Clinical trial NCT05571176: KetaMoHydBup: Pharmacokinetic Interaction of S-ketamine, Morphine, Hydromorphone and Buprenorphine
Official title: KetaMoHydBup: Pharmacokinetic Interaction of S-ketamine, Morphine, Hydromorphone and Buprenorphine
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE1
Conditions: The Effect of S-ketamine on Pharmacokinetics of Morphine, Hydromorphone, and Buprenorphine
Keywords: S-ketamine
hepatic UGT2B7 enzyme
pharmacokinetic interaction
morphine
hydromorphone
buprenorphine
Lead sponsor: Helsinki University Central Hospital
Sponsor class: OTHER
First posted: 2022-10-07
Enrollment: 12
Sex: ALL
Minimum age (years): 18
Maximum age (years): 45
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Intervention model description: This is a cross-over study with two phases on 12 healthy volunteers. Study participants will be administered S-ketamine 0.29mg/kg/h intravenously or placebo (NaCl 0.9%) for 4 hours. 30 minutes after the initiation of the study drug infusion, each subject will be given single boluses of morphine 0.01mg/kg, hydromorphone 0.002mg/kg and buprenorphine 0.003mg/kg IV. We will analyze pharmacokinetic parameters (Cmax, tmax, AUC, t1/2) for morphine, hydromorphone, and buprenorphine. The aim of the study is to evaluate whether S-ketamine has a pharmacokinetic interaction with the opioids (morphine, hydromorphone, buprenorphine) known to be metabolized via liver UGT2B7 enzyme.
Primary purpose: TREATMENT

Brief summary: S-ketamine is often administered as a part of multimodal analgesia to reduce postoperative pain and postoperative opioid consumption. Current data indicates that ketamine may be useful for patients with prior use of opioids whereas the benefit for opioid-naive patients is less clear. However, different opioids have variable pharmacokinetic characteristics. Therefore, it is important to evaluate S-ketamine's effect on the pharmacokinetics of opioids.

Detailed description: S-ketamine is often used as a part of multimodal analgesia to reduce postoperative pain and opioid consumption, in part by mitigating opioid tolerance and opioid-induced hyperalgesia. However, there are mixed results concerning the effect of ketamine for this indication. Different opioids have various pharmacokinetic characteristics. Ketamine is known to inhibit the liver UGT2B7-enzyme, that is responsible for e.g., morphine metabolism. Therefore, it is important to investigate whether there is a clinically important pharmacokinetic interaction between S-ketamine and opioids metabolized via liver UGT2B7 enzyme. These opioids include morphpine, hydromorphone and buprenoprhine.

Eligibility criteria: Inclusion Criteria:

* written informed consent
* age 18-45 years
* healthy
* Normal values in the following laboratory assessments: Hb, P-ALAT, P-AFOS, P-GT, P-creatinine, P-K, P-Na, chemical sample for urine (U-KemSeul). Pregnancy test (P-hCG-tot) must be negative.
* Urine sample for detection of any illegal drugs must be negative (U-Huum-PS)
* Normal EKG
* Normal blood pressure
* No prior use of illicit drugs

Exclusion Criteria:

* Tendency/predisposition to illicit drug use, illicit drug use in history
* Abnormal EKG
* smoking
* use of oral contraceptives
* pregnancy, lactation
* participating in a less tha 3 months ago
* Blood donation less than 3 months ago
* The subject's peripheral veins are hardly visible (predisposing difficulties in cannulation)
* weight less than 50 kg, body mass index (BMI) less than 18,5 or over 30

Primary outcomes:
measure: Area under the plasma concentration versus time curve (AUC) of morphine, hydromorphone and buprenorphine after intravenous S-ketamine infusion.
timeFrame: Time points for the measurements after the initiation of S-ketamine infusion: 0 minutes, 60 minutes, 90 minutes, 120 minutes, 180 minutes and 210 minutes
measure: Peak plasma concentrations (Cmax) of morphine, hydromorphone and buprenorphine after intravenous S-ketamine infusion
timeFrame: Time points for assessing peak plasma concentrations (Cmax) for morphine, hydromorphone and buprenorphine are the following: 0 minutes, 30 minutes, 60 minutes, 90 minutes, 120 minutes, 180 minutes, 210 minutes after the initiation of S-ketamine infusion.
measure: Half-life time (t1/2) of morphine, hydromorphone and buprenorphine concentrations after intravenous S-ketamine infusion.
timeFrame: Time points for assessing half-life time of morphine, hydromorphone and buprenorphine are 0 minutes, 30 minutes, 60 minutes, 90 minutes, 120 minutes, 180 minutes and 210 minutes after initiation of S-ketamine infusion.
Secondary outcomes:
measure: The effect of S-ketamine on brain-derived neurotrophic factor (BDNF) release
timeFrame: Time points for assessments: 30 minutes, 120 minutes, 240 minutes, 360 minutes, 480 minutes and at Day1 after the intiation of S-ketamine infusion
measure: The effect of S-ketamine on vascular endothelial growth factor (VEGF) release
timeFrame: Time points for assessments: 30 minutes, 120 minutes, 240 minutes, 360 minutes, 480 minutes and at Day1 after the intiation of S-ketamine infusion.
measure: The effect of S-ketamine infusion on prolactin release.
timeFrame: Time points for assessments: 30 minutes, 120 minutes, 240 minutes, 360 minutes, 480 minutes and at Day1 after the intiation of S-ketamine infusion
measure: The effect of S-ketamine infusion on cortisol release.
timeFrame: Time points for assessments: 30 minutes, 120 minutes, 240 minutes, 360 minutes, 480 minutes and at Day1 after the intiation of S-ketamine infusion
measure: The effect of S-ketamine infusion on thrombocyte aggregation.
timeFrame: At 2 hours after initiation of S-ketamine infusion.
Other outcomes:
Locations:
Study officials:
affiliation: University of Helsinki
name: Tuomas Lilius, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References: