Assessment of the Pharmacodynamic and Pharmacokinetic Interaction of Remimazolam and Remifentanil

NCT04670471 | Completed Phase 1

• 2 other identifiers: CNS7056-0252020-003806-30
• Study Type: interventional
• Target: 28
• Locations: 1 country
• Sites: 1

Brief Summary

This trial is designed to quantify the pharmacodynamic (PD) and pharmacokinetic (PK) interaction(s) between an anaesthetic drug (remimazolam) and an opioid (remifentanil). Remimazolam is a new anaesthetic drug with a sedative effect, which, in combination with an opioid can be used to achieve general anaesthesia. To date, however, no clinical trials have been conducted to specifically assess the potential for drug-drug interactions between remimazolam and remifentanil. Greater understanding of the potential for such interactions will help define more appropriate dosing regimens with less over-sedation and associated side effects.

Conditions

Anesthesia

Outcome Measures

Primary Outcomes (1)

• Exposure-response model describing the relationship between effect-site concentrations of remimazolam and plasma concentrations of remifentanil and MOAA/S corresponding to mild, moderate and deep sedation.

  Through study completion, approximately 3 weeks

Secondary Outcomes (7)

• Exposure-response model describing the relationship between effect-site concentrations of remimazolam and plasma concentrations of remifentanil and BIS corresponding to mild, moderate and deep sedation.

  Through study completion, approximately 3 weeks

• Performance characteristics for the TCI models used (remimazolam and remifentanil) according to Varvel et al. These include median absolute performance error, median performance error, wobble and divergence.

  Through study completion, approximately 3 weeks

• Exposure response models for tolerance to laryngoscopy

  Through study completion, approximately 3 weeks

• Exposure response models for tolerance to tetanic stimulus

  Through study completion, approximately 3 weeks

• Exposure response models for BIS

  Through study completion, approximately 3 weeks

Study Arms (4)

Remimazolam + Remifentanil plasma concentration of 2.0 ng/mL

EXPERIMENTAL

Each participant will receive study medication on three different occasions: Session 1: remimazolam alone Session 2: remimazolam plus remifentanil 0.5 ng/mL Session 3 : remimazolam plus reminfentanil 2.0 ng/mL During each session remimazolam will be dosed in a step-up / step-down manner while the remifentanil target concentration will be kept constant.

Drug: Remimazolam; Drug: Remifentanil

Remimazolam + Remifentanil plasma concentration of 4.0 ng/mL

EXPERIMENTAL

Each participant will receive study medication on three different occasions: Session 1: remimazolam alone Session 2: remimazolam plus remifentanil 0.5 ng/mL Session 3 : remimazolam plus reminfentanil 4.0 ng/mL During each session remimazolam will be dosed in a step-up / step-down manner while the remifentanil target concentration will be kept constant.

Drug: Remimazolam; Drug: Remifentanil

Remimazolam + Remifentanil plasma concentration of 0.1 ng/mL

EXPERIMENTAL

Each participant will receive study medication on three different occasions: Session 1: remimazolam alone Session 2: remimazolam plus remifentanil 0.5 ng/mL Session 3 : remimazolam plus reminfentanil 0.1 ng/mL During each session remimazolam will be dosed in a step-up / step-down manner while the remifentanil target concentration will be kept constant.

Drug: Remimazolam; Drug: Remifentanil

Remimazolam + Remifentanil plasma concentration of 1.0 ng/ml

EXPERIMENTAL

Each participant will receive study medication on three different occasions: Session 1: remimazolam alone Session 2: remimazolam plus remifentanil 0.5 ng/mL Session 3 : remimazolam plus reminfentanil 1.0 ng/mL During each session remimazolam will be dosed in a step-up / step-down manner while the remifentanil target concentration will be kept constant.

Drug: Remimazolam; Drug: Remifentanil

Interventions

Remimazolam DRUG

Remimazolam is an intravenous anaesthetic and sedative drug. Remimazolam exhibits its anaesthetic effects via the benzodiazepine binding site at the GABAA receptor.

Also known as: Byfavo, CNS7056

Remimazolam + Remifentanil plasma concentration of 0.1 ng/mL; Remimazolam + Remifentanil plasma concentration of 1.0 ng/ml; Remimazolam + Remifentanil plasma concentration of 2.0 ng/mL; Remimazolam + Remifentanil plasma concentration of 4.0 ng/mL

Remifentanil DRUG

Remifentanil is a commonly used opioid in anaesthetic practice. It is a potent and fast-acting analgesic.

Also known as: Ultiva

Remimazolam + Remifentanil plasma concentration of 0.1 ng/mL; Remimazolam + Remifentanil plasma concentration of 1.0 ng/ml; Remimazolam + Remifentanil plasma concentration of 2.0 ng/mL; Remimazolam + Remifentanil plasma concentration of 4.0 ng/mL

Eligibility Criteria

• Age: 18 Years - 70 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Healthy male or female adults ≥18 to ≤70 years old
• American Society of Anesthesiologists (ASA) Physical Status 1
• Body mass index (BMI) \>18 to \<30 kg/m2
• Bilateral patent a. radialis
• For female volunteers of childbearing potential: Negative results of 2 pregnancy tests, the first test taken at the start of Screening and the second test taken from the morning urine within 3 hours before the start of the administration of the IMP as well as consent to use highly effective birth control from the last menstrual cycle prior to the start of the IMP until the end of the trial follow-up procedures. Highly effective methods of birth control include:
• Combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation (oral/intravaginal/transdermal)
• Progestogen-only hormonal contraception associated with inhibition of ovulation (oral/injectable/implantable)
• Intrauterine device (IUD)
• Intrauterine hormone-releasing system (IUS)
• Bilateral tubal occlusion
• Vasectomised partner (provided that the partner is the sole sexual partner of the female patient of childbearing potential and that the vasectomised partner has received medical assessment of the surgical success).
• Sexual abstinence
• Women who had their last menstruation at least two years ago or who underwent surgical interventions (surgical birth control, bilateral oophorectomy, hysterectomy, etc.) are regarded as having no childbearing potential.
• For male participants, their partner must not become pregnant during the trial. They should inform their partner about this. They must also agree to use of barrier methods of contraception during the trial.
• Subject agrees not to use alcohol for 2 days, not to use nicotine for 1 week, and not to use recreational drugs for 2 weeks prior to the first period until End of Trial

You may not qualify if:

• Known intolerance to benzodiazepines, flumazenil, opioids or any ingredients of the remimazolam drug products (e.g., dextran, lactose)
• Pregnancy, or currently breastfeeding
• Have current neurological disorder(s) (epilepsy, the presence of a brain tumour, a history of brain surgery, hydrocephalic disorders, depression needing treatment with anti-depressive drugs, a history of brain trauma, a subarachnoidal bleeding, TIA or cerebral infarct, psychosis or dementia, schizophrenia, alcohol or drug abuse).
• Have a disease(s) involving the cardiovascular system (hypertension, coronary artery disease, prior acute myocardial infarction, any valvular and/or myocardial disease involving decrease in ejection fraction, arrhythmias, which are either symptomatic or require continuous medication/pacemaker/automatic internal cardioverter defibrillator)
• Recent (\<3 months) use of psycho-active medication (benzodiazepines, anti-epileptic drugs, Parkinson's medication, neuroleptics, anxiolytics, anti-depressant drugs, and opioid analgesics)
• A history of illicit drug or alcohol abuse within two years prior to screening
• Any ongoing condition considered by the Investigator as potentially relevant to the trial
• Any medical history considered by the Investigator as potentially relevant to the trial
• An employee or direct relative of an employee of the trial site, the CRO or the Sponsor.
• Resting HR \<45 bpm or ≥90 bpm OR resting SABP \<90 mmHg or ≥140 mmHg OR resting DABP \<50 mmHg or ≥90 mmHg, except for those cases where hypertension is accompanied by tachycardia as judged by the screening physician.
• Positive urine drug screening test (amphetamines, methamphetamines, benzodiazepines, barbiturates, marijuana, cocaine, and opioids).
• Positive Covid-19 screening test
• Any participant as judged by the PI or Sub-Investigator to be inappropriate for the trial for any other reason
• Clinically significant, as judged by the Investigator abnormal ECG
• Clinically significant abnormal laboratory values

Sponsors & Collaborators

• Paion UK Ltd.: lead
• University Medical Center Groningen: collaborator
• QPS Holdings LLC: collaborator

Study Sites (1)

University Medical Center Groningen

Groningen, 9700, Netherlands

Location

Related Publications (2)

• Varvel JR, Donoho DL, Shafer SL. Measuring the predictive performance of computer-controlled infusion pumps. J Pharmacokinet Biopharm. 1992 Feb;20(1):63-94. doi: 10.1007/BF01143186.

  PMID: 1588504 BACKGROUND

• Vellinga R, Koomen JV, Eleveld DJ, Stohr T, Pesic M, Struys MMRF, Colin PJ. Influence of Remifentanil on the Pharmacokinetics and Pharmacodynamics of Remimazolam in Healthy Volunteers. Anesthesiology. 2025 Apr 1;142(4):666-679. doi: 10.1097/ALN.0000000000005348. Epub 2025 Jan 15.

  PMID: 40067039 DERIVED

MeSH Terms

Interventions

remimazolam; Remifentanil

Intervention Hierarchy (Ancestors)

Propionates; Acids, Acyclic; Carboxylic Acids; Organic Chemicals; Piperidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Study Officials

• Remco Vellinga, MD

  University Medical Center Groningen (UMCG)

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 25, 2020
• First Posted: December 17, 2020
• Study Start: April 13, 2021
• Primary Completion: January 28, 2022
• Study Completion: January 28, 2022
• Last Updated: September 11, 2023

Record last verified: 2023-09

Data Sharing

• IPD Sharing: Will not share

Locations

NL (1)