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

Inclusion Criteria:

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

1. Participant understands the study procedures and agrees to participate in the studyby giving written informed consent prior to any study-mandated procedure.

2. Able to communicate well with the Investigator, to understand and comply with thestudy requirements.

3. Willing to comply with study restrictions stated in Section 5.3 (lifestyleconsiderations).

4. Male or female Caucasian subjects, between 18 and 75 years (inclusive) of age.

5. Body mass index (BMI) is between 18 to 35 kg/m2 at Screening.

6. Women of childbearing potential (WoCBP) must have a negative serum pregnancy test atScreening, a negative urine pregnancy test on Day -1, and agree to consistently andcorrectly use (from 30 days prior to dosing, during the entire study, and for atleast 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 daysbefore dosing.

• Intrauterine device.

• Intrauterine hormone-releasing system.

• Bilateral tubal occlusion.

• Vasectomized partner, provided that the partner is the sole sexual partner andthat the vasectomized partner has received medical assessment of the surgicalsuccess.

• Sexual abstinence, defined as refraining from heterosexual intercourse from 30days prior to dosing up to at least 30 days after dosing, if this is thepreferred and usual lifestyle of the subject. WoCBP must also agree not to donate ova from the time of informed consent until 30days after dosing

7. Women of non-childbearing potential (WoNCBP), i.e., postmenopausal (defined as 12consecutive months with no menses without an alternative medical cause, confirmed bya 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 10.4 [Appendix 4]).

8. Male participants are infertile, vasectomized (who has received medical assessmentof the surgical success) or must agree to abstain from, or to use a condom, duringheterosexual intercourse with a woman of childbearing potential (Section 10.4 [Appendix 4]).

9. Male participants must agree not to donate sperm, from the time of informed consentuntil 30 days after dosing.

10. Negative test results for anti-Human Immunodeficiency virus 1 and 2 antibodies (anti-HIV-1Ab and anti-HIV-2Ab), Hepatitis B surface antigen (HBsAg) andanti-Hepatitis Cvirus antibodies (anti-HCVAb).

11. Participant agrees to refrain from consuming grapefruit juice, grapefruits, andgrapefruitcontaining products from at least 7 days before the dose administration,and until the EOS Visit.

12. Able to tolerate venipuncture For participants with mild, moderate, or severe renal impairment, the followingcriteria must be met in addition:

13. Participants with impaired renal function should be hemodynamically stable.

14. Diagnosis of chronic (> 6 months), stable (no acute episodes of illness within theprevious 2 months due to deterioration in renal function) renal impairment.

15. Estimated GFR must range from:

16. 15-29 mL/min (severe renal impairment) or

17. 30-59 mL/min (moderate renal impairment) or

18. 60-89 mL/min (mild renal impairment) determined by the Cockcroft-Gaultequation, at the Screening Visit.

19. Stable concomitant medications for at least 21 days prior to dosing and up to theEOS visit.

20. Systolic blood pressure (SBP) 100-180 mmHg, diastolic blood pressure (DBP) 50-105mmHg and pulse rate 60-100 bpm (inclusive), measured on the same arm, after 5 min inthe supine position at Screening and Baseline. For participants with normal renal function, the following criteria must be met inaddition:

21. No clinically relevant diseases captured in medical history at Screening.

22. No clinically relevant abnormalities on physical examination at Screening andBaseline.

23. No clinically relevant abnormalities on clinical laboratory tests at Screening.

24. Normal renal function confirmed by estimated creatinine clearance (eCLcr) ≥ 90mL/min, as determined by the Cockcroft-Gault equation, at Screening.

25. Weight within ±15% to his/her matched participant(s) enrolled in the study.

26. Biological sex matched to his/her matched participant(s) enrolled in the study.

27. Age within ±10 years to his/her matched participant(s) enrolled in the study.

28. Normal BP measured on the same arm, after 5 min in the supine position at Screeningand Baseline defined as:

• SBP 90-140 mmHg, DBP 60-90 mmHg, and pulse rate 60-100 bpm (inclusive) forsubjects < 65 years of age.

• SBP 95-160 mmHg, DBP 65-95 mmHg, and pulse rate 60-100 bpm (inclusive) forsubjects ≥ 65 years of age.

Exclusion Criteria:

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

1. Pregnant or lactating women.

2. Participant is unlikely to comply with the protocol requirements, instructions andstudy related restrictions; e.g., uncooperative attitude, inability to return forthe EOS Visit and improbability of completing the clinical study.

3. Any psychological, emotional problems, any disorders or resultant therapy that islikely to invalidate informed consent, or limit the ability of the participant tocomply with the protocol requirements

4. History of hypersensitivity to rupatadine, desloratadine or any of the excipients,or to medicinal products with similar chemical structures.

5. History of clinically significant lactose, galactose, or fructose intolerance.

6. Any clinically relevant acute or chronic disease which could jeopardize the safetyof the participant or impact the validity of the study results.

7. Veins unsuitable for intravenous puncture on either arm (e.g., veins that aredifficult to locate, access or puncture; veins with a tendency to rupture during orafter puncture).

8. 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 clinicalstudies within 1 year prior to Screening.

9. History or presence of clinically significant angioedema.

10. Use of caffeine-containing beverages exceeding 800 mg per day (Section 5.3.2) atScreening.

11. Nicotine consumption (e.g., smoking, nicotine patch, nicotine chewing gum, orelectronic cigarettes) from 48 h prior to Baseline (Day -1) until discharge fromconfinement (Day 2).

12. 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 beallowed to be enrolled in the study even if the urine drug screen test is positive.

13. History of heart, kidney or liver transplantation.

14. History of stroke, chronic seizures, or major neurological disorder.

15. Active malignant neoplastic disease or carcinoma (including leukemia, lymphoma,malignant melanoma), or myeloproliferative disease, regardless of the time sincetreatment.

16. Intake of any creatine supplement from Screening to EOS.

17. Use of any of the following 2 weeks prior to investigational medicinal product (IMP)administration or 5 half-lives, whichever is longer:

18. 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)

19. CYP3A4 substrates with a narrow therapeutic index (e.g. ciclosporin,tacrolimus, sirolimus, everolimus, cisapride)

20. Desloratadine

21. Clinically significant abnormalities on ECG repolarization (QTcF > 450 ms in malesand >470 ms in females) at Screening.

22. Loss of 250 mL or more blood within 3 months prior to screening. For participants with mild, moderate or severe renal impairment the additionalcriteria must not be met:

23. Fluctuating or rapidly deteriorating renal function, as indicated by stronglyvarying or worsening of clinical and/or laboratory signs of renal impairment withinthe Screening Period.

24. Participants requiring dialysis.

25. History or clinical evidence of any disease (except for renal impairment) and/orexistence of any surgical or medical condition that might interfere with theabsorption, distribution, metabolism or excretion of rupatadine, and/or the abilityto complete the study. For participants with normal renal function, the additional criteria must not bemet:

26. History or presence of a clinically relevant abnormality in any organ system, thatis incapacitating, requires hospitalization, or in the opinion of the investigatormakes the participant ineligible for enrollment in the study.

27. History or clinical evidence of any disease and/or existence of any surgical ormedical condition that might have interfered with the absorption, distribution,metabolism, or excretion of rupatadine (appendectomy and herniotomy are allowed,cholecystectomy is not allowed).

28. 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 ofthe study as judged by the Investigator, within 14 days before the administration ofthe IMP or less than 5 times the half-life of that medication, whichever is longer (excluding contraceptives and hormone replacement therapy).