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

Sponsor

Universitaire Ziekenhuizen KU Leuven (Other)

Overall Status

Recruiting

CT.gov ID

NCT06042803

Collaborator

Innovative Medicines Initiative (Other), BELpREG (Other)

Enrollment

Location

26.9

Anticipated Duration (Months)

1.1

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Breast Feeding Human Milk	Other: Human milk collection Other: Optionally: maternal blood sample Other: Optionally: child blood sample

Detailed Description

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.

Study Design

Study Type:

Observational

Anticipated Enrollment :

30 participants

Observational Model:

Cohort

Time Perspective:

Prospective

Official Title:

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

Actual Study Start Date :

Feb 1, 2023

Anticipated Primary Completion Date :

Mar 1, 2025

Anticipated Study Completion Date :

May 1, 2025

Outcome Measures

Primary Outcome Measures

The concentration of maternal medicines in human milk [24 hours (sampling day)]
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.

Secondary Outcome Measures

The estimated intake of medicines in the nursing infant via human milk: DID [24 hours (sampling day)]
The daily infant dosage (DID)(mg/d) = ∑(total drug concentration in each milk collection x expressed milk volume in each milk collection)
The estimated intake of medicines in the nursing infant via human milk: eDID - maxDID [24 hours (sampling day)]
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
The estimated intake of medicines in the nursing infant via human milk: RID [24 hours (sampling day)]
The relative infant dose (RID)(%) = [eDID (mg/kg/d)/Maternal Dosage (mg/kg/d)] x 100
The estimated intake of medicines in the nursing infant via human milk: RIDtherapeutic [24 hours (sampling day)]
The relative infant therapeutic dose (RIDtherapeutic)(%) = [estimated daily infant dosage (mg/kg/d)/Daily therapeutic infant dosage (mg/kg/d)] x 100
The estimated intake of medicines in the nursing infant via human milk: Css, ave [24 hours (sampling day)]
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
The systemic exposure to medicines in the nursing infant via breastfeeding: infant systemic medicine concentration [24 hours (sampling day)]
The measured infant systemic medicine concentration if the parents give consent for collection of a blood sample from the infant;
The systemic exposure to medicines in the nursing infant via breastfeeding: infant/maternal plasma ratio [24 hours (sampling day)]
The infant/maternal plasma ratio if a blood sample from the infant is available;
The systemic exposure to medicines in the nursing infant via breastfeeding [24 hours (sampling day)]
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;
The general health status (including possible adverse effects) of the nursing infant [2 weeks (in case of an acute maternal treatment/condition) or 2 months (in case of an chronic maternal treatment/condition)]
The general health status of the infant, reported by maternal questionnaire.
Evaluation of physiologically-based pharmacokinetic (PBPK) models: Concentration-time profile [24 hours]
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.
Evaluation of physiologically-based pharmacokinetic (PBPK) models: M/P ratio [24 hours]
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.
Evaluation of physiologically-based pharmacokinetic (PBPK) models: Cmax [24 hours]
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.
Evaluation of physiologically-based pharmacokinetic (PBPK) models: AUC [24 hours]
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.
Evaluation of physiologically-based pharmacokinetic (PBPK) models: DID [24 hours]
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].
Evaluation of physiologically-based pharmacokinetic (PBPK) models: RID [24 hours]
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].

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

Female

Accepts Healthy Volunteers:

Yes

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