Drug Excretion in Breast Milk

Official title

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

Overview

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.

Interventions

• Drug Cimetidine 200 MG
  Cimetidine will serve as the probe drug

Primary outcome measures

• Mammary clearance of cimetidine [Time frame: 3-5 weeks, 3-4 months and 6-8 months postpartum]
• Mammary epithelial cell expression of BCRP [Time frame: 3-5 weeks, 3-4 months and 6-8 months postpartum]
• Mammary epithelial cell expression of OCT1 [Time frame: 3-5 weeks, 3-4 months and 6-8 months postpartum]

Secondary outcome measures (12)

• Cimetidine relative infant dose and infant concentration [Time frame: 3-5 weeks, 3-4 months and 6-8 months postpartum]
• Relationship between OCT1 expression and activity [Time frame: 3-5 weeks, 3-4 months and 6-8 months postpartum]
• Maternal cimetidine PK [Time frame: 3-5 weeks, 3-4 months and 6-8 months postpartum]
• Maternal cimetidine PK [Time frame: 3-5 weeks, 3-4 months and 6-8 months postpartum]
• Maternal cimetidine PK [Time frame: 3-5 weeks, 3-4 months and 6-8 months postpartum]
• Maternal cimetidine PK [Time frame: 3-5 weeks, 3-4 months and 6-8 months postpartum]
• Maternal cimetidine PK [Time frame: 3-5 weeks, 3-4 months and 6-8 months postpartum]
• Maternal cimetidine PK [Time frame: 3-5 weeks, 3-4 months and 6-8 months postpartum]
• Maternal cimetidine PK [Time frame: 3-5 weeks, 3-4 months and 6-8 months postpartum]
• Maternal cimetidine PK [Time frame: 3-5 weeks, 3-4 months and 6-8 months postpartum]
• Maternal cimetidine PK [Time frame: 3-5 weeks, 3-4 months and 6-8 months postpartum]
• Maternal cimetidine PK [Time frame: 3-5 weeks, 3-4 months and 6-8 months postpartum]

Eligibility criteria

Inclusion criteria

• Healthy postpartum women
• 18-50 years of age and their infants
• Able to provide written informed consent

Exclusion criteria

• Receiving cimetidine within the 3 days prior to each study day. Concomitant administration of cimetidine will confound interpretation of study results.
• Hypersensitivity to cimetidine Patients with known allergic reactions to cimetidine will be excluded for safety reasons
• 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.
• 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.
• 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.
• 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.
• 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.
• Smokers (tobacco or other nicotine containing products Nicotine interacts with OCT1 and will confound data analysis and interpretation

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: Yes

Study design

Allocation

N/A

Model

Sequential

Masking

Open label

Primary purpose

Basic science

Study locations

United States · 1 center

• University of Washington — Seattle

Identifiers

NCT: NCT06056583 · STUDY00018397 · R01HD112282

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗