The Effect of Dicloxacillin on Oral Absorption of Drugs

NCT05073627 | Completed Phase 1

• 2 other identifiers: AKF-4002021-003814-37
• Study Type: interventional
• Target: 12
• Locations: 1 country
• Sites: 1

Brief Summary

Worldwide there is an increase in antibiotic resistance which may have fatal long-term consequences. This is due to extensive use and sometimes misuse of antibiotics in the treatment of harmless infections. The primary aim of this study is to investigate if treatment with dicloxacillin can lead to drug-drug interactions through induction of the efflux transporter P-glycoprotein (P-gp). In this study it will also be investigated whether dicloxacillin induces its own metabolism. The hypothesis is based on a previous in vivo study showing that rifampicin induces the intestinal P-gp transporter, through activation of the pregnane X receptor (PXR). Dicloxacillin also activates the PXR receptor in vitro, which could result in an induction of P-gp in vivo. Trial subjects will ingest dicloxacillin for 30 days and at day 10 and 28 ingest dabigatran etexilate to determine if the P-gp transporter has been induced. Plasma and urine will be drawn over 32 hours to determine the concentration of dabigatran. Change in dicloxacillin concentration will also be measured at day 9 and 27 to establish if dicloxacillin induces its own metabolism.

Conditions

Healthy Volunteers; Drug-drug Interaction

Keywords

P-gp transporter, Induction of P-gp transporter

Outcome Measures

Primary Outcomes (1)

• Change in Area under the curve (AUC) of dabigatran

  Change in the activity of the drug transporter P-gp

  Baseline and day 28

Secondary Outcomes (22)

• Change in AUC of dabigatran

  Day 10 and 28

• Change in AUC of relevant metabolites of dabigatran etexilate

  Day 10 and 28

• Change in Peak Plasma concentration (Cmax) of dabigatran

  Day 10 and 28

• Change in Cmax of relevant metabolites of dabigatran etexilate

  Day 10 and 28

• Change in Time to reach Cmax (Tmax) of dabigatran

  Day 10 and 28

Study Arms (2)

Baseline

NO INTERVENTION

The investigators measure the baseline of dicloxacillin and the probe drug dabigatran etexilate.

Dicloxacillin treatment

EXPERIMENTAL

The investigators measure the concentration of dicloxacillin after 9 and 27 days and the concentration of dabigatran after 10 and 28 days of continuously taking dicloxacillin.

Drug: Dicloxacillin

Interventions

Dicloxacillin DRUG

Healthy volunteers will take 2x500 mg dicloxacillin 3 times a day for 30 days. The investigators will measure the baseline concentration of dabigatran and dicloxacillin before start of 30 days of dicloxacillin treatment. On day 9 and 27 the investigators will measure the concentration of dicloxacillin. On day 10 and 28 the investigators will measure the concentration of dabigatran.

Also known as: Dabigatran etexilate

Dicloxacillin treatment

Eligibility Criteria

• Age: 18 Years - 55 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Age 18-55 years
• The following data must be in the normal range or only clinical insignificantly different from this: Estimated glomerular filtration rate (eGFR), alanine aminotransferase (ALAT), bilirubin, HbA1c, hemoglobin
• BMI \>18.5 and \< 30 kg/m2
• Bodyweight ≥ 50 kg
• Non-smoker (abstained from smoking minimum 2 weeks before the first study day and during the trial)
• Generally healthy
• Willing to give informed consent

You may not qualify if:

• Known sensitivity to any of the used drugs or any excipients listed in section 6.1 in the Summary of Product Characteristics (SmPC)
• Participating in any other intervention trials
• Intake of any significant prescription drugs, over-the- counter drugs, herbal drugs, or dietary supplements\*. Contraindicated drugs include:
• Anticoagulants, antiplatelet aggregation medicinal products, ticagrelor, clopidogrel, acetylsalicylic acid, chronic NSAIDs use, amiodarone, verapamil, systemic ketoconazole, clarithromycin, cyclosporin, itraconazole, tacrolimus, posaconazole, dronedarone, glecaprevir/pibrentasvir, quinidine, ritonavir, digoxin, selective serotonin reuptake inhibitors (SSRIs), selective serotonin norephinephrine reuptake inhibitors (SNRIs), pantoprazole, ranitidine, previous use of dicloxacillin or other P-gp or Cytochrome P450 (CYP450) inhibitors/inducers within 4 weeks prior to the start of treatment, probenecid, tetracycline, methotrexate
• Alcohol abuse or if the Danish Health Authority recommendation regarding alcohol intake has been exceeded 2 weeks before the first study day (men 14 units alcohol/week, women 7 unites alcohol/week)
• Known penicillin allergy or reactions against cephalosporins, cephamycin, 1-oxa-ß-lactamer, or carbapenems
• Women who are breastfeeding
• Diagnosis of any of the following diseases (current or previous):
• Mechanical heart valve, congenital or acquired coagulation disorders, thrombocytopenia or functional platelet defects, biopsy within 4 weeks, major trauma, bacterial endocarditis, esophagitis, gastritis, gastroesophageal reflux, active meningitis, encephalitis, intracranial abscess, undergoing surgery, liver disease, history of thrombosis or diagnosed with antiphospholipid syndrome, active cancer

Sponsors & Collaborators

• University of Southern Denmark: lead

Study Sites (1)

University of Southern Denmark

Odense, Region Syddanmark, 5000, Denmark

Location

MeSH Terms

Interventions

Dicloxacillin; Dabigatran

Intervention Hierarchy (Ancestors)

Cloxacillin; Oxacillin; Penicillins; beta-Lactams; Lactams; Amides; Organic Chemicals; Sulfur Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Pyridines; Heterocyclic Compounds, 1-Ring; Benzimidazoles

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 28, 2021
• First Posted: October 11, 2021
• Study Start: February 7, 2022
• Primary Completion: June 22, 2022
• Study Completion: June 22, 2022
• Last Updated: July 21, 2022

Record last verified: 2022-07

Data Sharing

• IPD Sharing: Will not share

Locations

DK (1)