A Pharmacokinetic Study of Narlaprevir as a Single Dose or With Ritonavir Combination in Patients With Hepatic Impairment and Healthy Matched Volunteers

NCT03832426 | Completed Phase 1

• 1 other identifier: CJ05013007
• Study Type: interventional
• Target: 32
• Locations: 2 countries
• Sites: 3

Brief Summary

This study was conducted to evaluate narlaprevir (NVR) pharmacokinetics (PK) after a single dose with or without ritonavir (RTV) in cirrhotic Child-Pugh class A patients without active HCV infection versus healthy subjects as well as to assess safety and tolerability of such treatment combination.

Conditions

Hepatic Impairment

Outcome Measures

Primary Outcomes (7)

• AUC (0-last) of Narlaprevir

  the area under the concentration-time curve from the time of dosing (time 0) before the observation time of the last detectable concentration

  before drug administration and in 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 8, 12, 24, 36, 48, 72, 96 and 120 hours after dosing

• AUC (0-24) of Narlaprevir

  area under the concentration-time curve from time 0 to 24 hours

  before drug administration and in 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 8, 12, 24 hours after dosing

• AUC (0-48) of Narlaprevir

  the area under the concentration-time curve from time 0 to 48 hours

  before drug administration and in 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 8, 12, 24, 36, 48 hours after dosing

• AUC (0-inf) of Narlaprevir

  the area under the concentration-time curve from time 0 to the time extrapolated to infinity

  before drug administration and in 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 8, 12, 24, 36, 48, 72, 96 and 120 hours after dosing

• Cmax of Narlaprevir

  the maximum observed plasma concentration

  before drug administration and in 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 8, 12, 24, 36, 48, 72, 96 and 120 hours after dosing

• Tmax of Narlaprevir

  the time to reach Cmax

  before drug administration and in 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 8, 12, 24, 36, 48, 72, 96 and 120 hours after dosing

• t1/2 of Narlaprevir

  terminal half-life

  before drug administration and in 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 8, 12, 24, 36, 48, 72, 96 and 120 hours after dosing

Secondary Outcomes (6)

• Cu(t1-t2) of Narlaprevir

  before dosing, 0-4, 4-8, 8-12, 12-16 and 16-24 hours after dosing

• Vu(t1-t2)

  before dosing, 0-4, 4-8, 8-12, 12-16 and 16-24 hours after dosing

• Ae (0-t)

  before dosing, 0-4, 4-8, 8-12, 12-16 and 16-24 hours after dosing

• Ae (0-24)

  before dosing, 0-4, 4-8, 8-12, 12-16 and 16-24 hours after dosing

• Fe

  before dosing, 0-4, 4-8, 8-12, 12-16 and 16-24 hours after dosing

Other Outcomes (7)

• AUC (0-last) of Narlaprevir unbound fraction in plasma

  before drug administration and in 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 8, 12, 24, 36, 48, 72, 96 and 120 hours after dosing

• AUC (0-24) of Narlaprevir unbound fraction in plasma

  before drug administration and in 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 8, 12, 24 hours after dosing

• AUC (0-48) of Narlaprevir unbound fraction in plasma

  before drug administration and in 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 8, 12, 24, 36, 48 hours after dosing

Study Arms (4)

Narlaprevir single - Healthy

EXPERIMENTAL

2 tablets of 100 mg Narlaprevir once a day

Drug: Narlaprevir

Narlaprevir single - Hepatic Impairment

EXPERIMENTAL

2 tablets of 100 mg Narlaprevir once a day

Drug: Narlaprevir

Narlaprevir+Ritonavir - Healthy

EXPERIMENTAL

Narlaprevir 100 mg (1 tablet of 100 mg) and Ritonavir 100 mg (1 tablet of 100 mg) once a day

Drug: Narlaprevir; Drug: Ritonavir

Narlaprevir+Ritonavir - Hepatic Impairment

EXPERIMENTAL

Narlaprevir 100 mg (1 tablet of 100 mg) and Ritonavir 100 mg (1 tablet of 100 mg) once a day

Drug: Narlaprevir; Drug: Ritonavir

Interventions

Narlaprevir DRUG

100 mg film-coated tablets

Narlaprevir single - Healthy; Narlaprevir single - Hepatic Impairment; Narlaprevir+Ritonavir - Healthy; Narlaprevir+Ritonavir - Hepatic Impairment

Ritonavir DRUG

100 mg film-coated tablets

Narlaprevir+Ritonavir - Healthy; Narlaprevir+Ritonavir - Hepatic Impairment

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Common for patients and volunteers:
• The study patient/volunteer could understand and fulfill the requirements of the Protocol (according to the Investigator)
• The patient/volunteer signed and dated a written informed consent form and any other required permits for use of personal information prior to any study procedures.
• At screening, females capable of child-bearing had the result of a pregnancy test (β-hCG in blood plasma) corresponding to the absence of pregnancy and agreed to use adequate contraception during the study, starting at least 2 weeks prior to drug administration and the onset of menarche, but at least 2 weeks after drug administration; or passed the surgical sterilization at least 3 months prior to the study.
• Menopausal females could participate in the study if they had no menstruation for at least 1 year and had the appropriate age. Menopausal status was confirmed in the screening by the appropriate level of FSH.
• Males who were not surgically sterilized had to agree to use reliable methods of contraception after signing a consent form for the study for 90 days after administration of the study drug administration.
• The study patient/volunteer was ready to refrain from caffeine and alcohol for the period from 72 hours prior to obtaining a dose of the study drug (Day 1) and until the final visit.
• The study patient/volunteer was ready to refrain from excessive physical activity for the period from 72 hours prior to obtaining a dose of the study drug (Day 1) and until the final visit.
• The body weight of study patient/volunteer at screening and on Day 1 was not less than 45 kg, and body mass index (BMI) - from 18.0 to 35.0 kg/m2, inclusive. BMI was calculated by dividing body weight of patient/volunteer in kilograms by the square of their height in meters.
• The study patient/volunteer had no clinically significant abnormalities on the electrocardiogram (ECG) (QTc interval ≤450 msec in males and ≤470 msec in females) performed at the screening visit and before administration of the study drug on Day 1.
• The study patient/volunteer agreed not to take the use of grapefruit or products containing them for the period of at least 2 weeks prior to the study drug administration until the end of the study. It was forbidden to drink any fruit juice for the period from 24 hours before narlaprevir administration until the end of the period of collecting the samples for pharmacokinetic analysis.
• The study patient/volunteer agreed to refrain from the use of St. John's wort and products containing them and/or any other herbal medicines, organic and homeopathic medicines, dietary or nutritional supplements of any kind (except multivitamin drugs prescribed 1 per day) for at least 2 weeks prior to dosing and throughout the study.
• The study patient/volunteer understood the study procedures and confirmed consent to participate therein by signing a consent form.
• The study patient/volunteer was ready to provide a blood sample for pharmacogenetic analysis (optional).
• Evaluation of patient's liver function corresponds to 5-6 (mild hepatic insufficiency) on Child-Pugh scale at the screening visit.

You may not qualify if:

• A minor, mentally or legally incompetent patient/volunteer with a significant emotional disturbance at the screening visit, or those patients/volunteers who were assumed to have the development of such disorders during the study, or those who had a history of clinically significant mental disorders.
• A patient/volunteer received any other study drug within 90 days prior to receiving the study drug dose.
• A patient/volunteer received narlaprevir in a previous clinical study, or as a means for treating the disease.
• A patient/volunteer had hypersensitivity to any component of narlaprevir or related substances.
• A patient/volunteer had a positive urine test for prohibited drugs at the screening visit and on Day -1.
• History of drug dependence of a patient/volunteer (defined as the use of any drug for entertainment) or alcoholism, or excessive drinking during the last year. Excessive drinking defined as consumption per week on average over 14 (for females) and 21 (for males) of alcoholic units (1 unit of alcohol = 8-10 g of alcohol and equivalent to about 200 ml of wine or 250 ml of beer, or standard measures for strong alcoholic beverages).
• A patient/volunteer consumed excessive amounts of coffee, cola, tea or other caffeine-containing drinks per day. Excessive drinking was considered more than 6 servings (1 serving or about 120 mg of caffeine) per day.
• Pregnant and lactating females as well as females who planned to become pregnant or to deliver eggs for fertilization before, during, or within 1 month after taking part in the study. The males who planned to deliver sperm for fertilization during the study or within 12 weeks after it.
• A patient/volunteer had cancer in history other than basal cell carcinoma being in remission for at least 5 years before Day 1.
• At screening, a patient/volunteer had positive results of tests for surface antigen of hepatitis B virus (HBsAG), for antibodies to hepatitis C virus (HCV), for antigen/antibody to human immunodeficiency virus (HIV). Patients/volunteers with hepatitis B or C in history were not included in the study. The study could include patients/volunteers with a history of hepatitis A from which they recovered without any treatment, if there was no documentary evidence on complete resolution of the disease for at least 6 months prior to Day 1.
• A patient/volunteer underwent surgery, donated or lost 450 or more ml of blood (including plasmapheresis, or underwent transfusion of blood products within 90 days prior to Day 1.
• A patient/volunteer had a history of gastroesophageal reflux disease (GERD), eosinophilic esophagitis, duodenal ulcer, gastric ulcer, dyspepsia, Barrett's esophagus or Zollinger-Ellison syndrome, or had a history of or had at the time of the study (during 6 months before screening) gastrointestinal diseases that could conceivably affect the absorption of drugs.
• A history of strokes, seizures or severe chronic neurological disorders.
• A patient/volunteer had a history of or had at the time of the study clinically significant endocrine, gastrointestinal, cardiovascular, hematologic, immune, renal, respiratory or urinary disorders or diseases which the Investigator believed to affect the correct evaluation of the study or pose additional risks to a patient/volunteer's participation in the study.
• A patient/volunteer had creatinine clearance \<60 ml/min under Cockcroft-Gault calculation at screening.

Sponsors & Collaborators

• R-Pharm: lead
• Ascent: collaborator

Study Sites (3)

LLC Chapidze Emergency Cardiology Center

Tbilisi, Georgia

Location

LLC Guli (Heart) - Cardiology clinic

Tbilisi, Georgia

Location

- Institution of the Russian Academy of Sciences "RAS Hospital"

Troitsk, Russia

Location

Related Publications (1)

• Isakov V, Koloda D, Tikhonova N, Kikalishvili T, Krasavina E, Lekishvili K, Malaya I, Ryska M, Samsonov M, Tolkacheva V. Pharmacokinetics of the New Hepatitis C Virus NS3 Protease Inhibitor Narlaprevir following Single-Dose Use with or without Ritonavir in Patients with Liver Cirrhosis. Antimicrob Agents Chemother. 2016 Nov 21;60(12):7098-7104. doi: 10.1128/AAC.01044-16. Print 2016 Dec.

  PMID: 27645244 RESULT

MeSH Terms

Interventions

narlaprevir; Ritonavir

Intervention Hierarchy (Ancestors)

Thiazoles; Sulfur Compounds; Organic Chemicals; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Study Officials

• Mikhail Samsonov

  R-Pharm

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 5, 2019
• First Posted: February 6, 2019
• Study Start: November 8, 2013
• Primary Completion: October 24, 2014
• Study Completion: October 24, 2014
• Last Updated: May 22, 2019

Record last verified: 2019-05

Locations

RU (1); GE (2)