Prediction of infant drug exposure through breastfeeding: population PK modeling and simulation of fluoxetine

BACKGROUND: Risks of significant infant drug exposurethrough breastmilk are poorly defined for many drugs, and largescalepopulation data are lacking. We used population pharmacokinetics(PK) modeling to predict fluoxetine exposure levels ofinfants via mother's milk in a simulated population of 1000 motherinfantpairs.METHODS: Using our original data on fluoxetine PK of 25breastfeeding women, a population PK model was developed withNONMEM and parameters, including milk concentrations, wereestimated. An exponential distribution model was used to account forindividual variation. Simulation random and distribution-constrainedassignment of doses, dosing time, feeding intervals and milk volumewas conducted to generate 1000 mother-infant pairs with characteristicssuch as the steady-state serum concentrations (Css) and infantdose relative to the maternal weight-adjusted dose (relative infantdose: RID). Full bioavailability and a conservative point estimate of1-month-old infant CYP2D6 activity to be 20% of the adult value(adjusted by weigth) according to a recent study, were assumed forinfant Css calculations.RESULTS: A linear 2-compartment model was selected as thebest model. Derived parameters, including milk-to-plasma ratios(mean: 0.66; SD: 0.34; range, 0 - 1.1) were consistent with the valuesreported in the literature. The estimated RID was below 10% in &gt;95%of infants. The model predicted median infant-mother Css ratio was0.096 (range 0.035 - 0.25); literature reported mean was 0.07 (range0-0.59). Moreover, the predicted incidence of infant-mother Css ratioof &gt;0.2 was less than 1%.CONCLUSION: Our in silico model prediction is consistent withclinical observations, suggesting that substantial systemic fluoxetineexposure in infants through human milk is rare, but further analysisshould include active metabolites. Our approach may be valid forother drugs. [supported by CIHR and Swiss National Science Foundation(SNSF)]]]> eng oai:serval.unil.ch:BIB_64448644E59E 2022-02-19T02:22:49Z <oai_dc:dc xmlns:dc="http://purl.org/dc/elements/1.1/" xmlns:xs="http://www.w3.org/2001/XMLSchema" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" xmlns:oai_dc="http://www.openarchives.org/OAI/2.0/oai_dc/" xsi:schemaLocation="http://www.openarchives.org/OAI/2.0/oai_dc/ http://www.openarchives.org/OAI/2.0/oai_dc.xsd"> https://serval.unil.ch/notice/serval:BIB_64448644E59E Storia linguistica di Venezia urn:isbn:9788843055128 info:eu-repo/semantics/altIdentifier/isbn/9788843055128 Tomasin, Lorenzo info:eu-repo/semantics/book book 2010 ita oai:serval.unil.ch:BIB_6444B2C2264E 2022-02-19T02:22:49Z <oai_dc:dc xmlns:dc="http://purl.org/dc/elements/1.1/" xmlns:xs="http://www.w3.org/2001/XMLSchema" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" xmlns:oai_dc="http://www.openarchives.org/OAI/2.0/oai_dc/" xsi:schemaLocation="http://www.openarchives.org/OAI/2.0/oai_dc/ http://www.openarchives.org/OAI/2.0/oai_dc.xsd"> https://serval.unil.ch/notice/serval:BIB_6444B2C2264E L'utilisation du laser CO2 dans le cadre d'une consultation de colposcopie Hohlfeld, P. De Grandi, P. info:eu-repo/semantics/article article 1988 Médecine et Hygiène, vol. 46, pp. 1325-1329 info:eu-repo/semantics/altIdentifier/pissn/0025-6749 fre oai:serval.unil.ch:BIB_644527E87B99 2022-02-19T02:22:49Z <oai_dc:dc xmlns:dc="http://purl.org/dc/elements/1.1/" xmlns:xs="http://www.w3.org/2001/XMLSchema" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" xmlns:oai_dc="http://www.openarchives.org/OAI/2.0/oai_dc/" xsi:schemaLocation="http://www.openarchives.org/OAI/2.0/oai_dc/ http://www.openarchives.org/OAI/2.0/oai_dc.xsd"> https://serval.unil.ch/notice/serval:BIB_644527E87B99 A study on the clinical significance of the who aml subtype inv(3)(q21q26.2)/t(3;3)(q21;q26.2) and various other 3q chromosomal abnormalities in 6,819 aml cases Lugthart, S. Groeschel, S. Beverloo, H. Valk, P. Schanz, U. Bhola, S. Vellenga, E. Kayser, S. Ossenkoppele, G. Verhoef, G. Ferrant, A. van den Berg-de Ruiter, E. Ganser, A. Jotterand, M. Krauter, J. Pabst, T. Schlegelberger, B. Schlenk, R. Delwel, R. Doehner, K. Loewenberg, B. Doehner, H. info:eu-repo/semantics/conferenceObject inproceedings 2010 15th Annual Meeting of the European Hematology Association, vol. 95, pp. 482 info:eu-repo/semantics/altIdentifier/isbn/0390-6078 eng oai:serval.unil.ch:BIB_6445291F3B73 2022-02-19T02:22:49Z <oai_dc:dc xmlns:dc="http://purl.org/dc/elements/1.1/" xmlns:xs="http://www.w3.org/2001/XMLSchema" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" xmlns:oai_dc="http://www.openarchives.org/OAI/2.0/oai_dc/" xsi:schemaLocation="http://www.openarchives.org/OAI/2.0/oai_dc/ http://www.openarchives.org/OAI/2.0/oai_dc.xsd"> https://serval.unil.ch/notice/serval:BIB_6445291F3B73 Le politique et l’oblitération. 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Chapuis, G. info:eu-repo/semantics/article article 1989-05 Schweizerische Medizinische Wochenschrift, vol. 119, no. 21, pp. 729-30 info:eu-repo/semantics/altIdentifier/pissn/0036-7672 <![CDATA[Between 1976, date of the introduction of anti-H2, and 1987, 716 patients were hospitalized and operated on for ulcer disease in the surgical department of this hospital. 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Prediction of Infant Drug Exposure Through Breastfeeding: Population PK Modeling and Simulation of Fluoxetine Exposure.

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