Effect of staggered vs. simultaneous open-label administration on the pharmacokinetics of pravastatin and bempedoic acid in healthy volunteers
- Conditions
- MeSH term: Body processes [G] - Metabolic Phenomena [G03]
- Registration Number
- DRKS00029657
- Lead Sponsor
- Ruprecht-Karls-University Heidelberg, Medical Faculty, represented in law by Heidelberg University Hospital and its Commercial Managing Director
- Brief Summary
Not available
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- Complete
- Sex
- All
- Target Recruitment
- 17
1.Age 18-45 years (y) at the time of consent.
2.Healthy volunteers, without any significant findings in their medical assessment.
3.Males and females of child-bearing potential who are willing to use a method of contraception as defined below during the treatment and for at least one week after the last administration of the IMP, or women not of child-bearing potential (WNCBP), or individuals who are convincingly sexually abstinent,
WOCBP must use highly effective methods of contraception:
Combined hormonal contraception associated with inhibition of ovulation (p.o., intravaginal, or transdermal), progestogen-only hormonal contraception associated with inhibition of ovulation (p.o., injectable, or implantable), intrauterine device, intrauterine hormone-releasing system, bilateral tubal occlusion, vasectomized partner (provided that the partner is the sole sexual partner of the WOCBP trial participant and that the vasectomised partner has received medical assessment of the surgical success), or sexual abstinence (defined as refraining from heterosexual intercourse during the entire period of risk associated with the study treatments; only if preferred and usual lifestyle of individual).
WNCBP are defined as women who have been surgically sterilized (total hysterectomy or bilateral oophorectomy, bilateral tubal ligation, staples, or another type of sterilization) or who are postmenopausal for at least 2 y. Individuals who are convincingly sexually abstinent are also eligible.
Male participants must use a condom during the treatment and for at least one week after the last administration of the IMP.
4. Participation in a genotyping study (K093) to determine SLCO1B1 genotypes,
5. Understanding, ability, and willingness to fully comply with trial interventions and restrictions, and
6. Ability to provide written, personally signed and dated informed consent to participate in the trial, in accordance with the International Conference on Harmonisation (ICH) Good Clinical Practice (GCP) Guideline E6, and applicable regulations, prior to any trial-related interventions.
7. Severe acute respiratory syndrome coronavirus type 2 (SARS-CoV2) immunity as defined by pertinent national regulations. This currently includes a completed SARS-CoV2 vaccination status or a history of confirmed prior COVID disease within 3 months, or COVID disease > 3 months plus subsequent vaccination. Pertinent current national rules for definition of SARS-CoV2 immunity will be followed and may change during the trial.
At the time of SCR:
1. Clinically significant or relevant abnormalities in the medical history, physical examination, and laboratory evaluation as assessed by the investigator.
2. Any medical disorder that may require treatment or make the participant unlikely to fully complete the trial, or any condition that presents undue risk from the IMP or trial interventions.
3. Clinically relevant ongoing or clinically relevant history of physical or psychiatric illness as judged by the investigator.
4. Pregnancy or breast feeding.
5. Any acute or chronic illness or clinically relevant findings known or expected to modify absorption, distribution, metabolism, or excretion of pravastatin, midazolam, or bempedoic acid.
6. Any known history of severe allergic or anaphylactic reactions to drugs or food or any other clinically significant allergies.
7. Any known allergies or hypersensitivity to bempedoic acid, pravastatin, midazolam, omeprazole or yohimbine.
8. Clinically relevant findings in any of the following investigations at SCR. Minor deviations of laboratory values from the normal range can be acceptable, if judged by the investigator to be of no clinical relevance for this trial.
? Haemoglobin (Hb) < 12 g/dl (males) or < 11 g/dl (females),
? Creatinine (Crea) clearance (Cl) < 90 ml/min (Cockcroft-Gault),
? Bilirubin > upper limit of normal (ULN) x 1.2,
In case of suspected Gilbert’s disease: non-fasting total bilirubin = ULN x 1.2 and fasting total bilirubin = ULN x 1.5 are acceptable.
? Alanine aminotransferase (ALT) > ULN x 1.1,
? Aspartate aminotransferase (AST) > ULN x 1.2,
? Creatine kinase (CK) not within normal limits, and
? Thyroid stimulating hormone (TSH) not within normal limits,
9. A positive human immunodeficiency virus (HIV), hepatitis B (HBV) or C (HCV) antibody screen.
10. A positive result in the drug screening test at SCR.
11. Resting heart rates under 50 bpm or over 90 bpm.
12. Blood pressure < 100/50 mmHg and/or known symptomatic hypotension as well as blood pressure > 140/90 mmHg.
13. QTcF outside the range of 360 – 460 ms (women) and 360 – 440 ms (men).
14. A prior SARS-CoV2 vaccination within < 2 weeks before the baseline visit or any plans to get vaccinated during the expected trial duration trial.
15. Any intake of substances (prescription medication, over-the-counter medicine, or herbal preparations with active ingredients) known to inhibit drug metabolizing enzymes or transport enzymes within a period of less than 5 times the respective elimination half-life (t½) with regard to the expected date of first dose of IMP (except hormonal contraception, iodine, and levothyroxine),
16. Any intake of substances (prescription medication, over-the-counter medicine, or herbal preparations with active ingredients) known to induce drug metabolizing enzymes or transport enzymes within a period of 14 days with regard to the expected date of first dose of IMP.
17. Consumption of a clinically relevant amount of grapefruit within 5 d prior to the expected date of first dose of IMP and expected noncompliance to refrain from grapefruit intake until the last visit of this trial.
18. Expected noncompliance to refrain from alcohol 24 hours (h) prior to visit 1 until the end of this trial, or pathologic alcohol consumption (defined as more than 24 g/d pure alcohol for men and 12 g/d pure alcohol for women).
19. Use of an IMP within 30 d prior to the expected date of receiving the first dose of IMP or active
Study & Design
- Study Type
- interventional
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method • Geometric mean ratios of AUC and Cmax of a single dose of 40 mg pravastatin for simultaneous compared to delayed administration of bempedoic acid 180 mg.
- Secondary Outcome Measures
Name Time Method • Geometric mean ratios of AUC and Cmax of pravastatin for simultaneous or time-delayed administration of bempedoic acid in individuals with OATP1B1 wildtypes (*1a/*1a, *1a/X) compared to functional relevant genetic variants with SNPs (rs4149056 in haplotype OATB1B1*5 (521T>C) and rs4149056 combined to rs2306283 in the OATB1B1*15 haplotype (521T>C/388A>G).<br><br>• AUC2-4 and metabolic Cl of midazolam at baseline and at steady-state BA<br><br>• AUC0.5-4h of 50 µg yohimbine at baseline and at steady-state BA<br><br>• Hydroxylation index at 3 h of 100 µg omeprazole AUC at baseline and at steady-state BA.<br><br>• Frequency, severity, seriousness, relatedness, expectedness and outcome of AEs under trial medication.