Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1   Pharmacodynamic properties
Pharmacotherapeutic group: Antihistamines for systemic use, other antihistamines for systemic use ATC code RO6AX29.

Mechanism of action
Bilastine is a non-sedating, long-acting histamine antagonist with selective peripheral H1 receptor antagonist affinity and no affinity for muscarinic receptors.
Bilastine inhibited histamine-induced wheal and flare skin reactions for 24 hours following single doses.

Clinical efficacy and safety
In clinical trials performed in adult and adolescent patients with allergic rhinoconjunctivitis (seasonal and perennial), bilastine 20 mg, administered once daily for 14-28 days, was effective in relieving symptoms such as sneezing, nasal discharge, nasal itching, nasal congestion, ocular itching, tearing and ocular redness. Bilastine effectively controlled symptoms for 24 hours.

In two clinical trials performed in patients with chronic idiopathic urticaria, bilastine 20 mg, administered once daily for 28 days was effective in relieving the itching intensity and the number and size of wheals, as well as the patients discomfort due to urticaria. Patients improved their sleep conditions and their quality of life.

No clinically relevant prolongation of QTc interval or any other cardiovascular effect has been observed in the clinical trials performed with bilastine, even at doses of 200 mg daily (10 times the clinical dose) for 7 days in 9 subjects, or even when coadministered with P-gp inhibitors, such as ketoconazole (24 subjects) and erythromycin (24 subjects). Additionally, a thorough QT study including 30 volunteers has been performed.

In controlled clinical trials at the recommended dose of 20 mg once daily, the CNS safety profile of bilastine was similar to placebo and the incidence of somnolence was not statistically different from placebo. Bilastine at doses of up to 40 mg q.d. did not affect psychomotor performance in clinical trials and did not affect driving performance in a standard driving test.

Elderly patients (≥ 65 years) included in phase II and III studies showed no difference in efficacy or safety with respect to younger patients. A post-authorization study in 146 elderly patients showed no differences in the safety profile with respect to the adult population.

Paediatric population
Adolescents (12 years to 17 years) were included in the clinical development. 128 adolescents received bilastine during the clinical studies (81 in double blind studies in allergic rhino- conjunctivitis). A further 116 adolescent subjects were randomised to active comparators or placebo. No differences in efficacy and safety between adults and adolescents were seen.

Pharmacokinetic Properties

5.2   Pharmacokinetic properties

Absorption
Bilastine is rapidly absorbed after oral administration with a time to maximum plasma concentration of around 1.3 hours. No accumulation was observed. The mean value of bilastine oral bioavailability is 61%.

Distribution
In vitro and in vivo studies have shown that bilastine is a substrate of P-gp (see section 4.5 “Interaction with ketoconazole, erythromycin and diltiazem”) and OATP (see section 4.5 ”Interaction with grapefruit juice”). Bilastine does not appear to be a substrate of the transporter BCRP or renal transporters OCT2, OAT1 and OAT3. Based on in vitro studies, bilastine is not expected to inhibit the following transporters in the systemic circulation: P-gp, MRP2, BCRP, BSEP, OATP1B1, OATP1B3, OATP2B1, OAT1, OAT3, OCT1, OCT2, and NTCP, since only mild inhibition was detected for P-gp, OATP2B1 and OCT1, with an estimated IC50 ≥ 300 µM, much higher than the calculated clinical plasma Cmax and therefore these interactions will not be clinically relevant. However, based on these results inhibition by bilastine of transporters present in the intestinal mucosa, e.g. P-gp, cannot be excluded.

At therapeutic doses bilastine is 84-90% bound to plasma proteins.

Biotransformation
Bilastine did not induce or inhibit activity of CYP450 isoenzymes in in vitro studies.


Elimination
In a mass balance study performed in healthy adult volunteers, after administration of a single dose of 20 mg 14C-bilastine, almost 95% of the administered dose was recovered in urine (28.3%) and faeces (66.5%) as unchanged bilastine, confirming that bilastine is not significantly metabolized in humans.
The mean elimination half-life calculated in healthy volunteers was 14.5 h.

Linearity
Bilastine presents linear pharmacokinetics in the dose range studied (5 to 220 mg), with a low interindividual variability.

Renal impairment
In a study in subjects with renal impairment the mean (SD) AUC0- increased from 737.4 (±260.8) ng x hr/mL in subjects without impairment (GFR: > 80 mL/min/1.73 m2) to: 967.4 (±140.2) ng x hr/mL in subjects with mild impairment (GFR: 50-80 mL/min/1.73 m2), 1384.2 (±263.23) ng x hr/mL in subjects with moderate impairment (GFR: 30 - <50 mL/min/1.73 m2), and 1708.5 (±699.0) ng x hr/mL in subjects with severe impairment (GFR: < 30 mL/min/1.73 m2). Mean (SD) half-life of bilastine was 9.3 h (± 2.8) in subjects without impairment, 15.1 h (± 7.7) in subjects with mild impairment, 10.5 h (± 2.3) in subjects with moderate impairment and 18.4 h (± 11.4) in subjects with severe impairment. Urinary excretion of bilastine was essentially complete after 48 -72 h in all subjects. These pharmacokinetic changes are not expected to have a clinically relevant influence on the safety of bilastine, since bilastine plasma levels in patients with renal impairment are still within the safety range of bilastine.

Hepatic impairment
There are no pharmacokinetic data in subjects with hepatic impairment. Bilastine is not metabolized in human. Since the results of the renal impairment study indicate renal elimination to be a major contributor in the elimination, biliary excretion is expected to be only marginally involved in the elimination of bilastine. Changes in liver function are not expected to have a clinically relevant influence on bilastine pharmacokinetics.

Elderly
Only limited pharmacokinetic data are available in subjects older than 65 years. No statistically significant differences have been observed with regard to PK of bilastine in elderly aged over 65 years compared to adult population aged between 18 and 35 years.

Paediatric population
No pharmacokinetic data are available in adolescents (12 years to 17 years) as the extrapolation from adult data was deemed appropriate for this product.