Drug Excretion in Breast Milk

Sponsor

University of Washington (Other)

Overall Status

Recruiting

CT.gov ID

NCT06056583

Collaborator

Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) (NIH)

Enrollment

Location

Arm

Anticipated Duration (Months)

0.8

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Lactation	Drug: Cimetidine 200 MG	Phase 4

Detailed Description

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.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

50 participants

Allocation:

N/A

Intervention Model:

Sequential Assignment

Intervention 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.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)

Primary Purpose:

Basic Science

Official Title:

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

Anticipated Study Start Date :

Oct 1, 2023

Anticipated Primary Completion Date :

Sep 30, 2028

Anticipated Study Completion Date :

Sep 30, 2028

Arms and Interventions

Arm	Intervention/Treatment
Other: Healthy Lactating Women Healthy Lactating Women will be studied on 3 study days and serve as their own control.	Drug: Cimetidine 200 MG Cimetidine will serve as the probe drug Other Names: Tagamet

Arm

Intervention/Treatment

Other: Healthy Lactating Women

Healthy Lactating Women will be studied on 3 study days and serve as their own control.

Drug: Cimetidine 200 MG

Cimetidine will serve as the probe drug

Other Names:

Tagamet

Outcome Measures

Primary Outcome Measures

Mammary clearance of cimetidine [3-5 weeks, 3-4 months and 6-8 months postpartum]
Cimetidine excretion into breast milk at three postpartum stages
Mammary epithelial cell expression of BCRP [3-5 weeks, 3-4 months and 6-8 months postpartum]
BCRP protein expression in MECs at three postpartum stages
Mammary epithelial cell expression of OCT1 [3-5 weeks, 3-4 months and 6-8 months postpartum]
OCT1 protein expression in MECs at three postpartum stages

Secondary Outcome Measures

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

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 50 Years

Sexes Eligible for Study:

Female

Accepts Healthy Volunteers:

Yes

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