Pharmacokinetics and Safety of Rupatadine in Participants With Hepatic Impairment Compared to Control Participants.

This is an open-label, non-randomized, parallel group study comparing the PK after administration of a single 10 mg dose of rupatadine to participants with hepatic impairment with matched control participants with normal hepatic function (matched in terms of age, gender, and body weight).

For each participant, the study visits will consist of a screening period (Day -28 to Day -2), a baseline evaluation (Day -1), a single dose treatment period (Day 1), and an End of Study (EOS) Visit (Day 10). Additionally, from Day 2 to EOS participants will go back to the clinic every day for blood drawing.

Participants who meet the eligibility criteria at Screening and Baseline will be enrolled into the study.

All Baseline safety evaluation results must be reviewed prior to dosing. Participants will be domiciled at the clinic from Day -1 until 24 hours after dosing on Day 1 (Day 2).

On Day 1, participants will receive a single dose of rupatadine 10 mg after an overnight fast of 10 hours and will continue to fast for 4 hours postdose.

Participants will undergo sequential PK sampling over the following 192 hours along with other safety assessments as described in schedule of activities (SoA).

The participant groups will be consecutively enrolled into the study. Enrollment of participants with mild, moderate, and severe hepatic impairment will be staggered, so that dosing of participants with mild hepatic impairment will be started first. Dosing of the next group will be started only after evaluation of blood PK, safety and tolerability data until 72-hour postdose of at least 6 participants with hepatic impairment from the previous group and after the assessment of safety and tolerability results are judged to be satisfactory by Safety Committee.

An EOS assessment for each participant will occur at Day 10 after the administration of rupatadine.

The total study duration for each participant, including Screening, Baseline, Study Period, and EOS assessments, is approximately 38 days.

Inclusion criteria

Participants with normal hepatic function and participants with mild, moderate, or severe hepatic impairment who meet the following criteria will be considered eligible to participate in the clinical study:

• Participant understands the study procedures and agrees to participate in the study by giving written informed consent prior to any study-mandated procedure.
• Able to communicate well with the Investigator, to understand and comply with the study requirements.
• Willing to comply with study restrictions stated in Section 5.3 (lifestyle considerations).
• Male or female Caucasian subject, between 18 and 75 years (inclusive) of age.
• Body mass index (BMI) is between 18 to 35 kg/m2 at Screening.
• Women of childbearing potential (WoCBP) must have a negative serum pregnancy test at Screening, a negative urine pregnancy test on Day -1, and agree to consistently and correctly use (from 30 days prior to dosing, during the entire study, and for at least 30 days after dosing), a highly effective method of contraception (i.e., failure rate of < 1%) (Section 10.4 [Appendix 4]). Such methods include:

• Hormonal contraceptives: combined (estrogen- and progesterone-containing) contraception associated with inhibition of ovulation using oral, intravaginal, or transdermal route of administration.

Note: If a hormonal contraceptive is used, it must be initiated at least 30 days before dosing.

• Intrauterine device.
• Intrauterine hormone-releasing system.
• Bilateral tubal occlusion.
• Vasectomized partner, provided that the partner is the sole sexual partner and that the vasectomized partner has received medical assessment of the surgical success.
• Sexual abstinence, defined as refraining from heterosexual intercourse from 30 days prior to dosing up to at least 30 days after dosing, if this is the preferred and usual lifestyle of the subject. WoCBP must also agree not to donate ova from the time of informed consent until 30 days after dosing
• Women of non-childbearing potential (WoNCBP), i.e., postmenopausal (defined as 12 consecutive months with no menses without an alternative medical cause, confirmed by a follicular stimulating hormone [FSH] test), with previous bilateral salpingectomy, bilateral salpingo-oophorectomy or hysterectomy, or with premature ovarian failure (confirmed by a specialist), XY genotype, Turner syndrome, uterine agenesis (Section 0 [Appendix 4]).
• Male participants are infertile, vasectomized (who has received medical assessment of the surgical success) or must agree to abstain from, or to use a condom, during heterosexual intercourse with a woman of childbearing potential (Section 0 [Appendix 4]).
• Male participants must agree not to donate sperm, from the time of informed consent until 30 days after dosing.
• Participant agrees to refrain from consuming grapefruit juice, grapefruits, and grapefruitcontaining products from at least 7 days before the dose administration, and until the EOS Visit.
• Able to tolerate venipuncture.
• No clinically relevant abnormalities on rest vital signs.
• No clinically relevant abnormalities on 12-lead ECG.

For participants with normal hepatic function the following criteria must be met in addition:

• No clinically relevant diseases captured in medical history at Screening.
• No clinically relevant abnormalities on physical examination and Screening and Baseline.
• No clinically relevant abnormalities on clinical laboratory tests at Screening.
• Weight within ±15% to his/her matched participant(s) enrolled in the study.
• Biological sex matched to his/her matched participant(s) enrolled in the study.
• Age within ±10 years to his/her matched participant(s) enrolled in the study.
• Normal Blood Pressure (BP) measured on the same arm, after 5 min in the supine position at Screening and Baseline defined as:

• Systolic Blood Pressure (SBP) 90-140 mmHg, Diastolic Blood Pressure (DBP) 60-90 mmHg, and pulse rate 60-100 bpm (inclusive) for subjects < 65 years of age.
• SBP 95-160 mmHg, DBP 65-95 mmHg, and pulse rate 60-100 bpm (inclusive) for subjects ≥ 65 years of age.

For participants with mild, moderate, or severe hepatic impairment the following criteria must be met in addition:

• No clinically relevant abnormalities on clinical laboratory tests at Screening, except for those related to liver cirrhosis.
• SBP 90-160 mmHg, DBP 60-95 mmHg, and pulse rate 60-100 bpm (inclusive), measured on the same arm, after 5 min in the supine position at Screening and Baseline.
• Participant has a diagnosis of chronic (> 6 months), stable (no acute episodes of illness within the previous 2 months due to deterioration in hepatic function) hepatic impairment, defined by Child Pugh Classification, with features of cirrhosis due to any etiology.
• Child-Pugh scale score (see Section 4.2 for Child-Pugh Classification) from 5 to 6 (mild hepatic impairment), 7 to 9 (moderate hepatic impairment) or 10 to 15 (severe hepatic impairment) at the Screening Visit.
• Stable concomitant medications for at least 21 days prior to dosing and up to the EOS visit.

Exclusion criteria

Participants with normal hepatic function and participants with mild, moderate, or severe hepatic impairment who meet one or more of the following criteria will not be considered eligible to participate in the clinical study:

• Pregnant or lactating women.
• Participant is unlikely to comply with the protocol requirements, instructions and study related restrictions; e.g., uncooperative attitude, inability to return for the EOS Visit and improbability of completing the clinical study.
• Any psychological, emotional problems, any disorders or resultant therapy that is likely to invalidate informed consent, or limit the ability of the participant to comply with the protocol requirements.
• History of hypersensitivity to rupatadine, desloratadine or any of the excipients, or to medicinal products with similar chemical structures.
• History of clinically significant lactose, galactose, or fructose intolerance.
• Any clinically relevant acute or chronic disease which could jeopardize the safety of the participant or impact the validity of the study results.
• History or presence of clinically significant angioedema.
• Use of caffeine-containing beverages exceeding 800 mg per day (Section 5.3.2) at Screening.
• Nicotine consumption (e.g., smoking, nicotine patch, nicotine chewing gum, or electronic cigarettes) from 48 h prior to Baseline (Day -1) until discharge from confinement (Day 2).
• Positive test result for urine alcohol and drugs of abuse (amphetamines, benzodiazepines, cannabinoids, cocaine and opiates) at Screening and Baseline.

Note: Subjects receiving stable treatment of methadone and benzodiazepines will be allowed to be enrolled in the study even if the urine drug screen test is positive.

• Veins unsuitable for intravenous puncture on either arm (e.g., veins that are difficult to locate, access, or puncture, veins with a tendency to rupture during or after puncture).
• Participation in another clinical trial with an experimental drug within 2 months or 5 halflives (whichever is longer) before the Screening or in more than 2 clinical studies within 1 year prior to Screening.
• Positive results at Screening from either the hepatitis B or C serology based on hepatitis B surface antigen, hepatitis B surface antibody, hepatitis B core antibody (Ig M and total antihepatitis B core antibody), and hepatitis C virus antibody (HCV) markers, except for vaccinated subjects or subjects with past resolved hepatitis.

Note: If HCV antibody is present, HCV RNA analysis should be performed, and the result must be "not detected".

• History of heart, liver or kidney transplantation.
• Active malignant neoplastic disease or carcinoma (including leukemia, lymphoma, malignant melanoma), or myeloproliferative disease, regardless of the time since treatment.
• Use of any of the following within 2 weeks prior to investigational medicinal product (IMP) administration or 5 half-lives, whichever is longer:

• Enzyme-modifying drugs known to induce/inhibit hepatic drug metabolism (e.g., azole antifungals [ketoconazole, itraconazole, fluconazole, posaconazole, voriconazole], macrolide antibiotics [erythromycin, clarithromycin], diltiazem, human immunodeficiency virus (HIV) protease inhibitors, nefazodone, rifampicin, phenytoin, dexamethasone, troglitazone, and barbiturates)
• CYP3A4 substrates with a narrow therapeutic index (e.g., ciclosporin, tacrolimus, sirolimus, everolimus, cisapride)
• Desloratadine
• Clinically significant abnormalities on ECG repolarization (QTcF > 450 ms in males and > 470 ms in females) at Screening.
• Loss of 250 mL or more blood within 3 months prior to screening.

For participants with normal hepatic function, the additional criteria must not be met:

History or clinical evidence of alcohol or drug abuse within the 3 years prior to Screening.

• Estimated glomerular filtration rate (eGFR) < 90 mL/min for subjects aged ≤ 45 years, and <70 mL/min for subjects aged > 45 years, as determined by the Cockcroft-Gault equation, at Screening.
• Intake of any prescribed medication (including vaccines) including over-the-counter (OTC) medication (including herbal and dietary supplements such as St John's Wort, homeopathic preparations, vitamins and minerals) that could affect the outcome of the study as judged by the Investigator, within 14 days before the administration of the IMP or less than 5 times the half-life of that medication, whichever is longer (excluding contraceptives and hormone replacement therapy).

For participants with mild, moderate or severe renal impairment, the additional criteria must not be met:

• Severe portal hypertension or surgical porto-systemic shunts, including transjugular intrahepatic portosystemic shunt
• eGFR < 60 mL/min as determined by the Cockcroft-Gault equation, at Screening.
• History or clinical evidence of infection with hepatitis B and/or hepatitis C within the preceding 6 months.