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Handling Missing Dosing History in Population Pharmacokinetic Modeling: An Extension to MDM Method.

ABSTRACT: A major challenge in population pharmacokinetic modeling is handling data with missing or potentially incorrect dosing records. Leaving such records untreated or "commented out" will cause bias in parameter estimates. Several approaches were previously developed to address this challenge. Published in 2004, the missing dose method (MDM) demonstrated its robustness in handling missing dosing history in pharmacokinetic (PK) modeling. In this study, we presented two new extensions: a modified MDM method (MDM2) and a compartment initialization method (CIM). Their performance was examined with a large batch of simulated PK studies. For each method, 8,000 models were run, including different model structures, dosing routes, and missing dosing record scenarios. Both MDM2 and CIM exhibited robust performance and improved parameter estimation results. Specifically, CIM consistently outperformed other methods in fixed-effect and random-effect PK parameter estimation. The new methods demonstrate great potential in addressing missing dosing records challenges in PK analysis.

SUBMITTER: Wang Y

PROVIDER: S-EPMC6363138 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

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Handling Missing Dosing History in Population Pharmacokinetic Modeling: An Extension to MDM Method.

Wang Yuhuan Y Liu Xiaoxi X

CPT: pharmacometrics & systems pharmacology 20190117 1

A major challenge in population pharmacokinetic modeling is handling data with missing or potentially incorrect dosing records. Leaving such records untreated or "commented out" will cause bias in parameter estimates. Several approaches were previously developed to address this challenge. Published in 2004, the missing dose method (MDM) demonstrated its robustness in handling missing dosing history in pharmacokinetic (PK) modeling. In this study, we presented two new extensions: a modified MDM m ...[more]

PMID: 30536631

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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.

Dataset Information

Handling Missing Dosing History in Population Pharmacokinetic Modeling: An Extension to MDM Method.

Publications

Handling Missing Dosing History in Population Pharmacokinetic Modeling: An Extension to MDM Method.

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