Drug Transporter Interaction Study PHENTRA_2015_KPUK

Sponsor

University of Cologne (Other)

Overall Status

Completed

CT.gov ID

NCT02743260

Collaborator

Umm Al-Qura University (Other), Institute for Biomedical and Pharmaceutical Research (IBMP), Nürnberg-Heroldsberg, Germany (Other)

Enrollment

Location

Arms

Duration (Months)

1.2

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Healthy	Drug: pitavastatin Drug: Metformin Drug: digoxin Drug: Adefovir Drug: sitagliptin	Phase 4

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.

Study Design

Study Type:

Interventional

Actual Enrollment :

24 participants

Allocation:

Randomized

Intervention Model:

Crossover Assignment

Masking:

None (Open Label)

Primary Purpose:

Basic Science

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 Start Date :

Apr 1, 2016

Actual Primary Completion Date :

Dec 1, 2017

Actual Study Completion Date :

Dec 1, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: pitavastatin (OATP1B1) 2 mg pitavastatin single dose	Drug: pitavastatin Other Names: Livazo®
Experimental: metformin (MATE1, MATE2K, OCT1, OCT2) 500 mg metformin single dose	Drug: Metformin Other Names: Metformin-CT®
Experimental: digoxin (intestinal & renal P-glycoprotein) 0.5 mg digoxin single dose	Drug: digoxin Other Names: Digacin®
Experimental: adefovir dipivoxil (OAT1) 10 mg adefovir dipivoxil single dose	Drug: Adefovir Other Names: Hepsera®
Experimental: sitagliptin (OAT3) 100 mg sitagliptin single dose	Drug: sitagliptin Other Names: Januvia®
Experimental: cocktail (all substances) combination of all individual drugs at respective single doses	Drug: pitavastatin Other Names: Livazo® Drug: Metformin Other Names: Metformin-CT® Drug: digoxin Other Names: Digacin® Drug: Adefovir Other Names: Hepsera® Drug: sitagliptin Other Names: Januvia®

Outcome Measures

Primary Outcome Measures

organic anionic transporter polypeptide 1B1 (OATP1B1): Clearance over bioavailability (CL/F) of pitavastatin [24 hours]
PK parameter
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 [24 hours]
PK parameter
intestinal p-glycoprotein (P-gp): Peak Plasma Concentration (Cmax) of digoxin [24 hours]
PK parameter
renal p-glycoprotein (P-gp): Renal clearance (CLr) of digoxin: [24 hours]
PK parameter
organic anion transporter 1 (OAT1): Renal clearance (CLr) of adefovir [24 hours]
PK parameter
organic anion transporter 3 (OAT3): Renal clearance (CLr) of sitagliptin [24 hours]
PK parameter

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 85 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Yes

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)