Comparative Pharmacokinetic Study of Pirfenidone Modified-Release Tablets in Healthy Subjects Under Fasting and Fed Conditions

A Randomized, Open-Label, Single-Dose, Double-period, Double-Crossover Comparative Study on the Pharmacokinetics of Pirfenidone Modified-Release Tablets by Oral Administration in Healthy Chinese Subjects Under Fasting and Fed Conditions.

Primary objective:

To evaluate the food effect on test product by comparing their plasma concentrations and main Pharmacokinetics (PK) parameters by oral administration of test product in healthy Chinese subjects under fasting and fed conditions using Pirfenidone Modified-Release Tablets (strength: 600 mg/tablet) developed by Overseas Pharmaceuticals, Ltd. as the test product.

Secondary objective:

To evaluate the safety of Pirfenidone Modified-Release Tablets (test product) by oral administration in healthy Chinese subjects under fasting and fed conditions.

It is designed to be a single-center, randomized, open-label, two-period, double-crossover trial. All subjects must sign an informed consent form (ICF) prior to participation in the trial. Eightteen (18) eligible healthy subjects (male and female, with an appropriate sex ratio) screened through physical examination from Day-14 (D-14) to D-1 of dosing will be randomized into Group A-B and Group B-A, with 9 subjects in each group. The enrolled subjects will be admitted to phase I ward of the clinical study site 1 day before medication in each period and fasted for more than 10 h before medication.

On the morning of medication, after the collection of blank blood samples, Group A will orally take 1 tablet of Pirfenidone Modified-Release Tablets (600 mg/tablet, Overseas Pharmaceuticals, Ltd.) developed by Overseas Pharmaceuticals, Ltd. under fasting conditions; Group B will orally take 1 tablet of Pirfenidone Modified-Release Tablets (600 mg/tablet, Overseas Pharmaceuticals, Ltd.) under high-fat, high-calorie meals.

Group A (fasting): After fasting for at least 10 h overnight, about 4 mL of blank blood was collected within 60 minutes before administration on the morning of administration, and then 600 mg of the test drug was taken orally on fasting condition with 240 mL of warm water.

Group B (fed): After fasting for at least 10 h on the night, about 4 mL of blank blood was collected within 60 min before administration on the morning of administration. Then group B start to eat high-fat and high-heat breakfast, and meals are stopped at 10 min±30 s. 600 mg of the test product was orally administered with 240 mL warm water within 12 min after starting to eat. After taking the product, group B continue to eat high-fat and high-heat breakfast, and the total meal time should be controlled within 30 minutes .

No food is allowed to be taken within 4 h after medication. Standard lunch is served 4 h after administration, standard dinner 10 h later, water is prohibited before and within 1 h after administration (except 240 mL water for medication), and unified diet is required during the trial.

Unified diet is required during the trial. The trial method in period II is the same as that in period I, with a washout period of 6 days.

PK blood sampling and blood sample processing:

Cubital venous blood will be collected at 31 time points: before administration (0 h) and 0.25 h, 0.50 h, 1.00 h, 1.50 h, 2.00 h, 3.00 h, 4.00 h, 4.50 h, 5.00 h, 6.00 h, 7.00 h, 7.50 h, 8.00 h, 9.00 h, 10.00 h, 10.25 h, 10.50 h, 11.00 h, 11.50 h, 12.00 h, 12.50 h, 13.00 h, 14.00 h, 16.00 h, 18.00 h, 20.00 h, 24.00 h, 28.00 h, 36.00 h and 48.00 h after administration of each period.

Four milliliters (4 mL) (scale of 4 mL should be pre-marked on the blood collection tube) will be drawn and placed in a labeled EDTA-2K anticoagulant tube. The collection, processing and storage procedures of biological samples are subject to the final sample operation manual.

Sitting vital signs (including respiratory rate, body temperature, pulse rate, and sitting blood pressure) will be measured within 1 h before administration and at 2 ± 0.5 h, 8 ± 0.5 h, 24 ± 0.5 h and 48 ± 1 h after administration. Subjects should receive physical examination, vital signs, electrocardiograms (ECGs), and laboratory-related tests on D2 after the last dose. The subjective feelings of subjects as well as possible adverse reactions (ARs) and adverse events (AEs) occurred during the trial should be observed and inquired. All subjects will be followed up for 7 days after the end of the last dose to inquire the occurrence of any subsequent AEs. If occurred, AEs should be recorded and followed up. An AE emerged during the trial should be followed up until it is resolved.

Eligibility Criteria:
Inclusion Criteria:

1. Healthy male and female subjects over the age of 18 years (including those aged 18 years), with an appropriate sex ratio;
2. Male subjects with a body weight ≥ 50.0 kg, and female subjects with a body weight ≥ 45.0 kg; BMI (BMI = body weight (kg)/\[height (m)\]2) within the range of 19-26.0 kg/m2 (including the critical value);
3. Subjects with good health conditions, no clinically significant medical history in respiratory system, circulatory system, digestive system, urinary system, blood system, endocrine system, immune system, nervous system, and mental system;
4. Subjects (including partners) who have no plans of pregnancy and voluntarily take appropriate contraceptive measures from the date of signing the informed consent (14 days before signing the informed consent for female subjects) to 6 months after the end of the study;
5. Subjects who are able to communicate well with the investigator and understand and adhere to the study requirements. Subjects who fully understand the objective, nature, method and possible ARs of the trial, voluntarily act as subjects, and sign the ICF before any study procedures are started;

Exclusion Criteria:

1. Patients with an allergic history to the study drug or its excipients (such as lactose), or an allergic history to drug, food , pollen or a specific allergic history (asthma, allergic rhinitis, eczema);
2. Patients with a history of photosensitivity and existing skin irritation symptoms such as rash and pruritus;
3. Subjects who have special dietary requirements and cannot accept a unified diet;
4. Subjects with a history of dysphagia or any gastrointestinal disorder affecting drug absorption;
5. Subjects who cannot tolerate venipuncture and have a history of fear of needles and hemophobia;
6. Subjects with clinically significant hematological, endocrine, cardiovascular, hepatic, renal and pulmonary disorders that may affect drug absorption, distribution, metabolism and excretion;
7. Subjects with a surgical history or taking the study drug or participating in other drug clinical trials within 3 months prior to the study;
8. Subjects with blood donation or massive blood loss (\> 450 mL) within 3 months before the study;
9. Subjects taking special diet (including pitaya or grapefruit and products containing grapefruit ingredients) or having strenuous exercise within 7 days before taking the study drug, or having other factors affecting drug absorption, distribution, metabolism and excretion;
10. Subjects administered with any prescription drugs, over-the-counter, herbal, or health products within 14 days prior to taking the study drug;
11. Regular drinkers within 6 months prior to the study, i.e., drinking more than 14 units of alcohol per week (1 unit = 360 mL of beer or 45 mL of spirit containing 40% alcohol or 150 mL of wine);
12. Subjects smoking more than 5 cigarettes per day in the first 3 months of the study; Or positive results of tobacco test;
13. Subjects who have consumed chocolate, any caffeine-containing, or xanthine-rich food or beverage, such as coffee, strong tea, and cola 48 h before taking the study drug;
14. Subjects having taken any alcohol-containing products within 48 h before taking the study drug, or having a positive result for alcohol screening;
15. Female subjects with positive pregnancy test or lactating during the screening period or during the trial;
16. Subjects positive for HBsAg, HCV-Ab, anti-HIV or primary syphilis screening;
17. Subjects positive for drug screening or with a history of drug abuse within the past five years or using drugs 3 months before the trial;
18. Subjects with underlying medical, psychiatric, psychological or other discomfort conditions, poor compliance, or who, as judged by the investigator, are not suitable for the study.