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Latuda: Description. Clinical pharmacology

11. Description

Latuda is a psychotropic agent belonging to the chemical class of benzoisothiazol derivatives.

Its chemical name is (3aR,4S,7R,7aS)-2-{(1R,2R)-2-[4-(1,2-benzisothiazol-3-yl)piperazin-1-ylmethyl] cyclohexylmethyl}hexahydro-4,7-methano-2H-isoindole-1,3-dione hydrochloride. Its molecular formula is C28H36N4O2S-HCI and its molecular weight is 529.14.

The chemical structure is:

Lurasidone hydrochloride is a white to off-white powder. It is very slightly soluble in water, practically insoluble or insoluble in 0.1 N HCI, slightly soluble in ethanol, sparingly soluble in methanol, practically insoluble or insoluble in toluene and very slightly soluble in acetone.

Latuda tablets are intended for oral administration only. Each tablet contains 40 mg, or 80 mg of lurasidone hydrochloride.

Inactive ingredients are mannitol, pregelatinized starch, croscarmellose sodium, hypromellose, magnesium stearate, Opadry® and carnauba wax. Additionally, the 80 mg tablet contains yellow ferric oxide and FD&C Blue No.2 Aluminum Lake.

12.1. Mechanism of Action

The mechanism of action of lurasidone, as with other drugs having efficacy in schizophrenia, is unknown. It has been suggested that the efficacy of lurasidone in schizophrenia is mediated through a combination of central dopamine Type 2 (D2) and serotonin Type 2 (5HT2a) receptor antagonism.

12.2. Pharmacodynamics

In vitro receptor binding studies revealed that lurasidone is an antagonist with high affinity at dopamine D2 receptors (Ki = 0.994 nM) and the 5-hydroxytryptamine (5-HT, serotonin) receptors 5-HT2A(Ki = 0.47 nM) and 5-HT7 (Ki = 0.495 nM), is an antagonist with moderate affinity at human 02c adrenergic receptors (Ki = 10.8 nM), is a partial agonist at serotonin 5-HT1A(Ki = 6.38 nM) receptors, and is an antagonist at 02a adrenergic receptors (Ki = 40.7 nM). Lurasidone exhibits little or no affinity for histamine Hi and muscarinic Mi receptors (IC50 ≥ 1,000 nM and > 1,000 nM, respectively).

Latuda 20mg/ 40mg / 80mg/ 120mg

12.3. Pharmacokinetics

The activity of lurasidone is primarily due to the parent drug. The pharmacokinetics of lurasidone is dose-proportional within a total daily dose range of 20 mg to 160 mg. Steady-state concentrations of lurasidone are reached within 7 days of starting Latuda.

Following administration of 40 mg of Latuda, the mean (%CV) elimination half-life was 18 (7) hours.

Absorption and Distribution: Lurasidone is absorbed and reaches peak serum concentrations in approximately 1-3 hours. It is estimated that 9-19% of an administered dose is absorbed. Following administration of 40 mg of Latuda, the mean (%CV) apparent volume of distribution was 6173 (17.2) L. Lurasidone is highly bound (-99%) to serum proteins.

In a food effect study, lurasidone mean Cmaxand AUC were about 3-times and 2-times, respectively, when administered with food compared to the levels observed under fasting conditions. Lurasidone exposure was not affected as meal size was increased from 350 to 1000 calories and was independent of meal fat content [see Dosage and Administration (2.2)].

In clinical studies, establishing the safety and efficacy of Latuda, patients were instructed to take their daily dose with food [see Dosage and Administration (2.2)].

Metabolism and Elimination: Lurasidone is metabolized mainly via CYP3A4. The major biotransformation pathways are oxidative N-dealkylation, hydroxylation of norbornane ring, and S-oxidation. Lurasidone is metabolized into two active metabolites (ID-14283 and ID-14326) and two major non-active metabolites (ID-20219 and ID-20220).

Total excretion of radioactivity in urine and feces combined was approximately 89%, with about 80% recovered in feces and 9% recovered in urine, after a single dose of [14C]-labeled lurasidone.

Following administration of 40 mg of Latuda, the mean (%CV) apparent clearance was 3902 (18.0) mL/min.

Carcinogenesis: Lifetime carcinogenicity studies were conducted in ICR mice and Sprague-Dawley rats. Lurasidone was administered orally at doses of 30,100, 300, or 650 (the high dose was reduced from 1200 in males) mg/kg/day to ICR mice and 3, 12, or 36 (high dose reduced from 50) mg/kg/day to Sprague-Dawley rats.

In the mouse study, there were increased incidences of malignant mammary gland tumors and pituitary gland adenomas in females at all doses; the lowest dose tested produced plasma levels (AUC) 2 times those in humans receiving the maximum recommended human dose (MRHD) of 80 mg/day. No increases in tumors were seen in male mice up to the highest dose tested, which produced plasma levels (AUC) 15-25 times those in humans receiving the MRHD.

In rats, an increased incidence of mammary gland carcinomas was seen in females at the two higher doses; the no-effect dose of 3 mg/kg produced plasma levels (AUC) 0.7 times those in humans receiving the MRHD. No increases in tumors were seen in male rats up to highest dose tested, which produced plasma levels (AUC) 10 times those in humans receiving the MRHD.

Proliferative and/or neoplastic changes in the mammary and pituitary glands of rodents have been observed following chronic administration of antipsychotic drugs and are considered to be prolactin mediated. The relevance of this increased incidence of prolactin-mediated pituitary or mammary gland tumors in rodents in terms of human risk is unknown [see Warnings and Precautions (5.6)].

Mutagenesis: Lurasidone was not genotoxic in the Ames test, the in vitro chromosomal aberration test in Chinese Hamster Lung (CHL) cells, or the in vivo mouse bone marrow micronucleus test.

Impairment of Fertility: Lurasidone was administered orally to female rats at doses of 0.1,1.5,15, or 150 mg/kg/day for 15 consecutive days prior to mating, during the mating period, and through day 7 of gestation. Estrus cycle irregularities were seen at 1.5 mg/kg and above; the no-effect dose of 0.1 mg/kg is approximately 0.01 times the maximum recommended human dose (MRHD) of 80 mg/day based on body surface area. Fertility was reduced only at the highest dose and this was shown to be reversible after a 14 day drug-free period. The no-effect dose for reduced fertility was 15 mg/kg, which is 1.8 times the MRHD based on body surface area.

Fertility was not affected in male rats treated orally with lurasidone for 64 consecutive days prior to mating and during the mating period at doses up to 150 mg/kg/day (12 times the MRHD based on body surface area).

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