Lastacaft (Alcaftadine) - Description and Clinical Pharmacology

DESCRIPTION

LASTACAFT™ is a sterile, topically administered H₁ receptor antagonist containing alcaftadine for ophthalmic use.

Alcaftadine is a white to yellow powder with an empirical formula of C₁₉H₂₁N₃O and a molecular weight of 307.39.

Contains:

Active: alcaftadine 0.25% (2.5 mg/mL)

Preservative: benzalkonium chloride 0.005%

Inactives: edetate disodium, monobasic sodium phosphate, purified water, sodium chloride, sodium hydroxide and/or hydrochloric acid (to adjust pH)

Chemical Name: 6,11-dihydro-11-(1-methyl-4-piperidinylidene)-5 H -imidazo[2,1-b] [3] benzazepine-3-carboxaldehyde

Structural Formula:

The drug product has a pH of approximately 7 and an osmolality of approximately 290 mOsm/kg.

CLINICAL PHARMACOLOGY

Mechanism of Action

Alcaftadine is a H₁ histamine receptor antagonist and inhibitor of the release of histamine from mast cells. Decreased chemotaxis and inhibition of eosinophil activation has also been demonstrated.

Pharmacokinetics

Absorption

Following bilateral topical ocular administration of alcaftadine ophthalmic solution, 0.25%, the mean plasma C_max of alcaftadine was approximately 60 pg/mL and the median T_max occurred at 15 minutes. Plasma concentrations of alcaftadine were below the lower limit of quantification (10 pg/mL) by 3 hours after dosing. The mean C_max of the active carboxylic acid metabolite was approximately 3 ng/mL and occurred at 1 hour after dosing. Plasma concentrations of the carboxylic acid metabolite were below the lower limit of quantification (100 pg/mL) by 12 hours after dosing. There was no indication of systemic accumulation or changes in plasma exposure of alcaftadine or the active metabolite following daily topical ocular administration.

Distribution

The protein binding of alcaftadine and the active metabolite are 39.2% and 62.7%, respectively.

Metabolism

The metabolism of alcaftadine is mediated by non-CYP450 cytosolic enzymes to the active carboxylic acid metabolite.

Excretion

The elimination half-life of the carboxylic acid metabolite is approximately 2 hours following topical ocular administration. Based on data following oral administration of alcaftadine, the carboxylic acid metabolite is primarily eliminated unchanged in the urine.

In vitro studies showed that neither alcaftadine nor the carboxylic acid metabolite substantially inhibited reactions catalyzed by major CYP450 enzymes.

NONCLINICAL TOXICOLOGY

Carcinogenesis, Mutagenesis, Impairment of Fertility

Alcaftadine was not mutagenic or genotoxic in the Ames test, the mouse lymphoma assay or the mouse micronucleus assay.

Alcaftadine was found to have no effect on fertility of male and female rats at oral doses up to 20 mg/kg/day (approximately 200 times the plasma exposure at the recommended human ocular dose).

CLINICAL STUDIES

Clinical efficacy was evaluated in conjunctival allergen challenge (CAC) studies. LASTACAFT™ was more effective than its vehicle in preventing ocular itching in patients with allergic conjunctivitis induced by an ocular allergen challenge, both at 3 minutes post-dosing and at 16 hours post-dosing of LASTACAFT™.

The safety of LASTACAFT™ was evaluated in a randomized clinical study of 909 subjects over a period of 6 weeks.