Iloperidone treatment method

Abstract

An improved method of treatment is described for patients with a history of gout or who carry a gene variant associated with increased serum uric acid concentration induced by iloperidone, who require treatment with iloperidone or its active metabolite. The improved method includes monitoring the patient's serum uric acid level and, if the patient's serum uric acid level is above a normal level, initiating uric acid-lowering treatment or increasing the dose of uric acid-lowering treatment.

Description

【Technical Field】 【0001】 Cross - reference to Related Applications This patent application claims priority based on U.S. Provisional Patent Application No. 63 / 505,884, filed on June 2, 2023. 【0002】 The present invention generally relates to improvements in the treatment method using iloperidone. More specifically, the present invention relates to an improved treatment method using iloperidone that limits the risk of hyperuricemia and gout. 【Background Art】 【0003】 [Iloperidone] Iloperidone (1 - [4 - [3 - [4 - (6 - fluoro - 1,2 - benzisoxazol - 3 - yl) - 1 - piperidinyl]propoxy] - 3 - methoxyphenyl]ethanone) is an atypical antipsychotic drug disclosed in U.S. Reissue Patent No. 39198 (July 18, 2006). Iloperidone is approved for use in the United States for the treatment of schizophrenia in adults and for the acute treatment of manic or mixed episodes associated with bipolar I disorder in adults. Iloperidone is also being developed for use in the treatment of other psychotic symptoms, diseases, and disorders. 【0004】 1 - [4 - [3 - [4 - (6 - fluoro - 1,2 - benzisoxazol - 3 - yl) - 1 - piperidinyl]propoxy] - 3 - methoxyphenyl]ethanol) is also known by the chemical name 4 - [3 - [4 - (6 - fluoro - 1,2 - benzisoxazol - 3 - yl) - 1 - piperidinyl]propoxy] - 3 - methoxy - α - methylbenzene methanol and is the active metabolite of iloperidone, also known as (S) - P - 88 - 8891, S - P88, or P88. In humans, P88 is found only in the S - enantiomeric form, and the S - enantiomeric form has the following structure. 【0005】 【Chemical Formula】 【0006】 However, P88 can be synthesized in an R-enantiomer form, which has the following structure. 【0007】 [ka] 【0008】 P88 is described in U.S. Patent No. 7,977,356 (July 12, 2011), and its S- and R-enantiomer forms are described in U.S. Patent No. 10,874,659 (December 29, 2020). 【0009】 Other iloperidone metabolites include 1-[4-[3-[4-(6-fluoro-1,2-benzoisoxazole-3-yl)-1-piperidinyl]propoxy]-3-hydroxyphenyl]ethanone, 1-[4-[3-[4-(6-fluoro-1,2-benzoisoxazole-3-yl)-1-piperidinyl]propoxy]-3-methoxyphenyl]-2-hydroxyethanone, 4-[3-[4-(6-fluoro-1,2-benzoisoxazole-3-yl)-1-piperidinyl]propoxy]-3-hydroxy-α-methylbenzenemethanol, Examples include 4-[3-[4-(6-fluoro-1,2-benzoisoxazole-3-yl)-1-piperidinyl]propoxyl-2-hydroxy-5-methoxy-α-methylbenzenemethanol, 1-[4-[3-[4-(6-fluoro-1,2-benzoisoxazole-3-yl)-1-piperidinyl]propoxy]-2-hydroxy-5-methoxyphenyl]ethanone, and 1-[4-[3-[4-(6-fluoro-1,2-benzoisoxazole-3-yl)-1-piperidinyl]propoxy]-2,5-dihydroxyphenyl]ethanone. See, for example, U.S. Patent No. 5,364,866 (November 15, 1994) and International Patent Application Publication No. 95 / 11680(A1) (May 4, 1995). 【0010】 Previous studies have investigated the association between the efficacy of iloperidone and polymorphisms in genes and gene regions, including CFTR, NPAS3, XKR4, TNR, GRIA4, GFRA2, and NUDT9P1. These associations are described, for example, in U.S. Patent No. 9,328,387 (May 3, 2016), No. 9,458,507 (October 4, 2016), and No. 9,080,214 (July 14, 2015). Furthermore, the association between CYP2D6 genotype and changes in the QT interval after iloperidone administration is described in U.S. Patent No. 8,586,610 (November 19, 2013) and No. 9,138,432 (September 22, 2015). The association between KCNQ1 genotype and QT interval changes induced by iloperidone administration is described in U.S. Patent No. 8,999,638 (April 7, 2015) and U.S. Patent No. 9,157,121 (October 13, 2015). These findings regarding the safety and efficacy of iloperidone will help in selecting the optimal drug and administration regimen for specific patients. This, in turn, will help in the safe and effective treatment of psychotic symptoms, diseases, and disorders by reducing trial and error and minimizing adverse side effects. 【0011】 [Serum uric acid concentration (SUC)] Uric acid is the end product of purine metabolism in humans and primates, which lack the enzyme uricase to further oxidize this heterocyclic compound. Under normal conditions, uric acid anions are produced after the breakdown of excess purine nucleosides in the liver, and then most of the molecule is excreted in the urine via the kidneys. Hyperuricemia, or elevated serum uric acid (uric acid in the blood) levels, is a significant risk factor for gout, a common and complicated inflammatory arthritis characterized by painful, recurrent attacks accompanied by joint swelling and tenderness. Excess uric acid in the body causes gout through the deposition of monosodium urate crystals (i.e., tophi) in cartilage, tendons, and soft tissues. Crystal deposits can also form in the kidneys, leading to uric acid nephrolithiasis and, in chronic cases, renal failure. 【0012】 Serum uric acid levels in individuals are influenced by several factors, particularly genetic polymorphisms in renal transporters, medications, and diet. Serum uric acid levels correlate with blood pressure, metabolic syndrome, diabetes, gout, and cardiovascular disease. Serum uric acid imbalance is an established marker of underlying disease conditions and facilitates the diagnosis of gout, renal impairment or kidney damage, and rare hereditary conditions; therefore, commercially available clinical tests are routinely used to assess the presence of uric acid in the blood. 【0013】 The bidirectional transport of uric acid and the presence of hepatic uricase in non-primate mammalian models limited early studies of uric acid transport in humans. However, genetic methods have facilitated the discovery of transport proteins and the functional effects of genetic polymorphisms in the encoding genes. The SLC2A9 gene encodes a human high-capacity hexose-uric acid transporter, which is primarily expressed in the kidneys, liver, and intestines. Loss-of-function variants of SLC2A9 have been previously identified in association with hypouricemia, and recent genome-wide association studies have subsequently shown a correlation between common SLC2A9 genetic variants and elevated serum uric acid levels and gout. [Overview of the project] 【0014】 Various aspects of the present invention disclosed herein relate to improved methods for treating patients in need of treatment with iloperidone, while reducing the risk of hyperuricemia and gout. 【0015】 In a first embodiment, an improved method is provided for treating a patient with a history of gout who requires treatment with iloperidone, an active metabolite of iloperidone, such as P88, or a pharmaceutically acceptable salt of iloperidone or its metabolite. Such an improved method includes monitoring the patient's serum uric acid level and, if the patient's serum uric acid level is approaching or above a baseline level, initiating uric acid-lowering treatment or increasing the dose of uric acid-lowering treatment. 【0016】 A second embodiment provides an improved method for treating patients in need of treatment who have a genotype associated with an increase in serum uric acid concentration induced by iloperidone, such as the rs7442295 genotype at the SLC2A9 locus containing one or more rs7442295(G) alleles, with iloperidone, an active metabolite of iloperidone, such as P88, or a pharmaceutically acceptable salt of iloperidone or its metabolite. Such an improved method includes monitoring the patient's serum uric acid level and, if the patient's serum uric acid level is approaching or above a baseline level, initiating uric acid-lowering treatment or increasing the dose of uric acid-lowering treatment. 【0017】 These and other aspects, advantages, and notable features of the present invention will become apparent from the following detailed description disclosing embodiments of the invention, in conjunction with the accompanying drawings. [Brief explanation of the drawing] 【0018】 [Figure 1] This graph plots the mean change in serum uric acid levels from baseline to day 28 in cases observed over time in the studies described in Example 1 (bipolar mania) and Example 2 (schizophrenia). In the graph, error bars represent the standard error (SEM) of the mean. [Figure 2] Figure 2 plots the baseline evaluation of serum uric acid levels in the study described in Example 1, according to the patient's genotype and sex. [Figure 3] Figure 3 plots the changes in individual patients from baseline to day 28 in the trial described in Example 1, grouped by treatment group and prevalence of variant rs7442295. The red line in the figure represents the mean. [Figure 4] Figure 4 plots the mean serum uric acid concentrations of baseline and observed cases at day 28, categorized by genotype and treatment, in the study described in Example 1. Error bars represent the standard error of the mean. [Figure 5]Figure 5 plots the changes from the baseline of serum uric acid levels stratified by gender in the test described in Example 1. [Figure 6A] Figure 6A shows the proportion of individuals stratified by gender (female) and the variation in their serum uric acid concentrations. These figures demonstrate the clinical significance of the rs7442295 - G / G genotype, indicating that when treated with iloperidone, a significant number of individuals exceed the upper limit of normal (ULN) compared to placebo. [Figure 6B] Figure 6B shows the proportion of individuals stratified by gender (male) and the variation in their serum uric acid concentrations. These figures demonstrate the clinical significance of the rs7442295 - G / G genotype, indicating that when treated with iloperidone, a significant number of individuals (especially homozygous G / G males) exceed the upper limit of normal (ULN) compared to placebo. [Figure 7] Figure 7 plots the changes from the baseline of serum uric acid levels to the end of the study (EOS) in the test described in Example 2, stratified by treatment group and the status of rs7442295. The red line in the figure represents the mean, and the red error bars represent the standard error of the mean (SEM). [Figure 8] Figure 8 plots the mean serum uric acid levels at baseline and EOS stratified by the status of variant rs7442295 in the test described in Example 2. The error bars represent the standard error of the mean. [Figure 9] Figure 9 plots the changes from the baseline of serum uric acid levels stratified by gender in the test described in Example 2. MODE FOR CARRYING OUT THE INVENTION 【0019】 The drawings are intended to show only typical aspects of the present disclosure and should not be regarded as limiting the scope of the present disclosure. 【0020】 In various embodiments of the present invention, improved methods for treating patients with iloperidone, active metabolites of iloperidone, or pharmaceutically acceptable salts of iloperidone or its active metabolites are described herein. Such active metabolites may include, for example, P88. Such improved methods are useful for safely and effectively treating patients requiring treatment with iloperidone while limiting, mitigating, reducing, or avoiding the risks of several serious adverse events associated with iloperidone treatment, such as hyperuricemia and gout. 【0021】 As used herein, “patient,” “subject,” and “individual” refer to a mammal suffering from one or more disorders that are improved by the administration of iloperidone, such as schizophrenia, schizophrenic disorder, bipolar I disorder, acute manic and mixed episodes associated with bipolar I disorder, agitation associated with Alzheimer’s disease, agitation associated with dementia, agitation associated with autism, Parkinson’s psychosis, or other psychotic disorders or conditions. Guinea pigs, dogs, cats, rats, mice, horses, cattle, sheep, and humans are examples of mammals within the scope of this term. It is understood that the most preferred patient is human. "Patients requiring treatment with iloperidone" means patients suffering from or diagnosed with any of the conditions that would be treated or could be treated with iloperidone, an active metabolite of iloperidone, e.g., P88, or a pharmaceutically acceptable salt of iloperidone or its metabolite, e.g., any of the conditions listed above (but not limited to these). 【0022】 It is also recognized by those skilled in the art that by treating patients currently suffering from or preventively treating patients suffering from the disorders described herein with an effective amount of iloperidone, an active metabolite of iloperidone, such as P88, or a pharmaceutically acceptable salt of iloperidone or its metabolite, such disorders may be affected. Accordingly, the terms “treatment” and “treating” refer to any process that may result in slowing, interrupting, inhibiting, controlling, or stopping the progression of the disease or disorder described herein, or reducing the frequency of its episodes, and are intended to include preventive treatment of such disorders. “Treatment” does not necessarily mean the complete elimination of all symptoms of the disorder, but may include improvement thereof. 【0023】 As used herein, the term “effective dose” with respect to iloperidone, its active metabolite, e.g., P88, or pharmaceutically acceptable salts of iloperidone or its metabolites means an amount of the compound effective in treating the disorders described herein. Non-limiting exemplary effective doses or effective doses of iloperidone are, for example, U.S. Patent No. 8,586,610 (November 19, 2013), U.S. Patent No. 9,138,432 (September 22, 2015), U.S. Patent No. 10,272,076 (April 30, 2019), and U.S. Patent No. 10,441,580 (October 15, 2019). As disclosed in the Japanese Patent Publication No. 10,987,346 (April 27, 2021), the dosage ranges are 4-24 mg / day, 8-24 mg / day, 4-16 mg / day, 12-14 mg / day, 12-16 mg / day, 12-24 mg / day, 16-24 mg / day, 20-24 mg / day, 12 mg / day or less, or approximately 24 mg / day or less, for example, 6 mg Examples of titration doses include 8 mg / day, 12 mg / day, 14 mg / day, 16 mg / day, 20 mg / day, 24 mg / day, 8-24 mg / day given as 4-12 mg twice daily (bid), 12-16 mg / day given as 6-8 mg bid, 12-24 mg / day given as 6-12 mg bid, 16-24 mg / day given as 8-12 mg bid, 12 mg or less per day given as 6 mg or less bid, 16 mg or less per day given as 8 mg or less bid, 16 mg / day given as 8 mg bid, 24 mg / day given as 12 mg bid, or 24 mg / day given as 24 mg once daily (qd).Examples of effective doses or effective dosages of R-P88 include, for example, as disclosed in U.S. Patent No. 10,874,659 (December 29, 2020), 1-24 mg / day, 6-24 mg / day, 12-24 mg / day, 6-18 mg / day, or 6-12 mg / day, or 24 mg / day or less, for example, 1 mg / day, 2 mg / day, 3 mg / day, 4 mg / day, 5 mg / day, 6 mg / day, 7 mg / day, 8 mg / day, 9 mg / day, 10 mg / day, 11 mg / day, 12 mg / day, 14 mg / day, 16 mg / day, 18 mg / day, 20 mg / day, Examples of titration doses include 22 mg / day or 24 mg / day, 1-24 mg / day with a bid of 0.5-12 mg, 2-18 mg / day with a bid of 1-9 mg, 6-18 mg / day with a bid of 3-9 mg, 6-12 mg / day with a bid of 3-6 mg, 6-18 mg / day with a bid of 3-9 mg, 12 mg / day with a bid of 6 mg, 24 mg / day with a bid of 12 mg, or titration doses of 24 mg / day or less with a bid of 12 mg or less. 【0024】 Regarding administration, qd refers to once-daily administration, while bid administration typically means once in the morning and once in the evening, generally at intervals of approximately 8 hours or more and 16 hours or less, for example, 10-14 hours apart or 12 hours apart (Q12H). 【0025】 Where used herein, terms such as “first,” “second,” etc., do not indicate any order, quantity, or importance, but rather are used to distinguish one element from another, and the terms “a” and “an” herein do not indicate a limitation of quantity, but rather indicate that at least one of the items mentioned exists. The modifier “about” used in relation to quantity includes the stated value and has a meaning that is determined by the context (e.g., including the degree of error associated with the measurement of that particular quantity). The suffix “(s)” used herein includes both the singular and plural of the term it modifies and is therefore intended to include one or more such terms (e.g., milestone(s) includes one or more milestones). The ranges disclosed herein include endpoints and can be combined independently (e.g., the range “about 25 mg or less, or more specifically about 5 mg to about 20 mg” includes the endpoint of the range “about 5 mg to about 25 mg” and any intermediate values ​​within that range). 【0026】 One embodiment of the present invention provides an improvement in a method of treating a patient with a compound that is iloperidone, an active metabolite of iloperidone, such as P88, or a pharmaceutically acceptable salt of iloperidone or its metabolite. A patient may require treatment with iloperidone or its salt or metabolite to control and / or prevent relapse of symptoms such as, for example, schizophrenia, schizophrenia-like disorder, bipolar I disorder, bipolar mania, acute manic and mixed episodes associated with bipolar I disorder, agitation associated with Alzheimer's disease, agitation associated with dementia, agitation associated with autism, Parkinson's disease psychosis, and other psychotic disorders and disorders known and understood in the art. In some embodiments, treatment of the patient may include administration of iloperidone in doses of 24 mg / day or less, which may be given as divided doses twice daily. In some embodiments, the dosage may be 24 mg / day, which may be given with a bid of 12 mg, or other dosages such as 20 mg / day, 16 mg / day, or 12 mg / day, which may be given with a bid of 10 mg, 8 mg, or 6 mg, respectively. In another embodiment, the patient may be administered an active metabolite of iloperidone, such as P88, i.e., S-P88, R-P88, or any pharmaceutically acceptable salt thereof. In addition, the patient may have a history of gout, i.e., may have previously experienced symptoms of gout, or may have a family history of gout, such as having a first-degree relative such as a sibling or parent with a history of gout. 【0027】 According to this embodiment, improvements in such treatment include monitoring the patient's serum uric acid concentration or serum uric acid level. Such monitoring may include, for example, obtaining a biological sample from the patient, such as blood or plasma, and examining the biological sample to determine the serum uric acid concentration in the biological sample. The patient's serum uric acid concentration (SUC) can then be compared to a reference SUC. Reference levels for SUC are known to those skilled in the art and may include, for example, 400 μmol / L (male or female); 4.0-8.5 mg / dL or 0.24-0.51 mmol / L (male); approximately 453 μmol / L (male); 2.7-7.3 mg / dL or 0.16-0.43 mmol / L (female); or approximately 394 μmol / L (female). 【0028】 Such monitoring may be performed at one or more points in time with respect to the treatment of a patient with iloperidone, an active metabolite of iloperidone, e.g., P88, or a pharmaceutically acceptable salt of iloperidone or its metabolite, e.g., before administration, around day 28 of treatment, around day 21 of treatment, around day 14 of treatment, and around day 7 of treatment. In various embodiments, monitoring may be performed at one, two, three, four, or all five of the aforementioned points in time. Monitoring may also be continued periodically after day 28, for example, at intervals of approximately every 28 days thereafter. Such periodic monitoring may be continued over a predetermined period or over the entire treatment period of the patient. If periodic monitoring is continued over a predetermined period, the predetermined period may be tied to a specific time unit, for example, measured in weeks, months, or years. Alternatively, monitoring may be continued until the patient reaches a steady state or substantially steady state serum uric acid concentration, which can be defined as reaching a steady state or substantially steady state over a certain number of monitoring events. 【0029】 This method may further include determining whether the patient is currently receiving treatment for gout, such as uric acid-lowering drugs, such as probenecid, allopurinol, febuxostat, or pegroticase. 【0030】 If a patient's SUC exceeds an applicable threshold level and the patient is not currently receiving treatment for gout, the improved approach includes initiating and maintaining treatment with a uric acid-lowering drug while the patient is being treated with iloperidone. 【0031】 If a patient's SUC exceeds a normal level and the patient is currently receiving treatment for gout, the improved method includes increasing the dose of the uric acid-lowering agent while the patient is being treated with iloperidone. Alternatively and / or additionally, treatment with a different uric acid-lowering agent may be initiated, either alone or in combination with the first uric acid-lowering agent. 【0032】 If a patient's SUC is within the normal range and the patient is not currently receiving treatment for gout, treatment with iloperidone, an active metabolite of iloperidone, such as P88, or a pharmaceutically acceptable salt of iloperidone or its metabolite may be maintained without the use of any uric acid-lowering medication, depending on the results of future or ongoing monitoring of the patient's SUC. 【0033】 If a patient's SUC is within the normal range and the patient is currently receiving treatment for gout, both iloperidone (or its active metabolite, e.g., P88, or pharmaceutically acceptable salts of iloperidone or its metabolites) and uric acid-lowering therapy may be maintained at their respective dosages, depending on future or ongoing monitoring of the patient's SUC. 【0034】 If a patient's SUC is within the normal range but shows a tendency toward or approaching the normal range, for example, on day 7, 14, 21, 28 of treatment, or at other time points, various measures may be taken. For example, the frequency of monitoring may be increased and / or the duration of monitoring may be extended. In another example, treatment with uric acid-lowering drugs or upward dose adjustments of uric acid-lowering drugs may be used prophylactically to prevent the patient's SUC from exceeding the normal range. As will be understood by those skilled in the art, for example, a patient may be considered approaching the normal range if their SUC has increased to within approximately 5%, 10%, 15%, or 20% of the normal range, or if their SUC is within a predetermined range that includes the normal range (e.g., ±5 μmol / L, ±10 μmol / L, ±15 μmol / L, etc.). Also, a patient may be considered approaching the normal range if, for example, their SUC has increased over one or more time points and lies on a trajectory that can be extrapolated to a value exceeding the applicable normal range. For example, if, on day 14 or 21 after the initiation of iloperidone treatment, the patient's SUC is still on an upward trajectory and has not yet exceeded the reference limit, but is likely to exceed or will exceed the reference limit by day 28 assuming treatment is maintained, the patient may be considered to be approaching the reference level, and precautionary measures may be taken as described herein. 【0035】 Initiating uric acid-lowering therapy and / or increasing its dosage as described herein offers the benefit of reducing the likelihood of the patient developing hyperuricemia and experiencing its adverse effects, such as future gout attacks. 【0036】 In various embodiments, the patient may be male or female. 【0037】 In some embodiments, a patient may be found to be or known to be a carrier of the variant SLC2A9 allele associated with increased serum uric acid concentration induced by treatment with iloperidone, an active metabolite of iloperidone, e.g., P88, or a pharmaceutically acceptable salt of iloperidone or its metabolite. For example, a patient may have a genotype containing one or more SLC2A9 rs7442295(G) alleles. In some embodiments, the patient may be homozygous (rs7442295-G / G) with respect to the rs7442295(G) allele in the SLC2A9 gene. The patient's genotype at the relevant locus may be determined using methods known to those skilled in the art and / or methods described in the examples provided herein. In some embodiments, once the patient's SLC2A9 genotype is known, it may contribute to a decision on whether, or to what extent, the patient should be treated with a uric acid-lowering agent according to the improved methods described herein. For example, patients with the homozygous rs7442295-G / G genotype may be treated more aggressively with uric acid-lowering drugs than individuals with the heterozygous rs7442295-A / G genotype or the homozygous rs7442295-A / A genotype. 【0038】 According to a second embodiment of this disclosure, another improved method may be provided for treating a patient in need of treatment who is a carrier of the variant SLC2A9 allele associated with increased serum uric acid concentration induced by or associated with treatment with iloperidone, the active metabolite of iloperidone, e.g., P88, or a pharmaceutically acceptable salt of iloperidone or its metabolite, with iloperidone, the active metabolite of iloperidone, e.g., P88, or a pharmaceutically acceptable salt of iloperidone or its metabolite. The variant SLC2A9 allele may be the rs7442295(G) allele. In some embodiments, a patient may carry at least one, or more specifically two, rs7442295(G) alleles, e.g., the rs7442295(G / G) genotype. The patient's SLC2A9 genotype may be determined as described herein and / or by referring to the patient's medical records if such tests or tests including the relevant locus have been performed in the past. According to this embodiment, the improved method includes monitoring the patient's serum uric acid level and, if the patient's serum uric acid level is approaching or exceeding a reference level, initiating uric acid-lowering therapy or increasing the dosage of uric acid-lowering therapy. 【0039】 Patients may require treatment with iloperidone, an active metabolite of iloperidone, such as P88, or a pharmaceutically acceptable salt of iloperidone or its metabolite, to control and / or prevent relapse of symptoms of, for example, schizophrenia, schizophrenia-like disorder, bipolar I disorder, bipolar mania, acute manic and mixed episodes associated with bipolar I disorder, agitation associated with Alzheimer's disease, agitation associated with dementia, agitation associated with autism, Parkinson's disease psychosis, and other psychotic disorders and disorders known and understood in the art. In some embodiments, treatment of a patient may involve administration of iloperidone in doses of 24 mg / day or less, which may be given as divided doses twice daily. In some embodiments, the dosage may be 24 mg / day, with 12 mg as a bid, or other dosages such as 20 mg / day, 16 mg / day, or 12 mg / day, with 10 mg as a bid, 8 mg as a bid, or 6 mg as a bid, respectively. In addition, the patient may or may not have a history of gout, that is, may or may not have previously experienced symptoms of gout, or may or may not have a family history of gout, such as having a first-degree relative such as a sibling or parent with a history of gout. 【0040】 According to this embodiment, improvements in such treatment include monitoring the patient's serum uric acid concentration or serum uric acid level. Such monitoring may include, for example, obtaining a biological sample from the patient, such as blood or plasma, and examining the biological sample to determine the serum uric acid concentration in the biological sample. The patient's serum uric acid concentration (SUC) can then be compared to a reference SUC. Reference levels for SUC are known to those skilled in the art and may include, for example, 400 μmol / L (male or female); 4.0-8.5 mg / dL or 0.24-0.51 mmol / L (male); approximately 453 μmol / L (male); 2.7-7.3 mg / dL or 0.16-0.43 mmol / L (female); or approximately 394 μmol / L (female). In some embodiments, the patient may be male or female. 【0041】 The monitoring described herein may be performed at one or more points in time with respect to treatment with iloperidone, an active metabolite of iloperidone, such as P88, or a pharmaceutically acceptable salt of iloperidone or its metabolite, for example, before administration, around day 28 of treatment, around day 21 of treatment, around day 14 of treatment, and around day 7 of treatment. In various embodiments, monitoring may be performed at one, two, three, four, or all five of the aforementioned points in time. Furthermore, monitoring may be continued periodically after day 28, for example, at intervals of approximately every 28 days thereafter. Such periodic monitoring may be continued over a predetermined period or over the entire treatment period of the patient. If periodic monitoring is continued over a predetermined period, the predetermined period may be linked to specific time units measured in units of weeks, months, or years. Alternatively, monitoring may continue until the patient reaches a steady-state serum uric acid concentration or a substantially steady-state serum uric acid concentration, which can be defined as reaching such a point, for example, over a certain number of monitoring events. 【0042】 The method may further include determining whether a patient is currently receiving treatment for gout, such as treatment with uric acid-lowering drugs, such as probenecid, allopurinol, febuxostat, or pegroticase, particularly in embodiments where the individual carries a gene variant associated with increased serum uric acid concentration induced by treatment with iloperidone, an active metabolite of iloperidone, such as P88, or a pharmaceutically acceptable salt of iloperidone or its metabolite. Such a genotype may be, for example, rs7442295-G / G. 【0043】 If a patient's SUC exceeds a baseline level on day 7, day 14, day 21, day 28, or one or more of the other points in time, and the patient is not currently receiving treatment for gout, the improved method includes initiating treatment with a uric acid-lowering agent while the patient is being treated with iloperidone, an active metabolite of iloperidone, e.g., P88, or a pharmaceutically acceptable salt of iloperidone or its metabolite. 【0044】 If the patient's SUC exceeds the baseline level on day 7, day 14, day 21, day 28, or one or more of the other points in time, and the patient is currently receiving treatment for gout, the improved method includes increasing the dose of the uric acid-lowering agent while the patient is being treated with iloperidone. Alternatively and / or additionally, treatment with a different uric acid-lowering agent may be initiated, either alone or in combination with the first uric acid-lowering agent. 【0045】 If the patient's SUC is within the normal range on day 7, day 14, day 21, day 28, or any other point in time, and the patient is not currently receiving treatment for gout, treatment with iloperidone, an active metabolite of iloperidone, e.g., P88, or a pharmaceutically acceptable salt of iloperidone or its metabolite may be maintained without the use of any uric acid-lowering medication, depending on the results of future or ongoing monitoring of the patient's SUC. 【0046】 If the patient's SUC is within the normal range on day 7, day 14, day 21, day 28, or any other point in time, and the patient is currently receiving treatment for gout, both treatment with iloperidone, an active metabolite of iloperidone, e.g., P88, or a pharmaceutically acceptable salt of iloperidone or its metabolite, and uric acid-lowering agents may be maintained at their respective dosages, depending on the results of future or ongoing monitoring of the patient's SUC. 【0047】 If a patient's SUC is within the normal range but is trending toward or approaching the normal range at one or more of the following points in time (day 7, day 14, day 21, day 28, or other times), various measures may be taken. For example, the frequency of monitoring may be increased and / or the duration of monitoring may be extended. In another example, treatment with uric acid-lowering drugs or upward dose adjustments of existing uric acid-lowering drugs may be used prophylactically to prevent the patient's SUC from exceeding the normal range at the next or future point in time. As will be understood by those skilled in the art, for example, a patient may be considered approaching the normal range if their SUC has increased to within approximately 5%, 10%, 15%, or 20% of the normal range, or if their SUC is within a predetermined range encompassing the normal range (e.g., ±5 μmol / L, ±10 μmol / L, ±15 μmol / L, etc.). Furthermore, a patient may be considered approaching the baseline level if, for example, the patient's SUC is increasing over one or more points in time and is on a trajectory that can be extrapolated to a value that may exceed or exceeds the baseline level. For example, if, on day 14 or 21 after the start of treatment with iloperidone, an active metabolite of iloperidone, e.g., P88, or a pharmaceutically acceptable salt of iloperidone or its metabolite, the patient's SUC is on an upward trajectory that has not yet exceeded the baseline limit, but is expected to exceed the baseline limit by, for example, day 28, assuming treatment is maintained, the patient may be considered approaching the baseline level, and precautionary measures may be taken as described herein. 【0048】 Initiating and / or increasing the dosage of uric acid-lowering drugs as described herein provides the benefit of reducing the likelihood that a patient will develop hyperuricemia and experience its adverse effects, such as future gout attacks. 【0049】 Those skilled in the art will understand that additional preferred embodiments may be selected by combining the preferred embodiments described above or by referring to the examples provided herein. [Examples] 【0050】 Example 1 A multicenter, randomized, double-blind, placebo-controlled trial ("Trial 3201") will be conducted to evaluate the safety and efficacy of iloperidone over four weeks in the treatment of patients with acute manic episodes associated with bipolar I disorder. In the trial, patients will be randomly assigned to receive either iloperidone orally as a divided dose of 12 mg twice daily (bid), totaling 24 mg / day, or to receive the corresponding placebo orally. 【0051】 Analysis of chemical test results revealed that patients treated with iloperidone showed a four-fold increase in serum uric acid levels from baseline at day 28 compared to the placebo group (a change of 33.4 μmol / L for iloperidone; a change of 4.2 μmol / L for placebo). These increases are shown in Figure 1 using filled data points. Analysis of patient data using the ANCOVA model revealed a statistically significant increase in serum uric acid levels with iloperidone compared to placebo (Table 1). The mean change in LS from baseline to endpoint was 27.2 μmol / L for iloperidone compared to 0.1 μmol / L for placebo. 【0052】 [Table 1] 【0053】 To test the hypothesis that serum uric acid levels change in relation to variants in the SLC2A9 gene, whole-genome sequencing was performed on blood samples, genotypes were obtained using standard data analysis, and a linear model for SLC2A9 variants was applied to uric acid concentrations in samples collected at baseline (adjusted for PC, age, and sex) and at end-of-study (EOS). 【0054】 One of the most significant variants detected is rs7442295 (p-value 10). -5(BETA = -23.12). The more common allele, rs7442295(A), is associated with higher baseline serum uric acid levels and hyperuricemia (defined as serum uric acid concentration above 400 μmol / L), with a reported odds ratio of 1.89 (CI: 1.36-2.61, p = 5 × 10⁻¹⁰). -5 Overall, 79% of European Caucasians carry one or two rs7442295(A) alleles, which result in higher serum uric acid levels. Each copy results in a mean increase of 20 μmol / L in baseline serum uric acid concentration and an approximate doubling of the risk of hyperuricemia. The rs7442295 variant has a minor allele frequency (MAF) of 0.24 overall, with the highest MAF reported in patients with African American ancestry (0.40). 【0055】 Figure 2 shows baseline assessment of serum uric acid levels according to patient genotype and sex. The data points in the leftmost three columns represent female patients (GG(15), AG(75), and AA(90)), and the data points in the rightmost three columns represent male patients (GG(19), AG(88), and AA(112)). The bars in each column represent the mean level of serum uric acid. In both males and females, individuals with the rs7442295(A / A) genotype have a higher mean baseline serum uric acid concentration than individuals of the same sex with the A / G or G / G genotype. Similarly, in both sexes, individuals with the rs7442295(G / G) genotype have a lower mean baseline serum uric acid concentration than individuals of the same sex with the A / G or AA genotype. The difference in serum uric acid levels between GG men and AA men is small, while the difference is large between GG women and AA women, indicating that the effect of the minor allele (G) at baseline is more pronounced in women. In general, male patients have higher mean serum uric acid concentrations at baseline than female patients. 【0056】 As shown in Figures 3 and 4, the target rs7442295 variant has a statistically significant effect on iloperidone-induced changes in serum uric acid levels from baseline to day 28 in patients with bipolar disorder. Figure 3 shows the change in serum uric acid levels (in μmol / L) from baseline to day 28 for individual patients grouped by treatment group (iloperidone or placebo) and prevalence of the rs7442295 variant, while Figure 4 shows the mean serum levels at baseline and day 28 in patient assessments, categorized by treatment group (iloperidone or placebo) and prevalence of the rs7442295 variant. Significant interactions affecting the changes are observed, particularly between genotype, sex, and treatment (full model: multiple R-squared: 0.09251, adjusted R-squared: 0.07078, F-statistic: 4.256 (DF8 and 334), p=0.00006942). 【0057】 These observations are statistically significant when comparing genotypes using EOS, and also when comparing GG genotypes with AG and AA genotypes between the treatment and placebo groups for both males and females combined. Table 2 (below) shows the mean change from baseline to day 28, separated by treatment group and prevalence of variant rs7442295. Table 3 (below) shows the mean change in serum uric acid levels (LS) from baseline to day 28, separated by treatment group and prevalence of variant rs7442295 (SD = standard deviation). 【0058】 [Table 2] 【0059】 [Table 3] 【0060】 These data demonstrate that the increase in serum uric acid levels associated with iloperidone is significant in individuals homozygous for the rs7442295(G) allele, i.e., individuals with the SLC2A9 rs7442295-G / G genotype. The change in serum uric acid levels from baseline to the study endpoint associated with the rs7442295-G / G genotype is particularly pronounced in males, as shown in Table 4 and Figure 5. 【0061】 [Table 4] 【0062】 The reference range for the upper normal number (ULN) of serum uric acid levels is 453 μmol / L for adult male patients and 394 μmol / L for adult female patients. Iloperidone-related increases in serum uric acid levels result in serum uric acid concentrations exceeding the ULN value, particularly in males who are homozygous (GG) for the rs7442295(G) allele of the SLC2A9 gene. As shown in Table 5 (below) and Figures 6A-6B, the proportion of male individuals with the rs7442295-G / G genotype and high uric acid levels (Figure 6B) increased approximately fourfold after iloperidone treatment, from about 8.3% at baseline to about 33.3% at the end of the study. 【0063】 [Table 5] 【0064】 These data indicate that iloperidone is associated with increased serum uric acid levels compared to placebo. The increase in serum uric acid levels is nearly double in iloperidone-treated patients who are homozygous for the common variant rs7442295(G) of the SLC2A9 transporter gene (i.e., patients with the (GG) genotype). 【0065】 Example 2 A study ("Study 3101") will be conducted to evaluate the efficacy and safety of iloperidone compared to placebo and an active control (ziprasidone) in subjects with acute schizophrenia. Patients will be randomly assigned to receive one of the following: iloperidone (24 mg / day, administered as a divided dose of 12 mg twice daily), active control ziprasidone, or placebo. At day 28, chemical analysis will show that the increase from baseline in serum uric acid levels in patients in the iloperidone treatment arm of the study is approximately four times greater than in the placebo group and more than twice as greater than the change from baseline observed in the ziprasidone arm. Uric acid results will be converted to SI units using the conversion of 1 mg / dL = 59.5 μmol / L. 【0066】 Analysis of patient data using the ANCOVA model revealed a statistically significant increase in serum uric acid levels in patients with acute schizophrenia with iloperidone compared to the placebo group. The mean change in LS from baseline to endpoint showed a similar relationship to that described in Example 1 above (see Table 1). Results including a 28.0 μmol / L increase with iloperidone compared to a 4.2 μmol / L decrease in the placebo group are shown in Table 6 below. The ziprasidone treatment arm showed an increase of 13.1 μmol / L, approximately half that seen with iloperidone treatment. 【0067】 [Table 6] 【0068】 Patient genotypes are obtained using a commercially available 500k SNP Gene Chip Human Mapping Array. To test the hypothesis that serum uric acid levels change in relation to variants in SLC2A9, a linear model for SLC2A9 variants is performed for baseline uric acid levels (adjusted for PC, age, and sex), and then applied to samples collected at end of study (EOS). 【0069】 Similar to Example 1 described herein, the target variant rs7442295(G) has a statistically significant effect on iloperidone-induced changes in serum uric acid levels from baseline in patients with schizophrenia, as measured at end-of-study (EOS). Figure 7 shows the change in serum uric acid levels from baseline to end-of-study, separated by the treatment group and the prevalence of variant rs7442295 in patients with schizophrenia. For each of the three genotypes (GG, AG, AA), the baseline and individual patient values ​​at the study endpoint are shown according to the treatment arm. Figure 8 shows the mean (SEM) serum uric acid levels at baseline and end-of-study (EOS), separated by the prevalence of variant rs7442295 in patients with schizophrenia. The results are presented in Tables 7 and 8. 【0070】 [Table 7] 【0071】 The observed and derived mean difference is most pronounced in the GG phenotype. This effect is statistically significant according to ANCOVA model analysis (see Table 7). 【0072】 [Table 8] 【0073】 Iloperidone-induced changes in serum uric acid levels from baseline, associated with the GG genotype, are particularly pronounced in male schizophrenic patients (see Figure 9). These findings mirror those observed in bipolar disorder in Example 1 above. 【0074】 conclusion The studies described in Examples 1 and 2 demonstrate that iloperidone is associated with increased serum uric acid levels compared to placebo in multiple clinical trials, including patients with bipolar disorder and patients with schizophrenia. 【0075】 In interaction with iloperidone treatment, the homozygous rs7442295(G / G) genotype is associated with increased iloperidone-induced changes in serum uric acid concentration. The increase in serum uric acid levels is nearly double in iloperidone-treated patients with the rs7442295(G / G) genotype in the SLC2A9 transporter gene. This effect is particularly pronounced in male patients. 【0076】 The replication of these findings across multiple trials and patient populations supports generalizing these findings to these and other patient populations (including generalizing to all individuals being treated, being treated, or potentially treated with iloperidone). 【0077】 As a result of the interactions described herein, patients receiving iloperidone with a history of gout or a family history of gout, and carriers of one or more rs7442295(G) alleles, are advised to undergo monitoring of their serum uric acid levels. This is because such individuals may need to increase the dosage of their respective uric acid-lowering therapies or initiate uric acid-lowering therapies to prevent or treat gout. 【0078】 While various embodiments are described herein, it will be understood from this specification that elements, modifications, or improvements therein can be combined in various ways by those skilled in the art, and that these are within the scope of the present invention. Furthermore, many modifications can be made without departing from the essential scope of the invention in order to adapt the teachings of the invention to specific situations or materials. Thus, the present invention is not limited to the specific embodiments disclosed, and is intended to encompass all embodiments included in the appended claims.

Claims

[Claim 1] An improvement to a method of treating patients with a history of gout who require treatment with iloperidone, a pharmaceutically acceptable salt of iloperidone, P88, or a compound that is a pharmaceutically acceptable salt of P88, To monitor the serum uric acid concentration (SUC) of the aforementioned patient, and If the SUC is approaching or exceeding the reference level, initiate uric acid-lowering therapy or increase the dosage of uric acid-lowering therapy. The improvements described above include. [Claim 2] The improvement according to claim 1, wherein the patient has one or more rs7442295-G alleles in the SLC2A9 gene. [Claim 3] The improvement according to claim 2, wherein the patient is homozygous (rs7442295-G / G) with respect to the rs7442295(G) allele in the SLC2A9 gene. [Claim 4] An improvement to a method of treating patients in need of treatment who have the rs7442295 genotype containing one or more rs7442295(G) alleles in the SLC2A9 gene with a compound that is iloperidone, a pharmaceutically acceptable salt of iloperidone, P88, or a pharmaceutically acceptable salt of P88, To monitor the serum uric acid concentration (SUC) of the aforementioned patient, and If the patient's SUC is approaching or exceeding the normal level, initiating uric acid-lowering therapy or increasing the dosage of uric acid-lowering therapy. The improvements described above include. [Claim 5] The improvement according to claim 1 or claim 4, wherein the compound is iloperidone, and the treatment comprises administering iloperidone at a dose of 24 mg / day or less. [Claim 6] The improvement according to claim 5, wherein the dose is 24 mg / day. [Claim 7] The improvement according to claim 6, wherein the dose of 24 mg / day is administered as 12 mg twice daily (bid). [Claim 8] The improvement according to claim 5, wherein the dose of 24 mg / day or less is given as a divided dose in two doses per day. [Claim 9] The improvement according to claim 1 or claim 4, wherein the reference level is 453 μmol / L if the patient is male, and 394 μmol / L if the patient is female. [Claim 10] The improvement according to claim 1 or claim 4, wherein the patient is female. [Claim 11] The improvement according to claim 1 or claim 4, wherein the patient is male. [Claim 12] The improvement according to claim 4, wherein the patient is homozygous (rs7442295-G / G) with respect to the rs7442295(G) allele in the SLC2A9 gene. [Claim 13] The improvement according to claim 1 or 4, wherein the initiation or increase reduces the likelihood that the patient will experience a gout attack in the future. [Claim 14] The improvement according to claim 1 or 4, wherein if the patient has an SUC within approximately 10% of the reference level, the patient is deemed to be approaching the reference level. [Claim 15] The aforementioned monitoring, To obtain a biological sample from the aforementioned patient, and To examine the biological sample and determine the concentration of uric acid in the biological sample. The improvement according to claim 1 or claim 4, including the improvement described in claim 1 or claim 4. [Claim 16] The aforementioned monitoring, On the 28th day or around the 28th day of the patient's treatment with iloperidone, On the 21st day or around the 21st day of treatment with the patient with iloperidone, On the 14th day or around the 14th day of the patient's treatment with iloperidone, On the 7th day or around the 7th day of the patient's treatment with iloperidone, and Before the patient's treatment with iloperidone The improvement according to claim 15, further comprising monitoring at one or more of the following points in time. [Claim 17] The improvement according to claim 16, wherein the monitoring further comprises performing monitoring at two or more of the aforementioned time points. [Claim 18] The improvement according to claim 17, further comprising performing monitoring at three or more of the aforementioned time points. [Claim 19] The improvement according to claim 18, further comprising performing monitoring at four or more of the aforementioned time points. [Claim 20] The improvement according to claim 19, wherein the monitoring further comprises performing monitoring at five of the aforementioned time points. [Claim 21] The improvement according to claim 4, wherein the patient has a history of gout. [Claim 22] The improvement according to claim 1 or claim 21, wherein the gout history is the patient's personal history of gout. [Claim 23] The improvement according to claim 1 or claim 21, wherein the history of gout is a family history of gout. [Claim 24] The improvement according to any one of claims 1 to 23, wherein the patient requires treatment for schizophrenia or bipolar disorder with iloperidone, the pharmaceutically acceptable salt of iloperidone, P88, or the pharmaceutically acceptable salt of P88. [Claim 25] The improvement according to any one of claims 1 to 24, wherein the patient requires treatment with iloperidone, the pharmaceutically acceptable salt of iloperidone, P88, or the pharmaceutically acceptable salt of P88 for schizophrenic disorder, acute manic episodes and mixed episodes associated with bipolar I disorder, agitation associated with Alzheimer's disease, agitation associated with dementia, agitation associated with autism, Parkinson's disease psychosis, or other psychotic disorder or disorder. [Claim 26] The improvement according to any one of claims 1 to 25, wherein the compound is P88 or a pharmaceutically acceptable salt thereof.

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