Pharmacotherapeutic Group: Antipsychotics. ATC Classification: N05AE05 - lurasidone; belongs to the class of other antipsychotics.
Pharmacology: Pharmacodynamics: LATUDA is an antagonist with high affinity at dopamine D2 receptors (Ki=1 nM) and the 5-hydroxytryptamine (5-HT, serotonin) receptors 5-HT2A (Ki=0.5 nM) and 5-HT7 (Ki=0.5 nM) receptors. It also binds with moderate affinity to the human α2C adrenergic receptors (Ki=11 nM), is a partial agonist at serotonin 5-HT1A (Ki=6.4 nM) receptors, and is an antagonist at the α2A adrenergic receptors (Ki=41 nM). LATUDA exhibits little or no affinity for histamine H1 and muscarinic M1 receptors (IC50 >1,000 nM).
ECG Changes: The effects of LATUDA on the QTc interval were evaluated in a randomized, double-blind, multiple-dose, parallel-dedicated thorough QT study in 43 patients with schizophrenia or schizoaffective disorder, who were treated with LATUDA doses of 120 mg daily, 600 mg daily and completed the study. The maximum mean (upper 1-sided, 95% CI) increase in baseline-adjusted QTc intervals based on individual correction method (QTcI) was 7.5 (11.7) ms and 4.6 (9.5) ms, for the 120 mg and 600 mg dose groups respectively, observed at 2 to 4 hours after dosing. In this study, there was no apparent dose (exposure)-response relationship.
In short-term, placebo-controlled studies in schizophrenia, no post-baseline QT prolongations exceeding 500 msec were reported in patients treated with LATUDA or placebo.
Mechanism of Action: The mechanism of action of LATUDA in the treatment of schizophrenia is unknown. However, its efficacy in schizophrenia could be mediated through a combination of central dopamine Type 2 (D2) and serotonin Type 2 (5-HT2A) receptor antagonism.
Clinical Studies: Schizophrenia: Short-term Studies: The efficacy of LATUDA for the treatment of schizophrenia was established in five short-term (6-week), placebo-controlled studies in adult patients (mean age of 38.4 years, range 18-72) who met DSM-IV criteria for schizophrenia. An active-control arm (olanzapine or quetiapine extended-release) was included in two studies to assess assay sensitivity.
Several instruments were used for assessing psychiatric signs and symptoms in these studies: 1. Positive and Negative Syndrome Scale (PANSS), is a multi-item inventory of general psychopathology used to evaluate the effects of drug treatment in schizophrenia. PANSS total scores may range from 30 to 210.
2. Brief Psychiatric Rating Scale derived (BPRSd), derived from the PANSS, is a multi-item inventory primarily focusing on positive symptoms of schizophrenia, whereas the PANSS includes a wider range of positive, negative and other symptoms of schizophrenia. The BPRSd consists of 18 items rated on a scale of 1 (not present) to 7 (severe). BPRSd scores may range from 18 to 126.
3. The Clinical Global Impression severity scale (CGI-S) is a clinician-rated scale that measures the subject's current illness state on a 1- to 7- point scale.
The endpoint associated with each instrument is change from baseline in the total score to the end of week 6. These changes are then compared to placebo changes for the drug and control groups.
The results of the studies follow: Study 1: In a 6-week, placebo-controlled trial (N=145) involving two fixed doses of LATUDA (40 or 120 mg/day), both doses of LATUDA at Endpoint were superior to placebo on the BPRSd total score, and the CGI-S.
Study 2: In a 6-week, placebo-controlled trial (N=180) involving a fixed dose of LATUDA (80 mg/day), LATUDA at Endpoint was superior to placebo on the BPRSd total score, and the CGI -S.
Study 3: In a 6-week, placebo- and active-controlled trial (N=473) involving two fixed doses of LATUDA (40 or 120 mg/day) and an active control (olanzapine), both LATUDA doses and the active control at Endpoint were superior to placebo on the PANSS total score, and the CGI-S.
Study 4: In a 6-week, placebo-controll editorial (N=489) involving three fixed doses of LATUDA (40, 80 or 120 mg/day), only the 80 mg/day dose of LATUDA at Endpoint was superior to placebo on the PANSS total score, and the CGI-S.
Study 5: In a 6-week, placebo- and active-controlled trial (N=482) involving two fixed doses of LATUDA (80 or 160 mg/day) and an active control (quetiapine extended-release), both LATUDA doses and the active control at Endpoint were superior to placebo on the PANSS total score, and the CGI-S.
Thus, the efficacy of LATUDA at doses of 40, 80, 120 and 160 mg/day has been established (see Table 2).
Click on icon to see table/diagram/image
Examination of population subgroups based on age (there were few patients over 65), gender and race did not reveal any clear evidence of differential responsiveness.
Pharmacokinetics: The activity of LATUDA is primarily due to the parent drug. The pharmacokinetics of LATUDA is dose-proportional within a total daily dose range of 20 mg to 160 mg. Steady-state concentrations of LATUDA are reached within 7 days of starting LATUDA. Following administration of 40 mg the mean (%CV) elimination half-life was 18 (7) hours.
Absorption and Distribution: LATUDA 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. LATUDA is highly bound (~99%) to serum proteins.
In a food effect study, LATUDA mean Cmax and AUC were about 3-times and 2-times, respectively, when administered with food compared to the levels observed under fasting conditions. LATUDA exposure was not affected as meal size was increased from 350 to 1000 calories and was independent of meal fat content (see Dosage & Administration). In clinical studies, establishing the safety and efficacy of LATUDA, patients were instructed to take their daily dose with food (see Dosage & Administration).
Metabolism and Elimination: LATUDA is metabolized mainly via CYP3A4. The major biotransformation pathways are oxidative N-dealkylation, hydroxylation of norbornane ring, and S-oxidation. LATUDA is metabolized into two active metabolites (ID-14283 and ID-14326) and two major non-active metabolites (ID-20219 and ID-20220). Based on in vitro studies , LATUDA is not a substrate of CYP1A1, CYP1A2, CYP2A6, CYP4A11, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 or CYP2E1 enzymes. Because LATUDA is not a substrate for CYP1A2, smoking is not expected to have an effect on the pharmacokinetics of LATUDA.
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 LATUDA.
Following administration of 40 mg of LATUDA the mean (%CV) apparent clearance was 3902 (18.0) mL/min.
Toxicology: Carcinogenesis, Mutagenesis, Impairment of Fertility: Carcinogenesis: LATUDA increased incidences of malignant mammary gland tumors and pituitary gland adenomas in female mice orally dosed with 30, 100, 300, or 650 mg/kg/day. The lowest dose produced plasma levels (AUC) approximately equal to those in humans receiving the MRHD of 160 mg/day. No increases in tumors were seen in male mice up to the highest dose tested, which produced plasma levels (AUC) 14-times those in humans receiving the MRHD.
LATUDA increased the incidence of mammary gland carcinomas in females rats orally dosed at 12 and 36 mg/kg/day: the lowest dose; 3 mg/kg/day is the no-effect dose which produced plasma levels (AUC) 0.4-times those in humans receiving the MRHD. No increases in tumors were seen in male rats up to the highest dose tested, which produced plasma levels (AUC) 6-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 Precautions).
Mutagenesis: LATUDA did not cause mutation or chromosomal aberration when tested in vitro and in vivo. LATUDA was negative in the Ames gene mutation test, the Chinese Hamster Lung (CHL) cells, and in the in vivo mouse bone marrow micronucleus test up to 2000 mg/kg (61 times the MRHD of 160 mg/day based on mg/m2 body surface area).
Impairment of Fertility: Estrus cycle irregularities were seen in rats orally administered LATUDA at 1.5, 15 and 150 mg/kg/day for 15 consecutive days prior to mating, during the mating period, and through day 7 of gestation. The no-effect dose is 0.1 mg/kg which is approximately 0.006-times the MRHD of 160 mg/day based on body surface area. Fertility was reduced only at the highest dose, which was reversible after a 14-day drug-free period. The no-effect dose for reduced fertility was 15 mg/kg, which is approximately equal to the MRHD based on body surface area.
LATUDA had no effect on fertility in male rats treated orally with LATUDA for 64 consecutive days prior to mating and during the mating period at doses up to 150 mg/kg/day (9-times the MRHD based on mg/m2 body surface area).