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`US 20030144220Al
`
`(19) United States
`(12) Patent Application Publication
`Obach
`
`(10) Pub. No.: US 2003/0144220 A1
`Jul. 31, 2003
`(43) Pub. Date:
`
`(54) USE OF CYP2D6 INHIBITORS IN
`COMBINATION THERAPIES
`
`(76)
`
`Inventor: R. Scott Obach, Gales Ferry, CT (US)
`
`Correspondence Address:
`PFIZER INC
`150 EAST 42ND STREET
`5TH FLOOR - STOP 49
`NEW YORK, NY 10017-5612 (US)
`
`( *)
`
`Notice:
`
`This is a publication of a continued pros-
`ecution application (CPA) filed under 37
`CFR 1.53(d).
`
`(21)
`
`Appl. No.:
`
`09/528,978
`
`(22)
`
`Filed:
`
`Mar. 21, 2000
`
`Related U.S. Application Data
`
`(60)
`
`Provisional application No. 60/128,136, filed on Apr.
`7, 1999.
`
`Publication Classification
`
`(51)
`
`Int. Cl? ................ A61K 31/7056; A61K 31/4745;
`A61K 31!542; A61K 31!137;
`A61K 31/498
`(52) U.S. Cl. ............................ 514/43; 514/249; 514/283;
`514/305; 514/603; 514/317;
`514/225.2; 514/650
`
`(57)
`
`ABSTRACT
`
`This invention relates to the use of a CYP2D6 inhibitor in
`combination with a drug having CYP2D6 catalyzed metabo(cid:173)
`lism, wherein the drug and the CYP2D6 inhibitor are not the
`same compound; and pharmaceutical compositions for said
`use.
`
`Roxane Labs., Inc.
`Exhibit 1012
`Page 001
`
`

`
`US 2003/0144220 A1
`
`Jul. 31, 2003
`
`1
`
`USE OF CYP2D6 INHIBITORS IN COMBINATION
`THERAPIES
`
`BACKGROUND
`
`[0001] This invention relates to the use of a CYP2D6
`inhibitor in combination with a drug having CYP2D6 cata(cid:173)
`lyzed metabolism in order to improve the drug's pharma(cid:173)
`cokinetic profile.
`
`[0002] The clearance of drugs in humans can occur by
`several mechanisms, such as metabolism, excretion in urine,
`excretion in bile, etc. Despite the many types of clearance
`mechanisms, a large proportion of drugs are eliminated in
`humans via hepatic metabolism. Hepatic metabolism can
`consist of oxidative (e.g., hydroxylation, heteroatom dealky(cid:173)
`lation) and conjugative (e.g., glucuronidation, acetylation)
`reactions. Again, despite the many possibilities of types of
`metabolic reactions, a preponderance of drugs are metabo(cid:173)
`lized via oxidative pathways. Thus, the primary route of
`clearance of a vast majority of drugs is oxidative hepatic
`metabolism.
`
`[0003] Of the enzymes involved in the oxidative metabo(cid:173)
`lism of drugs, the cytochrome P-450 (CYP) superfamily of
`enzymes are major contributors. CYP constitutes a class of
`over 200 enzymes that are able to catalyze a variety of types
`of oxidative reactions (via a hypothesized common reaction
`mechanism) on a wide range of xenobiotic substrate struc(cid:173)
`tures. In humans, the CYP catalyzed metabolism of most
`drugs is carried out by one of five isoforms: CYP1A2,
`CYP2C19, CYP2C9, CYP2D6, and CYP3A4, with the latter
`three being the most important of these enzymes.
`
`[0004] Of all of the known human CYP isoforms, the most
`highly developed knowledge base of substrate specificity is
`for CYP2D6. This isoform is almost exclusively involved in
`the oxidative metabolism of lipophilic amine drugs. Well
`known CYP2D6 substrates include neuroleptics, type 1C
`antiarrhythmics, ~-blockers, antidepressants (tricyclic anti(cid:173)
`depressants, selective serotonin reuptake inhibitors and
`monoamine oxidase inhibitors), and others such as codeine
`and dextromethorphan. This apparent specificity for amines
`as substrates is hypothesized to arise from the presence of an
`acidic amino acid residue in the substrate binding site. This
`residue can form an ionic interaction with amine substrates
`while positioning sites for oxidation in propinquity to the
`reactive iron center of the heme of CYP. Structure activity
`relationships for CYP2D6 and the metabolism of amines
`have led to the development of a predictive model for this
`enzyme which states that the position of oxidation of a
`CYP2D6 substrate is 5 to 7 A from the basic amine nitrogen.
`Some additional steric requirements are also hypothesized.
`
`[0005] Many compounds for which the major clearance
`mechanism in humans is CYP2D6 mediated oxidative
`biotransformation commonly exhibit one or more detrimen(cid:173)
`tal characteristics with regard to human pharmacokinetics.
`These characteristics are: (1) wide disparity in exposure
`between individuals possessing and lacking a copy of the
`CYP2D6 gene ("extensive and poor metabolizers"); (2) high
`inter-individual variability in exposure among extensive
`metabolizers; (3) propensity for supraproportional dose(cid:173)
`exposure relationships; ( 4) frequent drug -drug interactions;
`and (5) short half-lives and poor oral bioavailability due to
`extensive first-pass hepatic clearance.
`
`[0006] While not all CYP2D6 substrates possess these
`characteristics, most CYP2D6 substrates are subject to one
`or more.
`
`[0007]
`In the mid-1980s observations were made concern(cid:173)
`ing the disparity in exposure to drugs in a small subset of the
`population. In some cases, the high exposures observed in
`the minority of individuals were also associated with
`adverse reactions. These observations led to the discovery of
`the CYP2D6 genetic polymorphism. The CYP2D6 gene is
`absent in 5-10% of the Caucasian population (referred to as
`poor metabolizers or PM's). Such individuals can be distin(cid:173)
`guished from the rest of the population (extensive metabo(cid:173)
`lizers or EM's) by an examination of genotype through
`restriction fragment
`length polymorphism analysis or
`through determination of phenotype by measurement of the
`urinary dextrorphan/dextromethorphan ratio after adminis(cid:173)
`tration of the latter compound. When population histograms
`of exposure to prototypical CYP2D6-cleared compounds are
`constructed, a bimodal distribution
`is observed. For
`example, the mean terminal phase half-life of propafenone,
`a well known CYP2D6 cleared compound, is 5.5 hours in
`extensive metabolizers, but is 17.2 hours in poor metabo(cid:173)
`lizers. EM-PM differences are typically exacerbated upon
`oral administration of CYP2D6 cleared compounds due to
`wide disparities in first-pass extraction. Propafenone expo(cid:173)
`sure after oral administration is 4.2-fold greater in PM's vs.
`EM's. Thus, CYP2D6 cleared compounds can be subject to
`increased incidences of adverse effects, due to elevated
`systemic exposures observed in PM's.
`
`[0008] Regardless of the genetic polymorphism, a high
`degree of interindividual variability exists in the exposure to
`CYP2D6 cleared compounds among those individuals con(cid:173)
`sidered to be extensive metabolizers. While a reason for this
`variability is not presently known, it does not appear to be
`due to an increase in CYP2D6 gene copy number (although
`one such genotype has been reported in the literature in
`Sweden), nor does it appear to be due to environmental
`factors as this CYP isoform has never been demonstrated to
`be inducible. An example of this variability phenomenon is
`demonstrated by the exposure to the antidepressant agent
`imipramine and its metabolite desipramine, which demon(cid:173)
`strates a 20-fold range of steady state plasma concentrations
`after oral administration. For compounds with wide thera(cid:173)
`peutic indices, this variability may not be problematic.
`However, if the therapeutic index for a CYP2D6 cleared
`compound approaches 10, increased incidences of adverse
`effects are likely to be observed.
`
`[0009] Metabolic clearance is a potentially saturable pro(cid:173)
`cess. The intrinsic clearance (Cl'int' the ability of an organ to
`clear a compound without constraints imposed by organ
`blood flow or plasma protein binding) is a function of
`Michaelis-Menten parameters:
`
`-,-------cx:Ct =~
`KM + [S]
`oral exposure
`
`mt
`
`[0010] where both V max and KM are fixed constants and
`[S] represents the concentration of the drug in the clearing
`organ. For most drugs, concentrations of drug typically
`attained in vivo are well below the KM and thus the denomi(cid:173)
`nator of the above expression degenerates to a constant
`
`Roxane Labs., Inc.
`Exhibit 1012
`Page 002
`
`

`
`US 2003/0144220 Al
`
`Jul. 31, 2003
`
`2
`
`[0013] There are several compounds known to inhibit
`CYP2D6 reactions, either by 'pure' inhibition or by acting as
`competitive substrates. Unlike many other CYP enzymes,
`there are some potent inhibitors known for CYP2D6. Again,
`it is believed that the ionic interaction between the cationic
`amine group of the inhibitor and the anionic amino acid
`residue of CYP2D6 is at least partially responsible for the
`potency of CYP2D6 inhibitors. Two examples of potent
`CYP2D6 inhibitors are quinidine and ajmalacine:
`
`value of KM. However, for many CYP2D6 catalyzed reac(cid:173)
`tions, KM values are typically low. This is hypothesized to be
`due to the strong (relative to other CYP enzymes) ionic bond
`formation between cationic amine substrates and an anionic
`amino acid in the substrate binding site of CYP2D6. Thus
`for compounds cleared by CYP2D6, drug concentrations
`can approach and exceed KM values resulting in intrinsic
`clearance values that decrease with increasing drug concen(cid:173)
`tration. Since drug concentration is related to dose, clearance
`is observed to decrease with increasing dose. With decreases
`in clearance with increases in dose, exposure is thus
`observed to increase in a supraproportional manner with
`increasing dose. Such a relationship has been described in
`the scientific literature for the CYP2D6 cleared compounds
`propafenone and paroxetine. Interestingly, this phenomenon
`is not observed in poor metabolizers, since the CYP2D6
`isoform is not present in these individuals.
`
`[0011] The parameter KM is a complex function of enzy(cid:173)
`matic rate constants that, for CYP, has a strong component
`of substrate binding rate constants. The potential exists that
`competitive inhibition of the metabolism of one drug can
`occur via catalytically competent substrate binding of a
`second drug. Since the KM for CYP enzymes are closely
`related to binding constants, they approximate K; values in
`many cases. For CYP2D6, low KM values for typical sub(cid:173)
`strates can also result in low K; values for these same
`substrates as competitive inhibitors. Low K; values reflect a
`greater potential to result in drug -drug interactions, since
`lower concentrations and doses of drug are adequate to
`exhibit inhibition. Thus, the potential for drug -drug interac(cid:173)
`tions is a more likely concern with CYP2D6 substrates than
`other CYP substrates, due to the greater binding affinities of
`the former. Thus, since K; values typically track KM values,
`the potential for drug-drug interactions usually go hand-in(cid:173)
`hand with the potential for supraproportional dose-exposure
`relationships.
`
`[0012] As mentioned above, clearance is related to the
`term v maxfKM. For compounds with similar v max values, the
`lower the value for KM, the higher the clearance. Since many
`CYP2D6 substrates have very low KM values, these com(cid:173)
`pounds, as a class, are more likely to exhibit high hepatic
`clearance in vivo. High hepatic clearance results in shorter
`half-lives. It also results in greater first-pass hepatic extrac(cid:173)
`tion which can result in low oral bioavailabilities. This point
`is represented by the compounds (7S,9S)-2-(2-pyrimidyl)-
`7 -(succinamidomethyl)-prehydro-1H -pyrido-[1,2-a ]pyra(cid:173)
`zine) ("sunipetron") (KM of about 1 ,uM, human half-life of
`about 1 hour), (2S,3S)-2-phenyl-3-(2-methoxyphenyl)-me(cid:173)
`thylaminopiperidine (KM of about 1 ,uM, human half-life of
`about 4.7 hours), (1S,2S)-1-( 4-hydroxyphenyl)-2-( 4-hy(cid:173)
`droxy-4-phenylpiperidin-1-yl)-1-propanol (KM of about 3-4
`,uM, human half-life of about 3-4 hours), and (2S,3S)-2-
`phenyl-3-(2-methoxy-5-trifluoromethoxyphenyl)-methy(cid:173)
`lamina-piperidine (KM of about: 1 ,uM, human half-life of
`about 8 hours), all of which are CYP2D6 substrates. The
`former two compounds have KM values in the 1 ,uM range.
`The human half-lives for these two compounds are 1.1 and
`4.7 hours, and human oral bioavailability values for these
`two compounds are 4.6 and 1.0%, respectively. The clear(cid:173)
`ance values for the former two compounds, measured after
`intravenous administration to humans, are in the range of
`blood-flow limiting values, suggesting that hepatic extrac(cid:173)
`tion exceeds 90%.
`
`~ H,,
`
`,,,,
`
`HO
`''''··
`
`N
`
`quinidine, Ki = 80 nM
`
`ajmalacine, Ki = 4.6 nM
`
`[0014] Quinidine represents a commonly utilized antiar(cid:173)
`rhythmic agent whereas ajmalacine is a less well-known
`natural product with vasodilation activity. Since quinidine is
`a commonly administered substance, drug interaction stud(cid:173)
`ies have been conducted in vivo for this drug and CYP2D6
`cleared compounds. Quinidine has the effect of converting
`an extensive metabolizer to the poor metabolizer phenotype
`via inhibition of CYP2D6.
`
`[0015]
`In addition, extracts of St. John's wort have
`recently been found to contain constituent substances that
`exhibit CYP inhibitory activity, including inhibition of
`CYP2D6. Examples of constituent substances of St. John's
`extract that exhibit CYP inhibitory activity are hyperforin,
`13, 118-biapigenin, hypericin, and quercetin. Other uniden(cid:173)
`tified components also exhibit CYP inhibitory activity.
`
`[0016] For CYP2D6 cleared compounds, the problem that
`is frequently focused on is the disparity in the exposures
`between extensive and poor metabolizers and the high
`variability demonstrated by the extensive metabolizers.
`However, what is commonly overlooked is the fact that these
`compounds typically have very satisfactory pharmacokinet(cid:173)
`ics in the poor metabolizers. In subjects lacking the CYP2D6
`enzyme, CYP2D6 cleared compounds: (1) typically have
`long t112 values and high oral bioavailability and (2) do not
`exhibit supraproportional dose-exposure relationships. By
`lacking the CYP2D6 enzyme, the variability of drug expo-
`
`Roxane Labs., Inc.
`Exhibit 1012
`Page 003
`
`

`
`US 2003/0144220 Al
`
`Jul. 31, 2003
`
`3
`
`[0023] A preferred embodiment of this invention relates to
`the Combination Method, wherein the drug for which the
`major clearance mechanism in humans is CYP2D6 mediated
`oxidative biotransformation, is (2S,3S)-2-phenyl-3-(2-meth(cid:173)
`oxy-5-trifiuoromethoxyphenyl)methylamino-piperidine or a
`pharmaceutically acceptable salt thereof.
`
`[0024] A preferred embodiment of this invention relates to
`the Combination Method, wherein the drug for which the
`major clearance mechanism in humans is CYP2D6 mediated
`oxidative biotransformation, is sunipetron or a pharmaceu(cid:173)
`tically acceptable salt thereof.
`
`[0025] Sunipetron has the following structure
`
`sures in poor metabolizers is no greater than variabilities
`exhibited by non-CYP2D6 cleared compounds. Although
`attempts have been made to link poor metabolizer status
`with proclivity to various pathological states, a definitive
`cause-effect relationship has yet to be established. Thus,
`since poor metabolizers represent a normal and healthy
`segment of the population, it is not anticipated that convert(cid:173)
`ing extensive metabolizers to poor metabolizers via admin(cid:173)
`istration of a specific CYP2D6 inhibitor would result in any
`untoward effects related to inhibition of this enzyme.
`
`[0017] This invention relates to the coformulation or com(cid:173)
`bined use of a CYP2D6 inhibitor and a CYP2D6 cleared
`compound. Thus, instead of avoiding a drug-drug interac(cid:173)
`tion, this invention involves developing such an interaction
`intentionally in order to improve the pharmacokinetics of
`therapeutically useful, but pharmacokinetically flawed com(cid:173)
`pounds. Such an approach is analogous to the utilization of
`sustained-release formulations to enhance the pharmacoki(cid:173)
`netics of drugs. However, instead of modulating drug elimi(cid:173)
`nation via input rate limitation, this approach seeks to do the
`same by modulating the elimination rate directly. Further(cid:173)
`more, in addition to lengthening half-life, a CYP2D6 inhibi(cid:173)
`tor would enhance oral exposure due to a suppression of
`hepatic first-pass extraction.
`
`SUMMARY OF THE INVENTION
`
`[0026] wherein Y is a group of the formula
`
`[0018] This invention relates to a method of administering
`a drug for which the major clearance mechanism in humans
`is CYP2D6 mediated oxidative biotransformation (also
`referred to throughout this document as a "Therapeutic
`Drug"), or a pharmaceutically acceptable salt thereof, in
`combination with a CYP2D6 inhibitor, or a pharmaceuti(cid:173)
`cally acceptable salt thereof, to a human in need of the
`intended pharmaceutical activity of such drug, wherein the
`Therapeutic Drug and the CYP2D6 inhibitor are not the
`same compound. The above method is hereinafter referred to
`as the "Combination Method".
`
`[0019] This invention also relates to the Combination
`Method, wherein the drug for which the major clearance
`mechanism in humans is CYP2D6 mediated oxidative
`biotransformation is a selective serotonin reuptake inhibitor
`containing a primary, secondary or tertiary alkylamine moi(cid:173)
`ety (e.g., sertraline or fiuoxetine ).
`
`[0020] This invention also relates to the Combination
`Method, wherein the drug for which the major clearance
`mechanism in humans is CYP2D6 mediated oxidative
`biotransformation is an NMDA (N-methyl-D-aspartate)
`receptor antagonist containing a primary, secondary or ter(cid:173)
`tiary alkylamine moiety.
`
`[0021] This invention also relates to the Combination
`Method, wherein the drug for which the major clearance
`mechanism in humans is CYP2D6 mediated oxidative
`biotransformation is a neurokinin-! (NK-1) receptor antago(cid:173)
`nist containing a primary, secondary or tertiary alkylamine
`moiety.
`
`[0022] This invention also relates to the Combination
`Method, wherein the drug for which the major clearance
`mechanism in humans is CYP2D6 mediated oxidative
`biotransformation is a tricyclic antidepressant containing a
`primary, secondary or tertiary alkylamine moiety (e.g.,
`desipramine, imipramine or clomipramine).
`
`[0027] Another preferred embodiment of this invention
`relates to the Combination Method, wherein the drug for
`which the major clearance mechanism in humans is
`CYP2D6 mediated oxidative biotransformation is (1S,2S)(cid:173)
`l-( 4-hydroxyphenyl)-2-( 4-hydroxy4-phenylpiperidin-1-yl)(cid:173)
`lpropanol or a pharmaceutically acceptable salt thereof.
`
`[0028] Examples of other drugs for which the major
`clearance mechanism in humans is CYP2D6 mediated oxi(cid:173)
`dative biotransformation are the following: mequitazine (J.
`Pharmacal. Exp. Ther., 284, 437442 (1998)); tamsulosin
`(Xenobiotica, 28, 909-22 (1998)); oxybutynin (Pharmaco(cid:173)
`gen., 8, 449-51 (1998)); ritonavir (Clin. PK, 35, 275-291
`(1998)); iloperidone (J. Pharmacal. Exp. Ther., 286, 1285-
`93 (1998)); ibogaine (Drug Metab. Dispos., 26, 764-8
`(1998)); delavirdine (Drug Metab. Dispos., 26, 631-9
`(1998)); tolteridine (Clin. Pharmcol. Ther., 63 529-39
`(1998)); promethazine (Rinshoyakon, 29, 231-38 (1998));
`pimozide, J. Pharmacal. Exp. Ther., 285, 428-37 (1998));
`epinastine (Res. Comm. Md. Path. Pharmacal., 98, 273-92
`(1997)); tramodol (Eur. J. Clin. Pharm., 53, 235-239
`(Pharmacogenetics, 7, 381-90
`(1997)); procainamide
`(1997)); methamphetamine (Drug Metab. Dispos., 25,1059-
`64 (1997)); tamoxifen (Cancer Res., 57, 3402-06 (1997));
`nicergoline (Br. J. Pharm., 42, 707-11 (1996)); and fiuox(cid:173)
`etine (Clin. Pharmcol. Ther., 60, 512-21 (1996)). All of the
`foregoing references are incorporated herein by references
`in their entireties.
`
`Roxane Labs., Inc.
`Exhibit 1012
`Page 004
`
`

`
`US 2003/0144220 Al
`
`Jul. 31, 2003
`
`4
`
`[0029] Examples of other drugs for which the major
`clearance mechanism in humans is CYP2D6 mediated oxi(cid:173)
`dative biotransformation, all of which are referred to, along
`with their respective pathways of CPY2D6 mediated oxi(cid:173)
`dative biotransformation (e.g., 0-demethylation, hydroxy(cid:173)
`lation, etc.), by M. F. Fromm et al. in Advanced Drug
`Delivery Reviews, 27, 171-199 (1997), are the following:
`alprenolol, amifiamine, amitriptyline, aprindine, brofarom(cid:173)
`ine, buturalol, cinnarizine, clomipramine, codeine, debriso(cid:173)
`quine, desipramine, desmethylcitalopram, dexfenfiuramine,
`dextromethorphan, dihydrocodine, dolasetron, encainide,
`ethylmorphine, fiecainide, fiunarizine, fiuvoxamine, guan(cid:173)
`oxan, haloperidol, hydrocodone, indoramin, imipramine,
`maprotiline, methoxyamphetamine, methoxyphenamine,
`methylenedioxymethamphetamine, metoprolol, mexiletine,
`mianserin, minaprine, procodeine, nortriptyline, N-propyla(cid:173)
`jmaline, ondansetron, oxycodone, paroxetine, perhexiline,
`perphenazine, phenformine, promethazine, propafenone,
`propanolol, risperidone, sparteine, thioridazine, timolol,
`tomoxetine, tropisetron, venlafaxine and zuclopenthixol.
`
`[0030] Other preferred embodiments of this invention
`relate to the Combination Method wherein the CYP2D6
`inhibitor, or pharmaceutically acceptable salt thereof, that is
`employed in such method is quinidine or ajmalacine or a
`pharmaceutically acceptable salt of one of these compounds.
`
`[0031] Other embodiments of this invention relate to the
`Combination Method, wherein the CYP2D6 inhibitor, or
`pharmaceutically acceptable salt thereof, that is employed in
`such method, is selected from the following compounds and
`their pharmaceutically acceptable salts: sertraline (J. Clin.
`Psychopharm. 18, 55-61 (1998)); venlafaxine (Br. J.
`Pharm., 43, 619-26 (1997)); dexmedetomidine (DMD, 25,
`651-55 (1997));
`tripennelamine, premethazine, hydrox(cid:173)
`yzine, (Drug Metab. Dispos., 26, 531-39 (1998)); halofrin(cid:173)
`tane and chloroquine, (Br. J. Clin. Pharm., 45, 315-(1998));
`and moclobemide (Psychopharm., 135, 22-26 (1998)).
`
`[0032] A further embodiment of this invention relates to
`the Combination Method wherein the CYP2D6 inhibitor
`that is employed in such method is St. John's wort or an
`extract or constituent thereof.
`
`[0033] This invention also relates to a pharmaceutical
`composition comprising:
`
`[0034]
`(a) a therapeutically effective amount of a
`drug for which the major clearance mechanism in
`humans is CYP2D6 mediated oxidative biotransfor(cid:173)
`mation (also referred to throughout this document as
`a "Therapeutic Drug"), or a pharmaceutically accept(cid:173)
`able salt thereof;
`
`[0035]
`(b) an amount of a CYP2D6 inhibitor, or a
`pharmaceutically acceptable salt thereof, that is
`effective in treating the disorder or condition for
`which the Therapeutic Drug referred to in (a) is
`intended to treat; and
`
`[0036]
`
`(c) a pharmaceutically acceptable carrier;
`
`[0037] wherein said drug and said CYP2D6 inhibitor are
`not the same compound.
`
`[0038] The above pharmaceutical composition is herein(cid:173)
`after referred to as the "Combination Pharmaceutical Com(cid:173)
`position".
`
`[0039] Preferred embodiments of this invention relate to
`Combination Pharmaceutical Compositions wherein the
`drug for which the major clearance mechanism in humans is
`CYP2D6 mediated oxidative biotransformation, or pharma(cid:173)
`ceutically acceptable salt thereof, that is contained in such
`pharmaceutical composition is (2S,3S)-2-phenyl-3-(2-meth(cid:173)
`oxy-5-trifiuoromethoxyphenyl)methylaminopiperidine or a
`pharmaceutically acceptable salt thereof.
`
`[0040] Other preferred embodiments of this invention
`relate
`to Combination Pharmaceutical Compositions
`wherein the drug for which the major clearance mechanism
`in humans is CYP2D6 mediated oxidative biotransforma(cid:173)
`tion, or pharmaceutically acceptable salt thereof, that is
`contained in such pharmaceutical composition is (1S,2S)-1-
`( 4-hydroxyphenyl)-2-( 4-hydroxy-4-phenylpiperidin-1yl)-
`1propanol or a pharmaceutically acceptable salt thereof.
`
`[0041] Other preferred embodiments of this invention
`to Combination Pharmaceutical Compositions
`relate
`wherein the drug for which the major clearance mechanism
`in humans is CYP2D6 mediated oxidative biotransforma(cid:173)
`tion, or pharmaceutically acceptable salt thereof, that is
`contained in such pharmaceutical composition is sunipetron
`or a pharmaceutically acceptable salt thereof.
`
`[0042] Other embodiments of this invention relate to
`Combination Pharmaceutical Compositions wherein the
`drug for which the major clearance mechanism in humans is
`CYP2D6 mediated oxidative biotransformation, or pharma(cid:173)
`ceutically acceptable salt thereof, that is contained in such
`compositions is selected from the following compounds and
`their pharmaceutically acceptable salts: mequitazine (J.
`Pharmacal. Exp. Ther., 284, 437-442 (1998)); tamsulosin
`(Xenobiotica, 28, 909-22 (1998)); oxybutynin (Pharmaco(cid:173)
`gen., 8, 449-51 (1998)); ritonavir (Clin. PK, 35, 275-291
`(1998)); iloperidone (J. Pharmacal. Exp. Ther., 286, 1285-
`93 (1998)); ibogaine (Drug Metab. Dispos., 26, 764-8
`(1998)); delavirdine (Drug Metab. Dispos., 26, 631-9
`(1998)); tolteridine (Clin. Pharmcol. Ther., 63, 529-39
`(1998)); promethazine (Rinshovakon, 29, 231-38 (1998));
`pimozide, J. Pharmacal. Exp. Ther., 285, 428-37 (1998));
`epinastine (Res. Comm. Md. Path. Pharmacal., 98, 273-92
`(1997)); tramodol (Eur. J. Clin. Pharm., 53, 235-239
`(Pharmacogenetics, 7, 381-90
`(1997)); procainamide
`(1997)); methamphetamine (Drug Metab. Dispos., 25,1059-
`64 (1997)); tamoxifen (Cancer Res., 57, 3402-06 (1997));
`nicergoline (Br. J. Pharm., 42, 707-11 (1996)); and fiuox(cid:173)
`etine (Clin. Pharmcol. Ther., 60, 512-21 (1996)). All of the
`foregoing references are incorporated herein by references
`in their entireties.
`
`[0043] Other embodiments of this invention relate to
`Combination Pharmaceutical Compositions wherein the
`drug for which the major clearance mechanism in humans is
`CYP2D6 mediated oxidative biotransformation, or pharma(cid:173)
`ceutically acceptable salt thereof, that is contained in such
`compositions is selected from the following compounds and
`their pharmaceutically acceptable salts, all of which are
`referred to, along with their respective pathways of CYP2D6
`mediated oxidative biotransformation (e.g., 0-demethyla(cid:173)
`tion, hydroxylation, etc.), by M. F. Fromm et al. in Advanced
`Drug Delivery Reviews, 27, 171-199 (1997): alprenolol,
`amifiamine, amitriptyline, aprindine, brofaromine, butur(cid:173)
`alol, cinnarizine, clomipramine, codeine, debrisoquine,
`desipramine, desmethylcitalopram, dexfenfiuramine, dex-
`
`Roxane Labs., Inc.
`Exhibit 1012
`Page 005
`
`

`
`US 2003/0144220 Al
`
`Jul. 31, 2003
`
`5
`
`tromethorphan, dihydrocodine, dolasetron, encainide, ethyl(cid:173)
`morphine, fiecainide, fiunarizine, fiuvoxamine, guanoxan,
`haloperidol, hydrocodone, indoramin, imipramine, mapro(cid:173)
`tiline, methoxyamphetamine, methoxyphenamine, methyl(cid:173)
`enedioxymethamphetamine,
`metoprolol,
`mexiletine,
`mianserin, minaprine, procodeine, nortriptyline, N-propyla(cid:173)
`jmaline, ondansetron, oxycodone, paroxetine, perhexiline,
`perphenazine, phenformine, promethazine, propafenone,
`propanolol, risperidone, sparteine, thioridazine, timolol,
`tomoxetine, tropisetron, venlafaxine and zuclopenthixol.
`
`[0044] Other embodiments of this invention relate to
`Combination Pharmaceutical Compositions wherein the
`CYP2D6 inhibitor, or pharmaceutically acceptable salt
`thereof, that is contained in such composition is selected
`from the following compounds and their pharmaceutically
`acceptable salts: sertraline (J. Clin. Psychopharm., 18, 55-61
`(1998)); venlafaxine (Br. J. Pharm., 43, 619-26 (1997));
`dexmedetomidine (DMD, 25, 651-55 (1997));
`tripen(cid:173)
`nelamine, premethazine, hydroxyzine, (Drug Metab. Dis(cid:173)
`pas., 26, 531-39 (1998)); halofrintane and chloroquine, (Br.
`J. Clin. Pharm., 45, 315-(1998)); and moclobemide (Psy(cid:173)
`chopharm., 135, 22-26 (1998)).
`
`[0045] A further embodiment of this invention relates to
`the Combination Method wherein the CYP2D6 inhibitor
`that is employed in such method is St. John's wort or an
`extract or constituent thereof.
`
`[0046] This invention also relates to a Combination Phar(cid:173)
`maceutical Composition, wherein the drug for which the
`major clearance mechanism in humans is CYP2D6 mediated
`oxidative biotransformation is a selective serotonin reuptake
`inhibitor containing a primary, secondary or tertiary alky(cid:173)
`lamine moiety (e.g., sertraline or fiuoxetine ).
`
`[0047] This invention also relates to a Combination Phar(cid:173)
`maceutical Composition, wherein the drug for which the
`major clearance mechanism in humans is CYP2D6 mediated
`oxidative biotransformation is an NMDA (N-methyl-D(cid:173)
`aspartate) receptor antagonist containing a primary, second(cid:173)
`ary or tertiary alkylamine moiety.
`
`[0048] This invention also relates to a Combination Phar(cid:173)
`maceutical Composition, wherein the drug for which the
`major clearance mechanism in humans is CYP2D6 mediated
`oxidative biotransformation is an a neurokinin-1(NK-1)
`receptor antagonist containing a primary, secondary or ter(cid:173)
`tiary alkylamine moiety.
`
`[0049] This invention also relates to a Combination Phar(cid:173)
`maceutical Composition, wherein the drug for which the
`major clearance mechanism in humans is CYP2D6 mediated
`oxidative biotransformation is a tricyclic antidepressant con(cid:173)
`taining a primary, secondary or tertiary alkylamine moiety
`(e.g., desipramine, imipramine or clomipramine).
`
`[0050] The term "treatment", as used herein, refers to
`reversing, alleviating, inhibiting the progress of, or prevent(cid:173)
`ing the disorder or condition to which such term applies, or
`one or more symptoms of such condition or disorder. The
`term "treatment", as used herein, refers to the act of treating,
`as "treating" is defined immediately above.
`
`[0051] The term "CYP2D6 mediated oxidative transfor(cid:173)
`mation", as used herein, refers to the CYP2D6 catalyzed
`oxidation reactions (e.g., benzylic, aromatic or aliphatic
`
`hydroxylation, 0-dealkylation, N-dealkylation, sidechain,
`sulfoxidation) through which metabolism of CPY2D6 sub(cid:173)
`strate drugs proceeds.
`
`DETAILED DESCRIPTION OF THE
`INVENTION
`
`[0052] This invention relates both to Combination Meth(cid:173)
`ods, as defined above, in which the Therapeutic Drug, or
`pharmaceutically acceptable salt thereof, and the CYP2D6
`inhibitor, or pharmaceutically acceptable salt thereof, are
`administered together, as part of the same pharmaceutical
`composition, and to Combination Methods in which these
`two active agents are administered separately as part of an
`appropriate dose regimen designed to obtain the benefits of
`the combination therapy.
`
`[0053] The appropriate dose regimen, the amount of each
`dose administered, and specific intervals between doses of
`each active agent will depend on the patient being treated,
`and the source and severity of the condition. Generally, in
`carrying out the methods of this invention, the Therapeutic
`Drug will be administered in an amount ranging from one
`order of magnitude less than the amount that is known to be
`efficacious and therapeutically acceptable for use of the
`Therapeutic Drug alone (i.e., as a single active agent) to the
`amount that is known to be efficacious and therapeutically
`acceptable for use of the Therapeutic Drug alone. For
`example,
`(2S,3S)-2-phenyl-3-(2-methoxy-5-trifiuo(cid:173)
`romethoxyphenyl)methylaminopiperidine will generally be
`administered to an average weight (approximately 70 kg)
`adult human in an amount ranging from about 5 to about
`1500 mg per day, in single or divided doses, preferably from
`about 0.07 to about 21 mg/kg. (1S,2S)-1-( 4-hydroxyphe(cid:173)
`nyl)-2-( 4-hydroxy-4-phenylpiperidin-1yl)-1or a pharmaceu(cid:173)
`tically acceptable salt thereof will generally be administered
`to an average weight adult human in an amount ranging from
`about 0.02 to about 250 mg per day, in single or divided
`doses, preferably from about 0.15 to about 250 mg per day.
`Sunipetron will generally be administered to an average
`weight adult human in an amount ranging from about 2 to
`about 200 mg per day, in single or divided doses. Variations
`may nevertheless occur depending upon the physical con(cid:173)
`dition of the patient being treated and his or her individual
`response to said medicament, as well as on the type of
`pharmaceutical formulation chosen and the time period and
`interval at which such administration is carried out. In some
`instances, dosage levels below the lower limit of the afore(cid:173)
`said range may be more than adequate, while in