EP1115871A2 - Composition pharmaceutique de pretraitement d'un patient necessitant un medicament ou un promedicament - Google Patents

Composition pharmaceutique de pretraitement d'un patient necessitant un medicament ou un promedicament

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Publication number
EP1115871A2
EP1115871A2 EP99950530A EP99950530A EP1115871A2 EP 1115871 A2 EP1115871 A2 EP 1115871A2 EP 99950530 A EP99950530 A EP 99950530A EP 99950530 A EP99950530 A EP 99950530A EP 1115871 A2 EP1115871 A2 EP 1115871A2
Authority
EP
European Patent Office
Prior art keywords
drug
enzyme
pro
patient
polynucleotide
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP99950530A
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German (de)
English (en)
Inventor
Alfred Slanetz
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Transgene SA
Original Assignee
Transgene SA
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Filing date
Publication date
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Publication of EP1115871A2 publication Critical patent/EP1115871A2/fr
Withdrawn legal-status Critical Current

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Classifications

    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7088—Compounds having three or more nucleosides or nucleotides
    • A61K31/7105—Natural ribonucleic acids, i.e. containing only riboses attached to adenine, guanine, cytosine or uracil and having 3'-5' phosphodiester links
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/43—Enzymes; Proenzymes; Derivatives thereof
    • A61K38/44—Oxidoreductases (1)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/43—Enzymes; Proenzymes; Derivatives thereof
    • A61K38/44—Oxidoreductases (1)
    • A61K38/443—Oxidoreductases (1) acting on CH-OH groups as donors, e.g. glucose oxidase, lactate dehydrogenase (1.1)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/32—Alcohol-abuse
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/36—Opioid-abuse
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
    • C12N9/0004—Oxidoreductases (1.)
    • C12N9/0071—Oxidoreductases (1.) acting on paired donors with incorporation of molecular oxygen (1.14)
    • C12N9/0077—Oxidoreductases (1.) acting on paired donors with incorporation of molecular oxygen (1.14) with a reduced iron-sulfur protein as one donor (1.14.15)
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
    • C12N9/10—Transferases (2.)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K48/00—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy

Definitions

  • the present invention concerns the preparation of a pharmaceutical composition for the pre-treatment of a patient in need of a drug or a pro-drug wherein said drug or pro-drug is over or under metabolized in said patient, and uses of such pharmaceutical composition.
  • Drugs or pro-drugs after their in vivo administration are metabolized in order to be eliminated either by excretion or by metabolism to one or more active or inactive metabolites (Meyer, J. Pharmacokinet. Biopharm. 24 (1996), 449-459).
  • the systems which are involved in these metabolisms are enzymatic pathways (involving for example, cytochrome P450, dehydrogenases, oxidases, esterases, reductases and a number of conjugating enzymatic systems including methyl transferase, glutathione-s-transferase, arylhydrocarbon hydroxylase, sulfotransferase, glucuronyl transferase or N-acetyl transferase) localized in specific organs (mainly in the liver) (Ferrero, Adv. Pharmacol. 43 (1997), 131-169).
  • enzymatic pathways involving for example, cytochrome P450, dehydrogenases, oxidases, esterases, reductases and a number of conjugating enzymatic systems including methyl transferase, glutathione-s-transferase, arylhydrocarbon hydroxylase, sulfotransferase, glucuronyl
  • the cytochrome p450 enzyme which is responsible for the metabolism of the majority of drugs given to human, bears the brunt of the load metabolizing drugs into products that are more readily excreted into the urine and feces. It is furthermore well known that the level of these enzymes can affect the rate of metabolism of drugs/pro-drugs and that these levels can be induced by certain drugs or be correlated to genetic polymorphisms between individuals (e.g. amplification of the genes encoding said enzymes). Similarly, inter-individual variability can result of genetic alterations (e.g. deletions) that lead to low expression of the enzymes or expression of deficient isoforms of the enzymes.
  • the metabolism rate is also high and therefore a) the drug is rapidly cleared leading to an inefficient concentration of the drug in blood or tissue and to a resistance to the implemented therapy or b) the pro-drug is excessively converted into its active form which can reach toxic levels in the patient.
  • the metabolism rate is also low leading to c) an inefficient drug clearance, toxic drug concentration in the blood and tissue or d) an inefficient pro-drug conversion, low rate of active drug and therefore inefficient treatment (see, for review, Ozama, J. Toxicol. Sci. 21 (1996), 323-329).
  • P450 enzymes are involved in the metabolism of numerous physiological substrates such as steroids, fatty acids, prostaglandins, cytokines, bile acids (Nebert and Nelson, 1991 , Methods in Enzymology, 206, 3-11 ).
  • P450 enzyme is a super-family of various enzymes, many of which metabolize a wide range of foreign chemicals including drugs. Genetic polymorphisms have been identified, for example among six of the P450 enzymes named CYP1A1 , CYP2C9, CYP2C19, CYP2E1 , CYP3A4 and CYP2D6 which can alter enzymatic response to drugs and define slow or ultrarapid metabolizer isoforms (Guengerich, Chem.
  • N-acetyltransferase isoforms can divide patients into slow acetylators, ultrarapid acetylators and moderate acetylators (wild type).
  • the level of expression of the CYP enzymes can also enhance/inhibit the rate of metabolism of specific drugs and lower/improve plasma levels of targeted drugs, such as warfarin or quinidin.
  • This enzyme expression can furthermore be induced/inhibited to an extent which varies from patient to patient by other drugs, such as phenobarbitol or rifampin.
  • some administered drugs e.g. coumarin
  • have a narrow therapeutic window which, if metabolism is too slow, can result in excessive anticoagulation effect.
  • many of the adverse drug interactions can occur due to mutual interaction with the same enzymes.
  • CYP3A is a major route of metabolism for cyclosporine, quinidine, lovastatin, warfarin, nifedipine, lidocaine, terfenadine, astemizole, cisapride, methylprednisolone, carbamazepine, midazolam, triazolam or erythromycin, for example.
  • Inhibition of CYP3A by gene alteration (slow isoform) or inhibition of CYP3A gene expression with another drug, such as ketoconazole, itraconazole, fluconazole, diltiazem, nicardipine or verapamil can result in increased side effects which can induce organ damages.
  • CYP2D6 is the main metabolizing enzyme for antiarrhythmic agents (e.g. propaferone, flecainide), beta-ad renoreceptor blockers (e.g. timolol, metoprolol or alprenolol), tricyclic antidepressants (e.g. nortriptyline, desipramine, imipramine or clomipramine), neuroleptic drugs (e.g. perphenazine, thioridazine or haloperidol), selective serotonin reuptake inhibitors (e.g. fluoxetine or paroxetine) and opiates (e.g. codeine or dextromethorphan).
  • antiarrhythmic agents e.g. propaferone, flecainide
  • beta-ad renoreceptor blockers e.g. timolol, metoprolol or alprenolol
  • tricyclic antidepressants e.g. nor
  • poor ability to metabolize codeine translates into impaired production of the active metabolite morphine resulting in a lower analgesic effect.
  • Poor ability to metabolize can also result in systemic side effects for many of drugs.
  • ophtalmic administration of timilol in a patient with slow metabolizer CYP2D6 isoform can result in systemic beta-adrenoreceptor blockade.
  • 20% of Caucasians are slow metabolizers of drugs due to impaired CYP2D6 activity.
  • CYP2C19 metabolizes drugs such as mephenytoin, omeprazole, proguanil, diazepam or citalopram.
  • Patients with the slow metabolizer isoform of CYP2C19 are 100 to 200 fold less efficient than normal patients at metabolizing said drugs.
  • a regular dose of mephenytoin to slow metabolizers will result in higher drug levels, exaggerated pharmacologic responses and toxicity.
  • 5% of Caucasians and 20% of Orientals are slow metabolizers due to impaired CYP2C19 activity.
  • Isoniazid, hydralazine, procainamide as well as other drugs are metabolized in the liver by N-acetyltransferase. If a drug is converted into its active form or is eliminated by acetylation, the pharmacologic response and toxicity will be exaggerated in the slow and ultrarapid acetylator patients subsets, respectively. 28% of Caucasians and 7% of Orientals are slow acetylators while 5% of Caucasians and 15% of Orientals are ultrarapid acetylators due to different isoforms of N-acetyltransferase (NAT-1 , NAT-2).
  • pharmacogenomics has been proposed as a tool useful in the identification and selection of patients which can respond to a particular drug without side effects.
  • This identification/selection can be based upon molecular diagnosis of genetic polymorphisms by genotyping DNA from leukocytes in the blood of patient, for example, and characterization of disease (Bertz, Clin. Pharmacokinet. 32 (1997), 210-256; Engel, J. Chromatogra. B. Biomed. Appl. 678 (1996), 93-103).
  • a promising drug/pro-drug could be cleared from the market because it is not universal or economically not satisfactory because targeted to a restricted patient population and segmented market; a drug/pro-drug can be approvable but its use should provide improved dosing recommendations in product labeling by allowing the prescriber to anticipate, without any guarantee related to the security, necessary to dose adjustments depending on the considered patient group, with a real risk of causing harm or death by prescribing the wrong drug to the wrong patients at the wrong dose; no solution are proposed for patients with slow or ultrarapid metabolism ; many drugs in cancer care, for example, are quite toxic, but they are approvable because cancer is a fatal illness with no known cure and in this particular case, pharmacogenomic selection presents no utility.
  • the present invention proposes a way to recapture missed patients for a particular drug/pro-drug therapy, to decrease side effects related to altered metabolism of drug/pro-drug and to inhibit drug interaction.
  • the present invention first concerns the use of a first polynucleotide which encodes or is complementary to the sequence which encodes a functional first enzyme isoform, said first enzyme being involved in in vivo metabolism of a first drug or pro-drug, for the preparation of a pharmaceutical composition for the pre- treatment by gene therapy of a patient in need of said first drug or pro-drug wherein said first drug or pro-drug is over or under metabolized by said first enzyme in said patient.
  • in vivo metabolism of a drug or pro-drug means that the drug or pro-drug are enzymatically transformed into soluble and excretable metabolites in order to clear it from the body or processed from an inactive pro-drug form into an active one, respectively (Meyer, J. Pharmacokinet Biopharm. 24 (1996), 449-459, is herein included as part of the description).
  • “Over metabolized” means that the drug/pro-drug is very actively and rapidly cleared from the body (eg. in feces or urine) leading to an inefficient concentration of the drug in blood or tissue and to a resistance to the implemented therapy; or that the pro-drug is excessively converted into its active form which can reach toxic levels in the patient.
  • This over metabolization can be associated with an over expression of the metabolizing enzyme (and therefore over concentration of this enzyme in blood or tissue); or with the expression of an ultrarapid enzyme isoform.
  • Under metabolized means that the drug/pro-drug is insufficiently cleared from the body leading to toxic drug level; or that the pro-drug is insufficiently converted into its active form leading to a low rate of active drug in blood or tissue and therefore inefficient treatment.
  • This under metabolization can be associated with an under expression of the metabolizing enzyme or with synthesis of altered enzyme isoform (slow isoform).
  • Gene therapy is understood as a method for the introduction of a polynucleotide into cells.
  • it concerns the case where the gene product (enzyme for example) is expressed in a target tissue as well as the case where the gene product is excreted, especially into the blood stream.
  • lipid-mediated transfection compounds are DOTMA (Feigner, PNAS 84 (1987), 7413-7417), DOGS or TransfectamTM (Behr, PNAS 86 (1989), 6982-6986), DMRIE or DORIE (Feigner, Methods 5 (1993), 67- 75), DC-CHOL (Gao, BBRC 179 (1991 ), 280-285), DOTAPTM (McLachlan, Gene
  • non-viral delivery systems have been developed which are based on polymer-mediated transfection.
  • anionic polymers such as, for example, polyamidoamine (Haensler, Bioconjugate Chem. 4 (1993), 372-379), dendritic polymer (WO 95/24221 ), polyethylene imine or polypropylene imine (WO 96/02655), polylysine (US-A-5,595,897 or FR-A-2 719 316).
  • Polynucleotide may be a DNA and/or RNA fragment, single or double-stranded, linear or circular, natural or synthetic, modified or not (see US 5,525,711 ; US 4,711 ,955 or EP 302 175 for modification examples) defining a fragment or a portion of a nucleic acid, without size limitation. It may be, inter alia, a genomic DNA, a cDNA, a mRNA, an antisense RNA, a ribozyme, or DNA encoding such RNAs. "Polynucleotides” and “nucleic acids” are synonyms with regard to the present invention.
  • the polynucleotide may also be in the form of a plasmid or linear polynucleotide which contains at least one coding sequence of polynucleotide that can be transcribed and translated to generate enzyme involved in in vivo metabolism of drug or pro-drug.
  • the polynucleotide can also be an oligonucleotide which is to be delivered to the cell, e.g., for antisense or ribozyme functions.
  • said polynucleotide can also be formulated with viral proteins, or cationic lipids, or cationic polymers as vectors facilitating polynucleotide uptake into cells.
  • both DNA and RNA can be delivered to cells to form therein all or part of enzyme, this product being able to metabolize in vivo drug or pro-drug. This product may further stay within the cell or be secreted from the cell.
  • plasmid DNA is preferred. If the nucleic acids contain the proper genetic information, they will direct the synthesis of relatively large amounts of the encoded enzyme.
  • the genetic information necessary for expression by a target cell comprise all the elements required for transcription of said DNA into mRNA and for translation of mRNA into polypeptide. Transcriptional promoters suitable for use in various vertebrate systems are well known.
  • suitable promoters include viral promoters RSV, MPSV, SV40, CMV or 7.5k, vaccinia promoter, inducible promoters, etc.
  • Nucleic acids can also include intron sequences, targeting sequences, transport sequences, sequences involved in replication or integration. Said sequences have been reported in the literature and can be readily obtained by those skilled in the art. Nucleic acids can also be stabilized with specific components such as spermine. According to the invention, the polynucleotide can be homologous or heterologous to the target expressing cells.
  • a functional enzyme isoform (also called “moderate” or “wild type isoform”) designates ail or part of a polypeptide showing enzymatic properties comparable to those of the functional enzyme (wild type) naturally involved in drug metabolism pathway.
  • “Slow metabolizers isoforms of an enzyme” designates enzyme isoforms which have low or no ability to metabolize drugs compared to the functional isoform.
  • Pre-treatment of patient means that the pharmaceutical preparation of the present invention is intended to be administered to patients in conjunction with or separately, simultaneously or preferably prior, to a drug/pro-drug administration to patients in need of said drug/pro-drug treatment.
  • “Slow metabolizer patient” means that in said patient drug/pro-drug is under metabolized by the related metabolizing enzyme.
  • “ultrarapid metabolizer patient” means that in said patient drug/pro-drug is over metabolized by the related metabolizing enzyme.
  • the patient is an ultrarapid metabolizer patient which means that in this patient, before pre-treatment with the pharmaceutical composition of the invention, said first drug or pro-drug is over metabolized by said first enzyme.
  • the ultrarapid metabolizer phenotype can be correlated to an enhanced expression of the gene encoding said first enzyme into the patient cells or to an enhancement of the activity of said first enzyme (ultrarapid first enzyme isoform).
  • said first polynucleotide is an antisense RNA complementary to all or part of the sequence which encodes said first enzyme. In this specific case, the observed over metabolism in the patient is associated to high level expression of said enzyme.
  • Antisense gene therapy has been widely disclosed in literature (for a review see for example Gura, Science 270 (1995), 575-577). By computerized analysis, antisense sequences can easily be determined which can bind in vivo to the gene or the RNA encoding said first enzyme in order to block its synthesis and reduce its level into the patient.
  • said first drug or pro-drug is under metabolized by said first enzyme in said patient.
  • This patient is a slow metabolizer patient which means that in this patient, before pre-treatment with the pharmaceutical composition of the invention, said first drug or pro-drug is under metabolized by said first enzyme.
  • the polynucleotide encodes a functional isoform of said first enzyme.
  • This first enzyme can also be selected in the group including enzymes responsible for acetylation, methylation, glucuronidation, sulfation or de-esterification.
  • said first enzyme is an enzyme produced by the liver, and more specifically is selected in the group consisting in cytochrome p450, UDP- glucuronosyl transferase, methyl transferase and N-acetyl transferase and their isoforms.
  • said first enzyme is selected in the group consisting in cytochrome p450 enzymes named CYP1A1 , CYP2C9, CYP2C19, CYP2E1 , CYP3A4 and CYP2D6.
  • said first drug or pro-drug is selected from the group consisting in propafenone, flecainide, trimolol, metropolol, alprenolol, nortriptyline, desipramine, imipramine, clomipramine, perphenazine, thioridazine, haloperidol, fluoxetine, paroxetine, codeine and dextromethorphan.
  • said first drug or pro-drug is selected from the group consisting in cyclosporine, erythromycin, methylprednisolone, carbazepine, midazolam, triazolam, quinidine, lovastin, warfarin, nifedipine, lidoca ⁇ ne, terfenadine, astemizolam and cisapride.
  • said first enzyme is the cytochrome p450 enzyme named CYP2C19
  • said first drug or pro-drug is selected from the group consisting in mephenytoin, omoprazole, proguanil, diazepam and citalopram.
  • said first enzyme is the N-acetyl transferase
  • said first drug or pro-drug is selected from the group consisting in isoniazid, hydralazine and procainamide.
  • the invention is therefore further directed to the use of a first polynucleotide which encodes or is complementary to the sequence which encodes a functional first enzyme isoform, said first enzyme being involved in in vivo metabolism of a first drug or pro-drug, said first drug or pro-drug being involved in activation or inhibition of the expression of a second polynucleotide which encodes a second enzyme involved in a second drug or pro-drug in vivo metabolism, for the preparation of a pharmaceutical composition for the pre-treatment of patient in need of said first and second drug or pro-drug wherein said second drug or pro-drug is over or under- metabolized by said second enzyme and said first drug or pro-drug is under- metabolized in said patient.
  • the activation/inhibition of the second drug/pro-drug metabolism can result of activation/inhibition by a first drug/pro-drug a) of the expression level of the polynucleotide encoding said second enzyme or b) of the enzymatic activity of said second enzyme.
  • the second enzyme is defined as previously described for the first one.
  • the first and second enzymes are selected in the group consisting in cytochrome p450 enzymes named CYP1A1 , CYP2C9, CYP2C19, CYP2E1 , CYP3A4 and CYP2D6.
  • said first and second enzymes are different and are involved in metabolism of different first and second drug/pro-drug, respectively.
  • the first drug or pro-drug is involved in activation of said second enzyme.
  • said first drug or pro-drug is phenobarbitol or rifampicin and said second enzyme is a cytochrome P450 isoform.
  • the first drug or pro-drug is involved in inhibition of said second enzyme.
  • said first drug or pro-drug is quinine
  • said second enzyme is a CYP2D6 isoform
  • said first enzyme is CYP3A4.
  • said first drug or pro-drug is selected in the group consisting in cyclosporine, erythromycine, ketoconazole, itraconazole, fluconazole, diltiazen, nicardipine and verapamil involved in inhibition of said second enzyme which is a CYP isoform and said second drug is selected in the group consisting in cyclosporine, quinidine, lovastine, warfarin, nifectipine, loidocaine, terfenadine, astemizole, cisapride, erythromycin, methylprednisolone, carbamazepine, midazolam and triazolam.
  • the targeted patient is in need of at least a first drug/pro-drug but is also a slow or ultrarapid metabolizer for said first drug/pro- drug. Therefore, administration of said drug/pro-drug to said patient can be correlated to inefficient or toxic level of active drug in blood or tissue and consequently to possible organ damages or toxicity.
  • the invention further relates to uses as previously disclosed to prevent or to treat organ damage or toxicity in patient, and more particularly hepatic or renal damages or toxicity.
  • said hepatic damage is alcoholism. Alcoholism could be a side effect of drug/pro-drug delivery and inefficient metabolism. It can also result from the deleterious effects of alcohol which are caused by its metabolism.
  • Brown Pharmacogenetics 8 (1998), 335-342) have focused their attention upon gene encoding ethanol metabolizing enzymes. They have identified related polymorphisms in gene loci-cytochrome p4502E1 (CYP2E1 ) and alcohol dehydrogenase 3 (ADH3). In this special case, ethanol could be considered as a drug equivalent even when this drug is not administered with therapeutic prospect.
  • CYP2E1 gene loci-cytochrome p4502E1
  • ADH3 alcohol dehydrogenase 3
  • the targeted patient can be an opiate or cocaine user.
  • Ibogaine for example, is a psychoactive alkaloid that possesses potential as an agent to treat opiate or cocaine addiction.
  • the primary metabolite arises via O-demethylation at the 12-position to yield 12-hydroxyibogamine.
  • Obach, (Drug Metab. Dispos. 26 (1998), 764-768) have presented evidence that the O- demethylation of ibogaine observed in the liver is catalyzed primarily by the polymorphically expressed cytochrome p4502D6 (CYP2D6). Therefore, over- or under-metabolism of ibogaine, or related drug/pro-drug involved in treatment of drug addiction, could have effect in said treatment.
  • CYP2D6 polymorphically expressed cytochrome p4502D6
  • the invention is also related to uses to improve or enable efficacy of first and or second drug/pro-drug.
  • the present invention concerns preparation of therapeutic composition for administration into vertebrate target tissues, and more specifically into the liver. Said administration can be performed by different delivery routes (systemic delivery and targeted delivery).
  • the prepared therapeutic composition is preferably administered into organ involved in drug/pro-drug metabolism, however prepared therapeutic composition administration can also occur in other tissues of the vertebrate body including those of muscle, skin, brain, lung, liver, spleen, bone marrow, thymus, heart, lymph, bone, cartilage, pancreas, kidney, gall bladder, stomach, intestine, testis, ovary, uterus, rectum, nervous system, eye, gland, connective tissue, blood, tumor, etc.
  • the polynucleotide encoded enzyme can thus be excreted in body fluids (e.g., blood) allowing its delivery in metabolizing organs or said polynucleotide can be associated with targeting molecules which are capable to point its uptake into targeted cells.
  • Gene therapy literature provides many mechanisms for efficient and targeted delivery and expression of genetic information within the cells of a living organism (see for example European patent application EP-0 401 108.0).
  • Said administration may be made by intradermal, subdermal, intravenous, intramuscular, intranasal, intracerebral, intratracheal, intraarterial, intraperitoneal, intravesical, intrapleural, intracoronary or intratumoral injection, with a syringe or other devices.
  • Transdermal administration is also contemplated, as are inhalation or aerosol routes.
  • the invention also pertains to a pharmaceutical composition for the pre-treatment of patient in need of a drug or pro-drug wherein said drug or pro-drug is over or under metabolized by a natural enzyme in said patient, said composition comprising a polynucleotide which encodes or is complementary to the sequence which encodes a functional enzyme isoform, said enzyme being involved in in vivo metabolism of a drug or pro-drug .
  • the pharmaceutical composition in accordance with the present invention comprises a polynucleotide which encodes or is complementary to the sequence which encodes a functional isoform of an enzyme produced by the liver, and more specifically which is selected in the group consisting in cytochrome p450, UDP- glucuronosyl transferase, methyl transferase, N-acetyl transferase and alcohol dehydrogenase 3 (ADH3).
  • said enzyme is selected in the group consisting in cytochrome p450 enzymes named CYP1A1 , CYP2C9, CYP2C19, CYP2E1 , CYP3A4 and CYP2D6.
  • the pharmaceutical composition comprises an antisense RNA complementary to all or part the sequence which encodes said first enzyme.
  • the polynucleotide which is contained in the pharmaceutical composition is a DNA.
  • Other particular embodiments of the invention are pharmaceutical compositions wherein said polynucleotide is naked, associated with viral polypeptides or complexed with cationic components, more preferably with cationic lipids.
  • the concentration of polynucleotide in the pharmaceutical compositions is from about 0.1 ⁇ g/ml to about 20 mg/mi.
  • the pharmaceutical composition further comprises a pharmaceutically acceptable injectable carrier.
  • the carrier is preferably isotonic, hypotonic or weakly hypertonic and has a relatively low ionic strength, such as provided by a sucrose solution. It includes any relevant solvent, aqueous or partly aqueous liquid carrier comprising sterile, pyrogen-free water, dispersion media, coatings, and equivalents.
  • the pH of the pharmaceutical preparation is suitably adjusted and buffered.
  • the pharmaceutical composition of the present invention comprises an instruction for use of said pharmaceutical composition (e.g., a leaflet) describing that said pharmaceutical composition is used according to the present invention, i.e. for the pre-treatment of a patient in need of above said first drug or pro-drug, wherein said first drug or pro-drug is over or under metabolized by above said first enzyme in said patient.
  • said instruction for use describes that the pharmaceutical composition of the present invention is used for the pre-treatment of a patient in need of above said first and second drug or pro- drug, wherein said second drug or pro-drug is over or under metabolized by said second enzyme and said first drug or pro-drug is under metabolized in said patient.
  • the constructs below described have been made according to the molecular cloning methods described in Maniatis et al., (1989, Laboratory Manual, Cold Spring Harbor, Laboratory Press, Cold Spring Harbor, NY).
  • the homologous recombinant steps are preferably realized in E. coli BJ 5183 strain (Hanahan, J. Mol. Biol. 166 (1983), 557-580).
  • the adenoviral fragments used are defined with reference to their position in the Adenovirus 5 genome sequence as disclosed in GenBank, Accession number M73260. Cells are transfected and cultured according to technique widely used in the art.
  • CYP1A1 The coding region of CYP1A1 has been amplified by PCR using a human cDNA library and primer oligonucleotides, defined with reference to CYP1A1 sequence available on GenBank, Accession number NM 000499, and comprising EcoRI and Xbal restriction sites:
  • EcoRI and Xbal restriction sites have been respectively introduced in 5' and 3' end of the CYP1A1 coding sequence.
  • the PCR fragment is then digested with EcoRI and Xbal, and inserted into pCI-neo plasmid (Promega Corp) leading to pCI- neoCYP1A1.
  • the fragment Xhol-Xbal of pCI-neoCYP1A1 including the CYP1A1 coding sequence is isolated and subcloned into the vector pTG6600 (Lathe et al, 1987, Gene 57, 193-201 ) linearized wit the same enzymes.
  • the resulting transfert vector is named pTG6600 CYP1 A1.
  • the adenoviral vector Ad CYP1 A1 is produced by homologous recombination in E. coli BJ 5183 strain between the Pacl-BstEII fragment of pTG6600 CYP1A1 and vector pTG6624 linearized with Clal.
  • the final construct Ad CYP1A1 comprises the E1 (nucleotides 459 to 3328) and E3 (nucleotides 28249 to 30758) deleted Ad5, comprising in the E1 region an expression cassette containing CYP1A1 coding sequence under the control of CMV promoter.
  • Adenoviral particles are produced after transfection of 293 cell line (ATCC CRL1573).
  • Said recombinant adenoviral vector might be used for preparing the composition of the present invention by combining it with a sucrose solution which is known as a pharmaceutically acceptable injectable carrier.
  • CYP2C19 coding sequence (GenBank Accession number NM 000769), CYP2E1 (GenBank Accession number D11131 ), CYP2D6 coding sequence (GenBank Accession number NM 000106) or ADH3 coding sequence (GenBank Accession number NM 000669).
  • CYP1A1 coding sequence available on GenBank, Accession number NM 000499, CYP2C19 coding sequence (GenBank Accession number NM 000769), CYP2E1 coding sequence (GenBank Accession number AF 084225), CYP3A4 coding sequence (GenBank Accession number D11131 ), CYP2D6 coding sequence (GenBank Accession number NM 000106) or ADH3 coding sequence (GenBank Accession number NM 000669).

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Abstract

L'invention concerne des compositions pharmaceutiques destinées au prétraitement d'un patient nécessitant un médicament ou un promédicament, ce médicament ou ce promédicament étant surmétabolisé ou sous-métabolisé chez le patient. L'invention concerne également les utilisations de ces compositions pharmaceutiques.
EP99950530A 1998-09-21 1999-09-21 Composition pharmaceutique de pretraitement d'un patient necessitant un medicament ou un promedicament Withdrawn EP1115871A2 (fr)

Applications Claiming Priority (3)

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US15736698A 1998-09-21 1998-09-21
US157366 1998-09-21
PCT/EP1999/006973 WO2000017366A2 (fr) 1998-09-21 1999-09-21 Composition pharmaceutique de pretraitement d'un patient necessitant un medicament ou un promedicament

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AU2001263197B2 (en) * 2000-05-17 2006-11-09 The Board Of Regents Of The University Of Nebraska Antisense enzyme inhibitors for metabolic redirection
TWI326214B (en) 2002-07-17 2010-06-21 Avanir Pharmaceuticals Inc Pharmaceutical compositions comprising dextromethorphan and quinidine for the treatment of neurological disorders
US9561233B2 (en) 2014-03-13 2017-02-07 Demerx, Inc. Use of ibogaine for the treatment of pain
US9592239B2 (en) 2014-09-12 2017-03-14 Demerx, Inc. Methods and compositions for ibogaine treatment of impulse control disorder, anxiety-related disorders, violence and/or anger, or regulating food intake
WO2023039187A1 (fr) * 2021-09-10 2023-03-16 ATAI Life Sciences AG Polythérapie par ibogaïne

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US5688773A (en) * 1994-08-17 1997-11-18 The General Hospital Corporation Method of selectively destroying neoplastic cells
PL188323B1 (pl) * 1996-03-27 2005-01-31 Bavarian Nordic As Kapsuła zawierająca komórki i jej zastosowanie oraz kompozycja i środek farmaceutyczny
US6160006A (en) * 1996-10-18 2000-12-12 Wayne State University 6',7'-dihydroxybergamottin, a cytochrome P450 inhibitor in grapefruit

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WO2000017366A2 (fr) 2000-03-30

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