Pharmacokinetics of Antimalarials in Breastfeeding Ugandan Mother-infant Pairs

Study Overview
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Brief Summary
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Lactating women requiring treatment for uncomplicated malaria will be identified and invited for sampling. The decision to treat them with first-line treatment will have been made by the clinician, not by a member of the study team. The study team will not make any adjustments to the prescribed treatment. Artemether-lumefantrine comprises six doses of medication, with the initial two doses given 8 hours apart on Day 1, and dosing 12-hourly on Day 2 and Day 3. Intensive pharmacokinetic sampling will be undertaken after Dose 5, as indicated in the schema under Section 5: plasma and breastmilk samples will be obtained pre-dose and at 2, 4, 6, 8 hours after dose. In addition, sparse sampling will be undertaken on either of these occasions; at pre-dose and between 1 to 6 hours after the first dose; a trough (pre-dose) sample after the Dose 3 or Dose 4 and lastly at 5, 7, and up to 14-days after the first dose. A heelprick sample will also be obtained from the breastfed infants at maternal trough (prior to maternal dose) and at a random timepoint (once per infant) over the 8-hour pharmacokinetic sampling visit to characterize concentrations of these drugs over an 8-hour dosing interval. In addition, a single heelprick sample will be obtained from the infant whenever the mother returns after treatment for the late sampling time points (5, 7, and 14 days post the first dose). Due to the long half-life of lumefantrine of approximately 6 days plasma sampling will be performed up to day 14 to characterise the terminal elimination of the drug. Concentrations of total plasma and breastmilk lumefantrine and desbutyl-lumefantrine will be determined.

Detailed Description
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The endpoints of this study relate to the amount of antimalarial drug present in maternal blood, breastmilk and infant blood. The study is not powered for antimalarial efficacy, and therefore formal assessment of parasitological clearance is not required. The participants will be followed up until 30-40 days after completion of antimalarial therapy, and if recurrent symptoms occur, management will be as clinically indicated. Details regarding further clinical investigations and management required by either mother or infant during the follow-up period will be recorded on the CRF.

Official Title
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Pharmacokinetics of Drugs Used to Treat Uncomplicated Malaria in Breastfeeding Mother-infant Pairs: An Observational Pharmacokinetic Study

Conditions
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Malaria,Falciparum

Intervention / Treatment
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* Drug: Artemether-lumefantrine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: A personally signed and dated informed consent document indicating that the participant has been informed of all pertinent aspects of the study. Participants who are willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures. Woman is aged 18 years or older, and mothers between the age of 14-17, who are considered emancipated minors. Receiving treatment for uncomplicated malaria Breastfeeding at enrolment Exclusion Criteria: Severe maternal or infant illness which in the opinion of the patient's clinician would interfere with her participation in the study Breastfed infant is aged over 12 months Partner objection to participate in the study Maternal objection to infant participation

Ages Eligible for Study
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Minimum Age: 14 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Participants<br>Breastfeeding women who have been prescribed (by a clinician independent from the study team) artemether-lumefantrine to treat uncomplicated malaria | Drug: Artemether-lumefantrine<br>* National policy recommendation for treatment of uncomplicated malaria in Uganda<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| AUC0-24 of lumefantrine in maternal plasma and breastmilk | Maternal plasma exposure of lumefantrine | 0-24 hours after dose | 
| AUC0-24 of lumefantrine breastmilk | Breastmilk exposure of lumefantrine | 0-24 hours after dose | 
| Milk to plasma ratio of lumefantrine | Ratio of AUC in breastmilk to maternal plasma | 0-24 hours after dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| AUC desbutyl-lumefantrine plasma | Plasma exposure of active metabolite | 0-24 hours after dose | 
| AUC desbutyl-lumefantrine breastmilk | Breastmilk exposure of active metabolite | 0-24 hours after dose | 
| Milk to plasma ratio of desbutyl-lumefantrine | Ratio of breastmilk to maternal plasma of active metabolite | 0-24 hours after dose | 
| Infant concentration lumefantrine | Infant lumefantrine exposure | 0-8 hours after maternal dose | 
| Infant concentration desbutyl-lumefantrine | Infant exposure to active metabolite | 0-8 hours after maternal dose | 
| Infant development | Infant assessment using Gross Motor Development Score (IGMDS) | 0-1 year old | 
| Depression and anxiety in mothers | Patient Health Questionnaire (PHQ9) | 0-1 year postpartum | 
| Depression and anxiety in mothers | General Anxiety Disorder (GAD7) | 0-1 year postpartum | 
| Maternal beliefs about medicines | Beliefs about Medicines questionnaire (BMQ) | 0-1 year postpartum |