Pharmacokinetic Study in Healthy Volunteers
Conditions
Keywords
genetic polymorphisms, pharmacokinetics, CYP2D6, yohimbine, drug metabolism, solanidine
Brief summary
This study investigates the evaluation of solanidine as an exogenous biomarker to phenotype CYP2D6-activity in humans. Participants will be classified by their CYP2D6 genotype into poor metabolizers (PM), low intermediate metabolizers (LIM), extensive metabolizers (EM) and ultra-rapid metabolizers (UM), forming four distinct study arms: Arm 1) Poor Metabolizers (PM) n=10 Arm 2) Low Intermediate Metabolizers (LIM) n=5 Arm 3) Extensive Metabolizers (EM) n=10 Arm 4) Ultra-rapid Metabolizers (UM) n=5 Participants will be given a standardized potato-rich meal, serving as the natural source of solanidine, and will be phenotyped for CYP2D6 activity with a single oral microdose of the probe drug yohimbine. The objectives of the study are as follows: 1. To evaluate the suitability of the SSDA/solanidine and m414/solanidine metabolic ratio as an exogenous biomarker to phenotype CYP2D6 activity in humans. 2. To characterize the postprandial plasma concentration profile of solanidine, its CYP2D6-dependent metabolites, and its parent molecules α-solanine and α-chaconine following a potato-rich meal.
Detailed description
The study follows an open-label, controlled, parallel-cohort design with four study arms based on CYP2D6 genotype. The study consists of two parts: a Yohimbine and a Potato Part. Yohimbine Part: Participants will receive a single oral microdose of 50 μg of yohimbine, administered in a fasted state as 2 x 1 tablets of Yohimbinum hydrochloricum D4® (Deutsche Homöopathie Union, Karlsruhe, Germany, containing 25 μg per tablet). A total of 6 blood samples will be collected at defined time points (baseline; 10; 20; 30; 60; 120 min). At each time point, 5 mL of blood will be drawn for plasma separation to determine yohimbine and the primary metabolite 11-OH-yohimbine. The blood sampling protocol is based on the findings of the YOKI-1 study (protocol number: IPHA-2025-011, Greifswald Ethics Committee Registration number BB 069/25). At baseline, an additional blood sample will be collected for a random determination of solanidine and its metabolites. During the 2.5-hour stay in the CRU, participants will be asked to stay in bed. Potato Part: Between the Potato and the Yohimbine Part, a period of 4 weeks in any order is acceptable. The Potato Part is divided into two sequential phases: Phase 1 and Phase 2, both featuring supervised meal ingestion at the clincal research unit. During the three days before each Potato Phase and up to 60 hours afterward, no potato products should be eaten. Otherwise, ad libitum food intake is permitted beginning six hours after the potato-rich meal. Blood samples will be analyzed for solanidine, its CYP2D6-dependent metabolites, and its parent molecules α-solanine and α-chaconine in both Potato Phases. Both Potato Phases must be separated by at least one week. Phase 1 (0-12 hours postprandial): An initial baseline blood sample will be collected prior to the ingestion of the potato-rich meal. Participants will receive the potato-rich meal at 8 a.m., and a total of 7 blood samples will be collected at defined time points (baseline, 2, 4, 6, 8, 10, and 12 h).Upon successful completion of the 12-hour blood draw, participants will be discharged from the CRU. Phase 2 (12-60 hours postprandial): On a separate scheduled study day, participants will report to the CRU at 7:30 p.m. A baseline blood sample will be collected prior to meal ingestion. Participants will then ingest an identical, defined potato-rich meal at 8:00 p.m. Following meal consumption, participants are permitted to go home for the night. The next morning, starting at 7:30 a.m., blood sampling collections will begin at the designated time points. A total of ten blood samples will be collected at defined time points (baseline, 12, 14, 16, 18, 20, 22, 24 h, 36 h in the next morning and at 60 h in the morning thereafter).
Interventions
DIETARY_SUPPLEMENTYohimbine
A single oral dose of 50 µg yohimbine, administered as 2 x 1 tablets of Yohimbinum hydrochloricum D4® will be administered as drinking solution with 240mL of water under overnight fasting conditions. A total of 6 blood samples will be collected at defined time points (baseline; 10; 20; 30; 60; 120 min). At each time point, 5 mL of blood will be drawn for plasma separation to determine yohimbine and the primary metabolite 11-OH-yohimbine.
OTHERConsumption of a defined potato-rich meal
Potato Intervention (2 phases): Diet restriction: No potato products 3 days before and until 60h after each meal. Ad libitum food intake is allowed from 6h post-meal. Blood will be analyzed for solanidine, its metabolites and its parent molecules α-solanine, and α-chaconine. Phase 1 (0-12h postprandial): Baseline blood draw at 8:00 AM, followed by supervised ingestion of a potato-rich meal. A total of 7 blood samples will be collected (baseline, 2, 4, 6, 8, 10, 12h) before discharge from the CRU. Phase 2 (12-60h postprandial): Baseline blood draw at 7:30 PM, identical meal ingestion at 8:00 PM. Participants can go home afterwards and return to the CRU the next morning at 8:00 AM for their 12 hour post meal blood draw. A total of 10 blood samples will be collected (baseline, 12, 14, 16, 18, 20, 22, 24h, 36h next morning, 60h subsequent morning).
Sponsors
University Medicine Greifswald
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
BASIC_SCIENCE
Masking
NONE
Masking description
This is an open-label study; no parties involved are masked.
Intervention model description
The study is designed as an open-label, controlled, parallel-cohort design with four study arms based on CYP2D6 genotype.
Eligibility
Sex/Gender
ALL
Age
18 Years to 40 Years
Healthy volunteers
Yes
Inclusion criteria
1. individuals of both biological sexes, assigned as women or men at birth 2. age: ≥ 18 and ≤ 40 years 3. possesses the ability to understand the study purpose and design 4. contractually capable and provides signed informed consent form 5. in good general health or with mild and/or well-managed conditions such as allergies, asthma, hypertension or orthopedic diseases 6. taking no more than three chronic medications 7. ability to maintain and record a detailed dietary protocol focusing on the consumption of potato-based products for the specified duration of the study 8. individuals classified as either ultrarapid metabolizers (UM), extensive metabolizers (EM), low intermediate metabolizers (LIM) or poor metabolizers (PM) based on their CYP2D6 genotype: Poor Metabolizer (PM, Gen-Score 0): homozygous or compound heterozygous for CYP2D6 \*3, CYP2D6 \*4, CYP2D6\*5, CYP2D6 \*6 Low Intermediate Metabolizer (LIM, Gen-Score 0,25 or 0,5): Homozygous or compound heterozygous for CYP2D6 \*9, \*10, \*41 or compound heterozygous with one allele of CYP2D6 \*3, CYP2D6 \*4, CYP2D6\*5, or CYP2D6\*6 and one allele of CYP2D6 \*17 (0,5) or CYP2D6 \*9, \*10, or \*41 (0,25) Extensive Metabolizer (EM, Gene-Score 2): homozygous or compound heterozygous for CYP2D6 \*1, CYP2D6 \*2, CYP2D6\*35 Ultrarapid Metabolizer (UM, Gen-Score ≥ 3): homozygous or compound heterozygous for CYP2D6 \*1, CYP2D6 \*2, CYP2D6\*35 with at least one allele duplicated or multiplied
Exclusion criteria
1. BMI \> 30 kg/m2 and \< 18 kg/m2 2. body weight \< 48 kg 3. women: known pregnancy or lactation period; positive urine pregnancy test at screening or kinetic visit 4. men: hemoglobin \< 13 g/dl (8,07 mmol/l) women: hemoglobin \< 12 g/dl (7,45 mmol/l) 5. elevated liver function tests (1 or more of ALAT, ASAT, yGT, Bilirubin \> 2x ULN) 6. reduced renal function (eGFRMDRD \< 60 mL/min/1,7 m2) 7. QTcF \> 450 ms in screening ECG 8. current or recent psychiatric disorders requiring treatment including depression, bipolar disorder, schizophrenia, psychosis or severe anxiety disorders 9. drug dependency at the time of visit 10. use of recreational drugs more than twice a week 11. intake of drugs interfering with CYP2D6 during the past seven days 12. any known hypersensitivity or allergic reactions to yohimbine 13. intake of yohimbine within 48 hours prior to study participation 14. history of hypersensitivity or allergy to potatoes or nightshade vegetables 15. intake of potato-containing meals during the three days before and after eating the potato-rich test meal 16. history of severe hypersensitivity reactions and/or anaphylaxis 17. poor venous conditions that make it impossible to place a peripheral venous catheter and regularly draw blood through it 18. engagement in extreme physical activity within 48 hours prior to study participation
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Metabolic ratio of SSDA/solanidine | From enrollment to 60 hours after eating the potato-rich meal. | This study determines the sensitivity of the metabolic ratio of SSDA/solanidine and the metabolic ratio of m414/solanidine to correctly identify the CYP2D6 metabolizer status. Each MR will be considered separately in order to identify the most suitable one. As we will recruit individuals from the lowest and highest level of CYP2D6 activity, we will test the sensitivity independently for the prediction of the lowest activity level (PM + LIM) and the highest activity level (EM + UM). The "true" CYP2D6 metabolizer status will be determined by the combination of the CYP2D6 genotype and the yohimbine-determined phenotype in recruited individuals. Those individuals with a perfect match of genotype and phenotype are considered the controls to which the solanidine results are then compared as the ratio of phenotype predicted (by solandine MR)/ phenotype determined (by genotyping + yohimbine-phenotyping) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| AUC for solanidine, SSDA, m414, α-solanine and α-chaconine | 60 hours | Plasma concentrations expressed as area under the curve (AUC) will be determined for solanidine, its CYP2D6-dependent metabolites SSDA and m414, and its parent molecules α-solanine and α-chaconine for each metabolizer status cohort (PM, LIM, EM, UM). |
| Cmax for solanidine, SSDA, m414, α-solanine and α-chaconine | 60 hours | The maximum concentration (Cmax) will be determined for solanidine, its CYP2D6-dependent metabolites SSDA and m414, and its parent molecules α-solanine and α-chaconine for each metabolizer status cohort (PM, LIM, EM, UM). |
| Tmax for solanidine, SSDA, m414, α-solanine and α-chaconine | 60 hours | Time to maximum concentration (tmax) of solanidine, its CYP2D6-dependent metabolites SSDA and m414, and its parent molecules α-solanine and α-chaconine will be determined for each metabolizer status cohort (PM, LIM, EM, UM). |
Countries
Germany
Contacts
CONTACTStefan Engeli, Prof. Dr.
Outcome results
None listed