Clin Pharmacokinet
`DOI 10.1007/s40262-016-0465-5
`
`R E V I E W A R T I C L E
`
`Pharmacokinetics and Pharmacodynamics of Lurasidone
`Hydrochloride, a Second-Generation Antipsychotic: A Systematic
`Review of the Published Literature
`
`William M. Greenberg1,2
`
`• Leslie Citrome3
`
`Ó Springer International Publishing Switzerland 2016
`
`Abstract Lurasidone
`benzisothiazol
`a
`hydrochloride,
`derivative, is a second-generation (atypical) antipsychotic
`agent that has received regulatory approval for the treat-
`ment of schizophrenia in the US, Canada,
`the EU,
`Switzerland, and Australia, and also for bipolar depression
`in the US and Canada. In addition to its principal antago-
`nist activity at dopamine D2 and serotonin 5-HT2A recep-
`tors, lurasidone has distinctive 5-HT7 antagonistic activity,
`and displays partial agonism at 5-HT1A receptors, as well
`as modest antagonism at noradrenergic a2A and a2C
`receptors. Lurasidone is devoid of antihistaminic and
`anticholinergic activities. It
`is administered once daily
`within the range of 40–160 mg/day for schizophrenia and
`20–120 mg/day for bipolar depression, and its pharma-
`cokinetic profile requires administration with food. In adult
`healthy subjects and patients, a 40 mg dose results in peak
`plasma concentrations in 1–3 h, a mean elimination half-
`life of 18 h (mostly eliminated in the feces), and apparent
`volume of distribution of 6173 L; it is approximately 99 %
`bound to serum plasma proteins. Lurasidone’s pharma-
`cokinetics are approximately dose proportional in healthy
`adults and clinical populations within the approved dosing
`range, and this was also found in a clinical study of chil-
`dren and adolescents. Lurasidone is principally metabo-
`lized by cytochrome P450 (CYP) 3A4 with minor
`metabolites and should not be coadministered with strong
`
`CYP3A4 inducers or inhibitors. Lurasidone does not sig-
`nificantly inhibit or induce CYP450 hepatic enzymes.
`
`Key Points
`
`Lurasidone, a second-generation antipsychotic
`approved for the treatment of patients with
`schizophrenia or bipolar depression, is a potent
`antagonist at dopamine D2, serotonin 5-HT2A and
`5-HT7 receptors, and partial agonist at 5-HT1A
`receptors, but is devoid of antihistaminic or
`anticholinergic activities.
`
`Lurasidone has limited bioavailability after oral
`ingestion, and should be taken with at least 350 kcal
`of food.
`
`Lurasidone does not significantly affect the
`metabolism of other pharmaceuticals, but is
`dependent on CYP3A4 for its metabolism and should
`not be coadministered with very strong CYP3A4
`inducers or inhibitors.
`
`& William M. Greenberg
`wmg1019@optonline.net
`
`1
`
`St. George’s University School of Medicine, True Blue,
`Grenada
`
`2 Mental Health Association of Rockland County,
`Valley Cottage, NY, USA
`
`3 New York Medical College, Valhalla, NY, USA
`
`1 Introduction
`
`Despite the availability of multiple approved antipsychotic
`medications, it remains challenging to optimize therapies for
`patients with severe and persistent mental illness, in view of
`heterogeneity in therapeutic response among individual
`patients [1], differences in expectable adverse event profiles
`among the various options [2], and differences in potential
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`drug–drug and disease–drug interactions for an individual
`patient’s current regimen [3, 4]. In general,
`in clinical
`practice, patients’ unique experiences of, and tolerances for,
`specific medications often presents the practical need for
`complex trade-offs and careful individualization of treat-
`ment regimens. Therefore, a substantial number of thera-
`peutic options that offer variability in pharmacokinetic and
`pharmacodynamic profiles is very desirable.
`
`2 Methods
`
`An initial search using the US National Library of Medi-
`cine PubMed.gov resource conducted on 16 February 2016
`using the terms ‘lurasidone AND (pharmacokinetic OR
`pharmacodynamic OR receptor)’ yielded 78 entries, and
`when updated on 9 June 2016, two additional records were
`found. Both authors reviewed the results of the search with
`regard to the relevance of the identified articles, as well as
`the articles referenced in those publications, focusing pri-
`marily on English-language studies involving human data,
`although some preclinical animal data were reviewed
`where applicable. Original data were from pharmacokinetic
`and pharmacodynamic studies conducted by, or supported
`by, the manufacturer. Additional information was obtained
`from the prescribing information and the US FDA drug
`approval package and European Medicines Agency (EMA)
`assessment report [5–7].
`
`3 Physicochemical Properties
`
`Lurasidone [(3aR,4S,7R,7aS)-2-{(1R,2R)-2-[4-(1,2-ben-
`zisothiazol-3-yl)piperazin-1-ylmethyl]cyclohexylmethyl]
`hexahydro-4,7-methano-2H-isoindole-1,3-dione hydrochlo-
`Ò
`ride] (brand name Latuda
`) is a benzisothiazol derivative
`approved by the US FDA for the treatment of schizophrenia
`(recommended dose 40–160 mg/day), and for depressive
`episodes associated with bipolar I disorder (bipolar depres-
`sion) as monotherapy or adjunctive treatment with lithium or
`valproate (recommended dose 20–120 mg/day) [5, 6]. It has
`also been approved by the EMA for the treatment of
`schizophrenia in adults, and by Health Canada for the acute
`treatment of patients with schizophrenia, and for bipolar
`depression [7, 8]. Lurasidone has been generally referred to as
`an ‘atypical’ or ‘second-generation’ antipsychotic, but a
`recent proposed nomenclature recommends adopting func-
`tional classifications, and would categorize it as a dopamine
`and serotonin antagonist [9]. More specifically, lurasidone is
`principally pharmaceutically active as a D2 and 5-HT2A
`
`W. M. Greenberg, L. Citrome
`
`antagonist, characteristics that are believed to underlie
`antipsychotic efficacy, and with the latter action also helping
`limit extrapyramidal adverse effects and perhaps improve
`negative symptoms of schizophrenia [10, 11]. It is available in
`the form of immediate-release lurasidone hydrochloride
`(molecular formula C28H36N4O2S.HCl; molecular weight
`529.14) tablets in 20, 40, 60, 80 and 120 mg strengths. Inac-
`tive excipients include mannitol, pregelatinized starch,
`croscarmellose sodium, hypromellose, magnesium stearate,
`Ò
`Opadry
`and carnuba wax. The 80 mg tablet also contains
`yellow ferric oxide and FD&C Blue No. 2 Aluminum Lake
`coloring [6]. It is only very slightly soluble in water.
`
`4 Pharmacokinetics in Adults
`
`4.1 Absorption
`
`Lurasidone hydrochloride is poorly soluble in water
`(0.224 mg/ml at 20 °C), and is poorly absorbed after oral
`ingestion in a healthy volunteer population; bioavailability
`is estimated to be 9–19 % when taken with a recommended
`meal of at least 350 calories [5]. The most definitive data
`on food effects derive from two open-label, randomized,
`crossover,
`bioavailability
`studies
`in
`patients
`aged
`18–65 years with schizophrenia or schizoaffective disorder
`who were clinically stable, had a body mass index of
`19.5–37.0 kg/m2, and were not taking medications known
`to be inhibitors or inducers of CYP3A4. These patients
`were administered a single daily dose of 120 mg of
`lurasidone administered with and without food, and max-
`imum concentration (Cmax) and area under the concentra-
`tion–time curve during a dosing interval (AUCs) were
`examined on the fifth day [12]. The first study of 16 indi-
`viduals compared ingesting lurasidone in a fasting state
`with taking it with meals of 100 kcal with medium fat,
`200 kcal of medium fat, and 800–1000 kcal with high fat.
`The geometric Cmax and AUCs were approximately twice
`as high for the 800–1000 kcal meal compared with the
`fasted state; bioavailability was significantly better with the
`high-calorie meal compared with the two other low-calorie
`meals. The second study, in 26 subjects, compared the
`bioavailability of lurasidone taken in the fasting state with
`that taken with meals of 350 kcal with high fat, 500 kcal
`with low fat, 500 kcal with high fat, 800–1000 kcal with
`low fat, and 800–1000 kcal with high fat. This study also
`demonstrated Cmax values that were approximately three
`times higher, and AUCs that was approximately two times
`higher, for the fed conditions of meal sizes of at least
`350 kcal compared with the fasting condition. These
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`PK/PD of Lurasidone
`
`studies did not find a differentiation in absorption between
`low- and high-fat meals, and did not demonstrate a sig-
`nificant difference in absorption for meals across the range
`of 350–1000 kcal, which led to the recommendation in
`labeling to take lurasidone with a meal of at least 350 kcal,
`without regard to the fat content [6].
`Lurasidone’s time to reach Cmax (tmax) is approximately
`1–3 h after an oral dose of 40 mg (reported as 1.5 h after a
`single dose and 3 h after multiple-dose administration),
`with steady-state concentrations achieved within 7 days of
`dosing. Lurasidone AUC and Cmax are approximately
`proportional in the range of 20–160 mg/day dose admin-
`istration [5, 6, 13]. Single- and multiple-dose statistics for
`the Cmax, AUC from time zero to 24 h (AUC24) and min-
`imum concentration (Cmin) were approximately linear [5].
`
`4.2 Distribution
`
`Lurasidone is very highly plasma protein-bound, reported
`as 99.8 %,
`independent of concentration, principally
`binding to albumin and a1-acid glycoprotein [7, 14].
`Although plasma albumin decreases with age, and a1-acid
`glycoprotein increases with age, population pharmacoki-
`netic analyses suggested that lurasidone use in the elderly
`would not incur significant safety or efficacy issues based
`on these changes [7]. The plasma protein binding of the
`two active metabolites was reported as 98.8–99.0 % [5, 7],
`and the mean fraction of lurasidone in whole blood dis-
`tributed in red blood cells is approximately 12 % [5]. The
`mean apparent volume of distribution after single-dose
`administration ranged from 4182 to 11,236 L, and between
`3220 and 4410 L after multiple-dose administration [5].
`A preclinical study of the intravenous administration of
`lurasidone in male Sprague–Dawley rats
`found that
`lurasidone was widely distributed in all nine tissues
`examined (brain, liver, kidneys, heart, spleen, lungs, small
`intestine, muscle, and adipose tissues), with tissue-to-
`plasma concentration ratios ranging from 1.04 for the brain
`to the highest values in the small intestine (3.84) and adi-
`pose tissue (9.16). Estimated brain uptake clearance sup-
`ported lurasidone’s good penetration but somewhat slow
`distribution to the brain, presumably related to its very high
`plasma-protein binding and thus very low unbound con-
`centration. This intravenous study, as well as a similar oral
`administration study with rats, supported the conclusion
`that absorption, distribution and elimination of lurasidone
`were mediated by linear processes,
`in the dose range
`examined [15].
`11C-raclopride was used to measure the dopamine D2
`receptor occupancy in the brain, in an open-label positron
`
`emission tomography (PET) study, using either 10, 20, 40,
`60 or 80 mg single oral doses of lurasidone in 20 healthy
`male volunteers, 30 min after they had a meal. D2 receptor
`occupancy levels were measured in the putamen, caudate
`nucleus and cerebellum, with similar findings in these
`areas. A dose-dependent increase in D2 occupancy levels
`up to the 60 mg dose was observed, which was associated
`with a maximal D2 receptor occupancy of 75–85 %; the
`80 mg dose was associated with slightly lower values [16].
`Although it has been posited that at least 60 % or so
`occupancy is needed for a therapeutic clinical response in
`patients with schizophrenia, and that higher occupancy
`levels are more often associated with more adverse effects
`[17, 18], it is also true that clozapine, accepted as the most
`effective antipsychotic, is associated with lower occupancy
`levels [19, 20]. A PET study using 18F-fallypride was also
`conducted in 17 patients with schizophrenia or schizoaf-
`fective disorder who were treated with a dose of lurasidone
`80, 120, or 160 mg for 1 week before the PET scans. This
`study did not find significant correlations between the dose
`group and brain D2 occupancy at tmax, despite good cor-
`relations between serum lurasidone concentrations and D2
`occupancy [21]. Although the two radioligands used in
`these studies were non-selective with regard to D2 and D3
`receptors, as lurasidone’s relative affinity for D2 compared
`with D3 receptors is in the order of 16-fold, these findings
`realistically reflect D2 occupancy values.
`In animal models, lurasidone is widely distributed, but
`particularly retained in pigmented tissues, such as the eyes.
`It is excreted in breast milk and crosses over into the pla-
`centa and fetus in Sprague–Dawley rats [5].
`
`4.3 Metabolism
`
`Metabolism is principally by CYP3A4, mostly via oxida-
`tive N-dealklyation, hydroxylation of the norbornane ring
`or cyclohexane ring, S-oxidation, reductive cleavage of the
`isothiazole ring, followed by S-methylation, or combina-
`tions of these pathways [5]. There are two active metabo-
`lites, but only one is present to a significant degree: the
`mean Cmax and AUC24 of ID-14283 were 23–26 and
`24–29 % of lurasidone,
`respectively, while the corre-
`sponding values for the other active metabolite, ID-14326,
`were 2–3 and 2–4 % (as determined in a study of lurasi-
`done administration in Japanese male and female patients
`with schizophrenia at steady state) [5]. CYP3A5 has
`polymorphisms that could affect metabolism of substrates,
`but
`lurasidone is not significantly metabolized by the
`CYP3A5 enzyme [7]. Lurasidone and its principal
`metabolite ID-14283 are reportedly not substrates for
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`P-glycoprotein (P-gp), although one study in transfected
`cells did demonstrate some potential P-gp inhibition
`[5, 22]. The major metabolites ID-20219 and ID-20220
`were described as not active, as was the very minor
`metabolite ID-11614. ID-14283, the major active metabo-
`lite, has a shorter elimination half-life compared with
`lurasidone, thus lurasidone’s pharmacodynamic activities
`are believed to be mainly due to lurasidone itself [5, 14].
`Although lurasidone AUC and Cmax were reported to be
`approximately linear in the dose range of 20–160 mg, in
`human microsome studies lurasidone was reported to be a
`modest inhibitor of CYP3A4 (50 % maximal inhibitory
`concentration [IC50], Ki = 17 lM), therefore some non-
`linear increase in exposure might conceivably be expected
`at higher doses. There was a similar finding for CYP2C19
`(Ki = 10 lM), and weaker inhibitory effects on CYP2C8,
`CYP2C9 and CYP2B6, as well as negligible effects on
`CYP1A2, CYP2D6, CYP1A2 and CYP2E1, although the
`FDA-approved product insert simply states that lurasidone
`is not a substrate of CYP1A1, CYP1A2, CYP2A6,
`CYP4A11, CYP2B6, CYP2C6, CYP2C8, CYP2C9,
`CYP2C19, CYP2D6, or CYP2E1 enzymes [5–7]. It was
`also reported that when coadministered with digoxin,
`midazolam, or an oral contraceptive containing ethinyl
`estradiol and norelgestromin, the concentrations of these
`pharmaceuticals were not significantly affected, suggesting
`that the in vitro moderate inhibition may generally not
`result in clinically significant drug interactions.
`
`4.4 Elimination
`
`Elimination is mostly gastrointestinal. As studied, 80.1 %
`of a total dose was recovered in feces and 9.2 % in urine,
`with 10.7 % unrecovered [5]. Elimination time as mea-
`sured by half-life is somewhat increased for higher doses,
`being 18 h for the 40 mg dose, 22 h for the 80 mg dose,
`and 31 h for the 120 mg dose [5]. The mean (percentage
`coefficient of variation [%CV]) apparent clearance after
`administration of a 40 mg dose was 3902 (18.0) mL/min
`[6].
`
`5 Effects of Intrinsic Factors on Lurasidone
`Pharmacokinetics
`
`5.1 Effects of Hepatic Impairment
`
`Compared with matched controls with normal hepatic
`function, inpatients with mild, moderate or severe hepatic
`
`W. M. Greenberg, L. Citrome
`
`impairment were demonstrated to have lurasidone Cmax
`increased by 26, 20 and 25 %, and AUC more significantly
`by 35–49, 66–75 % and threefold, respectively [5]. A dose
`adjustment is not recommended for patients with mild
`hepatic impairment;
`for moderate and severe hepatic
`impairment it is recommended that the dose should initially
`be 20 mg/day, with a maximum of 80 mg/day for those
`with moderate hepatic impairment and 40 mg/day for those
`with severe hepatic impairment [6].
`
`5.2 Effects of Renal Impairment
`
`Compared with matched controls with normal renal func-
`tion, patients with mild, moderate and severe renal
`impairment had lurasidone Cmax increased by 40, 92 and
`54 %, and AUC by 53, 91 and 103 %, respectively [5]. A
`dose adjustment is not recommended for patients with mild
`renal impairment; for moderate and severe renal impair-
`ment, it is recommended that the dose should initially be
`20 mg/day, with a maximum dosage of 80 mg/day [6].
`
`6 Effects of Age
`
`Although a formal study in the elderly was not conducted,
`the FDA’s analysis of lurasidone studies submitted for the
`initial product approval found a modest 21 % higher AUC
`in the elderly population (age 65–85 years), compared with
`the non-elderly adult study population. A dose adjustment
`in the elderly was not recommended based on this finding
`[5, 6].
`The pharmacokinetics of lurasidone were studied in a
`multicenter, open-label, single- and multiple-ascending-
`dose study in 105 enrolled child and adolescent patients
`who had a variety of psychiatric diagnoses (mainly atten-
`tion deficit/hyperactivity disorder with aggressive behavior
`or bipolar spectrum disorder). These patients were stratified
`into four different age groups (6–9, 10–12, 13–15 and
`16–17 years of age). Both Cmax and AUC24 for lurasidone
`and its three active metabolites (ID-14283, ID14326 and
`ID-11614) increased linearly with dose across the range of
`20–160 mg/day, and were similar to the exposure values
`found in the adult population, although exposure levels
`were somewhat higher in the 6- to 9-year-old cohort.
`Apparent oral clearance ranged from 317 to 346 L/h, and
`apparent volume of distribution at terminal phase ranged
`from 6940 to 8700 L, respectively, across the dose groups;
`these values were also similar to those reported for the
`adult population [23].
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`PK/PD of Lurasidone
`
`7 Effects of Other Intrinsic Factors
`
`The FDA review noted that their statistical exploration of
`the effects of sex and race did not demonstrate any sig-
`nificant differences in lurasidone exposures. However, the
`FDA review did note that in the four pivotal clinical trials
`of patients with schizophrenia, patients from US sites had a
`median AUC of approximately 32–44 % lower compared
`with non-US patients, which was posited to be due to the
`lower body weight of study patients enrolled in the non-US
`regions. A reanalysis requested by the EMA supported that
`Asian race was more relevant in explaining these findings
`of increased exposure, rather than decreased body weight
`[7].
`Based on the submitted studies, the FDA did not rec-
`ommend dosage adjustments based on ethnicity or sex, and
`also determined that the pharmacokinetics of lurasidone
`did not differ in healthy volunteers, compared with patients
`with schizophrenia or schizoaffective disorder [5].
`
`8 Effects of Extrinsic Factors on Lurasidone
`Pharmacokinetics
`
`Human liver microsome studies found that quinidine and
`cimetidine did not significantly affect lurasidone metabo-
`lism [7]. Intravenous administration of the CYP3A4 sub-
`strates biperiden, flunitrazepam, haloperidol and diazepam
`did not affect the protein binding of lurasidone, nor was
`lurasidone metabolism inhibited by these pharmaceuticals
`when they were studied in human liver microsomes [7].
`However, lurasidone metabolism’s principal dependence
`on CYP3A4 would imply sensitivity to strong CYP3A4
`inhibitors or inducers, and this has been found to be the
`case. Coadministration of the strong CYP3A4 inhibitor
`ketoconazole caused a 9.3-fold increase in lurasidone
`AUC, and a 6.8-fold increase in Cmax. On the other hand,
`the moderate CYP3A4 inhibitor diltiazem increased
`lurasidone AUC by 116 % and Cmax by 110 % when
`coadministered, while the strong CYP3A4 inducer rifam-
`pin decreased lurasidone AUC by 83 % and Cmax by 85 %
`when coadministered (i.e. both by sevenfold) [5]. There
`was no significant effect of lithium coadministration on
`lurasidone AUC or Cmax [22]. It is recommended that
`lurasidone not be used in a patient
`receiving strong
`CYP3A4 inducers (such as rifampin) or inhibitors (such as
`ketoconazole); these are specifically listed as contraindi-
`cations in the FDA product label [6]. An example of a
`strong CYP3A4 inducer that is approved for use in persons
`with bipolar disorder is an extended-release (XR) formu-
`lation of carbamazepine [24]. For those taking a moderate
`
`CYP3A4 inhibitor, such as diltiazem, it is recommended
`that the dose of lurasidone be reduced in half; if starting
`lurasidone, it is recommended that the starting dose be
`20 mg/day, with a maximum recommended dose of
`80 mg/day. For those taking a moderate CYP3A4 inducer,
`the dose may need to be increased [5]. Examples of a
`moderate inducer of CYP3A4 are modafinil and armoda-
`finil, the latter having been extensively studied for the
`treatment of bipolar depression, and thus the combination
`of lurasidone and armodafinil may be encountered in
`clinical practice [25].
`
`9 Effect of Lurasidone on Other Drugs
`
`In vitro studies also explored the effect of lurasidone on
`transporters. Lurasidone was
`found to not
`inhibit
`OATP1B1, OATP1B3, OCT2, OAT1, OAT3, MATE1,
`MATE2-K and BSEP; but was shown to inhibit BCRP and
`OCT1 [7]. It was noted that at the pH of the small intestine
`lurasidone had very low solubility, and would be present at
`concentrations that should not inhibit intestinal P-gp in a
`clinically significant manner [7].
`The co-administration of steady-state lurasidone was
`studied in vivo for potential interactions on the pharma-
`cokinetics of digoxin, midazolam, and the oral contraceptive
`norgestimate/ethinyl estradiol (Ortho Tri-Cyclen). Digoxin
`was studied as its elimination is affected by the transporter
`P-gp, and an in vitro assay had found that lurasidone influ-
`enced digoxin transport; digoxin is also a medication that
`might be co-administered in clinical practice, the efficacy
`and toxicity of which are sensitive to its remaining in a
`therapeutic concentration range. Midazolam and the oral
`contraceptive were studied as they are metabolized by
`CYP3A4. Lurasidone 120 mg/day at steady state, adminis-
`tered to patients, increased the digoxin Cmax and AUC24 by 9
`and 13 %, respectively, and of midazolam Cmax and AUC0-
`24 by 21 and 44 %, respectively. Lurasidone 40 mg/day was
`co-administered to healthy female volunteers in a double-
`blind, placebo-controlled crossover study of its effect on
`ethinyl estradiol and norelgestromin exposure levels; the
`resulting geometric means were well within the prespecified
`90 % confidence level of 80–125 %. Data from two double-
`blind, placebo-controlled clinical trials of flexibly-adminis-
`tered lurasidone 20–120 mg/day as an adjunctive treatment
`for bipolar depression were available to examine the
`potential effects of lurasidone on exposure data for lithium
`and valproate. The 90 % confidence intervals for Ctrough
`blood values of lithium and valproate concentrations were
`well within the prespecified range of 80–125 %, indicating
`little potential for clinically meaningful interactions [22].
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`10 Pharmacodynamics
`
`lurasidone
`The receptor-binding pharmacodynamics of
`have been explored in assay systems using rat, guinea pig
`and human recombinant cells. Most prominently, lurasi-
`done is an antagonist with high affinity for dopamine D2L
`(Ki = 0.329 or 0.994), 5-HT2A (Ki = 0.357, 0.470 or
`2.03 nM), 5-HT7 receptors (Ki = 0.495 or 2.10 nM), and
`noradrenergic a2C receptors (10.8 or 16.2 nM), a partial
`agonist (maximum effect [Emax] of 33 % of serotonin) with
`high affinity for 5-HT1A receptors (Ki = 6.38 or 6.75 nM)
`[data from Ishibashi et al. and the FDA Summary Basis of
`Decision: multiple values indicate variation depending on
`the experimental system] [5, 26]. It has somewhat lower
`binding affinity for noradrenergic a1 (Ki = 47.9 nM) and
`a2A
`receptors
`(Ki = 40.7 nM),
`and
`dopamine D3
`(Ki = 15.7 nM) and D4.4 (Ki = 29.7 nM). In vitro func-
`tional studies and animal behavioral model studies were
`consistent with these findings, and supported the functional
`activities at receptors noted above. There was low affinity
`for dopamine D1 (Ki = 262 nM), the serotonin 5-HT2C
`receptor (Ki = 415 nM), the phenylalkylamine site of the
`L-type Ca2? channel (Ki = 641 nM) and the voltage-gated
`Na? channel (Ki = 398 nM). For other receptors studied,
`binding affinities were very low (Ki [ 1000 nM): adeno-
`sine A1 and A2; benzodiazepine, cholecystokinin CCKA
`and CCKB; L-type (dihydropyridine and benzothiazepine
`sites) and N-type Ca2? channel; dopamine D4, GABAA,
`AMPA, kainate and NMDA glutamate; glycine, histamine
`H1, muscarinic M1 and M2, nicotine, noradrenaline ß, ß1
`and ß2; opiate, 5-HT3 and 5-HT4; sigma, the dopamine and
`serotonin reuptake sites; and K? channels (KA, KATP, KV)
`[5, 14, 26–28]. No study regarding binding affinity to the
`noradrenaline reuptake receptor was identified. Binding
`site affinities for the active metabolites ID-14283 and ID-
`14326 are similar to those of lurasidone.
`Lurasidone inhibited the human ether-a-go-go-related
`gene (hERG) channel current with an IC50 of 108 nM, and
`caused a significant QTc prolongation at dosing associ-
`ated with a Cmax of 3 lg/ml in conscious dogs, but not in
`the cat or guinea pig [5]. A thorough QT study in patients
`with schizophrenia or schizoaffective disorder was con-
`ducted, employing a randomized, double-blind, double-
`dummy design, with three treatment condition arms of
`lurasidone 120 mg/day, a
`supratherapeutic dose of
`lurasidone 600 mg/day, and a positive control arm using
`ziprasidone 160 mg/day, administered over 11 days to
`ensure steady-state conditions. Using delta individual-
`specific corrected QT interval
`(QTcI) changes from
`baseline as the principal outcome, as per the International
`
`W. M. Greenberg, L. Citrome
`
`Conference on Harmonisation (ICH) E14 guideline, the
`result was inconclusive as the maximum upper bound of
`the 90 % confidence interval exceeded 10 ms at the 2 and
`3 h post-dose time points for the 120 mg/day lurasidone
`condition, as well as
`several
`time points
`for
`the
`supratherapeutic 600 mg/day dose condition; the mean
`values for those treated in the ziprasidone arm was sig-
`nificantly higher. However, for the lurasidone conditions,
`no apparent dose–response relationship was observed, and
`no patients experienced clinically significant QTcI abso-
`lute values (QTcI [ 450 ms) or changes from baseline
`(delta QTcI [ 30 ms) [5, 6, 29, 30].
`
`11 Discussion: Distinguishing Features
`of Pharmacodynamic Profile
`
`As previously noted, lurasidone is a D2 and 5-HT2A antag-
`onist, shared characteristics of newer generation antipsy-
`chotics that effectuate antipsychotic efficacy, with the
`5-HT2A antagonism theoretically helping limit D2-antago-
`nist-induced extrapyramidal adverse effects (e.g. parkinso-
`nian muscle rigidity and tremor, dystonic reactions,
`akathisia) and prolactin elevation (associated with amenor-
`rhea, galactorrhea, sexual dysfunction), and perhaps improve
`negative symptoms (infra) of schizophrenia [31, 32].
`A relatively distinctive aspect of the pharmacodynamic
`profile of lurasidone is its potent activity at the 5-HT7
`receptor, which was of particular interest in developing this
`drug. Although the early therapeutic focus of attention in
`schizophrenia was targeting the so-called ‘positive symp-
`toms’ (e.g. delusions, hallucinations, disorganization in
`thought and speech), and later, in the 1990s, the ‘negative
`symptoms’ (e.g.
`lack of expressed emotions in facial
`expressions and tone of voice, lack of experienced plea-
`surable emotions, paucity of speech, and lack of motivation
`and volition), it became apparent that perhaps the greatest
`determinant limiting the work and social functioning for
`many were the cognitive deficits usually associated with
`this disorder (e.g. deficits in executive functioning, prob-
`lems maintaining focus or attention, deficits in working
`memory, declarative memory, processing speed, etc.),
`which persisted even in times of good clinical response or
`remission [33–38]. Although there is some evidence of the
`newer generation atypical antipsychotic medications being
`somewhat more beneficial in treating these cognitive defi-
`cits (e.g. risperidone, olanzapine, clozapine), it has been
`very challenging to demonstrate these as consistent and
`robust findings [39–43]. That functional activity studies
`established lurasidone as a very potent 5-HT7 antagonist
`
`Par Pharm., Inc.
`Exhibit 1052
`Page 006
`
`

`

`PK/PD of Lurasidone
`
`was of great interest because this mechanism of action is
`thought to have procognitive effects. These would pre-
`sumably be mediated by the inhibition of 5-HT7 receptors
`indirectly enhancing the glutamatergic output of prefrontal
`cortical pyramidal neurons, and perhaps similar actions via
`5-HT7 receptors in the hippocampus and dorsal raphe,
`although several animal models have also suggested that
`intact 5-HT7 activity is necessary for some cognitive tasks
`[26, 44–49]. Multiple animal studies have supported
`lurasidone’s value in improving cognition in specific con-
`texts. Moreover, 5-HT7 antagonism has been touted for
`possible antidepressant value, demonstrated in several
`animal models, as well as in stabilizing circadian rhythm
`synchronization [50–53].
`Lurasidone also has relatively strong binding affinity for
`the 5-HT1A receptor, at which it is a partial agonist. 5-HT1A
`partial agonism has been believed to have anxiolytic and
`antidepressant value, effected by actions at autoreceptors in
`the raphe nuclei and heteroreceptors elsewhere in cortical
`and limbic circuitry [54]. Buspirone is an azapirone
`5-HT1A partial agonist approved by the FDA to treat anx-
`iety disorders; other antidepressants such as trazodone and
`vilazodone, as well as antipsychotics such as aripiprazole,
`brexpiprazole and ziprasidone, also have 5-HT1A partial
`agonist activity, which may contribute to their therapeutic
`actions, although definitive demonstration of potential
`benefits in terms of superior efficacy, faster onset of action
`or decreased adverse sexual effects have not been estab-
`lished [55–57]. Buspirone has also been used as an
`adjunctive medication for treatment-resistant depression,
`and vilazodone has been posited to cause fewer serotonin
`reuptake inhibitor-related sexual adverse reactions because
`of its 5-HT1A partial agonism [58, 59]. Other psychotropic
`medications have different 5-HT1A activities: the antide-
`pressant vortioxetine is a 5-HT1A full agonist, and the
`antipsychotic risperidone is a 5-HT1A antagonist [60]. A
`principal problem in evaluating the contributions of
`available 5-HT1A pharmaceutical actions in clinical popu-
`lations is that most of these medications have various
`activities
`at
`alternative
`serotonergic,
`noradrenergic,
`dopaminergic, and other receptors and transporters; even
`buspirone, routinely referred to as a 5-HT1A partial agonist,
`has antidopaminergic and other serotonin receptor actions.
`Recently, gepirone, an antidepressant that acts solely as a
`full agonist at the presynaptic 5-HT1A autoreceptor and a
`partial agonist at the post-synaptic 5-HT1A receptor, has
`been the subject of a regulatory re-review [61]. Addition-
`ally, complex interactions have been demonstrated between
`5-HT1A and 5-HT7 receptor activities with regard to cog-
`nitive functioning and emotional memory, which may also
`be differentially influenced by whether the relevant sero-
`tonin release is tonic or phasic [62].
`
`Relevant to the current theory that the cognitive deficits
`in schizophrenia are related to hypofunction of prefrontal
`cortical dopaminergic and glutamatergic neurons, lurasi-
`done has been demonstrated to reverse the effects of
`administration of NMDA receptor antagonists, such as
`phencyclidine and MK-801, in animals, and to enhance
`NMDA receptor-mediated synaptic responses [63, 64].
`This has been hypothesized to be related to lurasidone’s
`5-HT7 receptor antagonism, but studies of cognition using
`the object retrieval detour task in marmosets were also
`interpreted as suggesting that lurasidone’s relatively weak
`D4 receptor binding affinity played a positive role in cog-
`nitive improvement in this model [65].
`Lurasidone has significant binding affinity and antago-
`nism at the noradrenergic a2c receptor, and this receptor
`has recently become of interest with regard to the treatment
`of patients with schizophrenia, with suggestions from ani-
`mal studies that noradrenergic a2c receptor blockade may
`have beneficial effects on cognit