Drug Transporter Interaction Study PHENTRA_2015_KPUK

Study Overview
=================
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.

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

Conditions
-----------------
Healthy

Intervention / Treatment
-----------------
* Drug: pitavastatin
* Drug: Metformin
* Drug: digoxin
* Drug: Adefovir
* Drug: sitagliptin


Participation Criteria
=================
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)

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 85 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

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

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
phenotype, transporter, cocktail