KF2025#1 Trial: Ketamine, Cannabidiol and Cobicistat Interaction Study

Обзор

Ketamine is a dissociative anesthetic developed approximately 60 years ago. Both ketamine and its isomer, esketamine, have been used for over 20 years in the treatment of treatment-resistant depression. Other treatment options for this type of depression include combinations of antidepressants, other medications used in depression treatment (such as lithium), psychotherapy, electroconvulsive therapy, and repetitive transcranial magnetic stimulation. The advantage of ketamine and its stereoisomer, esketamine, over other treatment options is their rapidly emerging antidepressant effect, which becomes apparent within the first few days of treatment. Ketamine is primarily metabolized by the cytochrome P450 (CYP) 3A4 enzyme, but also by the CYP2B6 and CYP2C9 enzymes. However, information on the significance of these different enzymes in ketamine metabolism is incomplete. Due to extensive first-pass metabolism, the bioavailability of orally administered ketamine varies significantly and is, on average, only 8-24%. This makes ketamine unsuitable for oral administration. In the treatment of depression, ketamine is administered as a slow intravenous infusion. The concurrent use of medications that inhibit ketamine metabolism can significantly increase the bioavailability of orally administered ketamine. Cobicistat is a potent inhibitor of the CYP3A4 enzyme, which can significantly increase ketamine bioavailability and reduce interindividual variability by inhibiting ketamine's CYP3A4-mediated metabolism. This might enable the oral use of ketamine. Cannabidiol is a cannabinoid that does not have addictive effects, but may have antidepressant and anxiolytic effects. Cannabidiol might reduce the dissociative side effects associated with ketamine treatment. Clinically, cannabidiol appears to moderately inhibit CYP enzymes in the order of potency: CYP2C19 \> CYP2C9 \> CYP3A \> CYP1A2, and based on in vitro data, it also somewhat inhibits the CYP2B6 enzyme, which is involved in ketamine metabolism. However, its effect on ketamine concentrations cannot be assessed based on current knowledge. The purpose of this study is to investigate the potential effects of cannabidiol, cobicistat, and their concurrent administration on the pharmacokinetics of orally administered ketamine. A secondary objective is to study the effect of cannabidiol on ketamine-induced side effects. Study Methodology: This is a four-phase, randomized, open-label, crossover study involving 12 healthy volunteers. On study days, participants will receive a 56 mg oral dose of ketamine in the research facility, alternately with water, cannabidiol, cobicistat, or both cannabidiol and cobicistat. There will be at least a two-week washout period between study days. The pharmacokinetics of ketamine and other study drugs will be investigated by taking blood samples according to a separate schedule for 11 hours after administration on the study day and the following morning. Pharmacokinetic parameters will be calculated from plasma concentrations of ketamine, cobicistat, cannabidiol, and their metabolites. The primary outcome measure is the total area under the curve (AUC0-∞) of ketamine. Additionally, the effects of the drugs on blood pressure, heart rate, and subjective adverse feeling of the study participants will be examined.

Вмешательства

• Препарат Ketamine 10 mg/ml oral solution, UK special
  1 x 56 mg (5,6 ml) p.o.
• Препарат Cobisistat Tybost 150 mg
  1 x 150 mg p.o.
• Препарат Cannabidiol Epidyolex 100 mg/ml
  1 x 700 mg (7 ml) p.o.

Первичные конечные точки

• Area under the plasma concentration - time curve (AUC) of ketamine [Срок оценки: Prior to and 15, 30, 45, 60, 75, 90 minutes and 2, 3, 4, 5, 7, 9, 11 and 23 hours after administration the drug.]

Вторичные конечные точки (8)

• Area under the plasma concentration - time curve (AUC) for kobisistat, cannabidiol and their metabolites [Срок оценки: Prior to and 15, 30, 45, 60, 75, 90 minutes and 2, 3, 4, 5, 7, 9, 11 and 23 hours after administration the drug.]
• Area under the plasma concentration - time curve (AUC) for ketamine metabolites [Срок оценки: Prior to and 15, 30, 45, 60, 75, 90 minutes and 2, 3, 4, 5, 7, 9, 11 and 23 hours after administration the drug.]
• Peak plasma concentration for ketamine, kobisistat, cannabidiol and their metabolites [Срок оценки: Prior to and 15, 30, 45, 60, 75, 90 minutes and 2, 3, 4, 5, 7, 9, 11 and 23 hours after administration the drug.]
• Half-life for ketamine, kobisistat, cannabidiola and their metabolites [Срок оценки: Prior to and 15, 30, 45, 60, 75, 90 minutes and 2, 3, 4, 5, 7, 9, 11 and 23 hours after administration the drug.]
• Time to peak plasma concentration for ketamine, kobisistat, cannabidiola and their metabolites [Срок оценки: Prior to and 15, 30, 45, 60, 75, 90 minutes and 2, 3, 4, 5, 7, 9, 11 and 23 hours after administration the drug.]
• Blood pressure [Срок оценки: 0, 60, 12 and 240 minutes after administration]
• Heart rate [Срок оценки: 0, 60, 12 and 240 minutes after administration]
• Subjective adverse effects of ketamine and cannabidiol [Срок оценки: 0, 30, 60, 120, 240 and 360 minutes after administration]

Критерии участия

Критерии включения

• written informed consent
• age 18-45 years
• healthy
• no indications of substance abuse
• acceptable values in laboratory tests: hemoglobin must be at least at the lower limit of the reference range (men 134 g/l, women 117 g/l), liver values at most at the upper limit of the reference range (P -ALAT: women below 35 U/l, men below 50 U/l; P -AFOS: 35 U/l - 105 U/l; P -GT: women less than 40 U/l, men less than 60 U/l; P -Bil: less than 20 umol/l) and in other results (B -PVKT, P -Krea, P -K and P -Na) only minor values that deviate from normal values, which according to the examining physician's assessment are clinically insignificant. Drug screening (U -Huum-PS) and in women the pregnancy test (P-hCG-tot) should be negative.
• No significant abnormalities in the ECG

Критерии исключения

• significant illness
• mood disorder or suicidality
• substance abuse
• systolic blood pressure over 150 mmHg
• conduction disorder or other significant abnormality in the ECG
• smoking
• regular medication, excluding contraceptives that do not contain estrogens
• pregnancy or its planning or breastfeeding
• less than 3 months from the previous clinical trial
• less than 3 months since donating blood
• significant overweight or underweight
• difficult to find elbow veins
• hypersensitivity to investigational drugs or excipients of medicinal products
• use of natural products (such as St. John's wort).

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Да

Дизайн исследования

Распределение

Рандомизированное

Модель

Перекрёстный дизайн

Маскирование

Открытое

Основная цель

Фундаментальное исследование

Центры проведения

Финляндия · 1 центр

• Department of Clinical Pharmacology — Helsinki

Идентификаторы

NCT: NCT07462559 · KF2025#1 · 2025-523817-27-00

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

Открыть это исследование на ClinicalTrials.gov ↗