Population PK modelling and simulation based on fluoxetine and norfluoxetine concentrations in milk: a milk concentration-based prediction model

Reo Tanoshima, Facundo G arcia Bournissen, Yusuke Tanigawara, Judith H. Kristensen, Anna Taddio, Kenneth F. Ilett, Evan J. Begg, Izhar Wallach, Shinya Ito

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

AIMS: Population pharmacokinetic (pop PK) modelling can be used for PK assessment of drugs in breast milk. However, complex mechanistic modelling of a parent and an active metabolite using both blood and milk samples is challenging. We aimed to develop a simple predictive pop PK model for milk concentration-time profiles of a parent and a metabolite, using data on fluoxetine (FX) and its active metabolite, norfluoxetine (NFX), in milk.

METHODS: Using a previously published data set of drug concentrations in milk from 25 women treated with FX, a pop PK model predictive of milk concentration-time profiles of FX and NFX was developed. Simulation was performed with the model to generate FX and NFX concentration-time profiles in milk of 1000 mothers. This milk concentration-based pop PK model was compared with the previously validated plasma/milk concentration-based pop PK model of FX.

RESULTS: Milk FX and NFX concentration-time profiles were described reasonably well by a one compartment model with a FX-to-NFX conversion coefficient. Median values of the simulated relative infant dose on a weight basis (sRID: weight-adjusted daily doses of FX and NFX through breastmilk to the infant, expressed as a fraction of therapeutic FX daily dose per body weight) were 0.028 for FX and 0.029 for NFX. The FX sRID estimates were consistent with those of the plasma/milk-based pop PK model.

CONCLUSIONS: A predictive pop PK model based on only milk concentrations can be developed for simultaneous estimation of milk concentration-time profiles of a parent (FX) and an active metabolite (NFX).

Original languageEnglish
Pages (from-to)918-928
Number of pages11
JournalBritish Journal of Clinical Pharmacology
Volume78
Issue number4
DOIs
Publication statusPublished - 2014 Oct 1
Externally publishedYes

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Keywords

  • breast milk
  • fluoxetine
  • modelling
  • population pharmacokinetics
  • simulation

ASJC Scopus subject areas

  • Medicine(all)

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