Clinical trial NCT02743260: Drug Transporter Interaction Study PHENTRA_2015_KPUK
Official title: Single Centre in Vivo Cocktail Phenotyping Study on OATP1B1, OCT1/2, MATE1/2K, OAT1/3, and P-gp Drug Transporters in Healthy Volunteers
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Healthy
Keywords: phenotype
transporter
cocktail
Lead sponsor: University of Cologne
Sponsor class: OTHER
Collaborators: name: Umm Al-Qura University
name: Institute for Biomedical and Pharmaceutical Research (IBMP), Nürnberg-Heroldsberg, Germany
First posted: 2016-04-19
Enrollment: 24
Sex: ALL
Minimum age (years): 18
Maximum age (years): 85
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: BASIC_SCIENCE

Brief summary: The objective of the present study is to contribute to establishing in vivo phenotyping procedures for organic anionic transporter polypeptide 1B1 (OATP1B1), organic cation transporters 1 and 2 (OCT1/2), multidrug and toxic compound extrusion transporters 1 and 2,kidney splice variant (MATE1/2K), organic anion transporters 1 and 3 (OAT1/3), and p-glycoprotein (P-gp) transporters via a cocktail approach. To this end, marker substrates for each of the respective transporters are administered as single doses in one period each and as a cocktail in one period to 24 healthy volunteers, and phenotyping metrics are derived from plasma and urine concentrations.

Detailed description: Blood sampling: - 0:15 h pre-dose, 0:15, 0:30, 0:45, 1:00, 1:20, 1:40, 2:00, 2:20, 2:40, 3:00, 3:30, 4:00, 5:00, 6:00, 8:00, 12:00, 16:00, 24:00 hours post-dose

Urine Sampling: Pre-dose, 0-4 hours, 4-8 hours, 8-12 hours, 12-16 hours, 16-24 hours

Drug analysis: by liquid chromatography - tandem mass spectrometry (LC-MS/MS)

Pharmacokinetic Characteristics: Evaluation is carried out using standard noncompartmental characteristics including: area under the plasma concentration vs. time curve truncated at time t (AUC0-t), area under the plasma concentration vs. time curve extrapolated to infinity (AUC0-∞), peak plasma concentration (Cmax), time of occurrence of Cmax (tmax), apparent elimination half-life (t½), clearance over bioavailability (CL/F), renal clearance (CLr) and renal secretion. The evaluation may be completed by compartmental population pharmacokinetic approaches.

Statistical evaluation: Pharmacokinetic characteristics are compared for cocktail administration vs. individual administration by standard average bioequivalence assessment.

Safety, tolerability: Adverse events, laboratory and clinical parameters and vital signs will be assessed.

Eligibility criteria: Inclusion Criteria:

* Caucasian
* Body mass index (BMI) between and inclusive 18.5 and 30 kg/m2
* Willing and capable to confirm written consent prior to enrolment after ample information has been provided
* Normal findings in the medical history unless the principal investigator considers an abnormality to be clinically relevant.
* Considered to be healthy by the principal investigator on the basis of extensive pre-study screening-

Exclusion Criteria:

Standard for healthy volunteers, including:

* Female subjects only: positive results in pregnancy test
* Female subjects only: lactating women
* Female subjects only: subjects who do not use or do not agree to use appropriate contraceptive methods during the study as defined in Note for Guidance on Non-Clinical Safety Studies for the Conduct of Human Clinical Trials for Pharmaceuticals (CHMP/ICH/286/95 modification)

Primary outcomes:
measure: organic anionic transporter polypeptide 1B1 (OATP1B1): Clearance over bioavailability (CL/F) of pitavastatin
timeFrame: 24 hours
measure: organic cation transporters 1 and 2 (OCT1/2), multidrug and toxic compound extrusion transporters 1 and 2,kidney splice variant (MATE1/2K): Renal clearance (CLr) of metformin
timeFrame: 24 hours
measure: intestinal p-glycoprotein (P-gp): Peak Plasma Concentration (Cmax) of digoxin
timeFrame: 24 hours
measure: renal p-glycoprotein (P-gp): Renal clearance (CLr) of digoxin:
timeFrame: 24 hours
measure: organic anion transporter 1 (OAT1): Renal clearance (CLr) of adefovir
timeFrame: 24 hours
measure: organic anion transporter 3 (OAT3): Renal clearance (CLr) of sitagliptin
timeFrame: 24 hours
Secondary outcomes:
Other outcomes:
Locations:
city: Cologne
country: Germany
facility: Department of Pharmacology I, University Hospital Cologne
state: NRW
Study officials:
affiliation: Department of Pharmacology I, University Hospital Cologne Cologne, NRW, Germany, 50931
name: Uwe Fuhr, Prof. Dr.
role: PRINCIPAL_INVESTIGATOR
References:
citation: Hsin CH, Stoffel MS, Gazzaz M, Schaeffeler E, Schwab M, Fuhr U, Taubert M. Combinations of common SNPs of the transporter gene ABCB1 influence apparent bioavailability, but not renal elimination of oral digoxin. Sci Rep. 2020 Jul 27;10(1):12457. doi: 10.1038/s41598-020-69326-y.
citation: Trueck C, Hsin CH, Scherf-Clavel O, Schaeffeler E, Lenssen R, Gazzaz M, Gersie M, Taubert M, Quasdorff M, Schwab M, Kinzig M, Sorgel F, Stoffel MS, Fuhr U. A Clinical Drug-Drug Interaction Study Assessing a Novel Drug Transporter Phenotyping Cocktail With Adefovir, Sitagliptin, Metformin, Pitavastatin, and Digoxin. Clin Pharmacol Ther. 2019 Dec;106(6):1398-1407. doi: 10.1002/cpt.1564. Epub 2019 Aug 12.