Population PK modelling and simulation based on fluoxetine and norfluoxetine concentrations in milk: a milk concentration-based prediction model.
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).
['Tanoshima|Reo|R|', 'Bournissen|Facundo Garcia|FG|', 'Tanigawara|Yusuke|Y|', 'Kristensen|Judith H|JH|', 'Taddio|Anna|A|', 'Ilett|Kenneth F|KF|', 'Begg|Evan J|EJ|', 'Wallach|Izhar|I|', 'Ito|Shinya|S|']
D000328:Adult D002675:Child, Preschool D019389:Cytochrome P-450 CYP2D6 D005260:Female D005473:Fluoxetine D006801:Humans D007223:Infant D008895:Milk, Human D008954:Models, Biological
modelling simulation fluoxetine population pharmacokinetics breast milk