Drug Transporter Interaction Study PHENTRA_2015_KPUK

Single Centre in Vivo Cocktail Phenotyping Study on OATP1B1, OCT1/2, MATE1/2K, OAT1/3, and P-gp Drug Transporters in Healthy Volunteers

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.

Study Overview

• Status: Completed
• Conditions: Healthy
• Intervention / Treatment: Drug: Metformin; Drug: pitavastatin; Drug: Adefovir; Drug: digoxin; Drug: sitagliptin

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 Type: Interventional
• Enrollment (Actual): 24
• Phase: Phase 4

Contacts and Locations

Study Locations

• Germany
  • NRW
    • Cologne, NRW, Germany, 50931
      • Department of Pharmacology I, University Hospital Cologne

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 85 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: None (Open Label)

Number of Arms

6

Arms and Interventions

Participant Group / 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: Metformin; Other Names: Metformin-CT®; Drug: pitavastatin; Other Names: Livazo®; Drug: Adefovir; Other Names: Hepsera®; Drug: digoxin; Other Names: Digacin®; Drug: sitagliptin; Other Names: Januvia®

What is the study measuring?

Primary Outcome Measures

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

Collaborators and Investigators

• Sponsor: University of Cologne
• Collaborators: Umm Al-Qura University; Institute for Biomedical and Pharmaceutical Research (IBMP), Nürnberg-Heroldsberg, Germany
• Investigators: Principal Investigator: Uwe Fuhr, Prof. Dr., Department of Pharmacology I, University Hospital Cologne Cologne, NRW, Germany, 50931

Publications and helpful links

General Publications

• 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.
• 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.

Study record dates

Study Major Dates

• Study Start: April 1, 2016
• Primary Completion (Actual): December 1, 2017
• Study Completion (Actual): December 1, 2017

Study Registration Dates

• First Submitted: April 11, 2016
• First Submitted That Met QC Criteria: April 13, 2016
• First Posted (Estimate): April 19, 2016

Study Record Updates

• Last Update Posted (Actual): September 10, 2019
• Last Update Submitted That Met QC Criteria: September 6, 2019
• Last Verified: September 1, 2019

More Information

Terms related to this study

• Keywords: transporter; phenotype; cocktail
• Additional Relevant MeSH Terms: Hypoglycemic Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Arrhythmia Agents; Anti-Infective Agents; Antiviral Agents; Reverse Transcriptase Inhibitors; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Antimetabolites; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Protease Inhibitors; Protective Agents; Cardiotonic Agents; Anticholesteremic Agents; Hypolipidemic Agents; Lipid Regulating Agents; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Incretins; Dipeptidyl-Peptidase IV Inhibitors; Digoxin; Metformin; Sitagliptin Phosphate; Adefovir; Pitavastatin
• Other Study ID Numbers: PHENTRA_2015_KPUK

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No