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Development and Qualification of Physiologically Based Pharmacokinetic Models for Drugs With Atypical Distribution Behavior: A Desipramine Case Study.

ABSTRACT: Desipramine is a secondary tricyclic amine, which is primarily metabolized by cytochrome 2D6. It shows a high volume of distribution (Vss) (10-50 L/kg) due to its high lipophilicity, unspecific phospholipid binding, and lysosomal trapping. The objective of this study was to develop and qualify a physiologically based pharmacokinetic (PBPK) model for desipramine, which accounts for the high Vss of the drug following intravenous and oral administration of doses up to 100 mg. The model also accounts for the extended time to reach maximum concentration after oral dosing due to enterocyte trapping. Once developed and qualified in adults, we characterized the dynamic changes in metabolism and pharmacokinetics of desipramine after birth by scaling the system-specific parameters of the model from adults to pediatrics. The developed modeling strategy provides a prototypical workflow that can also be applied to other drugs with similar properties and a high volume of distribution.

SUBMITTER: Samant TS

PROVIDER: S-EPMC5697013 | biostudies-literature | 2017 May

REPOSITORIES: biostudies-literature

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Development and Qualification of Physiologically Based Pharmacokinetic Models for Drugs With Atypical Distribution Behavior: A Desipramine Case Study.

Samant T S TS Lukacova V V Schmidt S S

CPT: pharmacometrics & systems pharmacology 20170411 5

Desipramine is a secondary tricyclic amine, which is primarily metabolized by cytochrome 2D6. It shows a high volume of distribution (Vss) (10-50 L/kg) due to its high lipophilicity, unspecific phospholipid binding, and lysosomal trapping. The objective of this study was to develop and qualify a physiologically based pharmacokinetic (PBPK) model for desipramine, which accounts for the high Vss of the drug following intravenous and oral administration of doses up to 100 mg. The model also account ...[more]

PMID: 28398693

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Project description:Tuberculosis (TB) remains a global health problem and there is an ongoing effort to develop more effective therapies and new combination regimes that can reduce duration of treatment. The purpose of this study was to demonstrate utility of a physiologically-based pharmacokinetic modeling approach to predict plasma and lung concentrations of 11 compounds used or under development as TB therapies (bedaquiline [and N-desmethyl bedaquiline], clofazimine, cycloserine, ethambutol, ethionamide, isoniazid, kanamycin, linezolid, pyrazinamide, rifampicin, and rifapentine). Model accuracy was assessed by comparison of simulated plasma pharmacokinetic parameters with healthy volunteer data for compounds administered alone or in combination. Eighty-four percent (area under the curve [AUC]) and 91% (maximum concentration [Cmax ]) of simulated mean values were within 1.5-fold of the observed data and the simulated drug-drug interaction ratios were within 1.5-fold (AUC) and twofold (Cmax ) of the observed data for nine (AUC) and eight (Cmax ) of the 10 cases. Following satisfactory recovery of plasma concentrations in healthy volunteers, model accuracy was assessed further (where patients' with TB data were available) by comparing clinical data with simulated lung concentrations (9 compounds) and simulated lung: plasma concentration ratios (7 compounds). The 5th-95th percentiles for the simulated lung concentration data recovered between 13% (isoniazid and pyrazinamide) and 88% (pyrazinamide) of the observed data points (Am J Respir Crit Care Med, 198, 2018, 1208; Nat Med, 21, 2015, 1223; PLoS Med, 16, 2019, e1002773). The impact of uncertain model parameters, such as the fraction of drug unbound in lung tissue mass (fumass ), is discussed. Additionally, the variability associated with the patient lung concentration data, which was sparse and included extensive within-subject, interlaboratory, and experimental variability (as well interindividual variability) is reviewed. All presented models are transparently documented and are available as open-source to aid further research.

Dataset Information

Development and Qualification of Physiologically Based Pharmacokinetic Models for Drugs With Atypical Distribution Behavior: A Desipramine Case Study.

Publications

Development and Qualification of Physiologically Based Pharmacokinetic Models for Drugs With Atypical Distribution Behavior: A Desipramine Case Study.

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