The Effect of Dicloxacillin on Oral Absorption of Drugs

Healthy Volunteers Clinical Trial

Official title:

The Effect of Dicloxacillin on Oral Absorption of Drugs

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT05073627
• Other study ID #: AKF-400
• Secondary ID: 2021-003814-37
• Status: Completed
• Phase: Phase 1
• Start date: February 7, 2022
• Est. completion date: June 22, 2022

Study information

• Verified date: July 2022
• Source: University of Southern Denmark
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 12
• Est. completion date: June 22, 2022
• Est. primary completion date: June 22, 2022
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years to 55 Years

Eligibility

Inclusion Criteria:

• 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

Exclusion Criteria:

• 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)

• A positive pregnancy test at inclusion screening or any of the study days

• 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

Related Conditions & MeSH terms

• Drug-drug Interaction
• Healthy Volunteers

Intervention

Drug:
• Dicloxacillin
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.

Locations

Country	Name	City	State
Denmark	University of Southern Denmark	Odense	Region Of Southern Denmark

Sponsors (1)

Lead Sponsor	Collaborator
University of Southern Denmark

Country where clinical trial is conducted

Denmark, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Change in Area under the curve (AUC) of dabigatran	Change in the activity of the drug transporter P-gp	Baseline and day 28
Secondary	Change in AUC of dabigatran	Change in the activity of the drug transporter P-gp	Day 10 and 28
Secondary	Change in AUC of relevant metabolites of dabigatran etexilate	Change in the activity of the drug transporter P-gp	Day 10 and 28
Secondary	Change in Peak Plasma concentration (Cmax) of dabigatran	Change in the activity of the drug transporter P-gp	Day 10 and 28
Secondary	Change in Cmax of relevant metabolites of dabigatran etexilate	Change in the activity of the drug transporter P-gp	Day 10 and 28
Secondary	Change in Time to reach Cmax (Tmax) of dabigatran	Change in the activity of the drug transporter P-gp	Day 10 and 28
Secondary	Change in Tmax of relevant metabolites of dabigatran etexilate	Change in the activity of the drug transporter P-gp	Day 10 and 28
Secondary	Change in renal clearance (CLr) of dabigatran	Change in the activity of the drug transporter P-gp	Day 10 and 28
Secondary	Change in CLr of relevant metabolites of dabigatran etexilate	Change in the activity of the drug transporter P-gp	Day 10 and 28
Secondary	Change in Elimination half-life (T1/2) of dabigatran	Change in the activity of the drug transporter P-gp	Day 10 and 28
Secondary	Change in T1/2 of relevant metabolites of dabigatran etexilate	Change in the activity of the drug transporter P-gp	Day 10 and 28
Secondary	Change in AUC of dicloxacillin	Change in the activity of the enzyme responsible for metabolism of dicloxacillin	Day 9 and 27
Secondary	Change in AUC of the metabolite of dicloxacillin	Change in the activity of the enzyme responsible for metabolism of dicloxacillin	Day 9 and 27
Secondary	Change in Cmax of dicloxacillin	Change in the activity of the enzyme responsible for metabolism of dicloxacillin	Day 9 and 27
Secondary	Change in Cmax of the metabolite of dicloxacillin	Change in the activity of the enzyme responsible for metabolism of dicloxacillin	Day 9 and 27
Secondary	Change in Tmax of dicloxacillin	Change in the activity of the enzyme responsible for metabolism of dicloxacillin	Day 9 and 27
Secondary	Change in Tmax of the metabolite of dicloxacillin	Change in the activity of the enzyme responsible for metabolism of dicloxacillin	Day 9 and 27
Secondary	Change in CLr of dicloxacillin	Change in the activity of the enzyme responsible for metabolism of dicloxacillin	Day 9 and 27
Secondary	Change in CLr of the metabolite of dicloxacillin	Change in the activity of the enzyme responsible for metabolism of dicloxacillin	Day 9 and 27
Secondary	Change in T1/2 of dicloxacillin	Change in the activity of the enzyme responsible for metabolism of dicloxacillin	Day 9 and 27
Secondary	Change in T1/2 of the metabolite of dicloxacillin	Change in the activity of the enzyme responsible for metabolism of dicloxacillin	Day 9 and 27
Secondary	Change in biomarkers of drug metabolism enzymes and transporters (DMET)	Change in biomarkers for enzymes and transporters after dicloxacillin treatment	10 and 28
Secondary	Change in exosome-derived biomarkers	Change in exosome-derived biomarkers after dicloxacillin treatment to determine activity of CYP enzymes	10 and 28