Drug Excretion in Breast Milk

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

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.

Study Overview

• Status: Recruiting
• Conditions: Lactation; Postpartum; Drugs in Breast Milk; Mammary Drug Transporters; BCRP; OCT1
• Intervention / Treatment: Drug: Cimetidine 200 MG

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 Type: Interventional
• Enrollment (Estimated): 50
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Mary Hebert, PharmD, FCCP; Phone Number: 206-616-5016; Email: mhebert@uw.edu

Study Locations

• United States
  • Washington
    • Seattle, Washington, United States, 98195
      • Recruiting
      • University of Washington
      • Contact: Mary F Hebert, PharmD; Phone Number: 206-616-5016; Email: mhebert@uw.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult
• Accepts Healthy Volunteers: Yes

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: N/A
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / 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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: University of Washington
• Collaborators: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
• Investigators: Principal Investigator: Mary Hebert, PharmD, FCCP, University of Washington

Study record dates

Study Major Dates

• Study Start (Actual): December 4, 2023
• Primary Completion (Estimated): September 30, 2028
• Study Completion (Estimated): September 30, 2028

Study Registration Dates

• First Submitted: September 14, 2023
• First Submitted That Met QC Criteria: September 20, 2023
• First Posted (Actual): September 28, 2023

Study Record Updates

• Last Update Posted (Actual): August 6, 2024
• Last Update Submitted That Met QC Criteria: August 2, 2024
• Last Verified: August 1, 2024

More Information

Terms related to this study

• Keywords: pharmacokinetics; postpartum; lactation; breast milk; cimetidine; BCRP; proteomics; OCT2; OCT1; MRP1; OCTN2; PEPT2; ENT1; CNT3; OATP2B1; OATP3A1
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Gastrointestinal Agents; Cytochrome P-450 Enzyme Inhibitors; Anti-Ulcer Agents; Histamine Antagonists; Histamine Agents; Cytochrome P-450 CYP1A2 Inhibitors; Histamine H2 Antagonists; Cimetidine
• Other Study ID Numbers: STUDY00018397; R01HD112282 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: We are committed to share data with the academic community and researcher-at-large. We will adhere to the NIH Grant Policy on Sharing Research Data and Resources. That is, after final data collection and analysis and after full peer review is performed on our data, the de-identified data generated by this project will be made available when requested by the academic community and researchers-at-large contingent upon Material Transfer Agreements with the University of Washington.
• IPD Sharing Time Frame: After peer review and publication of data.
• IPD Sharing Access Criteria: We are committed to share data with the academic community and researcher-at-large. We will adhere to the NIH Grant Policy on Sharing Research Data and Resources. That is, after final data collection and analysis and after full peer review is performed on our data, the de-identified data generated by this project will be made available when requested by the academic community and researchers-at-large contingent upon Material Transfer Agreements with the University of Washington.
• IPD Sharing Supporting Information Type: CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No