Assessment of the influence of the gut microbiome on tacrolimus pharmacokinetics in healthy volunteers

Phase 1

• Conditions: Pharmacokinetic trial in healthy volunteers

• Registration Number: DRKS00032072
• Lead Sponsor: niversitätsklinikum Heidelberg, Im Wege der Auftragsverwaltung für die Universität Heidelberg, Medizinische Fakultät Heidelberg

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Study Start: 2023-08-02
• Study Completion: 2024-03-28
• Last Update Posted: 19 August 2024

Recruitment & Eligibility

• Status: Complete
• Sex: All
• Target Recruitment: 20

Inclusion Criteria

Written, personally signed and dated informed consent to participate in the trial prior to any trial-related interventions.

Understanding, ability, and willingness to fully comply with trial interventions and restrictions.

Body weight = 45 kg.

Willingness to use a highly effective method of contraception.

CYP3A5*3/*3 genotype.

Agreement to follow specified dietary requirements.

Willingness to adhere to rules and restrictions necessary to ensure adequate bowel cleansing.

Willingness to adhere to pandemic regulations if any may occur during the trial.

Exclusion Criteria

Clinically significant or relevant abnormalities as assessed by the investigator in the medical history, or findings from physical examination, or laboratory evaluation.

Any acute or chronic illness expected to influence the volunteer´s gut microbiome composition.

Intake of antibiotics (p.o. or i.v.) in the six weeks prior to expected first IMP administration.

Any acute or chronic illness or clinically relevant finding known or expected to modify absorption, distribution, metabolism, or excretion of tacrolimus or midazolam.

Any known history of severe anaphylactic reactions to drugs or vaccinations, or any other significant allergies.

Any known allergies to the trial drugs, to other macrolides, or further ingredients of the administered IMPs.

Glucose-6-phosphate dehydrogenase deficiency.

QTcF > 440 ms (males) or > 460 ms (females).

Use of an IMP within 30 d prior to the expected date of receiving the first dose of IMP or active enrolment in another drug or vaccine clinical trial.

Regular use of any medication (prescription medication, non-prescription medication including herbal preparations) with active ingredients (except hormonal contraception, iodine, and thyroid hormones).

Any systemically relevant intake of substances known to induce relevant drug metabolizing enzymes or drug transporters within a period of less than 14 d with regard to the expected date of the first dose of tacrolimus and midazolam.

Any systemically relevant intake of substances known to inhibit relevant drug metabolizing enzymes or transport enzymes within a period of less than 5 times the respective elimination half-life with regard to the expected date of first dose of tacrolimus and midazolam.

Consumption of grapefruit within 7 d prior to the expected date of first dose of IMP and expected noncompliance to refrain from grapefruit intake until the last visit of this trial.

A prior vaccination within < 2 weeks (< 4 weeks in case of live-attenuated vaccines) before the first IMP administration or any plans to get vaccinated during the running trial.

Expected noncompliance to refrain from alcohol 24 h before the PK days, or pathologic alcohol consumption.

Unable to refrain from smoking during trial days.

A positive human immunodeficiency virus (HIV) or hepatitis C (HCV) antibody screen, or positive result for Hepatitis-B-Surface-Antigen.

A positive result in the drug screening test at SCR.

Pregnancy or breast feeding.

Persons who are held in an institution by legal or official order or who are legally incapacitated.

Study & Design

• Study Type: interventional
• Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
To compare tacrolimus PK in healthy volunteers with unmanipulated <br>microbiome (at baseline) to tacrolimus PK after quantitative reduction of <br>the gut microbiome by bowel cleansing.

Secondary Outcome Measures

Name	Time	Method
- To compare the absolute bioavailability of tacrolimus with and without <br>bowel cleansing. <br>- To evaluate whether participants’ gut microbiome composition and/or the <br>abundance of defined microorganisms are associated with tacrolimus PK at baseline. <br>- To evaluate whether high ex-vivo microbial tacrolimus metabolism at <br>baseline is associated with low (in-vivo) bioavailibility of tacrolimus. <br>- To evaluate the association of the ex-vivo microbial tacrolimus <br>metabolism with changes in tacrolimus PK after bowel cleansing. <br>- To compare the changes in pharmacokinetic profiles caused by bowel <br>cleansing between prolonged-release tacrolimusand <br>immediate-release tacrolimus in a pilot population. <br>- To compare CYP3A4 activity in all trial phases using an oral midazolam <br>microdosing procedure.