Population PK modelling and simulation based on fluoxetine and norfluoxetine concentrations in milk: a milk concentration-based prediction model.
OBJECTIVE
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).
Division of Clinical Pharmacology and Toxicology, Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.
Reo
R
Tanoshima
Facundo Garcia
FG
Bournissen
Yusuke
Y
Tanigawara
Judith H
JH
Kristensen
Anna
A
Taddio
Kenneth F
KF
Ilett
Evan J
EJ
Begg
Izhar
I
Wallach
Shinya
S
Ito
D000328:Adult; D002675:Child, Preschool; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics; D005260:Female; D005473:Fluoxetine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics*; D006801:Humans; D007223:Infant; D008895:Milk, Human / Q000737:chemistry*; D008954:Models, Biological
D005473:Fluoxetine; D019389:Cytochrome P-450 CYP2D6; C036139:norfluoxetine
breast milk; fluoxetine; modelling; population pharmacokinetics; simulation