Pharmacokinetics and Bioequivalence of Molnupiravir, 200 mg Capsules and Lagevrio, 200 mg Capsules in Healthy Volunteers

Study Overview
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Brief Summary
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The study aimed for: Comparative evaluation of the safety of the drug Molnupiravir, capsules, 200 mg (JSC Valenta Pharm, Russia), and Lagevrio, capsules, 200 mg (Merck Sharp & Dohme (UK) Limited, UK), based on the analysis of adverse events (AEs); Comparative assessment of pharmacokinetic parameters and bioequivalence of the drug Molnupiravir, capsules, 200 mg (Valenta Pharm JSC, Russia), and Lagevrio, capsules, 200 mg (Merck Sharp & Dohme (UK) Limited, UK), in healthy volunteers in fasted conditions.

Official Title
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A Randomized, Open-label, Cross-over Adaptive Study of the Comparative Pharmacokinetics and Bioequivalence of the Drugs Molnupiravir, Capsules, 200 mg and Lagevrio, Capsules, 200 mg in Healthy Volunteers at Fasted Conditions

Conditions
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Viral Infection, COVID-19

Intervention / Treatment
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* Drug: Molnupiravir


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Presence of written consent of the volunteer to participate in the study in accordance with applicable law. Healthy male and female caucasian volunteers aged 18 to 45 years (inclusive). Verified diagnosis healthy: no deviations from the reference values of the data of standard clinical, laboratory and instrumental methods of examination. Systolic blood pressure (SBP) in the range of 110-130 mmHg; diastolic blood pressure (DBP) is 60-85 mmHg). 60-90 bpm at rest for heart rate (HR). 16-20 breaths/min for respiratory rate (RR). 35.5 to 36.9°C for body temperature. Body mass index (BMI) within the range of 18.5 ≤ BMI ≤ 30 kg/m2 with a body weight not less than 45 kg for female and not less than 55 kg for male volunteers. The consent of the volunteer (including the partner) to use adequate methods of contraception during the study and 30 days after its completion; for female volunteers - negative blood/urine test result for β-chorionic gonadotropin. Volunteers must behave adequately, coherent speech must be observed. Exclusion Criteria: A history of allergy; A history of drug intolerance to the active and/or excipients in the study drugs; Chronic diseases of the kidneys, liver, gastrointestinal tract (GIT), cardiovascular, lymphatic, respiratory, nervous, endocrine, musculoskeletal, genitourinary and immune systems, as well as skin, blood and vision; History of gastrointestinal surgery (except appendectomy at least 1 year prior to screening); Diseases/conditions that in the opinion of the investigator may affect the absorption, distribution, metabolism or excretion of the study drugs (drugs); Acute infectious disease less than 4 weeks prior to screening; Taking medications that significantly affect hemodynamics and medications that affect liver function (barbiturates, omeprazole, cimetidine, etc.) less than 2 months prior to screening; Regularly taking a medicines less than 2 weeks before screening and taking a single medicine less than 7 days before screening; Donating blood or plasma less than 3 months before screening; Use of hormonal contraceptives (in women) less than 2 months before screening; The use of depot injections of any drug less than 3 months before screening; Pregnancy or lactation; positive blood/urine β-CGH test for women with preserved reproductive potential; Women of preserved reproductive potential with a history of unprotected intercourse within 30 days prior to study drug administration with an unsterilized partner; Participation in another clinical trial less than 3 months prior to screening or concurrently with the present study; Taking more than 10 units of alcohol (1 unit of alcohol is equivalent to 330 mL of beer, 150 mL of wine or 40 mL of spirits) in the week in the last month before inclusion in the study or anamnestic evidence of alcoholism, drug addiction, drug abuse; Smoking more than 10 cigarettes per day currently, or a history of smoking the specified number of cigarettes during the 6 months prior to screening; disagreement to abstain from smoking for the duration of the hospital stay; Positive blood tests for antibodies to human immunodeficiency virus (HIV) 1 and 2, antibodies to Treponema pallidum antigens, hepatitis B surface antigen (HBsAg), antibodies to hepatitis C virus antigens, rapid tests of biomaterial (nasopharyngeal and/or oropharyngeal swab) for Severe Acute Respiratory Syndrome Coronavirus 2 antigen (SARS-CoV-2), Coronavirus Disease 2019 (COVID-19); Clinically significant abnormalities on the electrocardiogram (ECG); Positive urinalysis for narcotics and potent drugs; Positive test for the content of alcohol vapor in exhaled air. Scheduling an inpatient stay during the study period, for any reason other than hospitalization required by this protocol. Inability to meet the requirements of the protocol, perform the procedures prescribed in the protocol, follow the diet, activity regimen. Other conditions that, in the opinion of the Investigator, preclude inclusion of the volunteer in the study or may result in early withdrawal of the volunteer from the study, including fasting or a special diet (e.g. vegetarian, vegan, limited table salt) or a special lifestyle (night work, extreme physical activity). Withdrawal criteria: A volunteer withdraws from further participation in the study; Failure of the volunteer to comply with the rules of participation in the study (skipping study procedures, independent use of drugs prohibited in the study, violation of dietary and lifestyle restrictions, etc.); Occurrence of causes/occurrence during the study of situations that threaten the safety of the volunteer (e.g., hypersensitivity reactions, etc.); Volunteers selected for the study in violation of the inclusion/inclusion criteria; Volunteer's development of severe adverse event during the study; Missing 2 or more consecutive blood samples or 3 or more blood samples during the same Study Period. Occurrence of vomiting/diarrhea within 6 hours of study drug administration; Positive urine test for narcotics and drugs; Positive breath alcohol vapor test. Positive pregnancy test in women; Positive test for COVID-19; The occurrence in the course of the study of other reasons that prevent the study according to the protocol.

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: Other
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: RT-sequence<br>The volunteers will take 1 capsule (200 mg) of Lagevrio (R), 200 mg capsules (Merck Sharp & Dohme (UK) Limited, UK) in Period 1, and 1 capsule (200 mg) of Molnupiravir (T), 200 mg capsules (Valenta Pharm, Russia) in Period 2. | Drug: Molnupiravir<br>* A single dose of R or T drug in each of 2 periods of the study in fasted conditions<br>|
| Other: TR-sequence<br>The volunteers will take 1 capsule (200 mg) of the drug Molnupiravir (T), capsules, 200 mg (Valenta Pharm JSC, Russia) in Period 1, and 1 capsule (200 mg) of the drug Lagevrio (R), capsules, 200 mg (Merck Sharp & Dohme (UK) Limited, UK) in Period 2. | Drug: Molnupiravir<br>* A single dose of R or T drug in each of 2 periods of the study in fasted conditions<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetics - Cmax | Maximum plasma concentration (Cmax) of β-D-N-4-hydroxycytidine (NHC) | From 0 to 24 hours (Day 1-2 and Day 8-9) | 
| Pharmacokinetics - tmax | Time to reach Cmax (tmax) of NHC | From 0 to 24 hours (Day 1-2 and Day 8-9) | 
| Pharmacokinetics - AUC0-t | Area under the plasma concentration-time curve from time 0 to t (AUC0-t) of NHC | From 0 to 24 hours (Day 1-2 and Day 8-9) | 
| Pharmacokinetics - AUC0-inf | Area under the plasma concentration-time curve from time 0 to infinity (AUC0-inf) of NHC | From 0 to 24 hours (Day 1-2 and Day 8-9) | 
| Pharmacokinetics - AUCextr | Extrapolated AUC of NHC, defined as (AUC0-inf - AUC0-t)/AUC0-inf | From 0 to 24 hours (Day 1-2 and Day 8-9) | 
| Pharmacokinetics - t1/2 | Elimination half-life (t1/2) of NHC | From 0 to 24 hours (Day 1-2 and Day 8-9) | 
| Pharmacokinetics - kel | Elimination constant (kel) of NHC | From 0 to 24 hours (Day 1-2 and Day 8-9) | 
| Pharmacokinetics - MRT | Mean residence time (MRT) of NHC | From 0 to 24 hours (Day 1-2 and Day 8-9) | 
| Bioequivalence - ratio of Cmax | Ratio of geometric mean Cmax for NHC after intake of R or T (with 90% confidence intervals) | From 0 to 24 hours (Day 1-2 and Day 8-9) | 
| Bioequivalence - ratio of AUC0-t | Ratio of geometric mean AUC0-t for NHC after intake of R or T (with 90% confidence intervals) | From 0 to 24 hours (Day 1-2 and Day 8-9) | 
| Bioequivalence - ratio of AUC0-inf | Ratio of geometric mean AUC0-inf for NHC after intake of R or T (with 90% confidence intervals) | From 0 to 24 hours (Day 1-2 and Day 8-9) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety and Tolerability: adverse event (AE) number and frequency | Number and frequency of adverse events (AEs) or serious AEs (SAEs) | From the screening (and signing informed consent form) to Day 14 of the study or to an early termination visit within the time frame of the study (from Day 0 to Day 14) | 
| Safety and Tolerability: adverse event (AE) characteristics | Description and severity of AEs or serious AEs (SAEs), concomitant therapy for AEs/SAEs, causal relationship, outcomes. | From the screening (and signing informed consent form) to Day 14 of the study or to an early termination visit within the time frame of the study (from Day 0 to Day 14) | 
| Safety and Tolerability: vital signs - systolic blood pressure (SBP) | SBP, mmHg | Screening, from Day 0 to Day 2, from Day 7 to Day 9, and/or on early termination visit within the time frame of the study (from Day 0 to Day 14) | 
| Safety and Tolerability: vital signs - diastolic blood pressure (DBP) | DBP, mmHg | Screening, from Day 0 to Day 2, from Day 7 to Day 9, and/or on early termination visit within the time frame of the study (from Day 0 to Day 14) | 
| Safety and Tolerability: vital signs - respiratory rate (RR) | RR, breaths per minute | Screening, from Day 0 to Day 2, from Day 7 to Day 9, and/or on early termination visit within the time frame of the study (from Day 0 to Day 14) | 
| Safety and Tolerability: vital signs - heart rate (HR) | HR, beats per minute | Screening, from Day 0 to Day 2, from Day 7 to Day 9, and/or on early termination visit within the time frame of the study (from Day 0 to Day 14) | 
| Safety and Tolerability: vital signs - body temperature | Body temperature, centigrade scale | Screening, from Day 0 to Day 2, from Day 7 to Day 9, and/or on early termination visit within the time frame of the study (from Day 0 to Day 14) | 
| Safety and Tolerability: physical examination results | Physical examination results | Screening, from Day 0 to Day 2, from Day 7 to Day 9, and/or on early termination visit within the time frame of the study (from Day 0 to Day 14) | 
| Safety and Tolerability: urinalysis - color | Color of the urine | Screening, Day 3, Day 9 or on early termination visit within the time frame of the study (from Day 0 to Day 14) | 
| Safety and Tolerability: urinalysis - transparency | Transparency of the urine | Screening, Day 3, Day 9 or on early termination visit within the time frame of the study (from Day 0 to Day 14) | 
| Safety and Tolerability: urinalysis - pH | pH of the urine | Screening, Day 3, Day 9 or on early termination visit within the time frame of the study (from Day 0 to Day 14) | 
| Safety and Tolerability: urinalysis - specific gravity | Specific gravity of the urine | Screening, Day 3, Day 9 or on early termination visit within the time frame of the study (from Day 0 to Day 14) | 
| Safety and Tolerability: urinalysis - nitrites | Nitrites in the urine (+/-) | Screening, Day 3, Day 9 or on early termination visit within the time frame of the study (from Day 0 to Day 14) | 
| Safety and Tolerability: urinalysis - protein | Protein in the urine (g/L) | Screening, Day 3, Day 9 or on early termination visit within the time frame of the study (from Day 0 to Day 14) | 
| Safety and Tolerability: urinalysis - glucose | Glucose in the urine (mmol/L) | Screening, Day 3, Day 9 or on early termination visit within the time frame of the study (from Day 0 to Day 14) | 
| Safety and Tolerability: urinalysis - ketones | Ketones in the urine (mmol/L) | Screening, Day 3, Day 9 or on early termination visit within the time frame of the study (from Day 0 to Day 14) | 
| Safety and Tolerability: urinalysis - urobilinogen | Urobilinogen in the urine (mmol/L) | Screening, Day 3, Day 9 or on early termination visit within the time frame of the study (from Day 0 to Day 14) | 
| Safety and Tolerability: urinalysis - bilirubin | Bilirubin in the urine (+/-) | Screening, Day 3, Day 9 or on early termination visit within the time frame of the study (from Day 0 to Day 14) | 
| Safety and Tolerability: urinalysis (microscopy) - red blood cells | Red blood cells in the urine (number in sight) | Screening, Day 3, Day 9 or on early termination visit within the time frame of the study (from Day 0 to Day 14) | 
| Safety and Tolerability: urinalysis (microscopy) - white blood cells | White blood cells in the urine (number in sight) | Screening, Day 3, Day 9 or on early termination visit within the time frame of the study (from Day 0 to Day 14) | 
| Safety and Tolerability: urinalysis (microscopy) - cylinders (except hyaline) | Cylinders (except hyaline) in the urine (number in sight) | Screening, Day 3, Day 9 or on early termination visit within the time frame of the study (from Day 0 to Day 14) | 
| Safety and Tolerability: urinalysis (microscopy) - bacteria | Bacteria in the urine (number in sight) | Screening, Day 3, Day 9 or on early termination visit within the time frame of the study (from Day 0 to Day 14) | 
| Safety and Tolerability: complete blood count - hemoglobin | Hemoglobin, g/dL | Screening, Day 3, Day 9 or on early termination visit within the time frame of the study (from Day 0 to Day 14) | 
| Safety and Tolerability: complete blood count - red blood cells | Red blood cells, 10^6/uL | Screening, Day 3, Day 9 or on early termination visit within the time frame of the study (from Day 0 to Day 14) | 
| Safety and Tolerability: complete blood count - hematocrit | Hematocrit, % | Screening, Day 3, Day 9 or on early termination visit within the time frame of the study (from Day 0 to Day 14) | 
| Safety and Tolerability: complete blood count - platelets | Platelets, 10^3/uL | Screening, Day 3, Day 9 or on early termination visit within the time frame of the study (from Day 0 to Day 14) | 
| Safety and Tolerability: complete blood count - white blood cells | White blood cells, 10^3/uL | Screening, Day 3, Day 9 or on early termination visit within the time frame of the study (from Day 0 to Day 14) | 
| Safety and Tolerability: complete blood count - erythrocyte sedimentation rate | Erythrocyte sedimentation rate, mm per hour | Screening, Day 3, Day 9 or on early termination visit within the time frame of the study (from Day 0 to Day 14) | 
| Safety and Tolerability: complete blood count - neutrophils | Neutrophils, % | Screening, Day 3, Day 9 or on early termination visit within the time frame of the study (from Day 0 to Day 14) | 
| Safety and Tolerability: complete blood count - lymphocytes | Lymphocytes, % | Screening, Day 3, Day 9 or on early termination visit within the time frame of the study (from Day 0 to Day 14) | 
| Safety and Tolerability: complete blood count - eosinophils | Eosinophils, % | Screening, Day 3, Day 9 or on early termination visit within the time frame of the study (from Day 0 to Day 14) | 
| Safety and Tolerability: complete blood count - monocytes | Monocytes, % | Screening, Day 3, Day 9 or on early termination visit within the time frame of the study (from Day 0 to Day 14) | 
| Safety and Tolerability: complete blood count - basophils | Basophils, % | Screening, Day 3, Day 9 or on early termination visit within the time frame of the study (from Day 0 to Day 14) | 
| Safety and Tolerability: blood test results - total protein | Total protein in blood serum, g/L | Screening, Day 3, Day 9 or on early termination visit within the time frame of the study (from Day 0 to Day 14) | 
| Safety and Tolerability: blood test results - creatinine | Creatinine in blood serum, umol/L | Screening, Day 3, Day 9 or on early termination visit within the time frame of the study (from Day 0 to Day 14) | 
| Safety and Tolerability: blood test results - urea | Urea in blood serum, mmol/L | Screening, Day 3, Day 9 or on early termination visit within the time frame of the study (from Day 0 to Day 14) | 
| Safety and Tolerability: blood test results - glucose | Glucose in blood serum, mmol/L | Screening, Day 3, Day 9 or on early termination visit within the time frame of the study (from Day 0 to Day 14) | 
| Safety and Tolerability: blood test results - total bilirubin | Total bilirubin in blood serum, umol/L | Screening, Day 3, Day 9 or on early termination visit within the time frame of the study (from Day 0 to Day 14) | 
| Safety and Tolerability: blood test results - direct bilirubin | Direct bilirubin in blood serum, umol/L | Screening, Day 3, Day 9 or on early termination visit within the time frame of the study (from Day 0 to Day 14) | 
| Safety and Tolerability: blood test results - total cholesterol | Total cholesterol in blood serum, mmol/L | Screening, Day 3, Day 9 or on early termination visit within the time frame of the study (from Day 0 to Day 14) | 
| Safety and Tolerability: blood test results - triglycerides | Triglycerides in blood serum, mmol/L | Screening, Day 3, Day 9 or on early termination visit within the time frame of the study (from Day 0 to Day 14) | 
| Safety and Tolerability: blood test results - alanine transaminase (ALT) | ALT in blood serum, U/L | Screening, Day 3, Day 9 or on early termination visit within the time frame of the study (from Day 0 to Day 14) | 
| Safety and Tolerability: blood test results - aspartate transaminase (AST) | AST in blood serum, U/L | Screening, Day 3, Day 9 or on early termination visit within the time frame of the study (from Day 0 to Day 14) | 
| Safety and Tolerability: blood test results - alkaline phosphatase (ALP) | ALP in blood serum, U/L | Screening, Day 3, Day 9 or on early termination visit within the time frame of the study (from Day 0 to Day 14) | 
| Safety and Tolerability: 12-lead electrocardiogram (ECG) - heart rate | 12-lead ECG (I, II, III, aVR, aVL, aVF, V1-V6) taken while lying down: heart rate (beats per minute) | Screening, Day 3, Day 9 or on early termination visit within the time frame of the study (from Day 0 to Day 14) | 
| Safety and Tolerability: 12-lead electrocardiogram (ECG) - PQ interval | 12-lead ECG (I, II, III, aVR, aVL, aVF, V1-V6) taken while lying down: PQ interval (ms) | Screening, Day 3, Day 9 or on early termination visit within the time frame of the study (from Day 0 to Day 14) | 
| Safety and Tolerability: 12-lead electrocardiogram (ECG) - QRS complex | 12-lead ECG (I, II, III, aVR, aVL, aVF, V1-V6) taken while lying down: QRS complex (ms) | Screening, Day 3, Day 9 or on early termination visit within the time frame of the study (from Day 0 to Day 14) | 
| Safety and Tolerability: 12-lead electrocardiogram (ECG) - corrected QT interval (QTc) | 12-lead ECG (I, II, III, aVR, aVL, aVF, V1-V6) taken while lying down: QTc (ms) | Screening, Day 3, Day 9 or on early termination visit within the time frame of the study (from Day 0 to Day 14) |