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

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.

[1]  H. Manji,et al.  The pharmacologic treatment of depression. , 1991, The New England journal of medicine.

[2]  S. Faraone,et al.  Six-week, double-blind, placebo-controlled study of desipramine for adult attention deficit hyperactivity disorder. , 1996, The American journal of psychiatry.

[3]  J. Scatina,et al.  Venlafaxine: in vitro inhibition of CYP2D6 dependent imipramine and desipramine metabolism; comparative studies with selected SSRIs, and effects on human hepatic CYP3A4, CYP2C9 and CYP1A2. , 1997, British journal of clinical pharmacology.

[4]  Shaun S Kumar,et al.  State-of-the-Art Review on Physiologically Based Pharmacokinetic Modeling in Pediatric Drug Development , 2018, Clinical Pharmacokinetics.

[5]  S. Faraone,et al.  Absence of Effect of Stimulants on the Pharmacokinetics of Desipramine in Children , 1999, Pharmacotherapy.

[6]  Malcolm Rowland,et al.  Mechanistic Approaches to Volume of Distribution Predictions: Understanding the Processes , 2007, Pharmaceutical Research.

[7]  L. Berezhkovskiy,et al.  Volume of distribution at steady state for a linear pharmacokinetic system with peripheral elimination. , 2004, Journal of pharmaceutical sciences.

[8]  Sven Björkman,et al.  Prediction of drug disposition in infants and children by means of physiologically based pharmacokinetic (PBPK) modelling: theophylline and midazolam as model drugs. , 2005, British journal of clinical pharmacology.

[9]  Thomas Singer,et al.  Development of a Physiologically Based Model for Oseltamivir and Simulation of Pharmacokinetics in Neonates and Infants , 2011, Clinical pharmacokinetics.

[10]  Dale Hattis,et al.  Physiologically Based Pharmacokinetic (PBPK) Modeling of Caffeine and Theophylline in Neonates and Adults: Implications for Assessing Children's Risks from Environmental Agents , 2004, Journal of toxicology and environmental health. Part A.

[11]  G L Amidon,et al.  Transport approaches to the biopharmaceutical design of oral drug delivery systems: prediction of intestinal absorption. , 1996, Advanced drug delivery reviews.

[12]  F. Theil,et al.  Prediction of adipose tissue: plasma partition coefficients for structurally unrelated drugs. , 2001, Journal of pharmaceutical sciences.

[13]  Hans Lennernäs,et al.  Human in vivo regional intestinal permeability: importance for pharmaceutical drug development. , 2014, Molecular pharmaceutics.

[14]  W. Daniel,et al.  Contribution of lysosomal trapping to the total tissue uptake of psychotropic drugs. , 1997, Pharmacology & toxicology.

[15]  J. Dressman,et al.  Cytochrome P450-mediated metabolism in the human gut wall. , 2009, The Journal of pharmacy and pharmacology.

[16]  U. Honegger,et al.  The contribution of lysosomal trapping in the uptake of desipramine and chloroquine by different tissues. , 1995, Pharmacology & toxicology.

[17]  A. Edginton,et al.  Physiologically Based Pharmacokinetic Modeling and Simulation in Pediatric Drug Development , 2014, CPT: pharmacometrics & systems pharmacology.

[18]  S. Läer,et al.  Physiologically Based Pharmacokinetic Models in the Prediction of Oral Drug Exposure Over the Entire Pediatric Age Range—Sotalol as a Model Drug , 2014, The AAPS Journal.

[19]  J S Barrett,et al.  Application of Physiologically Based Pharmacokinetic Modeling to Predict Acetaminophen Metabolism and Pharmacokinetics in Children , 2013, CPT: pharmacometrics & systems pharmacology.

[20]  Amin Rostami-Hodjegan,et al.  Resurgence in the use of physiologically based pharmacokinetic models in pediatric clinical pharmacology: parallel shift in incorporating the knowledge of biological elements and increased applicability to drug development and clinical practice , 2011, Paediatric anaesthesia.

[21]  S. Otton,et al.  Imipramine demethylation and hydroxylation: Impact of the sparteine oxidation phenotype , 1986, Clinical pharmacology and therapeutics.

[22]  Shiew-Mei Huang,et al.  Application of Physiologically Based Pharmacokinetic (PBPK) Modeling to Support Dose Selection: Report of an FDA Public Workshop on PBPK , 2015, CPT: pharmacometrics & systems pharmacology.

[23]  J. Rapoport,et al.  Active metabolites of imipramine and desipramine in man , 1982, Clinical pharmacology and therapeutics.

[24]  Amin Rostami-Hodjegan,et al.  Physiologically based pharmacokinetic (PBPK) modeling: it is here to stay! , 2012, Biopharmaceutics & drug disposition.

[25]  W. Potter,et al.  Metabolism of Tricyclic Antidepressants , 1999, Cellular and Molecular Neurobiology.

[26]  F. Lemere.  Pharmacologic treatment of depression. , 1958, Northwest medicine.

[27]  R. Bergstrom,et al.  The effect of sertraline on the pharmacokinetics of desipramine and imipramine , 1997, Clinical pharmacology and therapeutics.

[28]  F. Theil,et al.  A priori prediction of tissue:plasma partition coefficients of drugs to facilitate the use of physiologically-based pharmacokinetic models in drug discovery. , 2000, Journal of pharmaceutical sciences.

[29]  M. Rowland,et al.  Physiologically based pharmacokinetic modelling 2: predicting the tissue distribution of acids, very weak bases, neutrals and zwitterions. , 2006, Journal of pharmaceutical sciences.

[30]  M. Rowland,et al.  Physiologically based pharmacokinetic modeling 1: predicting the tissue distribution of moderate-to-strong bases. , 2005, Journal of pharmaceutical sciences.

[31]  J. Rapoport,et al.  Treatment of childhood hyperactivity with desipramine: Plasma drug concentration, cardiovascular effects, plasma and urinary catecholamine levels, and clinical response , 1986, Clinical pharmacology and therapeutics.

[32]  D. Ciraulo,et al.  Clinical pharmacokinetics of imipramine and desipramine in alcoholics and normal volunteers , 1988, Clinical pharmacology and therapeutics.

[33]  D. Hattis,et al.  Evaluation of child/adult pharmacokinetic differences from a database derived from the therapeutic drug literature. , 2002, Toxicological sciences : an official journal of the Society of Toxicology.

[34]  R. Schultz,et al.  A placebo-controlled study of guanfacine in the treatment of children with tic disorders and attention deficit hyperactivity disorder. , 2001, The American journal of psychiatry.

[35]  J. Dressman,et al.  Cytochrome P450‐mediated metabolism in the human gut wall , 2009 .

[36]  V. Lukacova,et al.  Quantitative clinical pharmacology for size and age scaling in pediatric drug development: A systematic review , 2015, Journal of clinical pharmacology.

[37]  K. Brøsen,et al.  First‐pass metabolism of imipramine and desipramine: Impact of the sparteine oxidation phenotype , 1988, Clinical pharmacology and therapeutics.

[38]  G. Jones,et al.  Death of two subjects due to imipramine and desipramine metabolite accumulation during chronic therapy: a review of the literature and possible mechanisms. , 1997, Journal of forensic sciences.

[39]  R. Baldessarini,et al.  A double-blind placebo controlled study of desipramine in the treatment of ADD: I. Efficacy. , 1989, Journal of the American Academy of Child and Adolescent Psychiatry.

[40]  N. Ryan,et al.  Another sudden death in a child treated with desipramine. , 1993, Journal of the American Academy of Child and Adolescent Psychiatry.

[41]  C. DeVane,et al.  Desipramine and 2-hydroxy-desipramine pharmacokinetics in normal volunteers , 2004, European Journal of Clinical Pharmacology.

[42]  F. Sallee,et al.  Clinical Pharmacokinetics of Imipramine and Desipramine , 1990, Clinical pharmacokinetics.