UmbrelLACT Study: Clinical Lactation Study on the Exposure to Medicines Via Human Milk

Study Overview
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Brief Summary
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The goal of this observational study is to determine the concentration of medicines in human milk during maternal medicine intake. The main questions it aims to answer are: What is the concentration of maternal medicines in human milk? What is the (estimated) intake and exposure in the breastfed infant? Participants will be asked to fill out a questionnaire regarding medical data of the mother and child track medication intake for 3 days collect milk samples during 24 hours optionally, donate 2 blood samples of the mother and give consent to one blood sample of the child fill out a questionnaire regarding the general health of the child.

Detailed Description
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There is an immense information gap regarding safety of medicines during lactation which can result in a lack of breastfeeding adherence. According to literature, 50% of women need pharmacotherapy in the postpartum period. However, the proportion of nursing women in need of medication rises, due to later age pregnancies and the increased prevalence of chronic diseases. Evidence-based decisions on the use and selection of medicine during breastfeeding are challenging for many medicines, due to the lack of available information, such as cardiovascular compounds (e.g. atorvastatin, simvastatin), antidepressants (e.g. venlafaxine), anti-epileptics (e.g. topiramate, pregabalin), etc. This often results in unnecessary cessation of breastfeeding or poor adherence to/avoidance of pharmacological treatment. The objective of this prospective trial is to collect information about the human milk transfer of maternal medicines, subsequent infant exposure, and general health outcome of the infant. Furthermore, the data of this clinical lactation study will be used to verify the performance of pharmacologically-based pharmacokinetic (PBPK) models to predict disposition of medicines in human milk and subsequent neonatal exposure during lactation. An umbrella protocol approach is used. This means that each request or compound for which milk samples might be collected / offered by women, will be reviewed and evaluated for feasibility and relevance. The investigators expect to enroll 5, at maximum 15, mothers per year, who have been prescribed maternal medication for medical reasons and are breastfeeding their infant (/expressing milk) while taking this medication. The participating mother will be asked to collect milk samples and optionally to donate 2 blood samples during 24h: one at the time of milk pumping the first time after medication intake and one at the last pumping session of the 24h period. The parents can optionally consent for collecting a blood sample of the infant for the study (1-5% of the total blood volume, according to the FDA guidelines). In addition, clinical maternal and infant variables will be collected, as well as medication regimen, sampling details and general infant health information using 2 questionnaires. To conclude, with this study data about the concentration of maternal medication in human milk, and the exposure in the nursing infant will be generated. This information is an essential first step towards evidence-based risk assessment on the use of drugs during lactation.

Official Title
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Clinical Lactation Study on the Exposure to Medicines Via Human Milk: an Umbrella Study Protocol

Conditions
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Breast Feeding, Human Milk

Intervention / Treatment
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* Other: Human milk collection
* Other: Optionally: maternal blood sample
* Other: Optionally: child blood sample


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: For breastfeeding women Maternal age: ≥ 18 year Currently exclusively or partially breastfeeding (/expressing milk) at the time of milk sampling Using medicines for any indication, with at least 5 half-lives of the medicine taken Willing to express and collect human milk Signed informed consent to participate and for processing their personal data For infants Gestational age at birth: ≥24 weeks Parental signed informed consent to participate and for processing their personal data Exclusion Criteria: Maternal age <18 years Mother of twins Not meeting the inclusion criteria

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Arms and Interventions

| Intervention/Treatment |
| --- |
|Other: Human milk collection|Every time the mother would normally feed the child, we ask to collect the total milk volume for the feed from both breasts by an electric pump. For each collection, the volume and time will be noted, the container will be inverted and 5 to 10ml of that volume will be transferred in a polypropylene test tube or other tube type depending on the type of compounds (=sample to determine drug concentration in milk) for analysis (max 10% of the collected volume of each feed). The participant decides how the remainder of the collected milk is used. The milk samples will immediately be stored in the refrigerator (4°C) after being labeled. The samples will be collected by one of the investigators within 24 hours, will be transported on ice and frozen at -80°C until analysis.|
|Other: Optionally: maternal blood sample|Blood collection to determine the drug concentration in plasma (6 to 10mL EDTA or other tube type, depending on the type of compound) will be performed at least within 1 hour interval with the first feeding (pumping) after medication intake, and 24 hours after medication intake (with preferable milk collection within 1 hour of blood sampling). The sample label, date and time of sampling will be noted.|
|Other: Optionally: child blood sample|Blood collection of the infant to determine systemic exposure of child(1-5% of the total blood volume, according to the FDA guidelines, in an EDTA or other tube type, depending on the type of compound,) will be performed at the same day as the maternal sampling, if parental consent is obtained. The sample label, date and time of sampling will be noted.|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The concentration of maternal medicines in human milk | Quantification of the concentration of medicines in human milk: concentration, milk-to-plasma (M/P) ratio; The PK parameters of medicines and relevant metabolites in human milk: area under the milk concentration-time curve (AUC), the average concentration (AUC divided by dosing interval), peak and trough milk concentrations (if available, depending on dosing regimen and lactation regimen), and time to reach peak milk concentration. The PK parameters of medicines and relevant metabolites in plasma from lactating women compared to available scientific literature results, such as AUC, peak plasma concentration, time to peak plasma concentration, plasma clearance or apparent oral clearance, apparent volume of distribution and terminal half-life. | 24 hours (sampling day) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The estimated intake of medicines in the nursing infant via human milk: DID | The daily infant dosage (DID)(mg/d) = ∑(total drug concentration in each milk collection x expressed milk volume in each milk collection) | 24 hours (sampling day) | 
| The estimated intake of medicines in the nursing infant via human milk: eDID - maxDID | The estimated Daily infant dosage (eDID)(mg/kg/d) and the infant risk (maxDID) expressed as a daily weight normalized dose (mg/kg/d), with 150mL/kg/d and 200mL/kg/d as maximum estimated milk intake, respectively. The calculation of the M/P ratio is based on the AUC on multiple time points, if possible. = M/P ratio x average plasma concentration x estimated milk intake | 24 hours (sampling day) | 
| The estimated intake of medicines in the nursing infant via human milk: RID | The relative infant dose (RID)(%) = [eDID (mg/kg/d)/Maternal Dosage (mg/kg/d)] x 100 | 24 hours (sampling day) | 
| The estimated intake of medicines in the nursing infant via human milk: RIDtherapeutic | The relative infant therapeutic dose (RIDtherapeutic)(%) = [estimated daily infant dosage (mg/kg/d)/Daily therapeutic infant dosage (mg/kg/d)] x 100 | 24 hours (sampling day) | 
| The estimated intake of medicines in the nursing infant via human milk: Css, ave | The average infant medicine concentration at steady state (Css, ave)(ng/mL), if oral bioavailability (F) and drug clearance (CL) are known for the paediatric population = oral bioavailability (F) x [eDID (mg/kg/d)/Clearance (CL; L/d)]x1000 | 24 hours (sampling day) | 
| The systemic exposure to medicines in the nursing infant via breastfeeding: infant systemic medicine concentration | The measured infant systemic medicine concentration if the parents give consent for collection of a blood sample from the infant; | 24 hours (sampling day) | 
| The systemic exposure to medicines in the nursing infant via breastfeeding: infant/maternal plasma ratio | The infant/maternal plasma ratio if a blood sample from the infant is available; | 24 hours (sampling day) | 
| The systemic exposure to medicines in the nursing infant via breastfeeding | Rate of medicine absorption in infants through human milk (e.g., infant plasma concentration/milk concentration) if a blood sample from the infant is available; | 24 hours (sampling day) | 
| The general health status (including possible adverse effects) of the nursing infant | The general health status of the infant, reported by maternal questionnaire. | 2 weeks (in case of an acute maternal treatment/condition) or 2 months (in case of an chronic maternal treatment/condition) | 
| Evaluation of physiologically-based pharmacokinetic (PBPK) models: Concentration-time profile | Evaluation of the predictive performance of PBPK models by assessing whether the observed concentration-time profiles were within the 5th-95th percentile of the population prediction of the PBPK models. | 24 hours | 
| Evaluation of physiologically-based pharmacokinetic (PBPK) models: M/P ratio | Evaluation of the predictive performance of PBPK models by assessing whether the observed Milk-to-plasma ratio were within the 5th-95th percentile of the population prediction of the PBPK models. | 24 hours | 
| Evaluation of physiologically-based pharmacokinetic (PBPK) models: Cmax | Evaluation of the predictive performance of PBPK models by assessing whether the observed maximum concentration (Cmax) were within the 5th-95th percentile of the population prediction of the PBPK models. | 24 hours | 
| Evaluation of physiologically-based pharmacokinetic (PBPK) models: AUC | Evaluation of the predictive performance of PBPK models by assessing whether the observed Area-under-the-curve (AUC) were within the 5th-95th percentile of the population prediction of the PBPK models. | 24 hours | 
| Evaluation of physiologically-based pharmacokinetic (PBPK) models: DID | Evaluation of the predictive performance of PBPK models by comparing the predicted daily infant dosage (DID) with the calculated DID [The daily infant dosage (DID)(mg/d) = ∑(total drug concentration in each milk collection x expressed milk volume in each milk collection), calculated from the concentrations found in the human milk samples]. | 24 hours | 
| Evaluation of physiologically-based pharmacokinetic (PBPK) models: RID | Evaluation of the predictive performance of PBPK models by comparing the predicted relative infant dose (RID) with the calculated RID [The relative infant dose (RID)(%) = [eDID (mg/kg/d)/Maternal Dosage (mg/kg/d)] x 100]. | 24 hours | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Infant exposure, Physiologically-based pharmacokinetic models, Neonatology, breastfeeding, Pharmacology, Medicines, Drug transfer, Medication intake