Lurasidone is metabolized by CYP3A4 in which its major active metabolite is referred to as ID-14283 (25% of parent exposure). Its two minor metabolites are referred to as ID14326 and ID11614 which make up 3% and 1% of parent exposure respectively. Its two non-active metabolites are referred to as ID-20219 and ID-20220.
Lurasidone is highly bound (99.8%) to serum proteins, including albumin and alpha1-acid glycoprotein. The drug is metabolized mainly via CYP3A4. The major biotransformation pathways are oxidative N-dealkylation, hydroxylation of the norbornane ring, and S-oxidation. Lurasidone is metabolized into 2 active metabolites (ID-14283 and ID-14326) and 2 major inactive metabolites (ID-20219 and ID-20220).
IDENTIFICATION AND USE: Lurasidone is indicated for the treatment of patients with schizophrenia, as monotherapy for the treatment of patients with major depressive episodes associated with bipolar I disorder (bipolar depression), and as adjunctive therapy with either lithium or valproate for the treatment of patients with major depressive episodes associated with bipolar I disorder (bipolar depression). HUMAN EXPOSURE AND TOXICITY: An increased incidence of adverse cerebrovascular events (cerebrovascular accidents and transient ischemic attacks), including fatalities, has been observed in geriatric patients with dementia-related psychosis treated with certain atypical antipsychotic agents (aripiprazole, olanzapine, risperidone) in placebo-controlled studies. The manufacturer states that lurasidone is not approved for the treatment of patients with dementia-related psychosis. Neuroleptic malignant syndrome (NMS), a potentially fatal syndrome requiring immediate discontinuance of the drug and intensive symptomatic treatment, has been reported in patients receiving antipsychotic agents, including lurasidone. Rash and pruritus have been reported frequently and angioedema has been reported rarely in patients receiving lurasidone. Adverse effects occurring in 5% or more of patients receiving lurasidone for schizophrenia and at a frequency at least twice that reported with placebo include somnolence (including hypersomnia, hypersomnolence, and sedation), akathisia, nausea, parkinsonism, and agitation. Akathisia and somnolence appear to be dose-related adverse effects.The effect of lurasidone on labor and delivery is unknown. It is not known whether lurasidone and/or its metabolites are distributed into milk in humans. In geriatric patients (65-85 years of age) with psychosis, serum lurasidone concentrations were similar to those observed in younger adults. Geriatric patients with dementia-related psychosis treated with lurasidone are at an increased risk of death compared with those treated with placebo. Safety and effectiveness of lurasidone in pediatric and adolescent patients have not been established. ANIMAL STUDIES: Lurasidone 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. Lurasidone is distributed into milk in rats. Estrus cycle irregularities were seen in rats orally administered lurasidone 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. Lurasidone had no effect on fertility 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 (9-times the MRHD based on mg/m sq body surface area). The drug did not cause mutation or chromosomal aberration when tested in vitro and in vivo. It 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/ sq m body surface area).
Liver test abnormalities occur in 1% to 3% of patients on long term therapy with lurasidone, but similar rates have been reported with placebo therapy and with comparator agents. The ALT elevations are usually mild, transient and often resolve even without dose modification or drug discontinuation. There have been no published reports of clinically apparent liver injury with symptoms or jaundice attributed to lurasidone therapy.
◉ Summary of Use during Lactation:Lurasidone is more than 99% bound to plasma proteins, so it is unlikely that the drug would be excreted into milk in sufficient amounts to affect a breastfed infant. Data from one mother-infant pair appears to support the poor excretion into milk and lack of effect on the breastfed infant. Until more data are available, an alternate drug may be preferred, especially while nursing a newborn or preterm infant.
◉ Effects in Breastfed Infants:A woman with depressive type schizoaffective disorder was taking lurasidone 40 mg at night and desvenlafaxine 50 mg daily after giving birth. She exclusively breastfed her infant. The infant’s growth and development was good during a follow-up period of 39 days.
Patients enlisted in the National Pregnancy Registry for Atypical Antipsychotics who were taking a second-generation antipsychotic drug while breastfeeding (n = 576) were compared to control breastfeeding patients who were not treated with a second-generation antipsychotic (n = 818). Of the patients who were taking a second-generation antipsychotic drug, 60.4% were on more than one psychotropic. A review of the pediatric medical records, no adverse effects were noted among infants exposed or not exposed to second-generation antipsychotic monotherapy or to polytherapy. The number of women taking lurasidone was not reported.
◉ Effects on Lactation and Breastmilk:Increases in serum prolactin with lurasidone are generally infrequent, small and less than risperidone. A woman with elevated serum prolactin, breast tenderness and galactorrhea while taking risperidone improved when lurasidone was substituted for risperidone and these side effects subsided completely when the lurasidone dose was increased from 20 mg to 40 mg daily. The prolactin level in a mother with established lactation may not affect her ability to breastfeed.
Patients enlisted in the National Pregnancy Registry for Atypical Antipsychotics who were taking a second-generation antipsychotic drug while breastfeeding (n = 576) were compared to control breastfeeding patients who had primarily diagnoses of major depressive disorder and anxiety disorders, most often treated with SSRI or SNRI antidepressants, but not with a second-generation antipsychotic (n = 818). Among women on a second-generation antipsychotic, 60.4% were on more than one psychotropic compared with 24.4% among women in the control group. Of the women on a second-generation antipsychotic, 59.3% reported “ever breastfeeding” compared to 88.2% of women in the control group. At 3 months postpartum, 23% of women on a second-generation antipsychotic were exclusively breastfeeding compared to 47% of women in the control group. The number of women taking lurasidone was not reported.
A 14-year-old girl with hallucinatory schizophrenia was treated inadequately with aripiprazole, then paliperidone. As she was transitioned from paliperidone to lurasidone at age 16 years, her serum prolactin increased to 4240 mIU/L (normal range 60-400 mIU/L). As the lurasidone dose was titrated to a maximum of 111 mg daily, prolactin levels continued to increase and the patient experienced breast fullness and galactorrhea. Six of 7 serum prolactin measurements were in the range of 4240 to 6140 mIU/L. Once lurasidone was discontinued, her serum prolactin normalized.
In an Italian study of treatment of schizophrenic patients with lurasidone, 2.4% of patients developed hyperprolactinemia and galactorrhea.
◈ What is lurasidone?
Lurasidone is an antipsychotic medication that has been used to treat schizophrenia and bipolar depression. It is sold under the brand name Latuda®.Sometimes when people find out they are pregnant, they think about changing how they take their medication, or stopping their medication altogether. However, it is important to talk with your healthcare providers before making any changes to how you take this medication. Your healthcare providers can talk with you about the benefits of treating your condition and the risks of untreated illness during pregnancy.
◈ I take lurasidone. Can it make it harder for me to get pregnant?
Studies have not been done in humans to see if lurasidone can make it harder to get pregnant.
◈ Does taking lurasidone increase the chance for miscarriage?
Miscarriage can occur in any pregnancy. Studies have not been done to see if lurasidone can increase the chance for miscarriage.
◈ Does taking lurasidone increase the chance of birth defects?
Every pregnancy starts out with a 3-5% chance of having a birth defect. This is called the background risk. Information on the use of lurasidone in pregnancy is very limited. Lurasidone has not been shown to increase the chance of birth defects in animal studies done on rats and rabbits. There is one case report of a person taking lurasidone throughout pregnancy. The baby was born healthy and without birth defects.
◈ Does taking lurasidone in pregnancy increase the chance of other pregnancy-related problems?
Studies have not been done to see if lurasidone use in pregnancy increases the chance for pregnancy-related problems such as preterm delivery (birth before week 37) or low birth weight (weighing less than 5 pounds, 8 ounces [2500 grams] at birth).
◈ I need to take lurasidone throughout my entire pregnancy. Will it cause symptoms in my baby after birth?
Product labels written by the U.S. Food and Drug Administration (FDA) note a chance for symptoms in newborns exposed to antipsychotic drugs in the third trimester of pregnancy. Symptoms may include uncontrolled muscle movements, changes in muscle tone, being too sleepy, trouble with breathing, and/or trouble with feeding. Not all babies who are exposed to antipsychotic drugs during pregnancy will have these symptoms. These symptoms can be temporary and can go away on their own. Treatment of symptoms can be started, if needed.These symptoms have not been reported with exposure to lurasidone during pregnancy. The available information on the use of lurasidone in pregnancy is so limited that it is hard to know if these symptoms might happen. Let your healthcare providers know before delivery if you are taking lurasidone. If needed, babies can be monitored for symptoms.
◈ Does taking lurasidone in pregnancy affect future behavior or learning for the child?
Studies have not been done to see if lurasidone use in pregnancy can cause behavior or learning issues for the child.
◈ Breastfeeding while taking lurasidone:
Information on the use of lurasidone while breastfeeding is limited. There is a report of one person who was taking lurasidone while breastfeeding. No negative effects were reported in the nursing child. The benefit of using lurasidone may outweigh possible risks. Your healthcare providers can talk with you about using lurasidone and what treatment is best for you. Be sure to talk to your healthcare provider about all your breastfeeding questions.
◈ If a male takes lurasidone, could it affect fertility (ability to get partner pregnant) or increase the chance of birth defects?
Studies have not been done in humans to see if lurasidone could affect fertility or increase the chance of birth defects above the background risk. In general, exposures that fathers or sperm donors have are unlikely to increase the risks to a pregnancy. For more information, please see the MotherToBaby fact sheet Paternal Exposures at https://mothertobaby.org/fact-sheets/paternal-exposures-pregnancy/.
来源:Mother To Baby Fact Sheets
毒理性
相互作用
鲁拉西酮在体外不是CYP1A2的底物；因此，吸烟不应该改变该药物的药代动力学。
Lurasidone is not a substrate for CYP1A2 in vitro; therefore, smoking should not alter the pharmacokinetics of the drug.
Lurasidone is readily absorbed and quickly reaches maximal concentrations (Cmax) within 1-4 hours. When taken with food, there is a two-fold increase in exposure and time to maximal concentration is increased by 0.5-1.5 hours. This occurs regardless of fat or caloric content. Bioavailability = 9-19%.
来源:DrugBank
吸收、分配和排泄
消除途径
尿液（约9%）和粪便（约80%）
Urine (~9%) and feces (~80%)
来源:DrugBank
吸收、分配和排泄
分布容积
6173升
6173 L
来源:DrugBank
吸收、分配和排泄
清除
3902毫升/分钟
3902 mL/min
来源:DrugBank
吸收、分配和排泄
在给予单次放射性标记的卢拉西酮剂量后，大约80%和9%的剂量分别通过粪便和尿液排出。
Following administration of a single radiolabeled dose of lurasidone, approximately 80 and 9% of the dose is excreted in feces and urine, respectively.
[EN] PHARMACEUTICAL COMPOSITIONS COMPRISING GLYCEROL ESTERS<br/>[FR] COMPOSITIONS PHARMACEUTIQUES COMPRENANT DES ESTERS DE GLYCÉROL
申请人：ALKERMES PHARMA IRELAND LTD
公开号：WO2013142202A1
公开（公告）日：2013-09-26
The present invention relates to a pharmaceutical composition comprising glycerol esters of a fatty acid, wherein the compositions are useful for the delivery of anti-psychotic drugs.
The present invention relates to an injectable, pharmaceutical composition comprising a C1-6 alkyl ester of a C10-20 fatty acid. In an embodiment, the fatty acid is ethyl oleate, isopropyl oleate, ethyl myristate, or isopropyl myristate. These compositions are useful for the delivery of anti-psychotic drugs.
The present invention relates to a pharmaceutical composition comprising benzyl alcohol and polyoxyethylene derivatives of sorbitan esters of carboxylic acids that are useful for the delivery of anti-psychotic drugs.
本发明涉及一种药物组合物，包括苯甲醇和羧酸山梨醇酯的聚氧乙烯衍生物，用于输送抗精神病药物。
PROCESSES FOR MAKING ALKYLATED ARYLPIPERAZINE AND ALKYLATED ARYLPIPERIDINE COMPOUNDS INCLUDING NOVEL INTERMEDIATES
申请人：Johnson Matthey Public Limited Company
公开号：US20150361099A1
公开（公告）日：2015-12-17
Novel processes, and intermediates, for making alkylated arylpiperazine and alkylated arylpiperidine compounds of the general formulas (I) and (VII), respectively
wherein, R
1
and R
2
are individually selected from hydrogen, alkyl, substituted or alkyl; n=0, 1, or 2; Y=NR
3
R
4
, OR
5
, or SR
5
, where R
3
and R
4
are individually selected from acyl or sulfonyl, and where R
5
is aryl or heteroaryl, or heterocyclic; and Ar is an aryl, heteroaryl, or heterocyclic compound.
