Healthy
Conditions
Keywords
phenotype, transporter, cocktail
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.
Interventions
DRUGpitavastatin
DRUGMetformin
DRUGdigoxin
DRUGAdefovir
DRUGsitagliptin
Sponsors
Umm Al-Qura University
Institute for Biomedical and Pharmaceutical Research (IBMP), Nürnberg-Heroldsberg, Germany
University of Cologne
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
BASIC_SCIENCE
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 85 Years
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)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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 |
Countries
Germany
Outcome results
None listed