Premium
Population PK modelling and simulation based on fluoxetine and norfluoxetine concentrations in milk: a milk concentration‐based prediction model
Author(s) -
Tanoshima Reo,
Bournissen Facundo Garcia,
Tanigawara Yusuke,
Kristensen Judith H.,
Taddio Anna,
Ilett Kenneth F.,
Begg Evan J.,
Wallach Izhar,
Ito Shinya
Publication year - 2014
Publication title -
british journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.216
H-Index - 146
eISSN - 1365-2125
pISSN - 0306-5251
DOI - 10.1111/bcp.12409
Subject(s) - metabolite , breast milk , population , chemistry , pharmacokinetics , zoology , chromatography , medicine , biology , biochemistry , environmental health
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 ).