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

Abstract

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. Sur la dialectique de l’engagement Voirol, Olivier info:eu-repo/semantics/bookPart incollection 2015 Penser l’engagement, pp. 71-95 Ouelbani, Mélika (ed.) fre oai:serval.unil.ch:BIB_63D52E568CD1 2022-02-19T02:22:47Z <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_63D52E568CD1 La maladie ulcereuse gastro-duodenale: que reste-t-il des indications chirurgicales? [Gastroduodenal ulcer disease: what surgical indications are left?] info:eu-repo/semantics/altIdentifier/pmid/2569232 Cuttat, J. F. Ruchat, P. 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. The present study shows that 1. the annual number of operations has regressed by some 30%, 2. while the number of gastric ulcers remains constant on the whole, cases of acute duodenal ulcer have diminished by half, 3. cases of chronic, recurrent, or therapy-resistent duodenal ulcer have increased some tenfold (2 out of 78 in 1976 and 14 out of 45 in 1987), 4. the same is true of perforated ulcers (12 out of 78 in 1976 and 10 out of 45 in 1987) and hemorrhages (12 out of 78 and 10 out of 45), 5. surgery for stenosis has remained constant. -Proximal selective vagotomy has been the treatment of choice since 1981 in over 80% of duodenal ulcers. Operative mortality affects only elderly patients undergoing emergency surgery for complicated ulcer (two thirds perforations, one third hemorrhages). It is 2.6%. We thus confirm the reduced role of surgery in the treatment of gastric ulcer, while redefining the present surgical indications