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

6 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

Fingerprint

Fluoxetine
Milk
Population
Pharmacokinetics
norfluoxetine
Weights and Measures
Human Milk
Pharmaceutical Preparations
Body Weight
Mothers

Keywords

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

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Population PK modelling and simulation based on fluoxetine and norfluoxetine concentrations in milk : a milk concentration-based prediction model. / Tanoshima, Reo; Bournissen, Facundo G arcia; Tanigawara, Yusuke; Kristensen, Judith H.; Taddio, Anna; Ilett, Kenneth F.; Begg, Evan J.; Wallach, Izhar; Ito, Shinya.

In: British Journal of Clinical Pharmacology, Vol. 78, No. 4, 01.10.2014, p. 918-928.

Research output: Contribution to journalArticle

Tanoshima, Reo ; Bournissen, Facundo G arcia ; Tanigawara, Yusuke ; Kristensen, Judith H. ; Taddio, Anna ; Ilett, Kenneth F. ; Begg, Evan J. ; Wallach, Izhar ; Ito, Shinya. / Population PK modelling and simulation based on fluoxetine and norfluoxetine concentrations in milk : a milk concentration-based prediction model. In: British Journal of Clinical Pharmacology. 2014 ; Vol. 78, No. 4. pp. 918-928.
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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).",
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T1 - Population PK modelling and simulation based on fluoxetine and norfluoxetine concentrations in milk

T2 - a milk concentration-based prediction model

AU - Tanoshima, Reo

AU - Bournissen, Facundo G arcia

AU - Tanigawara, Yusuke

AU - Kristensen, Judith H.

AU - Taddio, Anna

AU - Ilett, Kenneth F.

AU - Begg, Evan J.

AU - Wallach, Izhar

AU - Ito, Shinya

PY - 2014/10/1

Y1 - 2014/10/1

N2 - 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).

AB - 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).

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KW - population pharmacokinetics

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