Genetic Polymorphisms of ABCG2/BCRP on the Transport of Nifedipine to Breast Milk.

Study Overview
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Brief Summary
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This study aims to investigate the influence of the c.421C>A genetic polymorphism of the ABCG2 / BCRP transporter in the concentration ratio of nifedipine in maternal milk:plasma in hypertensive breastfeeding women attended at the Gynecology and Obstetrics Service of the Medical School of Ribeirão Preto, of the University of São Paulo. Thus, plasma and breast milk samples are being collected from patients in chronic use of the drug (n=30) within 15 to 30 days postnatal.

Detailed Description
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The breast cancer resistance protein (ABCG2/BCRP) human transporter, encoded by the ABCG2 gene, is highly expressed on the human lactating breast. Nifedipine, a known substrate of ABCG2, is used for the treatment of hypertension in pregnancy and during breastfeeding. ABCG2 plays an important role on secreting drugs and xenobiotics into milk. The aim of the present study was to evaluate the effect of ABCG2 c.421C>A on nifedipine breast milk/plasma concentration ratio in hypertensive breastfeeding women. Nineteen hypertensive breastfeeding women treated with 20 mg slow-release nifedipine every 12 hours were investigated. Blood and breast milk samples were collected simultaneously 15-30 days after delivery and at least 15 days after drug treatment, in order to reach drug steady state. All patients were genotyped for ABCG2 c.421C>A using real time-PCR. Nifedipine concentration was determined in plasma and breast milk by high-performance liquid chromatography using UV detection. The comprehension of the variability in the transport of nifedipine to breast milk in hypertensive breastfeeding women will contribute to the evaluation of drug exposure in breast-fed infants to nifedipine and other ABCG2 substrates.

Official Title
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Influence of Genetic Polymorphisms of ABCG2/BCRP on the Transport of Nifedipine to Breast Milk in Hypertensive Breastfeeding Women.

Conditions
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Drug Transporter

Intervention / Treatment
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* Procedure: Blood and breast milk sampling
* Drug: Nifedipine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Chronic hypertensive breastfeeding women Patients being treated with 20 mg slow-release nifedipine every 12 hours for at least 15 days Exclusion Criteria: Patients in use of ABCG2 inhibitors (omeprazole, pantoprazole, ritonavir, saquinavir, imatinib, efavirenz, nicardipine, abacavir, tacrolimus, ciclosporin A, cannabidiol); Patients who presented nifedipine adverse drug reactions Patients whose blood pressure normalized after delivery Patients who interrupted breastfeeding during the study Patients who did not return to the hospital for the clinical protocol.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 45 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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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Wild homozygous for ABCG2 c.421C>A<br>Chronic hypertensive breastfeeding women (18-45 years old) genotyped as wild homozygous for ABCG2 c.421C>A. | Procedure: Blood and breast milk sampling<br>* At least 15 days after starting treatment with 20 mg slow-release nifedipine every 12 hours. Blood and breast milk will be sampled before first dosing in the morning.<br>* Other names: Biological samples for nifedipine analysis;Drug: Nifedipine<br>* Chronic hypertensive breastfeeding women will be treated with slow-release 20 mg nifedipine, twice a day.<br>* Other names: 20 mg nifedipine (slow-release);|
| Experimental: Variant genotypes for ABCG2 c.421C>A<br>Chronic hypertensive breastfeeding women (18-45 years old) genotyped as heterozygous or mutant homozygous for ABCG2 c.421C>A. | Procedure: Blood and breast milk sampling<br>* At least 15 days after starting treatment with 20 mg slow-release nifedipine every 12 hours. Blood and breast milk will be sampled before first dosing in the morning.<br>* Other names: Biological samples for nifedipine analysis;Drug: Nifedipine<br>* Chronic hypertensive breastfeeding women will be treated with slow-release 20 mg nifedipine, twice a day.<br>* Other names: 20 mg nifedipine (slow-release);|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Nifedipine concentration in plasma/milk ratio | The concentration ratio will be determined as (nifedipine concentration in plasma)/(nifedipine concentration in breast milk). | After reaching steady state (at least 15 days of treatment), samples will be collected before first nifedipine dosing in the morning. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Nifedipine concentration in plasma | The concentration of nifedipine in plasma determined by HPLC. | After reaching steady state (at least 15 days of treatment), samples will be collected before first nifedipine dosing in the morning. | 
| Nifedipine concentration in milk | The concentration of nifedipine in breast milk determined by HPLC. | After reaching steady state (at least 15 days of treatment), samples will be collected before first nifedipine dosing in the morning. |