Drug Excretion in Breast Milk

Study Overview
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Brief Summary
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This is a prospective, non-randomized, phase I study design evaluating the in vivo activities and expression of OCT1 and BCRP in mammary gland of lactating women at three time points postpartum.

Detailed Description
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Each woman will receive a single oral dose of cimetidine 200 mg on each of 3 study days (3-5 weeks, 3-4 months, and 6-8 months postpartum) followed by serial collection of blood, urine and breast milk samples over 12-hours. Cimetidine concentrations will be assay using a validated LC/MS/MS assay. Subjects will be genotyped for OCT1 and BCRP. Mammary epithelial cells will be isolated from breast milk and transporter expression will be quantified. Each woman will serve as her own control.

Official Title
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Postpartum Activity and Expression of BCRP and OCT1 Drug Transporters in the Mammary Gland

Conditions
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Lactation

Intervention / Treatment
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* Drug: Cimetidine 200 MG


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Study participants will include: healthy, lactating or pregnant and planning to breastfeed their infant, between 18-50 years of age, female and their nursing infant 3 weeks-8 months of age. Exclusion Criteria: • Age <18 or > 50 years old. Smokers Following multiple gestation (twins, triplets etc.) Allergy to cimetidine Pregnancy Receiving medications that could lead to a drug interaction e.g. A: antacids, alprazolam, amphetamines, atazanavir, acalabrutinib, alosetron, amiodarone, amitriptyline, azelastine, amoxapine, alfuzosin, B: bisacodyl, bupropion, bosutinib, C: citalopram, chloroquine, codeine, clozapine, carmustine, clopidogrel, cyclosporine, carvedilol, cannabis, cefpodoxime, ceftibuten, clomipramine, cefditoren, chlordiazepoxide, chlorpromazine, cholecalciferol, cisapride, clonazepam, clorazepate, clomethiazole, carbamazepine, D: dofetilide, dihydrocodeine, duloxetine, delavirdine, dasatinib, domperidone, dothiepin, dilevalol, diltiazem, dutasteride, desipramine, doxepin, diazepam, E: escitalopram, epirubicin, eliglustat, estazolam, ethanol (on study day), ergocalciferol, F: fezolinetant, fluorouracil, finerenone, fexinidazole, flecainide, fluconazole, flurazepam, fosamprenavir, femoxetine, G: gefitinib, glipizide, glyburide, gliclazide, glimepiride, H: hydroxychloroquine, halazepam, I: infigratinib, imipramine, itraconazole, K: ketoconazole, L: ledipasvir, lornoxicam, labetalol, lidocaine, levoketoconazole, levomethadyl, lomitapide, loratadine, M: meperidine, morphine, mirtazapine, midazolam, metformin, metoclopramide, memantine, metronidazole, moclobemide, N: neratinib, nicotine, nebivolol, nisoldipine, nifedipine, nortriptyline, nimodipine, nicardipine, nilotinib, nitrazepam, nilvadipine, nitrendipine, O: oxycodone, octreotide, oxymorphone, P: posaconazole, piperaquine, pazopanib, pentoxifylline, paroxetine, phenytoin, pramipexole, propranolol, procainamide, phenindione, perfloxacin, praziquantel, protriptyline, prazepam, pontinib, Q: quinidine, quazepam, quinine, R: rilpivirine, roflumilast, risperidone, risedronate, S: succinylcholine, selpercatinib, sirolimus, secretin, sotorasib, sparsentan, sofobuvir, saquinavir, sertraline, sucralfate, sildenafil, T: terbinafine, tramadol, theophylline, tacrolimus, tizanidine, tolazoline, trimetrexate, tocainide, tamsulosin, timolol, tacrine, tolbutamide, trimipramine, tamoxifen, trimazosin, tinidazole, triazolam, V: vismodegib, verapamil, velpatasvir, venlafaxine, vardenafil, W: warfarin, Z: zalcitabine, zaleplon, zolmitriptan BCRP inhibitors: dasatinib, celecoxib, erlotinib, lopinavir, fostamatinib, docetaxel, barcitinib, imatinib, gefitnib, venetoclax, sunitinib, elacridar, Palbociclib, regorafenib, rucaparib, nilotinib, sorafenib, vemurafenib, afatinib, nelfinavir, paclitaxel, quercetin and alectinib BCRP inducers: venlafaxine, and dovitinib OCT inhibitors: trimethoprim, ranitidine, codeine, rocuronium, ganciclovir, acyclovir, dinoprostone, progesterone, prazosin, phenoxybenzamine, phenformin, procainamide, nicotine, choline, verapamil, quinine, pancuronium, disopyramide, desipramine, guanidine, probenecid, saquinavir, nelfinavir, chlorpheniramine, indinavir, reserpine, rucaparib, estradiol, pitolisant, choline, quinidine, amantadine, dexchlorpheniramine, doxazosin, efavirenz, nevirapine, clopidogrel, dacomitinib, gilteritinib, palbociclib, linagliptin, nintedanib, dronedarone, lasmiditan, formoterol, guanfacine, salmeterol, levofloxacin, osilodrostat, lurbinectedin, tirbanibulin cyproheptadine, infigratinib, atagepant, asciminib, abrocitinib, pacritinib, olaparib, tepotinib, tafenoquine, propranolol, oxprenolol, metoprolol, quinine, thiamine, norepinephrine, imipramine, grepafloxacine, amantadine, metformin, desipramine, famotidine, probenecid, cisplatin, quinacrine, amiloride, epinephrine, disopyramide, diphenhydramine, imatinib, flurazepam, bupropion, amiodarone, clopidogrel, cocaine, lamotrigine OCT inducers: none identified

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 50 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: Basic Science
Intervention Model: Sequential Assignment
Interventional Model Description: This is a phase 1 study design of an approved drug to evaluate the time-course for the expression and activity of OCT1 and BCRP in the mammary gland 3-5 weeks, 3-4 months and 6-8 months postpartum.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Healthy Lactating Women<br>Healthy Lactating Women will be studied on 3 study days and serve as their own control. | Drug: Cimetidine 200 MG<br>* Cimetidine will serve as the probe drug<br>* Other names: Tagamet;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mammary clearance of cimetidine | Cimetidine excretion into breast milk at three postpartum stages | 3-5 weeks, 3-4 months and 6-8 months postpartum | 
| Mammary epithelial cell expression of BCRP | BCRP protein expression in MECs at three postpartum stages | 3-5 weeks, 3-4 months and 6-8 months postpartum | 
| Mammary epithelial cell expression of OCT1 | OCT1 protein expression in MECs at three postpartum stages | 3-5 weeks, 3-4 months and 6-8 months postpartum | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cimetidine relative infant dose and infant concentration | cimetidine relative infant dose (RID) and infant concentration | 3-5 weeks, 3-4 months and 6-8 months postpartum | 
| Relationship between OCT1 expression and activity | Effect of time postpartum on OCT1 protein expression in MECs and correlation with cimetidine mammary CL | 3-5 weeks, 3-4 months and 6-8 months postpartum | 
| Maternal cimetidine PK | Effects of time postpartum on cimetidine CL/F | 3-5 weeks, 3-4 months and 6-8 months postpartum | 
| Maternal cimetidine PK | Effects of time postpartum on cimetidine renal CL | 3-5 weeks, 3-4 months and 6-8 months postpartum | 
| Maternal cimetidine PK | Effects of time postpartum on cimetidine renal secretion CL | 3-5 weeks, 3-4 months and 6-8 months postpartum | 
| Maternal cimetidine PK | Effects of time postpartum on cimetidine mammary CL | 3-5 weeks, 3-4 months and 6-8 months postpartum | 
| Maternal cimetidine PK | Effects of time postpartum on cimetidine AUC | 3-5 weeks, 3-4 months and 6-8 months postpartum | 
| Maternal cimetidine PK | Effects of time postpartum on cimetidine Cmax | 3-5 weeks, 3-4 months and 6-8 months postpartum | 
| Maternal cimetidine PK | Effects of time postpartum on cimetidine Tmax | 3-5 weeks, 3-4 months and 6-8 months postpartum | 
| Maternal cimetidine PK | Effects of time postpartum on cimetidine half-life | 3-5 weeks, 3-4 months and 6-8 months postpartum | 
| Maternal cimetidine PK | Effects of time postpartum on cimetidine apparent oral volume of distribution | 3-5 weeks, 3-4 months and 6-8 months postpartum | 
| Maternal cimetidine PK | Effects of time postpartum on cimetidine elimination rate constant | 3-5 weeks, 3-4 months and 6-8 months postpartum | 
| Relationship between BCRP expression and activity | Effect of time postpartum on BCRP protein expression in MECs and correlation with cimetidine mammary CL | 3-5 weeks, 3-4 months and 6-8 months postpartum | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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breast milk, lactation, cimetidine, proteomics, OCT1, BCRP, OCTN2, PEPT2, ENT1, CNT3, MRP1, OATP2B1, OATP3A1, OCT2, postpartum, pharmacokinetics