Chemical formula: C₂₈H₃₆N₄O₂S Molecular mass: 492.676 g/mol PubChem compound: 213046
Lurasidone is a selective blocking agent of dopamine and monoamine effects. Lurasidone binds strongly to dopaminergic D2- and to serotonergic 5-HT2A- and 5-HT7- receptors with high binding affinity of 0.994, 0.47 and 0.495 nM, respectively. It also blocks α2c-adrenergic receptors and α2a-adrenergic receptors with a binding affinity of 10.8 and 40.7 nM respectively. Lurasidone also exhibits partial agonism at the 5-HT1A receptor with a binding affinity of 6.38 nM. Lurasidone does not bind to histaminergic or muscarinic receptors.
The mechanism of action of the minor active metabolite of lurasidone ID-14283 is similar to that of lurasidone.
Lurasidone doses ranging from 9 to 74 mg administered to healthy subjects produced a dose-dependent reduction in the binding of 11C-raclopride, a D2/D3 receptor ligand, in the caudate, putamen and ventral striatum detected by positron emission tomography.
Lurasidone reaches peak serum concentrations in approximately 1-3 hours.
In a food effect study, lurasidone mean Cmax and AUC increased approximately by 2-3-times and 1.5-2-times, respectively, when administered with food compared to the levels observed under fasting conditions.
Following administration of 37 mg of lurasidone, the mean approximate apparent volume of distribution was 6000 L. Lurasidone is highly bound (~99%) to serum proteins.
Lurasidone is metabolised mainly via CYP3A4. The major biotransformation pathways are oxidative N-dealkylation, hydroxylation of norbornane ring, and S-oxidation.
Lurasidone is metabolised into two active metabolites (ID-14283 and ID-14326) and two non-active metabolites (ID-20219 and ID-20220). Lurasidone and its metabolites ID-14283, ID-14326, ID-20219 and ID-20220 correspond to approximately 11.4, 4.1, 0.4, 24 and 11% respectively, of serum radioactivity respectively.
CYP3A4 is the major enzyme responsible for metabolism of the active metabolite ID-14283. Lurasidone and its active metabolite ID-14283 both contribute to the pharmacodynamic effect at the dopaminergic and serotonergic receptors.
Based on in vitro studies lurasidone is not a substrate of CYP1A1, CYP1A2, CYP2A6, CYP4A11, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 or CYP2E1 enzymes.
In vitro, lurasidone demonstrated no direct, or weak inhibition (direct or time-dependent) (IC50>5.9 μM) of the enzymes cytochrome P450 (CYP)1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4. Based on this data, lurasidone is not expected to affect the pharmacokinetics of medicinal products that are substrates of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP2E1.
Lurasidone is an in vitro substrate of the efflux transporters P-gp and BCRP. Lurasidone is not subject to active uptake transport by OATP1B1 or OATP1B3.
Lurasidone is an inhibitor of P-gp, BCRP and OCT1 in vitro. Lurasidone is not expected to have a clinically relevant inhibitory potential on transporters OATP1B1, OATP1B3, OCT2, OAT1, OAT3, MATE1, MATE2K or BSEP based on in vitro data.
Following administration of lurasidone, the elimination half-life was 20-40 hours. Following oral administration of a radiolabelled dose, approximately 67% dose was recovered in faeces and 19% in urine. Urine comprised mostly of a number of metabolites with minimal renal excretion of parent compound.
The pharmacokinetics of lurasidone is dose-proportional within a total daily dose range of 18.5 mg to 148 mg. Steady-state concentrations of lurasidone are reached within 7 days of starting lurasidone.
Limited data have been collected in healthy subjects ≥65 years. Of the data collected, similar exposure was obtained compared with subjects <65 years. However, an increase in exposure in elderly subjects may be expected for patients if they have impaired renal or hepatic function.
The serum concentrations of lurasidone are increased in healthy subjects with Child-Pugh Class A, B and C hepatic impairment with an increased exposure of 1.5-, 1.7- and 3-fold respectively.
The serum concentrations of lurasidone are increased in healthy subjects with mild, moderate and severe renal impairment with an increased exposure of 1.5, 1.9 and 2.0-fold respectively. Subjects with ESRD (CrCl<15 ml/min) have not been investigated.
There were no clinically relevant differences between genders in the pharmacokinetics of lurasidone in a population pharmacokinetic analysis in patients with schizophrenia.
There were no clinically relevant differences in the pharmacokinetics of lurasidone in a population pharmacokinetic analysis in patients with schizophrenia. It was noted that Asian subjects had 1.5 fold increased exposure to lurasidone compared to Caucasian subjects.
Based on in vitro studies utilising human liver enzymes, lurasidone is not a substrate for CYP1A2; smoking should, therefore, not have an effect on the pharmacokinetics of lurasidone.
The pharmacokinetics of lurasidone in paediatric patients was evaluated in 47 children aged 6-12 years and 234 adolescents aged 13-17 years. Lurasidone was administered as lurasidone hydrochloride at daily doses of either 20, 40, 80, 120 mg (6-17 years) or 160 mg (10-17 years only) for up to 42 days. There was no clear correlation between obtained serum exposure and age or body weight. The pharmacokinetics of lurasidone in paediatric patients aged 6–17 years was generally comparable to those observed in adults.
Nonclinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, and carcinogenic potential. Major findings in repeat-dose toxicity studies of lurasidone were centrally-mediated endocrine changes resulting from serum prolactin elevations in rats, dogs and monkeys. High serum prolactin levels in long-term repeat-dose studies in female rats were associated with effects on bones, adrenal glands, and reproductive tissues. In a long-term dog repeat-dose study, high serum prolactin levels were associated with effects on male and female reproductive tissues.
In rats, lurasidone had no effect on male and female reproduction at oral doses of 150 and 0.1 mg/kg/day lurasidone hydrochloride, respectively, or on early embryonic development at an oral dose of 15 mg/kg/day lurasidone hydrochloride.
A fertility study in female rats resulted in prolonged oestrous cycle and delayed copulation at ≥1.5 mg/kg/day lurasidone hydrochloride, whilst the copulation and fertility indices, and the numbers of corpora lutea, implantations and live foetuses were decreased at 150 mg/kg/day lurasidone hydrochloride. These effects were due to the hyperprolactinemia following lurasidone treatment, affecting the oestrous cycle and copulatory behaviour as well as the maintenance of corpus luteum of the female rats, resulting in a decrease in implantation and the number of live foetuses. These prolactin-related effects are not considered to be relevant to human reproduction.
A single dose of 10 mg/kg lurasidone hydrochloride to pregnant rats resulted in fetal exposure. In a dose range finding study in pregnant rats, 150 mg/kg/day lurasidone hydrochloride caused fetal growth retardation without signs of teratogenicity. Lurasidone was not teratogenic in rats or rabbits at an exposure similar to or below the maximum recommended human dose (148 mg lurasidone).
In the definitive juvenile rat toxicity study, no increased sensitivity of juvenile animals to lurasidone-related effects on body weight, food consumption, and clinical observations were apparent, but similar effects as in adult rat were noted (delays in growth and development and hyperprolactinaemia). Hyperactivity that was evident at ≥3 mg/kg/day during the posttreatment period has also been reported for other D2 receptor antagonists. Slightly lower birth weights and body weights/body weight gains during the postnatal period were noted in the offspring of juvenile rats previously treated with ≥30 mg/kg/day. At the NOAEL of 3 mg/kg/day, the exposures of lurasidone and most metabolites were lower than that achieved at the recommended clinical dose in adolescents aged 13 years or above. Lurasidone was excreted in milk of rats during lactation.
Lurasidone was not genotoxic in a battery of tests. Mammary gland and/or pituitary gland tumours were observed in the mouse and rat carcinogenicity studies and are most likely due to the increased blood prolactin levels. These findings are common in rodents treated with antipsychotic medicinal products with dopamine D2 blocking activity and are considered to be rodent-specific.
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