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

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.

Study Overview

• Status: Not yet recruiting
• Conditions: The Effect of S-ketamine on Pharmacokinetics of Morphine, Hydromorphone, and Buprenorphine
• Intervention / Treatment: Drug: S-ketamine

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.

• Study Type: Interventional
• Enrollment (Anticipated): 12
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Elina CV Brinck, MD, PhD; Phone Number: +358504286267; Email: elina.brinck@hus.fi
• Study Contact Backup: Name: Tuomas Lilius, MD, PhD; Phone Number: +358404843931; Email: tuomas.lilius@hus.fi

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 45 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

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

What is the study measuring?

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.

Collaborators and Investigators

• Sponsor: Elina Brinck
• Investigators: Principal Investigator: Tuomas Lilius, MD, PhD, University of Helsinki

Study record dates

Study Major Dates

• Study Start (Anticipated): January 1, 2023
• Primary Completion (Anticipated): June 1, 2023
• Study Completion (Anticipated): December 1, 2023

Study Registration Dates

• First Submitted: September 28, 2022
• First Submitted That Met QC Criteria: October 4, 2022
• First Posted (Actual): October 7, 2022

Study Record Updates

• Last Update Posted (Actual): October 7, 2022
• Last Update Submitted That Met QC Criteria: October 4, 2022
• Last Verified: September 1, 2022

More Information

Terms related to this study

• Keywords: buprenorphine; morphine; S-ketamine; hydromorphone; hepatic UGT2B7 enzyme; pharmacokinetic interaction
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Anesthetics, Dissociative; Anesthetics, Intravenous; Anesthetics, General; Anesthetics; Excitatory Amino Acid Antagonists; Excitatory Amino Acid Agents; Psychotropic Drugs; Antidepressive Agents; Ketamine; Esketamine
• Other Study ID Numbers: EBrinck; 2021-006011-28 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No