Clinical trial NCT06056583: Drug Excretion in Breast Milk
Official title: Postpartum Activity and Expression of BCRP and OCT1 Drug Transporters in the Mammary Gland
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE4
Conditions: Postpartum
Lactation
Drugs in Breast Milk
Mammary Drug Transporters
BCRP
OCT1
Keywords: breast milk
lactation
cimetidine
proteomics
OCT1
BCRP
OCTN2
PEPT2
ENT1
CNT3
MRP1
OATP2B1
OATP3A1
OCT2
postpartum
pharmacokinetics
Lead sponsor: University of Washington
Sponsor class: OTHER
Collaborators: name: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
First posted: 2023-09-28
Enrollment: 50
Sex: ALL
Minimum age (years): 14
Maximum age (years): 50
Standard ages: CHILD
ADULT
Accepts healthy volunteers: yes
Allocation: NA
Intervention model: SEQUENTIAL
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.
Primary purpose: BASIC_SCIENCE

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.

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.

Eligibility criteria: Inclusion criteria

1. Healthy postpartum women
2. 18-50 years of age and their infants
3. Able to provide written informed consent

Exclusion criteria

1. Receiving cimetidine within the 3 days prior to each study day. Concomitant administration of cimetidine will confound interpretation of study results.
2. Hypersensitivity to cimetidine Patients with known allergic reactions to cimetidine will be excluded for safety reasons
3. Receiving medication known to interact with cimetidine: OCT, BCRP, CYP3A4, CYP2D6, CYP1A2 and CYP2C9 substrates (e.g. amiodarone, clopidogrel, diazepam, ketoconazole, metformin, nifedipine, phenytoin, procainamide, theophylline,tricyclic antidepressants and warfarin) Patients with drug interactions will be excluded for safety reasons.
4. Receiving BCRP inhibitors/inducers (afatinib, aripipraxole, axitinib, cimetidine, cyclosporine, curcumin/tumeric, delavirdine, efavirenz, elacridar, elvitegravir, etravirine, FTC, 5-fluorouracil, fluvastatin, imatinib, lanzoprazole, lapatinib, lopinavir, maraviroc, nelfinavir, nebicapone, nilotinib, novobiocin, oltipraz, omeprazole, pantoprazole, phenobarbital, promazine, rabeprazole, riboflavin, rifampicin, risperidone, saquinavir, sirolimus, sorafenib, sulfasalazine, sunitinib, tacrolimus, tariquidar, telaprevir, telatinib, teriflunomide, tolcapone, triflunomide, trametinib, trifluoperazine, venlafaxine, zidonuvir), OCT1 inhibitors/inducers (acyclovir, amantadine, amiloride, amitriptyline, bucindolol, carvedilol, chlorpheniramine, chlorpromazine, cimetidine, citalopram, clonidine, clopidogrel, clotrimazole, clozapine, cocaine, corticosterone, cyclosporine, daclatasvir, darunavir, desipramine, dextromethorphan, diltiazem, disopyramide, dronedarone, efavirenz, famotidine, fentanyl, fluvoxamine, formoterol, fuloxetine, griseofulvin, doxazosine, ganciclovir, guanfacine, imipramine, indinavir, isavuconazole, itraconazole, ketoconazole, lamotrigine, lasmiditan, levofloxacin, levomepromazine, lidocaine, maprotiline, methylnicotinamide, morphine, moxifloxacin, nefazodone, nelfinavir, nevirapine, nicotine, nomifensine, ondansetron, oxybutynin, paroxetine, pentamidine, phenoxybenzamine, prazosin, probenecid, procainamide, propafenone, pyrazinamide, quetiapine,quinidine, quinine, reboxetine, remoxidpride, reseripine, rifampicin, ritonavir, salmeterol, saquinavir, tramadol, trimethoprim, trimipramine, verapamil) Inhibitors and inducers of the drug transporters will confound data analysis and interpretation.
5. Kidney disease could confound data analysis and interpretation. Therefore, patients with known kidney disease with documented renal function impairment will be excluded from the study. Current serum creatinine \> 1.2 mg/dL in their medical record will be excluded.
6. Known liver disease Liver disease will confound data analysis and interpretation. Therefore, patients with known significant liver disease will be excluded from the study. Current ALT exceeding 2-times the upper limit of normal in their medical record will be excluded.
7. Inability to fast for 4 hours prior to the study. To limit PK variability across study days, subjects will be requested to fast for 4 hours prior to each study day.
8. Smokers (tobacco or other nicotine containing products Nicotine interacts with OCT1 and will confound data analysis and interpretation

Primary outcomes:
measure: Mammary clearance of cimetidine
timeFrame: 3-5 weeks, 3-4 months and 6-8 months postpartum
measure: Mammary epithelial cell expression of BCRP
timeFrame: 3-5 weeks, 3-4 months and 6-8 months postpartum
measure: Mammary epithelial cell expression of OCT1
timeFrame: 3-5 weeks, 3-4 months and 6-8 months postpartum
Secondary outcomes:
measure: Cimetidine relative infant dose and infant concentration
timeFrame: 3-5 weeks, 3-4 months and 6-8 months postpartum
measure: Relationship between OCT1 expression and activity
timeFrame: 3-5 weeks, 3-4 months and 6-8 months postpartum
measure: Maternal cimetidine PK
timeFrame: 3-5 weeks, 3-4 months and 6-8 months postpartum
measure: Maternal cimetidine PK
timeFrame: 3-5 weeks, 3-4 months and 6-8 months postpartum
measure: Maternal cimetidine PK
timeFrame: 3-5 weeks, 3-4 months and 6-8 months postpartum
measure: Maternal cimetidine PK
timeFrame: 3-5 weeks, 3-4 months and 6-8 months postpartum
measure: Maternal cimetidine PK
timeFrame: 3-5 weeks, 3-4 months and 6-8 months postpartum
measure: Maternal cimetidine PK
timeFrame: 3-5 weeks, 3-4 months and 6-8 months postpartum
measure: Maternal cimetidine PK
timeFrame: 3-5 weeks, 3-4 months and 6-8 months postpartum
measure: Maternal cimetidine PK
timeFrame: 3-5 weeks, 3-4 months and 6-8 months postpartum
measure: Maternal cimetidine PK
timeFrame: 3-5 weeks, 3-4 months and 6-8 months postpartum
measure: Maternal cimetidine PK
timeFrame: 3-5 weeks, 3-4 months and 6-8 months postpartum
measure: Relationship between BCRP expression and activity
timeFrame: 3-5 weeks, 3-4 months and 6-8 months postpartum
Other outcomes:
Locations:
city: Seattle
country: United States
facility: University of Washington
state: Washington
Study officials:
affiliation: University of Washington
name: Mary Hebert, PharmD, FCCP
role: PRINCIPAL_INVESTIGATOR
References: