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

• Register: ClinicalTrials.gov
• Last refreshed on: 12 December 2020
• Main ID: NCT03832426
• Date of registration: 05/02/2019
• Prospective Registration: No
• Primary sponsor: R-Pharm
• Public title: A Pharmacokinetic Study of Narlaprevir as a Single Dose or With Ritonavir Combination in Patients With Hepatic Impairment and Healthy Matched Volunteers
• Scientific title: An Open Label, Parallel Design Study to Assess the Pharmacokinetics of Narlaprevir 200 mg as a Single Oral Dose and in Combination With Ritonavir 100 mg in Patients With Hepatic Impairment and Healthy Matched Volunteers
• Date of first enrolment: November 8, 2013
• Target sample size: 32
• Recruitment status: Completed
• URL: https://clinicaltrials.gov/show/NCT03832426
• Study type: Interventional
• Study design: Allocation: Non-Randomized. Intervention model: Parallel Assignment. Primary purpose: Treatment. Masking: None (Open Label).
• Phase: Phase 1

Countries of recruitment

Georgia, Russian Federation

Contacts

• Name: Mikhail Samsonov
• Affiliation: R-Pharm

Key inclusion & exclusion criteria

Inclusion Criteria:

1. 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.

- The study subject was a healthy adult man or woman (for inclusion in the group of
healthy volunteers) or had Child-Pugh Class A hepatic impairment (for inclusion
in the group with hepatic impairment).

- At screening, females capable of child-bearing had the result of a pregnancy test
(ß-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).

2. Specific inclusion criteria for patients with hepatic impairment:

- Evaluation of patient's liver function corresponds to 5-6 (mild hepatic
insufficiency) on Child-Pugh scale at the screening visit.

- On the basis of history, physical examination, vital signs and laboratory safety
tests carried out at the screening visit and/or before the study drug
administration, the patient did not have clinically significant diseases in
addition to the existing liver failure. Patients with the test results outside
the normal range that the Investigator considered clinically insignificant could
have been included in the study on the discretion of the Investigator if it was
not otherwise mentioned in the non-inclusion criteria.

- The patient was diagnosed with chronic (> 6 months ago), stable (in previous 2
months did not have periods of acute illness due to deterioration of liver
function) liver failure.

3. Specific inclusion criteria for the corresponding healthy volunteers:

- A volunteer weighing ±10% from the parameter of the body weight corresponding to
his/her patient with hepatic impairment included in the study.

- A volunteer was recognized as healthy on the basis of history, physical
examination, vital signs and laboratory safety tests carried out at the screening
visit and/or before the study drug administration (Day 1).

- A volunteer of the same race as the corresponding to his/her included patient
with hepatic impairment.

- A volunteer of the same gender as the corresponding to his/her included patient
with hepatic impairment.

- The age of a volunteer was within ±10 years from the age of the corresponding to
his/her included patient with hepatic impairment.

Exclusion Criteria:

1. General criteria for exclusion of patients/volunteers:

- 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.
Exce


Age minimum: 18 Years
Age maximum: 75 Years
Gender: All

Health Condition(s) or Problem(s) studied

Hepatic Impairment

Intervention(s)

Drug: Ritonavir

Drug: Narlaprevir

Primary Outcome(s)

t1/2 of Narlaprevir [Time Frame: 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 (0-48) of Narlaprevir [Time Frame: 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]

Cmax of Narlaprevir [Time Frame: 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-inf) of Narlaprevir [Time Frame: 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-last) of Narlaprevir [Time Frame: 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 [Time Frame: 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 [Time Frame: 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]

Secondary Outcome(s)

Ae (0-t) [Time Frame: before dosing, 0-4, 4-8, 8-12, 12-16 and 16-24 hours after dosing]

Fe [Time Frame: before dosing, 0-4, 4-8, 8-12, 12-16 and 16-24 hours after dosing]

Vu(t1-t2) [Time Frame: before dosing, 0-4, 4-8, 8-12, 12-16 and 16-24 hours after dosing]

Ae (0-24) [Time Frame: before dosing, 0-4, 4-8, 8-12, 12-16 and 16-24 hours after dosing]

Cu(t1-t2) of Narlaprevir [Time Frame: before dosing, 0-4, 4-8, 8-12, 12-16 and 16-24 hours after dosing]

CLr [Time Frame: before dosing, 0-4, 4-8, 8-12, 12-16 and 16-24 hours after dosing]

Secondary ID(s)

CJ05013007

Source(s) of Monetary Support

Please refer to primary and secondary sponsors

Secondary Sponsor(s)

Ascent