 10.ResultsA three-compartment PK model linked to a sigmoidal inhibitory Emax PD model by a first-order rate constant, adequately described the propofol concentration (n = 375) and BIS (n = 3334) data. TBW was the most predictive covariate for propofol clearance [CL (l·min(-1) ) = 1.65 × (TBW/70)(0.75)]. An effect-site propofol concentration of 3.19 μg·ml(-1) was estimated for half-maximal effect, with no identifiable predictive covariates. The proposed maintenance dosing regimen targeted to a BIS of 50 ± 10, based on our PK/PD model, was able to predict desired propofol concentrations and BIS in a representative obese teen when used in conjunction with accepted PK/PD models for children/obese adults (PK:Eleveld/PD: Cortinez), further supporting evidence for the dosing based on TBW.ConclusionThis is the first study to describe the PK/PD of propofol in SO adolescents. The proposed maintenance dosing regimen for propofol uses TBW in an allometric function as a dosing scalar, with an exponent of 0.75. Our results suggest no relevant effect of obesity on the propofol concentration-BIS relationship.

Project description:Background and objectiveHIV treatment options remain limited in children. Dolutegravir is a potent and well-tolerated, once-daily HIV-1 integrase inhibitor recommended for HIV-1 infection in both adults and children down to 4 weeks of age. To support pediatric dosing of dolutegravir in children, we used a population pharmacokinetic model with dolutegravir data from the P1093 and ODYSSEY clinical trials. The relationship between dolutegravir exposure and selected safety endpoints was also evaluated.MethodsA population pharmacokinetic model was developed with data from P1093 and ODYSSEY to characterize the pharmacokinetics and associated variability and to evaluate the impact of pharmacokinetic covariates. The final population pharmacokinetic model simulated exposures across weight bands, doses, and formulations that were compared with established adult reference data. Exploratory exposure-safety analyses evaluated the relationship between dolutegravir pharmacokinetic parameters and selected clinical laboratory parameters and adverse events.ResultsA total of N = 239 participants were included, baseline age ranged from 0.1 to 17.5 years, weight ranged from 3.9 to 91 kg, 50% were male, and 80% were black. The final population pharmacokinetic model was a one-compartment model with first-order absorption and elimination, enabling predictions of dolutegravir concentrations in the pediatric population across weight bands and doses/formulations. The predicted geometric mean trough concentration was comparable to the adult value following a 50-mg daily dose of dolutegravir for all weight bands at recommended doses. Body weight, age, and formulation were significant predictors of dolutegravir pharmacokinetics in pediatrics. Additionally, during an exploratory exposure-safety analysis, no correlation was found between dolutegravir exposure and selected safety endpoints or adverse events.ConclusionsThe dolutegravir dosing in children ≥ 4 weeks of age on an age/weight-band basis provides comparable exposures to those historically observed in adults. Observed pharmacokinetic variability was higher in this pediatric population and no additional safety concerns were observed. These results support the weight-banded dosing of dolutegravir in pediatric participants currently recommended by the World Health Organization.

Project description:Dolutegravir-based regimens are recommended as first-line therapy for HIV in low- and middle-income countries where tuberculosis is the most common opportunistic infection. Concurrent HIV/tuberculosis treatment is challenging because of drug-drug interactions. Our analysis aimed to characterize dolutegravir's population pharmacokinetics when coadministered with rifampicin and assess alternative dolutegravir dosing regimens. We developed a population pharmacokinetic model of dolutegravir in NONMEM with data from two healthy-volunteer studies (RADIO and ClinicalTrials.gov identifier NCT01231542) and validated it with data from the INSPIRING study, which consisted of participants living with HIV. The model was developed with 817 dolutegravir plasma concentrations from 41 participants. A 2-compartment model with first-order elimination and lagged absorption best described dolutegravir's pharmacokinetics. For a typical 70-kg individual, we estimated a clearance, absorption rate constant, central volume, and peripheral volume of 1.03 L/h, 1.61 h-1, 12.7 L, and 3.85 L, respectively. Rifampicin coadministration increased dolutegravir clearance by 144% (95% confidence interval [CI], 126 to 161%). Simulations showed that when 50 or 100 mg once-daily dolutegravir is coadministered with rifampicin in 70-kg individuals, 71.7% and 91.5% attain trough concentrations above 0.064 mg/L, the protein-adjusted 90% inhibitory concentration (PA-IC90), respectively. The model developed from healthy-volunteer data describes patient data reasonably well but underpredicts trough concentrations. Although 50 mg of dolutegravir given twice daily achieves target concentrations in more than 99% of individuals cotreated with rifampicin, 100 mg of dolutegravir, once daily, in the same population is predicted to achieve satisfactory pharmacokinetic target attainment. The efficacy of this regimen should be investigated since it presents an opportunity for treatment simplification.

Dataset Information

A Population-Based Pharmacokinetic Model Approach to Pantoprazole Dosing for Obese Children and Adolescents.

Publications

A Population-Based Pharmacokinetic Model Approach to Pantoprazole Dosing for Obese Children and Adolescents.

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