WO2011072244A1 - Méthode de traitement du cancer du sein utilisant le tamoxifène - Google Patents

Méthode de traitement du cancer du sein utilisant le tamoxifène Download PDF

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WO2011072244A1
WO2011072244A1 PCT/US2010/059927 US2010059927W WO2011072244A1 WO 2011072244 A1 WO2011072244 A1 WO 2011072244A1 US 2010059927 W US2010059927 W US 2010059927W WO 2011072244 A1 WO2011072244 A1 WO 2011072244A1
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tamoxifen
patient
dosage
levels
day
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PCT/US2010/059927
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English (en)
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Robert J. Desnick
Myra F. Barginear
George Raptis
Chunli Yu
Malgorzata Jaremko
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Mount Sinai School Of Medicine Of New York University
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Publication of WO2011072244A1 publication Critical patent/WO2011072244A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/138—Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
    • C12Q1/6883—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material
    • C12Q1/6886—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material for cancer
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/106—Pharmacogenomics, i.e. genetic variability in individual responses to drugs and drug metabolism

Definitions

  • Breast cancer is the most common non-cutaneous cancer in women in the Western world; the lifetime risk of developing invasive breast cancer in the United States is 12.6 percent (one in eight women). Jemal et al. (2008) CA Cancer J Clin 58:71-96. Two-thirds of breast cancer patients are estrogen receptor (ER)-positive and candidates for tamoxifen therapy, the drug used most worldwide for the prevention and treatment of hormone receptor- positive breast cancer. Aromatase inhibitors have become the first choice for adjuvant therapy in post-menopausal women with ER-positive breast cancer.
  • tamoxifen is the only hormonal agent approved by the United States Food and Drug Administration (FDA) for the prevention of breast cancer, the treatment of ductal carcinoma in situ, and the treatment of pre-menopausal breast cancer.
  • FDA United States Food and Drug Administration
  • Tamoxifen is also the hormonal agent most commonly employed in the treatment of early and advanced male breast cancer.
  • Tamoxifen (Z-l-(p-Dimethylaminoethoxyphenyl)-l,2-diphenyl-l-butene) is a prodrug that is converted to its therapeutically active metabolites, E-, Z- and Z' -4-hydroxy-N- desmethyltamoxifen (endoxifen) isomers and E-, Z- and Z' -4-hydroxy-tamoxifen (4-OH- Tam) isomers.
  • tamoxifen is demethylated by the cytochrome (CYP) P450 enzyme CYP3A4/5 to N-desmethyl-Tam, which is then hydroxylated to Z-endoxifen by CYP2D6 and to Z' -endoxifen by an unknown hepatic enzyme ( Figure 1).
  • Z-endoxifen and Z-4-OH-Tam both have an approximately 100-fold greater affinity for the ER and a 30- to 100-fold greater potency in suppressing estrogen-dependent cell proliferation.
  • the anti-estrogenic activities of the Z isomers of endoxifen and 4-OH-Tam are equivalent, while the Z' ⁇ endoxifen and Z' -4-OH-Tam are estimated to have about 10% of their Z isomer activity based upon in vitro studies.
  • the anti-estrogenic effects of endoxifen and 4-OH-Tam and presumably their Z and Z' isomers are suppression of ER-dependent proliferation of breast cancer cells, modulation of ER-mediated global gene expression, and ER degradation Lim et al. (2006) J Pharmacol Exp Ther 318:503-512.
  • the CYP2D6 gene is highly polymorphic, with more than 100 alleles having been identified to date (htt ://www .cypalleles .ki.se; Algeciras-Schimnich et al., 2008, Clin. Lab. Med. 28:553-567).
  • normal functional alleles include CYP2D6*1 , *2 and *35.
  • Homozygous normal individuals are classified phenotypically as extensive metabolizers (EM).
  • Duplicated normal alleles are classified as ultra-rapid metabolizers (UM).
  • Inactive alleles include CYP2D6*3-*8, * 11-* 16, *18-*21, *31, *38, *40, *42 and *44.
  • PM poor metabolizer
  • Reduced function alleles include CYP2D6*9, *10, *17, *29, *41 and *69.
  • Individuals having genotypes with one active and one inactive allele, or one inactive and one reduced function allele, or two reduced function alleles are classified phenotypically as intermediate metabolizers (IM), although those with one inactive and one reduced function allele also may be considered poor metabolizers (PM).
  • IM intermediate metabolizers
  • each CYP2D6 allele is assigned a value that reflects its expected enzymatic activity.
  • Fully functional CYP2D6 alleles (*1, *2, *2A) have a score of 1, and duplication of any of these alleles are given a score of 2.0.
  • Alleles associated with reduced enzyme activity (*9, *10, *17 and *41) are scored as 0.5, and CYP2D6 null alleles (*3-*8 ,*11, *12, *14 and *15) and their duplications are scored a 0.
  • the MPA score for and individual is the sum of their scores for both CYP2D6 alleles, which ranges between 0 and 3.0.
  • the present invention provides a method for the prevention and treatment of breast cancer with tamoxifen comprising the steps of determining the patient' s genotypic profile for one or more genes predictive of tamoxifen activity, and administering to the patient a dosage of tamoxifen based on the patient' s profile.
  • the present invention provides a method for treating a patient with tamoxifen, comprising the steps of: determining the patient's genotypic profile for one or more genes predictive of tamoxifen activity; administering tamoxifen to the patient at an initial dosage based on the patient's genotypic profile; performing a measurement of steady state plasma levels of one or more active metabolites of tamoxifen; and administering tamoxifen at an optimized dosage based on levels of active metabolites.
  • the present invention provides a method for treating a patient with tamoxifen, comprising the steps of: determining the patient's genotypic profile for one or more genes predictive of tamoxifen activity; administering tamoxifen to the patient at an initial dosage based on the patient's genotypic profile; performing a first measurement of steady state plasma levels of one or more active metabolites of tamoxifen; administering tamoxifen at a first optimized dosage based on levels of active metabolites in the first measurement; performing one or more subsequent measurements of steady state plasma levels of one or more active metabolites; and administering tamoxifen at an optimized dosage based upon the subsequent measurements of levels of active metabolites.
  • the present invention provides a method of optimizing treatment of breast cancer in a patient in need thereof comprising administering tamoxifen to the patient at an initial dosage of 20 mg/day, obtaining a sample of blood from the patient, measuring steady state plasma levels of one or more active tamoxifen metabolites in the sample, and administering an optimized dosage of tamoxifen to the patient based upon the level of one or more active tamoxifen metabolites.
  • tamoxifen dosage may be optimized using an Estrogen Receptor Activity Score based on the plasma levels of tamoxifen and its active metabolite isomers, and their relative anti-estrogenic activities.
  • Figure 1 depicts the pathways for conversion of tamoxifen to its therapeutically active metabolites. Part A depicts the pathway in CYP2D6 extensive and ultra-rapid metabolizers and part B depicts the pathway in CYP2D6 poor metabolizers.
  • Figures 2A-E show 60-day changes in plasma tamoxifen concentration of the women who received higher tamoxifen doses.
  • A Endoxifen
  • B 4-OH-Tamoxifen
  • C Z-Endoxifen
  • D Z'-Endoxifen.
  • E ER activity scores.
  • P- values indicate the effect of time and metabolic phenotype activity (MP A) score on the rate of change based on mixed models.
  • tamoxifen therapy can be optimized in breast cancer patients whose pharmacogenetic profile
  • IM or PM of tamoxifen as determined by pharmacogenetic profiles.
  • a therapeutic level of tamoxifen' s active metabolites is defined herein as a plasma endoxifen level of greater than or equal to about 40 nM or combined 4-OH-TAM and endoxifen levels of greater than or equal to about 50 nM.
  • the presence of genetic variants may alter uptake, metabolism, binding and excretion relative to wild-type such that therapeutic levels of tamoxifen's active metabolites are not achieved.
  • levels of endoxifen may be less than the accepted therapeutic level of greater than or equal to about 40 nM.
  • endoxifen can be achieved in patients having genetic variants associated with altered tamoxifen metabolism by increasing the standard dosage of tamoxifen to more than 20 mg/day, for example about 21 to about 50 mg/day, or about 25 to about 45 mg/day, or about 30 mg/day, or about 40 mg/day, or more preferably 30 mg/day or 40 mg/day.
  • tamoxifen as used in the present methods is defined as tamoxifen or its pharmaceutically acceptable salts such as tamoxifen citrate.
  • endoxifen and 4-OH-Tam include the Z and Z' isomers thereof.
  • the present invention provides a method for the prevention and treatment of breast cancer in a patient in need of such treatment comprising the steps of determining the patient's genotypic profile for one or more genes predictive of tamoxifen activity, and administering to the patient a dosage of tamoxifen based on the patient's profile.
  • the genes predictive of tamoxifen activity include the genes encoding CYP2D6, CYP3A5, CYP3A4, CYP2C19, UGT2B7, UGT2B15, UGT1A4 and SULTIAI.
  • genotypic profile is determined for one gene and the gene encodes CYP2D6. If the patient's genotype includes at least one null CYP2D6 allele, for example
  • the recommended initial dosage of tamoxifen is more than 20 mg/day.
  • the dosage of tamoxifen is from 21 to 50 mg/day, or from 25 to 45 mg/day. In other preferred embodiments, the dosage of tamoxifen is 30 mg/day or 40 mg/day. If the patient' s genotype includes at least one functional CYP2D6 allele, the dosage of tamoxifen is preferably 20 mg/day.
  • CYP allele nomenclature used herein is the art-recognized nomenclature of the Human Cytochrome P450 (CYP) Allele Nomenclature Committee.
  • the patient's genotypic profile can be determined by obtaining a nucleic acid- containing sample from the patient and performing genotyping methods known in the art.
  • the nucleic acid-containing sample may be, for example, whole blood, saliva, buccal cells, skin, hair, biopsies, and other nucleic acid-containing samples.
  • the nucleic acid-containing sample is whole blood.
  • Genotyping methods are known in the art and include, for example, multiplex allele specific primer extension and hybridization of extended primers to a solid support. Genotyping methods are disclosed, for example, by de Leon et al. (2006) Mol Diagn Ther 10:135-151 and in U.S. Patent Application Publications 2009/0215637 and 2010/0105041, the disclosures of which are incorporated herein by reference in their entireties. Kits for genotyping are also commercially available.
  • the present invention provides a method for treating a patient with tamoxifen comprising the steps of: determining the patient's genotypic profile for one or more genes predictive of tamoxifen activity; administering tamoxifen to the patient at an initial dosage based on the patient's genotypic profile; performing a measurement of steady state plasma levels of one or more active metabolites of tamoxifen; and administering tamoxifen at an optimized dosage based on levels of active metabolites and their relative individual anti-estrogenic activities.
  • the genes predictive of tamoxifen activity include the genes encoding CYP2D6, CYP3A5, CYP3A4, CYP2C19, UGT2B7, UGT2B15, UGT1A4 and SULTIAI.
  • the genotypic profile is determined for one gene and the gene encodes CYP2D6.
  • the patient's genotype includes at least one null CYP2D6 allele, for example CYP2D6*3-*8, *11, *12, *14 or *15, or at least one reduced function allele, for example CYP2D6*9, *10 , *17 or *41, and does not include a functional CYP2D6 allele, for example CYP2D6*1, *2, or *2A, then the initial dosage of tamoxifen is more than
  • the initial dosage of tamoxifen is from 21 to 50 mg/day, or from 25 to 45 mg/day. In other preferred embodiments, the initial dosage of tamoxifen is 30 mg/day or 40 mg/day. If the patient's genotype includes at least one functional CYP2D6 allele, the initial dosage of tamoxifen is preferably 20 mg/day. The patient' s genotypic profile can be determined by methods known in the art as described above.
  • the steady state plasma levels of one or more active metabolites of tamoxifen in the patient are measured.
  • the plasma levels are measured after at least about 30 days so that steady state levels of the metabolites have been reached.
  • the metabolite isomer levels may be measured after about 30 or more days, or after about 30 days of treatment at the initial dosage.
  • the tamoxifen active metabolite isomers are Z and Z' 4-OH-TAM and Z and Z' endoxifen.
  • the metabolites can be measured by obtaining a blood sample from the patient, and measuring the metabolite isomers by newer methods known in the art, including for example liquid chromatography/mass spectrometry.
  • the optimized dosage of tamoxifen is greater than the initial dosage, for example 30 mg/day or 40 mg/day. If the levels of active metabolite isomers are greater than or equal to therapeutic levels as defined hereinabove, the optimized dosage of tamoxifen is the same as or less than the initial dosage.
  • the levels of active metabolite isomers may optionally be monitored every month to annually and dosage optimized accordingly until steady state therapeutic levels of active metabolites are obtained.
  • the foregoing method may further comprise the steps of performing one or more subsequent measurements of steady state plasma levels of one or more active metabolite isomers, and administering tamoxifen at anoptimized dosage based upon the subsequent measurement of levels of active metabolite isomers.
  • the plasma levels are measured after at least about 30 days after treatment at the first optimized dosage so that steady state plasma levels of the active metabolite isomers have been reached.
  • the active metabolite isomer levels may be measured after about 30 or more days, or after 30 thirty days of treatment at the initial dosage. If the levels of active metabolite isomers are greater than or equal to therapeutic levels as defined hereinabove, the subsequent optimized
  • the present invention provides a method of optimizing treatment of breast cancer in a patient in need thereof comprising administering tamoxifen to the patient at an initial dosage of 20 mg/day, obtaining a sample of blood from the patient, measuring plasma levels of one or more active tamoxifen metabolite isomers in the sample, and administering an optimized dosage of tamoxifen to the patient based upon the level of one or more active tamoxifen metabolite isomers. If the levels of active metabolites are less than therapeutic levels as defined hereinabove, the optimized dosage of tamoxifen is greater than the initial dosage, for example 30 mg/day or 40 mg/day. If the levels of active metabolite isomers are greater than or equal to therapeutic levels as defined hereinabove, the optimized dosage of tamoxifen is the same as or less than the initial dosage.
  • tamoxifen dosage may be optimized based upon the steady state plasma levels of tamoxifen and the isomers of its active metabolites.
  • An anti-estrogenic activity estimate is calculated as Tam*0.01+Z-Endoxifen+Z'-Endoxifen*0.1+Z-4OH_Tam_+Z'-4OH- Tam*0.1 based on their individual anti-estrogenic activity and using steady state plasma concentrations (nM) of tamoxifen and its metabolites.
  • An anti-estrogenic activity estimate is considered therapeutically effective in a range preferably from about 30 to 50, more
  • Tamoxifen dosage may be increased if the anti-estrogenic activity estimate is below the effective range, and conversely, tamoxifen dosage may be decreased if the anti-estrogenic activity estimate is higher than the effective range.
  • tamoxifen may be administered orally or parentally.
  • Oral administration may be in solid dosage forms or liquid dosage forms.
  • Parenteral administration forms include, for example, emulsions and aqueous solutions of liposomes containing the active ingredient.
  • tamoxifen is administered orally in a solid dosage form such as a tablet.
  • tamoxifen is administered in the absence of administration of an agent that inhibits CYP2D6 or that produces an inhibitor through metabolism.
  • Inhibitors of CYP2D6 are known in the art and include, for example,
  • Medications leading to CYP2D6 inhibition were recorded according to their potency and defined as 1) weak, causing >1.25-fold, but ⁇ 2-fold increase in the plasma area under the curve (AUC), of endoxifen or 20-50% decrease in clearance, 2) moderate, causing a >2-fold increase in the plasma AUC values or 50-80% decrease in clearance, and 3) strong, causing a >5-fold increase in the plasma AUC values or more than 80% decrease in clearance.
  • AUC plasma area under the curve
  • For each patient medical histories, including self -reported race, a comprehensive list of current medications, and the results of clinical laboratory examinations were obtained. Peripheral blood samples were collected in heparinized tubes and plasma was separated within 1 hour of collection. Genotyping and tamoxifen metabolite levels were determined in the New York State and Clinical Laboratory Improvement Act (CLIA)- approved Genetic Testing
  • the study protocol was approved by the Institutional Review Boards at both study sites and all patients provided written informed consent.
  • Cytochrome P450 Allele Nomenclature Committee http://cypalleles.ki.se. Genotyping of functional (* 1, *2, *2A), reduced function (*9, *10, * 17 and *41) and non-functional (e.g., *3-*6, *8, *11, *12, * 14 and * 15) CYP2D6 alleles including their possible duplications was performed using Tag-ItTM Mutation Detection Kit P450-2D6 Version 2 (GeneMark).
  • the regions surrounding the mutations were multiplex polymerase chain reaction (PCR)- amplified, subjected to allele-specific primer extension, hybridized to specific Luminex ® beads via GeneMark Universal Tags, and sorted on a Luminex 100 xMAPTM platform (Luminex Corporation, Austin, TX).
  • PCR polymerase chain reaction
  • the CYP2D6 genotype for each participant was classified by the number of functional alleles to predict the individual's metabolizer phenotype. Individual's CYP2D6 alleles predicted his/her MPA score. Gaedigk et al. (2008 Clin Pharmacol Ther 83:234-242. Each CYP2D6 allele was assigned a value that reflected its expected enzymatic activity.
  • the ERAS was calculated from the plasma Tarn and active metabolite isomer concentrations as 0.01x[Tam] + lx[Z-endoxifen + Z-4-OH-Tam] + 0. lx[Z' -endoxifen + Z'-4-OH-Tam] based on their respective metabolite activity toward ER affinity.
  • Table 1 Patient Characteristics at Baseline.
  • patients may have been on more than 1 medication known to inhibit CYP2D6, see text.
  • Tables 6A and B Baseline Levels and up to 90-Day Plasma Tamoxifen Metabolite Concentration Changes of the 25 Women who Received Higher Dose
  • These subjects included patients who were CYP2D6 homozygous null (genotype*4/*4, no enzyme activity, MPA score of 0) (Patients #1 and #2; Table 6 and Figure 2). They received the higher dose for at least 60 days and increased their mean endoxifen and 4-OH-Tam levels by 24% from 32.5 to 40.4 nM and 45% from 9.5 to 13.8 nM, respectively.
  • the MAP score was significantly associated with the rate of change for Z and Z'- endoxifen levels, but not other metabolites.
  • MPA score of 1.5 or 2.0, respectively
  • Z-endoxifen levels increased more gradually than in other CYP2D6 carriers
  • their Z' -endoxifen levels remained the lowest compared to other genotype groups ( Figure 2C and 2D).
  • the mean ERAS for the 117 enrolled patients was 28.
  • the ERAS ranged from 7 to 27 at baseline.
  • the mean ERAS of patients in each MPA score increased.
  • the two patients with an MPA score of 0 increased from 14.4 to 18.8, or 24.5%; the five patients with a 0.5 MPA score increased from 14.2 to 36.4, or 122%; the nine with 1.0 MPA scores increased from 15.1 to 24.2, or 75.1%; the four patients with 1.5 MPA scores increased from 22.0 to 39.1, or 72.2%; and the four women with MPA scores of 2.0 increased from 14.4 to 40.2, or 110% (Table 6, Figure 2E).

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Abstract

L'invention concerne des procédés d'optimisation de la dose de tamoxifène pour prévenir ou traiter le cancer du sein, qui sont basés sur l'absorption, le métabolisme et l'excrétion de tamoxifène. Ces procédés servent principalement à guider des décisions thérapeutiques concernant des patients cancéreux individuels.
PCT/US2010/059927 2009-12-10 2010-12-10 Méthode de traitement du cancer du sein utilisant le tamoxifène WO2011072244A1 (fr)

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Cited By (4)

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Publication number Priority date Publication date Assignee Title
WO2015019030A1 (fr) * 2013-08-09 2015-02-12 Les Laboratoires Servier Nouvelle association entre le 6-({7-[(1-aminocyclopropyl)methoxy]-6-methoxyquinolein-4-yl}oxy)-n-methylnaphtalene-1-carboxamide et un anti-œstrogene dans le cancer du sein
US20150174082A1 (en) * 2012-06-01 2015-06-25 Bayer Technology Services Gmbh Genotype- or phenotype-based drug formulation
WO2017011623A1 (fr) * 2015-07-14 2017-01-19 Atossa Genetics Inc. Méthodes et compositions transpapillaires pour le traitement des affections mammaires
US11261151B2 (en) 2017-09-11 2022-03-01 Atossa Therapeutics, Inc. Methods for making and using endoxifen

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Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20150174082A1 (en) * 2012-06-01 2015-06-25 Bayer Technology Services Gmbh Genotype- or phenotype-based drug formulation
RU2683260C2 (ru) * 2012-06-01 2019-03-27 Байер Акциенгезельшафт Фармацевтические композиции на основе генотипа или фенотипа
US10285958B2 (en) 2012-06-01 2019-05-14 Bayer Aktiengesellschaft Genotype- or phenotype-based drug formulation
CN110075097A (zh) * 2012-06-01 2019-08-02 拜耳股份公司 基于基因型或表型的药物制剂
WO2015019030A1 (fr) * 2013-08-09 2015-02-12 Les Laboratoires Servier Nouvelle association entre le 6-({7-[(1-aminocyclopropyl)methoxy]-6-methoxyquinolein-4-yl}oxy)-n-methylnaphtalene-1-carboxamide et un anti-œstrogene dans le cancer du sein
FR3009497A1 (fr) * 2013-08-09 2015-02-13 Servier Lab Nouvelle association entre le 6-({7-[(1-aminocyclopropyl)methoxy]-6-methoxyquinolein-4-yl}oxy)-n-methylnaphtalene-1-carboxamide et un anti-oestrogene dans le cancer du sein
WO2017011623A1 (fr) * 2015-07-14 2017-01-19 Atossa Genetics Inc. Méthodes et compositions transpapillaires pour le traitement des affections mammaires
US11261151B2 (en) 2017-09-11 2022-03-01 Atossa Therapeutics, Inc. Methods for making and using endoxifen
US11572334B2 (en) 2017-09-11 2023-02-07 Atossa Therapeutics, Inc. Methods for making and using endoxifen
US11680036B1 (en) 2017-09-11 2023-06-20 Atossa Therapeutics, Inc. Methods for making and using endoxifen

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