Drug Transporter Interaction Study PHENTRA_2015_KPUK

University of Cologne

Status and phase: Completed; Phase 4

Conditions: Healthy

Treatments: Drug: sitagliptin; Drug: Metformin; Drug: Adefovir; Drug: pitavastatin; Drug: digoxin

Study type: Interventional

Funder types: Other

Identifiers

NCT02743260

PHENTRA_2015_KPUK

Details and patient eligibility

About

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.

Full 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.

Enrollment: 24 patients

Sex: All

Ages: 18 to 85 years old

Volunteers: Accepts Healthy Volunteers

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)

Trial design

Primary purpose: Basic Science

Allocation: Randomized

Interventional model: Crossover Assignment

Masking: None (Open label)

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24 participants in 6 patient groups

pitavastatin (OATP1B1)

Experimental group

Description:

2 mg pitavastatin single dose

Treatment:

Drug: pitavastatin

metformin (MATE1, MATE2K, OCT1, OCT2)

Experimental group

Description:

500 mg metformin single dose

Treatment:

Drug: Metformin

digoxin (intestinal & renal P-glycoprotein)

Experimental group

Description:

0.5 mg digoxin single dose

Treatment:

Drug: digoxin

adefovir dipivoxil (OAT1)

Experimental group

Description:

10 mg adefovir dipivoxil single dose

Treatment:

Drug: Adefovir

sitagliptin (OAT3)

Experimental group

Description:

100 mg sitagliptin single dose

Treatment:

Drug: sitagliptin

cocktail (all substances)

Experimental group

Description:

combination of all individual drugs at respective single doses

Treatment:

Drug: digoxin

Drug: pitavastatin

Drug: Adefovir

Drug: Metformin

Drug: sitagliptin