A Drug Interaction Study to Assess the Pharmacokinetics of Narlaprevir and Antiretroviral Drugs

The study purpose is to evaluate the potential for a pharmacokinetic drug-drug interaction, safety and tolerability when Narlaprevir, Ritonavir (used as a metabolic inhibitor) and Tenofovir disoproxil fumarate (part 1) and Narlaprevir, Ritonavir and Raltegravir (part 2) are administered in combination to healthy volunteers.

Study Overview

• Status: Completed
• Conditions: Healthy
• Intervention / Treatment: Drug: Narlaprevir; Drug: Ritonavir; Drug: Tenofovir Disoproxil Fumarate; Drug: Raltegravir

Detailed Description

The current study includes 2 parts, as the following drugs may be used concomitantly to treat hepatitis C virus (HCV)/HIV coinfection:

• Part 1 of the study is being conducted to evaluate the pharmacokinetic effect of coadministration of narlaprevir with ritonavir and tenofovir disoproxil fumarate.
• Part 2 of the study is being conducted to evaluate the pharmacokinetic effect of coadministration of narlaprevir/ritonavir and raltegravir.

Each part of the study is designed as a randomized 3-period crossover study and will assess if there is any effect of tenofovir disoproxil fumarate or raltegravir on the pharmacokinetics of narlaprevir and vice versa.

Subjects will be screened within 28 days before dosing in this multi-part study. All subjects eligible for protocol criteria will be randomized 1:1:1 to receive one of the following treatment sequences: A/B/C, or B/C/A, or C/A/B. Every subject will receive only one treatment (A or B or C) in one Period. Subjects will be confined to the study center throughout treatment in each period. Following completion of study procedures for each treatment period, subjects will be released from the clinic. After a 7-14 (maximum) days interval between dosing, subjects will return to start hospitalization for the next treatment period. Subjects will be discharged from the study upon completion of all study related procedures in Period 3. Phone call will be conducted after 5-7 days of follow-up period to assess safety data.

This drug interaction study is designed to investigate pharmacokinetic drug-drug interactions between Narlaprevir coadministered with Ritonavir and antiretroviral drugs (Tenofovir disoproxil fumarate and Raltegravir) for labeling and clinical dosing guidance purposes.

• Study Type: Interventional
• Enrollment (Actual): 36
• Phase: Phase 1

Contacts and Locations

Study Locations

• Russian Federation
  • Moscow, Russian Federation
    • Clinic "Bessalar" JSC

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 21 years to 55 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria (the subject must meet all the criteria listed below for entry at baseline and at Days -1 and 1 before each treatment Period):

• Subjects must be willing to give written informed consent for the trial and able to adhere to dose and visit schedules.
• Subjects having a Body Mass Index (BMI) between 18,5 and 30 kg/m^2, inclusive.
• Subjects should diagnosed as "healthy": no pathology of the gastrointestinal tract, liver, kidneys, cardiovascular system, central nervous system (previously carried out by standard clinical and lab tests which did not reveal the presence of any diseases. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) must not exceed the normal range; QT interval calculated by Bazett's formula (QTcB) for men should be ≤ 450 ms and ≤ 470 ms for women, the interval PR should be ≤ 200 ms).

• Vital sign measurements (taken after ~3 minutes in a supine or sitting position) must be within the following ranges:

  1. systolic blood pressure, 100 - 130 mm Hg;
  2. diastolic blood pressure, 60 -90 mm Hg;
  3. pulse rate, 60-80 bpm.

• Female subjects must be:

  1. postmenopausal (defined as 12 months with no menses; age > 40 years and with a follicle-stimulating hormone (FSH) level of >40 u/mL);
  2. surgically sterilized at least 3 months prior to baseline (e.g., documented hysterectomy or tubal ligation).
• Men must agree to use a medically accepted method of contraception (condom and spermicide) during the trial and for 3 months after stopping the medication.

Exclusion Criteria (the subject will be excluded from entry if any of the criteria listed below are met at baseline):

• Females with childbearing potential.
• Subjects who, in the opinion of the investigator, will not be able to participate optimally in the study.
• Positive results for hepatitis B surface antigen, hepatitis C antibodies or HIV, positive RW results.
• Allergic reactions in history.
• Intolerance to medication.
• Chronic disease of cardiovascular, bronchopulmonary, and/or neuroendocrine systems, gastrointestinal, liver, pancreas, kidney and/or blood disease.
• History or presence of impaired renal function, lactase deficiency, lactose intolerance, glucose-galactose malabsorption.
• History of urinary obstruction or difficulty in voiding.
• Gastrointestinal surgery in history (except of appendectomy).
• Acute infections less than 4 weeks before participation in the study.
• Subjects with a medical history of osteopenia and/or osteoporosis.
• Regular administration of any medicines less than 4 weeks before participation in the study.
• Administration of medicines with marked influence on hemodynamics, liver function et al (barbiturates, omeprazole, cimetidine et al) less than 30 days before participation in the study.
• Blood donation (450 ml or more of blood or plasma) less than 2 months before participation in the study.
• Intake of more than 10 units of alcohol in a week (1 unit of alcohol is equal to 0.5 L of beer, 200 mL of wine or 50 mL of spirits) or history of drug abuse or alcoholism.
• Smoking of more than 10 cigarettes or equivalent tobacco use per day.
• Participation in phase 1 clinical trial less than 3 months before participation in the study.
• Positive screen for drugs abuse and drugs use.
• Subjects with a medical history of psychiatric or personality disorders that in the opinion of the investigator and sponsor, affects the subject's ability to participate in the trial.
• Subjects who are part of the study staff personnel or family members of the study staff personnel.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: None (Open Label)

Number of Arms

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Treatment A (Part 1/ Part 2); Narlaprevir 200 mg once daily with Ritonavir 100 mg once daily for 5 days	Drug: Narlaprevir; 100 mg, film-coated tablets, taken as 200 mg per os daily; Other Names: Arlansa; Drug: Ritonavir; 100 mg, film-coated tablets, taken as 100 mg per os daily; Other Names: Norvir
Active Comparator: Treatment B (Part 1); Tenofovir disoproxil fumarate 300 mg once daily for 5 days	Drug: Tenofovir Disoproxil Fumarate; 300 mg, film-coated tablets, taken as 300 mg per os daily; Other Names: Viread; Tenofovir-TL
Active Comparator: Treatment B (Part 2); Raltegravir 400 mg twice daily for 5 days	Drug: Raltegravir; 400 mg, film-coated tablets, taken as 400 mg per os daily; Other Names: Isentress
Experimental: Treatment C (Part 1); Narlaprevir 200 mg once daily coadministered with ritonavir 100 mg once daily and Tenofovir disoproxil fumarate 300 mg once daily for 5 days	Drug: Narlaprevir; 100 mg, film-coated tablets, taken as 200 mg per os daily; Other Names: Arlansa; Drug: Ritonavir; 100 mg, film-coated tablets, taken as 100 mg per os daily; Other Names: Norvir; Drug: Tenofovir Disoproxil Fumarate; 300 mg, film-coated tablets, taken as 300 mg per os daily; Other Names: Viread; Tenofovir-TL
Experimental: Treatment C (Part 2); Narlaprevir 200 mg once daily coadministered with ritonavir 100 mg once daily and 400 mg raltegravir twice daily for 5 days	Drug: Narlaprevir; 100 mg, film-coated tablets, taken as 200 mg per os daily; Other Names: Arlansa; Drug: Ritonavir; 100 mg, film-coated tablets, taken as 100 mg per os daily; Other Names: Norvir; Drug: Raltegravir; 400 mg, film-coated tablets, taken as 400 mg per os daily; Other Names: Isentress

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cmax of Narlaprevir	Maximum observed Concentration of Narlaprevir at Day 5 of treatment A and C of Part 1 or 2 of the study	Day 5 Pre-dose and 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 16 and 24 hours post-dose on Day 5 of treatment A and C (Part 1/ Part 2)
AUCtau of Narlaprevir	Area Under the Concentration-time curve during a dosing interval τ at steady state of Narlaprevir at Day 5 of treatment A and C of Part 1/ Part 2 of the study	Day 5 Pre-dose and 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 16 and 24 hours post-dose on Day 5 of treatment A and C (Part 1/ Part 2)
Cmax of Tenofovir	Maximum observed Concentration of Tenofovir at Day 5 of treatment B and C of Part 1 of the study	Day 5 Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 18 and 24 hrs post-dose on Day 5 of treatment B and C (Part 1)
AUCtau of Tenofovir	Area Under the Concentration-time curve during a dosing interval τ at steady state of Tenofovir at Day 5 of treatment B and C of Part 1 of the study	Day 5 Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 18 and 24 hrs post-dose on Day 5 of treatment B and C (Part 1)
Cmax of Raltegravir	Maximum observed Concentration of Raltegravir at Day 5 of treatment B and C of Part 2 of the study	Day 5 Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 12 hrs post-dose of Day 5 of treatment B and C (Part 2)
AUCtau of Raltegravir	Area Under the Concentration-time curve during a dosing interval τ at steady state of Tenofovir at Day 5 of treatment B and C of Part 2 of the study	Day 5 Pre-dose and 0.5, 1, 2, 3, 4, 6, 8, 12 hrs post-dose of Day 5 of treatment B and C (Part 2)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Patients With Adverse Events		Up to 14 Days after the last dose of treatment in period 3 of each Part of the Study
Number of Patients With Changes in Vital Signs	There were no subjects with abnormal changes in vital signs	Up to 14 Days after the last dose of treatment in period 3 of each Part of the Study
Number of Patients With Abnormal Laboratory Values		Up to 14 Days after the last dose of treatment in period 3 of each Part of the Study
Number of Patients With Abnormal ECG Changes	There were no subjects with abnormal ECG changes during the study	Up to 14 Days after the last dose of treatment in period 3 of each Part of the Study

Collaborators and Investigators

• Sponsor: R-Pharm
• Collaborators: Almedis

Study record dates

Study Major Dates

• Study Start (Actual): April 24, 2017
• Primary Completion (Actual): June 24, 2017
• Study Completion (Actual): June 30, 2017

Study Registration Dates

• First Submitted: May 15, 2018
• First Submitted That Met QC Criteria: May 15, 2018
• First Posted (Actual): May 25, 2018

Study Record Updates

• Last Update Posted (Actual): February 19, 2019
• Last Update Submitted That Met QC Criteria: August 31, 2018
• Last Verified: August 1, 2018

More Information

Terms related to this study

• Keywords: HIV; pharmacokinetics; chronic; hepatitis C; coinfection; concomitant therapy
• Additional Relevant MeSH Terms: Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Reverse Transcriptase Inhibitors; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Anti-HIV Agents; Anti-Retroviral Agents; Protease Inhibitors; Cytochrome P-450 CYP3A Inhibitors; Cytochrome P-450 Enzyme Inhibitors; HIV Integrase Inhibitors; Integrase Inhibitors; HIV Protease Inhibitors; Viral Protease Inhibitors; Tenofovir; Raltegravir Potassium; Ritonavir
• Other Study ID Numbers: CJ05013019

Drug and device information, study documents

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