title: Prediction of infant drug exposure through breastfeeding: population PK modeling and simulation of fluoxetine exposure.
abstract: The likelihood of significant exposure to drugs in infants through breast milk is poorly defined, given the difficulties of conducting pharmacokinetics (PK) studies. Using fluoxetine (FX) as an example, we conducted a proof-of-principle study applying population PK (popPK) modeling and simulation to estimate drug exposure in infants through breast milk. We simulated data for 1,000 mother-infant pairs, assuming conservatively that the FX clearance in an infant is 20% of the allometrically adjusted value in adults. The model-generated estimate of the milk-to-plasma ratio for FX (mean: 0.59) was consistent with those reported in other studies. The median infant-to-mother ratio of FX steady-state plasma concentrations predicted by the simulation was 8.5%. Although the disposition of the active metabolite, norfluoxetine, could not be modeled, popPK-informed simulation may be valid for other drugs, particularly those without active metabolites, thereby providing a practical alternative to conventional PK studies for exposure risk assessment in this population.
authors.affiliation: Division of Clinical Pharmacology and Toxicology, Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: A
authors.initials: A
authors.lastname: Panchaud
authors.forename: F
authors.initials: F
authors.lastname: Garcia-Bournissen
authors.forename: C
authors.initials: C
authors.lastname: Csajka
authors.forename: J H
authors.initials: JH
authors.lastname: Kristensen
authors.forename: A
authors.initials: A
authors.lastname: Taddio
authors.forename: K F
authors.initials: KF
authors.lastname: Ilett
authors.forename: E J
authors.initials: EJ
authors.lastname: Begg
authors.forename: S
authors.initials: S
authors.lastname: Ito
mesh_terms: D000328:Adult; D000367:Age Factors; D001942:Breast Feeding / Q000009:adverse effects; D002675:Child, Preschool; D005260:Female; D005473:Fluoxetine / Q000097:blood / Q000493:pharmacokinetics*; D005544:Forecasting; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008895:Milk, Human / Q000187:drug effects* / Q000378:metabolism*; D017711:Nonlinear Dynamics; D012189:Retrospective Studies; D055815:Young Adult
chemical_list: D005473:Fluoxetine