CENTER FOR DRUG EVALUATION AND
`
`RESEARCH
`
`APPLICA TION NUMBER:
`
`NDA 21-799
`
`PHARMACOLOGY REVIEWg S!
`
`

`

` DEPARTMENT OF HEALTH AND HUMAN SERVICES
`
`PUBLIC HEALTH SERVICE
`FOOD AND DRUG ADMINISTRATION
`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`PHARMACOLOGY/TOXICOLOGY REVIEW AND EVALUATION
`
`NDA NUMBER:
`
`SERIAL NUMBER:
`
`21-799
`
`000
`
`DATE RECEIVED BY CENTER:
`
`10/13/04
`
`PRODUCT:
`
`Quinine Sulfate
`
`INTENDED CLINICAL POPULATION:
`
`SPONSOR:
`
`treatment of malaria (P. falcz'parum)
`
`Mutual Pharmaceutical Co., Inc.
`
`DOCUMENTS REVIEWED:
`
`electronic submission
`
`REVIEW DIVISION:
`
`PHARM/TOX REVIEWER:
`
`PHARM/TOX SUPERVISOR:
`
`DIVISION DIRECTOR:
`
`PROJECT MANAGER:
`
`Division
`
`of
`
`Special
`
`Pathogen
`
`and
`
`Immunologic Drug Products (HFD-590)
`Steven Kunder, Ph.D.
`
`Robert Osterberg, Ph.D.
`
`Renata Albrecht, MD
`
`Kristen Miller, PharmD
`
`Date of review submission to Division File System (DFS):
`
`

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`NDA 21—799 PAGE 2mPHARMACOLOGIST’S REVIEW
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`NDA 21-799
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`TABLE OF CONTENTS
`
`EXECUTIVE SUMMARY ............................................................................................. 5
`
`Nonclinical Pharmacology............................................................................................................. 6
`
`Toxicity........................................................................................................................................... 6
`
`Reproductive toxicity.................................................................................................................... 6
`
`GENOTOXICITY......................................................................................................................... 7
`
`2.6 PHARMACOLOGY/TOXICOLOGY REVIEW ................................................... 9
`
`2.6.1
`
`INTRODUCTION AND DRUG HISTORY................................................................... 9
`
`............ 14
`2.6.2 PHARMACOLOGY
`2.6.2.1
`Brief summary ...................................................................................................................... 14
`2.6.2.2
`Primary pharmacodynamics ................................................................................................. 14
`2.6.2.3
`Secondary pharmacodynamics ............................................................................................. 14
`2.6.2.4
`Safety pharmacology ............................................................................................................ 14
`2.6.2.5
`. Pharrnacodynamic drug interactions Preclinical drug interaction studies were not
`referenced 19
`
`2.6.3 PHARMACOLOGY TABULATED SUMMARY....................................................... 19
`2.6.4.1
`Brief summary ...................................................................................................................... 22
`2.6.4.2
`Methods of Analysis ............................................................................................................. 22
`2.6.4.3
`Absorption ............................................................................................................................ 22
`2.6.4.4
`Distribution ........................................................................................................................... 22
`2.6.4.5
`Metabolism ........................................................................................................................... 23
`2.6.4.6
`Excretion............................................................................................................................... 24
`2.6.4.7
`Pharmacokinetic drug interactions........................................................................................ 25
`2.6.4.8
`Other Pharmacokinetic Studies ............................................................................................. 25
`2.6.4.9
`Discussion and Conclusions ................................................................................................. 25
`2.6.4.10
`Tables and figures to include comparative TK summary ................................................. 26
`
`2.6.5 PHARMACOKINETICS TABULATED SUMMARY ............................................... 27
`
`2.6.6 TOXICOLOGY .............................................................................................................. 29
`2.6.6.1
`Overall toxicology summary ................................................................................................ 29
`2.6.6.2
`Single—dose toxicity .............................................................................................................. 31
`2.6.6.3
`Repeat-dose toxicity ............................................................................................................. 31
`2.6.6.4
`Genetic toxicology ................................................................................................................ 33
`2.6.6.5
`Carcinogenicity ..................................................................................................................... 35
`2.6.6.6
`Reproductive and developmental toxicology........................................................................ 35
`2.6.6.7
`Local tolerance ..................................................................................................................... 38
`2.6.6.8
`Special toxicology studies .................................................................................................... 38
`
`2.6.6.10
`
`TOXICOLOGY TABULATED SUMMARY ...................................................... 41
`
`OVERALL CONCLUSIONS AND RECOMMENDATIONS ............................................... 48
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`NDA 21-799
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`PAGE 5
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`EXECUTIVE SUMMAR Y
`
`1.
`
`Recommendations
`
`A. Recommendation on approvability
`This submission is acceptable with regard to pharmacology and toxicology issues. The
`main deficiencies , lack of nonrodent toxicity studies and male fertility studies, are
`compensated by the abundance of human clinical toxicity data from years of clinical
`usage experience.
`'
`
`B. Recommendation for nonclinical studies:
`No further nonclinical studies are recommended
`
`C. Recommendations on labeling:
`
`
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`PHARMACOLOGIST’S REVIEWNDA 21-799 PAGE 6W.
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`
`
`II.
`
`Summary of nonclinical findings
`
`A. Brief overview of nonclinical findings
`Nonclinical Pharmacology .
`Published nonclinical studies related to the safety pharmacology / secondary
`pharmacodynamics of quinine were provided. Cardiovascular effects of quinine include
`QT prolongation, antiarrhythmic activity in animal models, and lowered blood pressure,
`similar to those of quinidine, but quinine is less potent and effects are seen at
`concentrations higher than those achieved clinically. Other effects include those on
`skeletal muscle (decreased response to nerve impulse stimulation), the auditory system
`(ototoxicity by toxic effects on hair cells), and glucose control (hypoglycemia).
`
`Toxicity
`Repeated dose toxicity studies were performed in rats for 13 weeks (oral) and 15 months
`(drinking water). The chronic toxicity ofquinine sulfate (15 months) included mortality
`and adverse liver effects. The liver toxicities include periportal glycogen depletion in all
`lobular areas and mild periportal fibrosis, small areas of fibrosis of the bile duct, Kupffer
`cells with varying degrees of lipid accumulation in the form of large cytoplasmic
`droplets, abundant binucleate hepatocytes, and increased numbers of lysosomes. There
`was no hyperplasia or evidence of liver necrosis in the treated animals. The lS—month
`study was conducted with quinine sulfate in drinking water. The estimated dose was 100
`mg/kg/day, based on an assumed water consumption of 20 mL/rat/day.
`Subchronic toxicity studies (l3weeks) in rats showed tolerance up to 120 mg/kg/day
`without significant liver effects or mortality. Non—rodent toxicity data was not available.
`The extensive experience of human use for more than one hundred years and the
`available toxicological profile in rats negates the need for toxicity information from non-
`rodent species.
`
`Reproductive toxicity
`Teratogenic effects were observed in rabbits, guinea pigs, chinchilla,
`and dog, and not observed in mice, and monkeys; results were equivocal in rats.
`Teratogenic effects were observed in rabbits (death in utero, degenerated auditory nerve
`and spiral ganglion, CNS anomalies such as anencephaly and microcephaly), guinea pigs
`(hemorrhage and mitochondrial change in cochlea), and chinchillas (death and growth
`suppression in utero, CNS anomalies such as anencephaly and micrOcephaly). There
`were no teratogenic findings in mice and monkeys. Embryo—fetal deaths or toxicities
`were observed in mice, rabbits, chinchillas and dogs, but not in rats or monkeys.
`The lowest observed adverse effect levels (LOAELs) for teratogenicity were
`approximately 200 mg/kg/day or 1600 mg/mz/day (guinea pig), 130 mg/kg/day i.m. or
`1560 mg/mz/day (rabbit), and 150 mg/kg/day s.c. (chinchilla). The LOAELs were more
`than l—fold of the maximum recommended human dose of 32.4 mg/kg/day (or 1199
`mg/mz/day) for a 60—kg patient, on a mg/m2 basis. The no—observed adverse effect levels
`(NOAELS) for reproductive toxicity were 500 mg/kg/day or 1500 mg/mz/day (mouse),
`300 mg/kg/day p.o. or 1800 mg/mz/day (rat), 50 mg/kg/day, i.m. or 1000 mg/mz/day
`(dog), and 200 mg/kg/day p.o. or 2400 mg/mz/day (monkey). These NOAELS are
`approximately l.3,x(mouse), 0.8x (dog), 1.5x (rat) and 2.0x (monkey) of the maximum
`
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`NDA 21-799 PAGE 7WPHARMACOLOGIST’S REVIEW
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`
`
`recommended human dose of 32.4 mg/kg/day (or 1199 mg/mz/day) for a 60-kg patient,
`on 3 mg/m2 basis.
`In rats, no impairment of female fertility was observed at an estimated dose of
`20 mg/kg/day (or 120 mg/mz/day) of quinine sulfate administered in drinking water for a
`period from 2 weeks prior to mating and continuing during gestation and post-natal
`development. Animal data on the effect of quinine on male fertility were not available.
`These NOAELs are approximately 1/ 10—fold (female fertility) of the recommended
`human dose of 32.4 mg/kg/day (or 1199 mg/rnz/day) for a 60-kg patient, on a mg/m2
`basis.
`
`Quinine sulfate was shown to cause adverse effects on prenatal and postnatal
`development in rats. In female rats receiving quinine sulfate in drinking water from
`2 weeks prior to mating and continuing on during the entire pregnant and postnatal
`period, the pups showed impaired growth with lower body weights both at birth and
`during the lactation period, and delayed physical development of the teeth eruption and
`eyes opening during lactation period. The effects were observed at an estimated dose of
`20 mg/kg/day or' 120 mg/mz/day, which is approximately 1/ 10-fold of the maximum
`recommended human dose of 32.4 mg/kg/day or 1199 mg/m2/day for a 60—kg patient, on
`a mg/mz basis.
`
`GENOTOXICITY.
`
`Genotoxicity was seen in the in vitro bacterial reverse mutation assays with metabolic
`activation, the sister chromatid exchange assay and the chromosomal aberration assay .
`In the in vitro bacterial reverse mutation assays in Salmonella typhimurium,
`. quinine was demonstrated as positive in the presence of metabolic activation (strain
`TA98), but negative in the absence of metabolic activation whereas all other strains were
`negative either in the presence or absence of metabolic activation.
`In C3H mice, the in vivo micronucleus assay was positive following an oral dose of 110
`mg/kg. while nonpositive findings were obtained in NMRI male and female mice
`following intraperitoneal or oral administrations (0.5 mmole/kg or 199 mg/kg) or
`following an oral dose of 110 mg/kg in Chinese hamsters. The in vivo sister chromatid
`exchange (SCE) tests showed positive results in all strains of mice tested (NMRI, C3H
`and C5 7B 1), but negative in Chinese hamsters. The In vivo chromosomal aberration
`assays were not positive in NMRI and C3H mice at oral doses of 110 mg/kg. There were
`non—positive genotoxicity findings in the sex-linked recessive lethal test performed in
`Drosophila at a concentration of 0.39. g/ml.
`
`B. Pharmacologic activity
`The primary pharmacologic activity of quinine is its antimicrobial activity against the
`blood schizont form of Pfalciparum. Quinine sulfate acts primarily on the blood
`schizont form ofPfalcz'parum; it is not gametocidal and has little effect on the sporozoite
`or pre—erythrocytic forms. Because of this limited spectrum of antimalarial activity,
`quinine is not used for malaria prophylaxis. The antimalarial mechanism of action is
`proposed via inhibition of the Pfalczparum heme polymerase, which is required to
`Convert heme to the non-toxic malaria pigment hemozoin. Quinine sulfate is highly
`concentrated in the P. falciparum acidic food vacuoles, the putative site of inhibition of
`
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`NDA 21-799 PAGE 8WPHARMACOLOGIST’S REVIEW '
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`
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`the heme polymerase. It is unclear whether direct toxicity of the accumulated heme alone
`or involves a heme-quinine complex provides the antimalarial activity of quinine
`C. Nonclinical safety issues relevant to clinical use
`Nonclinical toxicities including QT prolongation, ototoxicity, and reproductive toxicity
`(teratogenesis, fetotoxicity and delayed development) are relevant to acute clinical use for
`treatment ofP. falcz'parum malaria, as confirmed by extensive clinical findings.
`
`APPEARS THIS WAY
`0H ORlGlML
`
`

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`' NDA 21-799
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`PHARMACOLOGIST’S REVIEW
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`PAGE 9
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`2.6 PHARMA COLOGY/TOXICOLOGY RE VIE W
`
`2.6.1
`
`INTRODUCTION'AND DRUG HISTORY
`
`NDA number: 21—799
`Review number: 001
`
`Sequence number/date/type of submission: 000/ Oct 13 2004/
`Information to sponsor: Yes ( ) No ( )
`Sponsor and/or agent: Mutual Pharmaceuticals Co. Inc.
`1100 Orthodox St.
`
`Philadelphia, PA 19124
`(215) 288-6500
`.Manufacturer for drug substance: "E: ,
`
`Reviewer name: Steven Kunder, Ph.D.
`Division name: Special Pathogen and Immunlogic Drug Products
`HFD #: 590
`
`Review completion date: Aug 5, 2005
`
`Drug:
`
`Trade name: Quinine sulfate
`Generic name: quinine sulfate
`Code name: none
`Chemical name: Cin‘chonan-9-ol, 6’-methoxy-, (80L,9R)—, sulfate (2: 1) (salt),
`dihydrate
`'
`
`Molecular formula/molecular weight: C20H24N202)2 - H2804 ~ 2H20 / 782.96
`Structure:
`
`
`
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`

`'NDA 21-799 PAGE 10MPHARMACOLOGIST’S REVIEW
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`
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`
`
`ReleVant INDs/NDAs/DMFS: IND 67, 012
`
`Drug class: antimalarial
`
`Intended clinical population: patients infected with P. falciparum
`
`Clinical formulation: quinine sulfate in 324 mg tablet with corn starch, magnesium
`' stearate, talc
`
`Route of administration: oral tablet
`
`Disclaimer: Tabular and graphical information are constructed by the reviewer unless
`cited otherwise.
`
`Data reliance : Except as specifically identified below, all data and information
`discussed below and necessary for approval of NDA 21—799 are owned by Mutual ~
`Pharmaceutical Co., Inc. or are data for which Mutual Pharmaceutical Co., Inc has
`obtained a written right of reference. Any information or data necessary for approval of
`NDA 21—799 that Mutual Pharmaceutical Co., Inc does not own or have a written right to
`reference constitutes one of the following: (I) published literature, or (2) a prior FDA
`finding of safety or effectiveness for a listed drug, as described in the drug’s approved
`labeling. Any data or information described or referenced below from a previously
`approved application that Mutual Pharmaceutical Co., Inc does not own (or from FDA
`reviews or summaries of a previously approved application) is for descriptive purposes
`only and is not relied upon for approval of NDA 21—799.
`
`As a 505 (b)2 submission, all toxicology support was provided by references from the
`scientific literature. The sponsor included the following statement regarding the source
`of their references in support of their submission:
`“The summary in this section is based on standard and comprehensive secondary
`references including the United States Pharmacopeia’s Drug Information for the
`Healthcare Professional (2001), Martindale’s Extra Pharmacopoeia (1996), and Goodman
`and Gilman’s The Pharmacological Basis of Therapeutics (2001) unless otherwise
`referenced. Information is also excerpted from product labeling currently in use. In
`addition, searches of the worldwide literature were undertaken in order to identify all
`relevant sources of information. The searches were done using Dialog® by a trained
`research associate. On each occasion, the following databases were searched:
`MEDLINE (1966 to present): Produced by the US. National Library of Medicine
`as a major source for biomedical literature.
`EMBASE (1974 to present): Comprehensive index of the world’s literature on
`human medicine and related disciplines (more comprehensive with respect to
`European studies than is MEDLINE).
`JlCST—Eplus (1985 to present): Covers Japanese and Asian literature in the fields of
`science, technology and medicine.
`Biosis Previews (1969 to present): Worldwide coverage of research in the
`
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`NDA 21-799
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`PHARMACOLOGIST’S REVIEW
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`PAGE 11
`
`biological and biomedical sciences (primarily identifies abstracts from meetings and
`symposia)
`ToxFile (1965 to present): Covers the toxicological, pharmacological, biochemical,
`and physiological effects of drugs and other chemicals.
`'
`Registry of Toxic Effects of Chemical Substances (RTECS) (through 2001):
`Comprehensive database of basic toxicity information for chemical substances. “
`
`.
`Studies reviewed within this submission:
`NDA 21—799 is a 505(b)2 application. The following is the listing of papers supplied by
`the sponsor in support of the application:
`
`5.6.1 Pharmacology
`Alvén G, Karlsson KK, Villén T. Reversible hearing impairment related to quinine blood
`concentrations in guinea pigs. Life Sci. 1989; 45:751-755.
`
`Clark RB, Sanchez—Chapula J, Salinas-Stefanon E, Duff HJ, Giles WR. Quinidineinduced
`open channel block of K+ current in rat ventricle. Br. J. Pharmacol. 1995;
`115:335-343.
`
`del Pozo BF, Perez—Vizcaino F, Villamor E, Zaragoza F, Tamargo J. Stereoselective
`effects of the enantiomers, quinidine and quinine, on depolarization— and agonistmediated
`responses in rat isolated aorta. Br. J. Pharmacol. 1996; 117:105-1 10.
`
`Hiatt EP. Effects of repeated oral doses of quinine and quinidine on the blood pressure
`and renal circulation of dogs with experimental neurogenic hypertension. Am. J. Physiol.
`1948; 1551114—117.
`
`Holloway PAH, Krishna S, White NJ. Plasmodium berghei: Lactic acidosis and
`hyposeycaemia in a rodent model of severe malaria; effects of glucose, quinine, and
`dichloroacetate. Exp. Parasitol. 1991; 72: 123-133.
`
`Jung TTK, Rhee C-K, Lee CS, Park Y-S, Choi D—C. Ototoxicity of salicylate,
`nonsteroidal anti-inflammatory drugs, and quinine. Ototoxicity. 1993; 26:791—810.
`
`Jurkiewicz NK, Rodzinski JA, Colatsky TJ. Antiarrhythmic action of quinidine: relative
`importance of QT-prolongation vs use—dependence. Circulation. 1985;
`7 1 (Suppl II):II—225. (Abstract)
`
`Klevans LR, Kelly RJ, Kovacs JL. Comparison of the antiarrhythmic activity of
`quinidine and quinine. Arch. Int. Pharmacodyn, 1977; 227:57-68.
`
`Lee CS, Heinrich J, Jung TTK, Miller SK. Quinine—induced Ototoxicity: Alterations in
`cochlear blood flow. Otolaryngol. Head Neck Surg. 1992; 1072233. (Abstract)
`
`Mecca TE, Elam JT, Nash CB, Caldwell RW. (—Adrenergic blocking properties of
`quinine HCI. Eur. J. Pharmacol. 1980; 63:159-166.
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`
`Michel D, Wegener JW, Nawrath H. Effects of quinine and quinidine on the transient
`outward and on the L-type Caz+ current in rat ventricular cardiomyocytes. Pharmacol.
`2002; 65:187-192.
`
`Okitolanda W, Pottier A-M, Henquin J—C. Glucose homeostasis in rats treated acutely
`and chronically with quinine. Eur. J. Pharmacol. 1986; 1322179-185.
`
`Sanchez—Chapula JA, Ferrer T, Navarro—Polanco RA, Sanguinetti MC. Voltage—
`Dependent Profile Of Human ether-a-go-go—related gene channel block is influenced by a
`single residue in the S6 transmembrane domain. Mol. Pharmacol. 2003; 63:1051-1058. ’
`
`Sheldon RS, Rahrnberg M, Duff HJ. Quinidine/quinine: Stereospecific
`electrophysiologic and antiarrhythmic effects in a canine model of ventricular
`tachycardia. J. of Cardiovas. Pharmacol. 1990; 16:818—823.
`
`Pharmacokinetic
`
`Clohisy DR, Gibson TP. Comparison of pharmacokinetic parameters of intravenous
`quinidine and quinine in dogs. J. Cardiovasc. Pharmacol. 1982; 4: 107—1 10.
`
`Coleman MD, Timony G, Fleckenstein L. The disposition of quinine in the rat isolated
`perfused liver: Effect of dose size. J. Pharrn. Pharmacol. 1990; 42:26-20.
`
`Czuba MA, Morgan DJ, Ching MS, Mihaly GW, Ghabrial H, Hardy KJ, Smallwood RA.
`Disposition of the diastereoisomers quinine and quinidine in the ovine fetus. J.
`Pharmaceut. Sci. 1991; 80:445-448.
`
`Mansor SM, Ward SA, Edwards G, Hoaksey PE, Breckenridge AM. The effect of
`malaria infection on the disposition of quinine and quinidine in the rat isolated perfiised
`liver preparation. J. Pharm. Pharmacol. 1990; 42:42 8-432.
`
`Mansor SM, Ward SA, Edwards G. The effect of fever on quinine and quinidine
`disposition in the rat. J. Pharrn. Pharmacol. 1991; 43:705-708.
`
`Mihaly GW, Hyman KM, Smallwood RA. High—performanCe liquid chromatagraph‘ic
`analysis of quinine and its diastereoisomer quinidine. J. Chromatog. 1987; 415: 177-182.
`
`Onyeji CO, Dixon PAF, Ugwu NC. Disposition of quinine in rats with induced renal
`failure. Pharmaceutisch Weekblad [Sci], 1992; 14:185—190.
`
`Pussard E, Bernier A, Fouquet E, Bouree P. Quinine distribution in mice with
`plasmodz'um berghei malaria. Eur. J. Drug Met. Pharmacokinetics. 2003; 28: 1 1—20.
`
`Wanwimolruk S, Wong CWS, Ho PC. ln—Vitro hepatic metabolism of quinine in cow,
`pig and sheep. Pharrnaceut. Sci. 1996; 22295—298.
`'
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`
`Zhang H, Ramsay N, Coville PF, Wanwimolruk S. Effect of erythromycin, rifampicin
`and isoniazid on the pharmacokinetics of quinine in rats. Pharm. Phannacol. Commun.
`1999; 5:467-472.
`
`Zhang H, Wong CW, Coville PF, Wanwimolruk S. Effect of the grapefruit flavonoid
`naringin on pharmacokinetics of quinine in rats. Drugs Met. Drug Interactions. 2000;
`17:351-363.
`
`Zhao X-J, Ishizaki T. The in vitro hepatic metabolism of quinine in mice, rats and dogs:
`comparison with human liver microsomes. J. Pharmacol. Exp. Ther. 1997;
`283:1168-1176.
`
`Texicology
`Colley JC, Edwards JA, Heywood R, Purser D. Toxicity studies with quinine
`hydrochloride. Toxicol. 1989; 54:219—226.
`
`Flaks B. Effects of chronic oral dosing with quinine sulphate in the rat. Path. Res. Pract.
`1978; 1632373—377.
`
`King M—T, Beikirch H, Eckhardt K, Gocke E, Wild D. Mutagenicity studies with x—ray —
`contrast media, analgesics, antipyretics, antirheumatics and some other pharmaceutical
`drugs in bacterial, Drosophila and mammalian test systems. Mutat. Res. 1979; 66:33—43.
`
`Lapointe G, Nosal G. Saccharin— or quinine—induced changes in the rat pups following
`prolonged ingestion by the dam. Biol. Neonate. 1979; 36:273-276.
`
`Mfinzner R, Renner HW. Mutagenicity testing of quinine with submammalian and
`mammalian systems. Toxicology. 1983 ; 26: 173-178.
`
`Pussard E, Bernier A, Fouquet E, Bouree P. Quinine distribution in mice with
`plasmoa’ium berghei malaria. Eur. J. Drug Met. Pharmacokinetics. 2003; 28: 1 1-20.
`
`Savini EC, Moulin MA, Herrou MDJ. Experimental study of the effects of quinine on
`rat, rabbit, and dog fetuses. Therapie, 1971; XXVI: 653-574. [FRENCH ORIGINAL;
`TRANSLATION]
`
`Sideropoulos AS, Specht SM, Jones MT. Feasibility of testing DNA repair inhibitors for
`mutagenicity by a simple method. Mut. Res. 1980; 74295-105.
`
`Tanimura T. The use of non-human primates in research on human reproduction. WHO
`Research and Training Centre on Human Reproduction Karolinska Institutet
`(Symposium), Stockholm, 1972; 293—308.
`
`Studies not reviewed within this submission:
`none
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`
`2.6.2 PHARMACOLOGY
`
`2.6.2.1 Brief summary
`The mechanism of the antimalarial activity of quinine sulfate is not fiilly understood but
`is proposed to be via inhibition of the Pfalcz'parum heme polymerase, required to convert
`heme to the non-toxic malaria pigment hemozoin. Quinine sulfate is highly concentrated
`in the P. falciparum acidic food vacuoles, the putative site of inhibition of the heme
`polymerase. It is unclear whether direct toxicity of the accumulated heme alone or
`involves a heme-quinine complex provides the antimalarial activity of quinine.
`
`2.6.2.2 Primary pharmacodynamics
`
`Mechanism of action: Antimicrobial activity against the blood schizont form of
`Pfalcz'parum
`
`Dr_ug activity_related to proposed indication: Quinine sulfate acts primarily on the blood
`schizont form of Pfalciparum; it is not gametocidal and has little effect on the sporozoite
`or pre—erythrocytic forms. Because of this limited spectrum of antimalarial activity,
`quinine is not used for malaria prophylaxis. The antimalarial mechanism of action is
`proposed via inhibition of the Pfalciparum heme polymerase, which is required to
`convert heme to the non—toXic malaria pigment hemozoin. Quinine sulfate is highly
`concentrated in the P. falcz‘parum acidic food vacuoles, the putative site of inhibition of
`the heme polymerase. It is unclear whether direct toxicity of the accumulated heme alone
`or involves a heme-quinine complex provides the antimalarial activity of quinine.
`
`2.6.2.3 Secondary pharmacodynamics
`
`2.6.2.4 Safety pharmacology
`Effects on skeletal muscle, the auditory system, and glucose control are discussed
`following the cardiovascular subsection.
`5.2.1 Cardiovascular Effects
`A stereoisomer of quinine, quinidine, was identified as the potent antiarrhythmic
`substances extracted from the plant. Quinidine has been used for that purpose since the
`early 1920’s. Quinine shares many of its cardiac properties, however, quinine is less
`potent and of shorter duration. It was also recognized early that therapeutic doses of
`quinine have little if any effect on the normal heart or blood pressure, but that large doses
`result in vasodilatation—induced hypotension. The electrophysiology of quinidine’s, and
`hence quinine’s, effects on cardiac conduction have been well elucidated in in vitro and
`in vivo studies. At concentrations as low as 0.78 ug/mL, quinine is an open-state blocker
`of Na+ channels (resulting in an increased threshold for excitability and decreased
`
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`automaticity) and blocks the rapid component of the K+ channel delayed rectifier (Ikr)
`(resulting in prolonged action potentials in most cardiac cells). As a result of these
`effects, refractoriness is prolonged in most tissues. At higher concentrations, quinine
`blocks the slow component of delayed rectifier, inward rectifier, transient outward
`current, and L-type Ca2+ current. In the intact animal, quinine has been shown to produce
`a-adrenergic receptor blockade and vagal inhibition.
`.
`Clinically, these properties may produce an increase in QRS duration and prolongation of
`the QT interval. Most of the agents that prolong QT intervals, prolong cardiac action
`potentials to a disproportionate extent when the underlying heart rate is slow. This effect,
`in turn, results in early after depolarizations (EADs) and related triggered activity in
`vitro, and can cause torsades-a’e pointes. The effect of the drug on the PR interval is
`variable as the vagolytic effects tend to inhibit the direct depressant effect on AV nodal
`conduction. Moreover, quinine’s vagolytic effect can result in increased AV nodal
`transmission of atrial tachycardias such as atrial flutter.
`In vitro Studies
`
`The most recent published studies have focused on better understanding of the molecular
`basis for the observed in vitro effects on ion channels. Four studies that illustrate the
`comparative potencies and/0r effects of quinine and quinidine are summarized below. In
`the paper by Michel and colleagues (Michel et al., 2002), the authors pointed out that
`differences in tubular secretion and/or stereoselective interaction with organic cation
`transporters may account for the greater potency of quinidine rather than suggest
`differences in their actions on cardiac ion channels. References were cited that supported
`this suggestion. However, the results of the in vitro studies discussed below suggest a
`stereoselective interaction with cardiac receptors in cells or tissue of isolated systems.
`Quinine, like quinidine and chloroquine, causes voltage—dependent block of Ikr. The
`poreforming alpha subunits of channels that conduct the rapid delayed rectifier K+ current
`are coded by the Human Ether-a—go-go—Related Gene (HERG). A series of studies were
`designed to elucidate the molecular mechanisms of HERG channel blockade (Sanchez—
`Chapula et al., 2003). Blockade of wild type Xenopus laevis oocyte HERG by quinidine
`and quinine was enhanced by progressive membrane depolarization and accompanied by
`a negative shift in the voltage dependence of channel activation. Quinine was more than
`10—fold less potent than quinidine: the median inhibitory concentration (ICso) values
`determined with voltage—clamp pulses to 0 mV were 3.6 ocg/mL and 44.6 ocg/mL for
`quinidine and quinine, respectively. By studying the effects of mutations of Y625A,
`Y625F, and V625A aromatic residues in the S6 domain of the HERG channel on voltage-
`dependent block, the study also showed the critical role for this putative binding site.
`Similar effects were seen for vesnarinone, an uncharged control drug that is not
`dependent on transmembrane voltage charge. These results suggest that voltagedependent
`block of HERG is not a transmembrane field effect but rather gating-dependent
`changes in orientation of Y652.
`Quinine and quinidine also have some other electrophysiological properties in common.
`Quinine and quinidine (each at 15.66 ug/mL) have been shown to reduce, but not block,
`K+ (Ito) and Ca2+ (Ica) currents in rat ventricular cardiomyocytes; only the latter effect was
`dependent on the frequency of stimulation, suggesting an effect on inactivated channels
`(Michel et al., 2002). Peak current amplitude (Imax) was reduced with ECso values of
`8.61 ug/mL and 11.75 ug/mL, respectively, for the 1m and 10.96 ug/mL and 7.83 ug/mL,
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`respectively, for Ica. The authors also indicate and provide supporting references
`suggesting that the effects are on the outer surface of the cell membrane, interacting with
`open K+ channels and inactivated Ca2+.
`Because quinidine and quinine are enantiomers, their differences in activity are often
`attributed to stereoselective effects. Studies of both compounds in the rat aorta indicate
`that quinidine is three to five times more potent than quinine in inhibition of KCl— and
`norepinephrine ~induce'd contractions (del Pozo et al., 1996) and the difference was
`attributed to stereoselective effect in cardiac tissue. The stereoselective inhibition of
`contractions in the vascular smooth muscle was attributed to Ca2+ channel blockade and
`the competitive antagonism of norepinephrine —induced contractions were mediated by
`- -adrenergic receptors. At high concentrations, the enantiomers also exerted a
`nonstereospecific inhibitory effect against contractions induced by 5—hydroxytryptamine
`(5-HT) and endothelin-1 (ET—1).
`Utilizing whole-cell patch clamp techniques on rat isolated ventricular myocytes, (Clark
`et al., 1995) the effects of quinidine sulfate (6 uM or 5.5 ocg/mL) were studied on rat
`ventricular resting action potentials, on the magnitude and rate of decay of the transient
`outward currents, on the “use—dependent” (channels are repetitively activated by a train of
`pulses) block of the transient outward current, and several studies designed to elucidate
`the kinetic basis of the use-dependent quinidine block. The results demonstrated that
`quinidine blocks two components of outward K+ current: a Ca2+-insensitive transient
`current, and a slowly inactivating delayed rectifier-like component. Further, these effects
`of quinidine on Ito were shown to be augmented by membrane depolarization in rat
`cardiomyocytes. These findings (time and membrane potential dependence of this block)
`indicate a preferential interaction of quinidine with open K+ channels. Further, the work
`of Sanchez—Chapula and colleagues (Sanchez-Chapula et al., 2003) demonstrated that the
`blocking effect of quinidine on K+ channels is voltage—dependent, increases with
`progressive membrane depolarization and serves to explain its propensity to induce long
`QT syndrome and torsades de pointes arrhythmia.
`In vivo Studies
`
`Quinine, like quinidine, has been shown to possess antiarrhythmic activity in animal
`models. In a canine model of acute ischemia, both quinine and quinidine (each given as
`10 mg/kg iv.) were equally effective in reducing the inci