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Evaluation of Solanidine as an Exogenous Biomarker to Phenotype CYP2D6 Activity in Humans
Condition(s) studied
Pharmacokinetic Study in Healthy Volunteers
Investigational drug(s) / intervention(s)
YohimbineConsumption of a defined potato-rich meal
Yohimbine: 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.
Consumption 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).
Study 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.
Eligibility
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
Primary outcome measure(s)
- 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)
Trial sites (1)
| Facility | City | Region | Status |
|---|
| University Medicine Greifswald |
Greifswald |
Mecklenburg-Vorpommern |
|
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