KetaMoHydBup: Pharmacokinetic Interaction of S-ketamine, Morphine, Hydromorphone and Buprenorphine

Study Overview
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Brief Summary
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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
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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.

Official Title
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KetaMoHydBup: Pharmacokinetic Interaction of S-ketamine, Morphine, Hydromorphone and Buprenorphine

Conditions
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The Effect of S-ketamine on Pharmacokinetics of Morphine, Hydromorphone, and Buprenorphine

Intervention / Treatment
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* Drug: S-ketamine


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 45 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional 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.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: S-ketamine infusion<br>12 healthy volunteers, S-ketamine infusion 0.29 mg/kg/h for 4 hours | Drug: S-ketamine<br>* S-ketamine infusion 0.29 mg/kg/h for 4 hours<br>|
| Placebo Comparator: Placebo (NaCl 0.9%) infusion<br>12 healthy volunteers, placebo (NaCl 0.9%) infusion for 4 hours | Drug: S-ketamine<br>* S-ketamine infusion 0.29 mg/kg/h for 4 hours<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area under the plasma concentration versus time curve (AUC) of morphine, hydromorphone and buprenorphine after intravenous S-ketamine infusion. | We aim to investigate whether there is a clinically significant pharmacokinetic interaction between S-ketamine and morphine, S-ketamine and hydromorphone and S-ketamine and buprenorphine. | 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 | 
| Peak plasma concentrations (Cmax) of morphine, hydromorphone and buprenorphine after intravenous S-ketamine infusion | We aim to investigate whether there is a clinically significant pharmacokinetic interaction between S-ketamine, morphine, S-ketamine and hydromorphone and S-ketamine and buprenorphine. | 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. | 
| Half-life time (t1/2) of morphine, hydromorphone and buprenorphine concentrations after intravenous S-ketamine infusion. | We aim to investigate whether there is a clinically significant pharmacokinetic interaction between S-ketamine, morphine, S-ketamine and hydromorphone and S-ketamine and buprenorphine. | 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The effect of S-ketamine on brain-derived neurotrophic factor (BDNF) release | We measure BDNF plasma levels (ng/ml) during and after intravenous S-ketamine infusion . | Time points for assessments: 30 minutes, 120 minutes, 240 minutes, 360 minutes, 480 minutes and at Day1 after the intiation of S-ketamine infusion | 
| The effect of S-ketamine on vascular endothelial growth factor (VEGF) release | We measure VEGF levels (ng/l) during and after intravenous S-ketamine infusion. | Time points for assessments: 30 minutes, 120 minutes, 240 minutes, 360 minutes, 480 minutes and at Day1 after the intiation of S-ketamine infusion. | 
| The effect of S-ketamine infusion on prolactin release. | We measure prolactin levels (mU/l) during and after intravenous S-ketamine infusion. | Time points for assessments: 30 minutes, 120 minutes, 240 minutes, 360 minutes, 480 minutes and at Day1 after the intiation of S-ketamine infusion | 
| The effect of S-ketamine infusion on cortisol release. | We measure cortisol levels (nmol/l) during and after intravenous S-ketamine infusion. | Time points for assessments: 30 minutes, 120 minutes, 240 minutes, 360 minutes, 480 minutes and at Day1 after the intiation of S-ketamine infusion | 
| The effect of S-ketamine infusion on thrombocyte aggregation. | We evaluate the effect of intravenous S-ketamine infusion on thrombocyte aggregation by using Platelet Function Analyzer (PFA), a method that is based on the property of platelets to adhere upon shear stress conditions and aggregate in consequence of agonist presence in the system. We assess the clotting time. Unit of analysis is seconds (s). | At 2 hours after initiation of S-ketamine infusion. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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S-ketamine, hepatic UGT2B7 enzyme, pharmacokinetic interaction, morphine, hydromorphone, buprenorphine