CENTER FOR DRUG EVALUATION AND
`RESEARCH
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`APPLICATION NUMBER:
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`202514Orig1s000
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`PHARMACOLOGY REVIEW(S)
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`Comments on NDA 202514 tafluprost
`From Abigail Jacobs, AD
`Date: July 25, 2011
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`1. I concur that there are no outstanding pharm/tox issues and that pregnancy category C is
`appropriate.
`
`2. I have made some other comments to the reviewer and supervisor and the reviewer will
`address them as appropriate
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`
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`Reference ID: 2978205
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`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
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`----------------------------------------------------
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`ABIGAIL ABBY C C JACOBS
`07/25/2011
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`Reference ID: 2978205
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`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`PUBLIC HEALTH SERVICE
`FOOD AND DRUG ADMINISTRATION
`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`
`PHARMACOLOGY/TOXICOLOGY NDA REVIEW AND EVALUATION
`
`Applicant:
`Review Division:
`
`Application number:
`Supporting document/s:
`Applicant’s letter date:
`CDER stamp date:
`Product:
`Indication:
`
`202514
`Supporting Document No. 2; New NDA
`January 7, 2011
`January 7, 2011
`Tafluprost, MK-2452
`Treatment of elevated intra-ocular pressure in
`open angle glaucoma or ocular hypertension.
`Merck Sharp & Dohme Corp.
`Division of Anti-Infectives and Ophthalmology
`Products.
`James S. Wild, Ph.D.
`Reviewer:
`Supervisor/Team Leader: Wendelyn J. Schmidt, Ph.D.
`Division Director: Wiley A. Chambers, M.D.
`Project Manager:
`Constantine Markos
`Template Version: September 1, 2010
`Disclaimer202514
`
`Except as specifically identified, all data and information discussed below and
`necessary for approval of NDA 202514 are owned by Merck Sharp & Dohme Corp. or
`are data for which Merck Sharp & Dohme Corp. has obtained a written right of
`reference. Any information or data necessary for approval of NDA 202514 that Merck
`Sharp & Dohme Corp. does not own or have a written right to reference constitutes one
`of the following: (1) published literature, or (2) a prior FDA finding of safety or
`effectiveness for a listed drug, as reflected in the drug’s approved labeling. Any data or
`information described or referenced below from reviews or publicly available summaries
`of a previously approved application is for descriptive purposes only and is not relied
`upon for approval of NDA 202514.
`
`Reference ID: 2975903
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`NDA # 202514
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`Reviewer: James Wild
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`TABLE OF CONTENTS
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` 1
`
` EXECUTIVE SUMMARY ......................................................................................... 9
`1.1
`INTRODUCTION.................................................................................................... 9
`1.2
`BRIEF DISCUSSION OF NONCLINICAL FINDINGS ...................................................... 9
`1.3 RECOMMENDATIONS.......................................................................................... 12
`2 DRUG INFORMATION .......................................................................................... 15
`2.1 DRUG............................................................................................................... 15
`2.2 RELEVANT INDS, NDAS, BLAS AND DMFS......................................................... 15
`2.3 DRUG FORMULATION ......................................................................................... 15
`2.4 COMMENTS ON NOVEL EXCIPIENTS..................................................................... 16
`2.5 COMMENTS ON IMPURITIES/DEGRADANTS OF CONCERN ....................................... 16
`2.6
`PROPOSED CLINICAL POPULATION AND DOSING REGIMEN .................................... 17
`2.7 REGULATORY BACKGROUND .............................................................................. 17
`3 STUDIES SUBMITTED.......................................................................................... 17
`3.1
`STUDIES REVIEWED........................................................................................... 17
`3.2
`STUDIES NOT REVIEWED ................................................................................... 22
`3.3
`PREVIOUS REVIEWS REFERENCED...................................................................... 23
`4 PHARMACOLOGY................................................................................................ 23
`PRIMARY PHARMACOLOGY................................................................................. 23
`4.1
`4.2
`SECONDARY PHARMACOLOGY............................................................................ 25
`4.3
`SAFETY PHARMACOLOGY................................................................................... 25
`5 PHARMACOKINETICS/ADME/TOXICOKINETICS .............................................. 34
`5.1
`PK/ADME........................................................................................................ 34
`6 GENERAL TOXICOLOGY..................................................................................... 69
`SINGLE-DOSE TOXICITY..................................................................................... 69
`6.1
`6.2 REPEAT-DOSE TOXICITY.................................................................................... 71
`7 GENETIC TOXICOLOGY .................................................................................... 101
`7.1
`IN VITRO REVERSE MUTATION ASSAY IN BACTERIAL CELLS (AMES)..................... 101
`IN VITRO ASSAYS IN MAMMALIAN CELLS............................................................ 103
`7.2
`IN VIVO CLASTOGENICITY ASSAY IN RODENT (MICRONUCLEUS ASSAY)................ 108
`7.3
`7.4 OTHER GENETIC TOXICITY STUDIES.................................................................. 110
`8 CARCINOGENICITY ........................................................................................... 110
`
`9 REPRODUCTIVE AND DEVELOPMENTAL TOXICOLOGY .............................. 131
`9.1
`FERTILITY AND EARLY EMBRYONIC DEVELOPMENT............................................. 131
`EMBRYONIC FETAL DEVELOPMENT ................................................................... 135
`9.2
`9.3
`PRENATAL AND POSTNATAL DEVELOPMENT....................................................... 150
`10
`SPECIAL TOXICOLOGY STUDIES................................................................. 155
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`NDA # 202514
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`Reviewer: James Wild
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`INTEGRATED SUMMARY AND SAFETY EVALUATION............................... 156
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`APPENDIX/ATTACHMENTS........................................................................... 170
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`12
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`NDA # 202514
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`Reviewer: James Wild
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`Table of Tables
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`Table 1: Safety Margin Assessment Based on Plasma Exposure Comparisons........... 13
`Table 2: Safety Margin Assessment Based on Body Surface Area............................... 13
`Table 3: Tafluprost Ophthalmic Solution (0.0015%) Formulation .................................. 16
`Table 4: Current Specifications of Tafluprost Drug Substance (Sponsor’s Table)......... 17
`Table 5: In Vitro Primary Pharmacology Studies with Tafluprost Acid (AFP-172) ......... 24
`Table 6: In Vivo Primary Pharmacology Studies with Tafluprost ................................... 24
`Table 7: In Vivo Primary Pharmacology Studies with Tafluprost Metabolites or
`Tafluprost in Combination with Timolol.......................................................................... 25
`Table 8: Mean Difference Between AFP-172 and Vehicle-Treated Groups (0.5 Hz)
`(Sponsor’s Table).......................................................................................................... 27
`Table 9: Mean Difference Between AFP-172 and Vehicle-Treated Groups (1 Hz)
`(Sponsor’s Table).......................................................................................................... 27
`Table 10: Effect of dl-Sotalol hydrochloride on Action Potential Parameters (0.5 Hz)
`(Sponsor’s Table).......................................................................................................... 28
`Table 11: Effects of AFP-168, Lantanoprost, and PGF2α on Respiratory and
`Cardiovascular Parameters in Dogs (Sponsor’s Table)................................................. 31
`Table 12: The Effects of AFP-172 and PGF2α on the Spontaneous Motility, Maximum
`Tension, and 10 Minute Resting Tension of Uteri from Non-Pregnant Rats.................. 33
`Table 13: The Effects of AFP-172 and PGF2α on Maximum Tension, and 10 Minute
`Resting Tension of Uteri from Non-Pregnant Rabbits. .................................................. 34
`Table 14: Summary of Aqueous Humor Pharmacokinetic Parameters for AFP-172
`Following Topical Ocular Administration of Preservative-Free Tafluprost (Test Products-
`1 and -2) or Tafluprost Containing Benzalkinium Chloride (Control for Test Products-1
`and -2) to Male NZW Rabbits. (Sponsor’s Table).......................................................... 38
`Table 15: The Tissues and Organs Prepared for Radioanalysis. (Sponsor’s Table)..... 39
`Table 16: Select Pharmacokinetic Parameters in Plasma After a Single Ocular dose of
`3H-AFP-168 to Male Monkeys. (Sponsor’s Table)......................................................... 40
`Table 17: Study Design for Study No.: MRL PK015. (Sponsor’s Table)........................ 41
`Table 18: Plasma Pharmacokinetic Parameters for Total Radioactivity Following Ocular
`or Intravenous Administration of 2 μg 3H-AFP-168 to Cynomolgus Monkeys. (Sponsor’s
`Table)............................................................................................................................ 41
`Table 19: Mean Tissue Concentrations of Radioactivity Following a Single Bilateral
`Ocular Administration of 3H-AFP-168 to Male Rats. (Sponsor’s Table)......................... 44
`Table 20: Mean Tissue Concentrations of Radioactivity Following a Single Bilateral
`Ocular Administration of 3H-AFP-168 to female rats. (Sponsor’s Table) ....................... 45
`Table 21: Mean Concentrations of Total Radioactivity in Milk, Plasma, and Whole-Blood
`following Single Ocular Administrations of 0.005% 3H-AFP-168 to Both Eyes of
`Lactating Maternal Rats. (Sponsor’s Table) .................................................................. 47
`Table 22: Select Milk, Plasma, and Whole-Blood Total Radioactivity Pharmacokinetic
`Parameters Following a Single Ocular Administration of 0.005% 3H-AFP-168 Solution to
`Lactating Maternal Rats. (Sponsor’s Table) .................................................................. 47
`Table 23: Mean Total Radioactivity in Tissues Following a Single Ocular Administration
`of 3H-AFP-168 to Pregnant Rats on Gestation Day 12. (Sponsor’s Table) ................... 48
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`NDA # 202514
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`Table 24: Mean Total Radioactivity in Tissues Following a Single Ocular Administration
`of 3H-AFP-168 to Pregnant Rats on Gestation Day 18. (Sponsor’s Table) ................... 49
`Table 25: Human Metabolites and the Corresponding Animal Equivalents. (Sponsor’s
`Table)............................................................................................................................ 52
`Table 26: Metabolism of 3H-AFP-168 by Cyopreserved Pooled Human Hepatocytes
`after 4 hours Incubation. (Sponsor’s Table) .................................................................. 53
`Table 27: Metabolites Identified in Rat, Monkey, and Human Hepatocytes After
`Incubation with Either 3H-AFP-168 or AFP-172. (Sponsor’s Table) .............................. 54
`Table 28: Concentrations of Radioactivity and the Amount of Tritiated Water in Plasma
`at Sacrifice After the Day 2 Intravenous Administration of 100 μg/kg/day 3H-AFP-168 to
`Male Rats Dosed Once Daily for Two Days. (Sponsor’s Table) .................................... 56
`Table 29: Percent of Radioactive Dose in Urine, Feces, Bile, Cage Wash, Cage Wipe,
`Bile Cannula, and Jacket Rinse, at Specified Intervals After a Single Intravenous
`Administration of 3H-AFP-168 to Male Rats Dosed Once Daily for Two Days. (Sponsor’s
`Table)............................................................................................................................ 57
`Table 30: Metabolites found in Plasma, Urine, and Bile in Male Rats Dosed Once Daily
`for Two Days with Intravenous 100 μg/kg/day 3H-AFP-168. (Sponsor’s Table) ............ 58
`Table 31: Study Design for MRL Study PK029. (Sponsor’s Table) ............................... 59
`Table 32: Mean Percent Radioactive dose in Urine, Feces, Cage Rinse, Cage Wash,
`and Cage Wipe at Specificed Intervals After Topical Ocular Administration of 3H-AFP-
`168 to Male and Female Cynomolgus monkeys. (Sponsor’s Table) ............................. 60
`Table 33: Concentrations of Radioactivity in Blood, Plasma, and Specific Ocular and
`Systemic Tissues at Specified Times After Topical Ocular Administration of 10 μg/eye of
`3H-AFP-168. (Sponsor’s Table)..................................................................................... 61
`Table 34: Percent of Radioactive Dose Recovered in Blood, Plasma, and Specific
`Ocular and Systemic Tissues at Specified Times After Topical Ocular Administration of
`10 μg/eye of 3H-AFP-168. (Sponsor’s Table) ................................................................ 62
`Table 35: AFP-168 Metabolites Following Topical Ocular Administration in Monkeys .. 62
`Table 36: Metabolite profile for Urine and Feces Following Topical Ocular Dosing of 3H-
`AFP-168 in Monkeys (Sponsor’s Table)........................................................................ 64
`Table 37: Mean Values for Liver Microsomal and Cytosolic Parameter Measurements
`for the AFP-168 High-Dose Group Expressed as a Percentage of the Corresponding
`Vehicle Control Group Mean (Sponsor’s Table)............................................................ 66
`Table 38: Total Amounts of the Principal AFP-168 Metabolites Excreted in Bile and
`Urine 24 Hours After Dosing and in Feces 48 hours After Dosing in Bile Cannulated
`Male and Female Rats. (Sponsor’s Table) .................................................................... 69
`Table 39: Single-Dose Studies with Oral or Intravenous AFP-168................................ 70
`Table 40: Studies Employing Multiple Topical Ocular Doses of AFP-168 in a Single Day.
`...................................................................................................................................... 70
`Table 41: Non-Pivotal Repeated-Intravenous-Dose Toxicology Studies....................... 71
`Table 42: Non-Pivotal Repeated-Ocular-Dose Toxicology Studies ............................... 72
`Table 43: Study Design for Study No.: MRL TT #01-5526. (Sponsor’s Table) .............. 74
`Table 44: Mortality Results in the 26-Week Intravenous-Dose Rat Toxicology Study.
`(Sponsor’s Table).......................................................................................................... 74
`Table 45: Significant Changes in Group Mean Hematology Parameters ...................... 76
`Table 46: Histopathology in Femoral and Sternum Bone Marrow. (Sponsor’s Table)... 78
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`Table 47: The Incidence and Severity of Spleen, Liver, and Femoral Bone Marrow
`Hematopoiesis. (Sponsor’s Table) ................................................................................ 79
`Table 48: The Incidence and Severity of Kidney Corticomedullary Mineralization
`(Sponsor’s Table).......................................................................................................... 79
`Table 49: Toxicokinetic Parameters Associated with Intravenous Administration of AFP-
`168 to Rats for 26 Weeks. (Sponsor’s Table)................................................................ 80
`Table 50: Study Design for Study No.: MRL TT #01-5530. (Sponsor’s Table) .............. 82
`Table 51: Mean Heart Rates. (Sponsor’s Table) ........................................................... 83
`Table 52: Group Incidence of AFP-168-Related Histopathology Findings. (Sponsor’s
`Table)............................................................................................................................ 86
`Table 53: Cmax Values for Plasma AFP-172 Following 39 Weeks of AFP-168
`Intravenous Dosing in Male and Female Dogs. (Sponsor’s Table) ............................... 87
`Table 54: AUC Plasma Exposure Values for AFP-172 Following 39 Weeks of AFP-168
`Intravenous Dosing in Male and Female Dogs. (Sponsor’s Table) ............................... 87
`Table 55: Tmax Values for Plasma AFP-172 Following 39 Weeks of AFP-168 Intravenous
`Dosing in Male and Female Dogs. (Sponsor’s Table) ................................................... 87
`Table 56: Actual Formulation Concentrations. (Sponsor’s Table) ................................. 88
`Table 57: Study Design for Study No.: MRL TT #11-7800. (Sponsor’s Table) .............. 90
`Table 58: Plasma Toxicokinetic Parameters for AFP-172 in Monkeys Following Topical
`Administration of DE-111 Ophthalmic Solution. ............................................................ 93
`Table 59: Plasma Toxicokinetic Parameters for Timolol in Monkeys Following Topical
`Administration of DE-111 Ophthalmic Solution. ............................................................ 94
`Table 60: Study Design for Study No.: MRL TT #01-5531 ............................................ 96
`Table 61: Select Toxicokinetic Parameters Following Topical Ocular Administration of
`High-Dose AFP-168 to Monkeys for 52 Weeks (Sponsor's Table).............................. 100
`Table 62: Concentrations Selected for Cytogenicity Analysis for Experiments 1 and 2
`(Sponsor’s Table)........................................................................................................ 105
`Table 63: Frequency of Cells With Polyploidy in the 3+17 hour Incubation Without S9.
`(Sponsor’s Table)........................................................................................................ 107
`Table 64: Summary of the Group Mean Frequencies of Micronucleated PCE for the 24
`Hour Sample Timepoint. (Sponsor’s Table) ................................................................ 109
`Table 65: Summary of the Group Mean Frequencies of Micronucleated PCE for the 48
`Hour Sample Timepoint. (Sponsor’s Table) ................................................................ 110
`Table 66: Spleen and Kidney Histopathology Associated with Daily Subcutaneous
`Administration of AFP-168 for 13 Weeks to Rats. (Sponsor’s Table).......................... 112
`Table 67: Select Toxicokinetic Parameters for AFP-172 Following Subcutaneous Dosing
`to Rats for 13 Weeks................................................................................................... 112
`Table 68: Select Plasma Toxicokinetic Parameters Associated with Daily Subcutaneous
`Dosing with AFP-168 for 13 Weeks in Mice. (Sponsor’s Table) .................................. 114
`Table 69: Rat Mortality Parameters for the Two year Rat Cancer Study..................... 117
`Table 70: Pituitary Tumors in Males and Females ...................................................... 121
`Table 71: Female Mammary Gland and Uterine Neoplastic Lesions .......................... 122
`Table 72: Non-Neoplastic Lesions in the Two-Year Rat Carcinogenesis Study.
`(Sponsor’s Table)........................................................................................................ 122
`Table 73: Schedule for Toxicokinetic Sampling in the Two-Year Rat Carcinogenesis
`Study........................................................................................................................... 123
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`NDA # 202514
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`Table 74: AFP-172 Toxicokinetic Parameters for Day 1, Week 13, and Week 26 in the
`Two Year Rat Carcinogenesis Study. (Sponsor’s Table) ............................................ 123
`Table 75: Study Design for the 78-Week Mouse Carcinogenicity Study. (Sponsor’s
`Table).......................................................................................................................... 126
`Table 76: Mortality in the 78-Week Mouse Carcinogenicity Study. (Sponsor’s Table).126
`Table 77: Tumor Incidence in Male Mice..................................................................... 129
`Table 78: Tumor Incidence in Female Mice ................................................................ 130
`Table 79: Toxicokinetic Collection Schedule for the 78-Week Mouse Carcinogenicity
`Study........................................................................................................................... 130
`Table 80: Selected Toxicokinetic Values for Plasma AFP-172 Associated with
`Subcutaneous AFP-168 Dosing in the Mouse Carcinogenicity Study. (Sponsor’s Table).
`.................................................................................................................................... 131
`Table 81: Study Design for the Rat Fertility Study. (Sponsor’s Table) ........................ 133
`Table 82: Non-Pivotal Range-Finding Embryo-Fetal Development Studies................ 135
`Table 83: Study Design for the Rat Embryo-Fetal Study. (Sponsor’s Table)............... 137
`Table 84: Toxicokinetics Parameters for AFP-172 Following AFP-168 Administration to
`Pregnant Rats. (Sponsor’s Table) ............................................................................... 138
`Table 85: Actual Concentrations of the AFP-168 Formulations. (Sponsor’s Table) .... 138
`Table 86: Maternal Caesarean Data ........................................................................... 140
`Table 87: Rat Fetal Malformations and Variations ...................................................... 141
`Table 88: Study Design for the First Rabbit Embryo-Fetal Study. (Sponsor’s Table).. 142
`Table 89: Actual Concentrations of the AFP-168 Dosing Solutions in the Rat Embryo-
`Fetal Study. (Sponsor’s Table).................................................................................... 144
`Table 90: Study Design for the Second Rabbit Embryo-Fetal Study. (Sponsor’s Table)
`.................................................................................................................................... 147
`Table 91: Incidence of Select Variations in the Second Rabbit Embryo-Fetal Study. . 150
`Table 92: Non-Pivotal Range-Finding Prenatal and Postnatal Development Studies . 151
`Table 93: Study Design for the Pre- and Post-Natal Development Study in Rats.
`(Sponsor’s Table)........................................................................................................ 152
`Table 94: Comparative Metabolism of Tafluprost in Rat, Dog, Monkey, and Human
`Hepatocytes. (Sponsor’s Table) .................................................................................. 160
`Table 95: Safety Analysis for Tafluprost-Related Systemic Toxicity Based on the
`Intravenous Dose Toxicology Studies in Dogs ............................................................ 162
`Table 96: Safety Analysis for Tafluprost-Related Systemic Toxicity Based on the Ocular
`Dose Toxicology Studies in Monkeys.......................................................................... 163
`Table 97: Safety Analysis for Tafluprost-Related Ocular Toxicity Based on the Ocular-
`Dose Toxicology Studies in Monkeys.......................................................................... 164
`Table 98: The AUC Exposure Ratio for AFP-172 Following Subcutaneous Dosing in
`Rats Versus Topical Ocular Dosing in Humans. ......................................................... 166
`Table 99: The AUC Exposure Ratio for AFP-172 Following Subcutaneous Dosing in
`Mice Versus Topical Ocular Dosing in Humans. ......................................................... 167
`Table 100: Hematology and Coagulation Parameter Table......................................... 170
`Table 101: Clinical Chemistry Parameter Table .......................................................... 171
`Table 102: Histopathology and Organ Weight Inventory Table ................................... 171
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`Table of Figures
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`Figure 1: Group Mean Body Weights for Male Rats. (Sponsor's Figure)..................... 118
`Figure 2: Group Mean Body Weights for Female Rats. (Sponsor's Figure) ................ 118
`Figure 3: Male Group Mean Body Weights. (Sponsor’s Figure) .................................. 127
`Figure 4: Female Group Mean Body Weights. (Sponsor’s Figure).............................. 128
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`NDA # 202514
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`Executive Summary
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`Reviewer: James Wild
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`Introduction
`1.1
`Tafluprost ophthalmic solutions are intended for the treatment of elevated intraocular
`pressure in open angle glaucoma or ocular hypertension. Tafluprost acid (AFP-172), the
`tafluprost metabolite and the pharmacologically active agent, is a fluorinated analogue
`of prostaglandin F2α (PGF2α) with high affinity and selectivity for the FP prostanoid
`receptor. The presumed mechanism of tafluprost with regard to glaucoma is reduction
`of intraocular pressure by increasing uveoscleral outflow of aqueous humor. Further
`activity may be mediated by tafluprost-induced relaxation of the ciliary muscle and
`changes in ciliary muscle extracelluar matrix thus facilitating increased outflow from the
`aqueous humor.
`
`Three other PGF2a analogues are currently approved for the treatment of elevated
`intraocular pressure in patients with open angle glaucoma or ocular hypertension.
`These are Xalatan® (latanoprost), Travatan® (travoprost), and Lumigan® (bimatoprost).
`According to their product labels, all of the approved PGF2α analogues are associated
`with specific ocular and eye adnexa adverse effects. These include increased
`pigmentation of the iris, periorbital tissue (eyelid), and eyelashes, and macular edema.
`1.2 Brief Discussion of Nonclinical Findings
`• Tafluprost (AFP-168) is a PGF2α analogue intended for topical ocular
`administration. The active metabolite, tafluprost acid (AFP-172) is the
`pharmacologically active agent. In primary pharmacology studies, tafluprost acid
`(AFP-172) was shown to bind to the FP prostanoid receptor with subnanomolar
`affinity, and binding was shown to be substantially selective for this receptor.
`
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`• The primary safety signals in safety pharmacology studies were a low incidence
`of central nervous effects in mice and a dose-dependent increase in blood
`pressure, heart rate, and Qtc intervals in anesthetized dogs. However, the
`cardiovascular effects occurred only minimally in repeated-intravenous dose
`toxicology studies in dogs, and did not occur in repeated-ocular dose studies in
`monkeys. Because clinical exposures are expected to be on the order of 100 fold
`lower than the exposures associated with the high ocular doses in the monkey
`studies, cardiovascular toxicity is not expected to be a clinical concern.
`
`• Preservative free tafluprost formulations and formulations containing 0.01%
`benzalkonium chloride demonstrated similar corneal penetration. Tafluprost was
`rapidly absorbed following topical ocular administration with a high bioavailability.
`Plasma T1/2 for tafluprost acid following ocular and intravenous dosing of
`tafluprost in monkeys was on the order of 10 hours. Plasma Cmax and AUC
`values for tafluprost acid increased in a roughly dose-proportional manner
`following ocular and intravenous dosing, and tafluprost acid did not accumulate in
`plasma following repeated-tafluprost administration by both routes.
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`Reference ID: 2975903
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`NDA # 202514
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`• Topical ocular administration of 3H-tafluprost in rats and monkeys resulted in
`widespread ocular distribution. Repeated dosing produced a similar ocular
`distribution pattern, and accumulation did not occur in any tissue other than the
`lens where concentrations increased approximately 50% after 21 days of dosing.
`
`• Tafluprost acid was >90% bound to serum albumin from rat, rabbit, dog and
`humans. Tafluprost demonstrated extensive tissue distribution consistent with
`renal and hepatobiliary excretion and limited CNS distribution. Tissue distribution
`following repeated ocular dosing was similar to that following a single dose
`indicating an absence of systemic tissue accumulation. Tafluprost administered
`topically to the eye or intravenously was excreted primarily in urine and through
`hepatobiliary excretion with final deposition in feces.
`
`•
`
`•
`
`3H-Tafluprost or its metabolites transferred into milk in lactating rats, and crossed
`the placental barrier in pregnant rats. Milk Cmax radioactivity levels were similar to
`those in plasma, and fetal exposure was approximately two thirds that of plasma
`exposure.
`
`In mice, rats, dogs, monkeys, and humans, tafluprost was shown to rapidly
`metabolize to its active metabolite, tafluprost acid. All of the putative metabolites
`occurring above 10% in human hepatocytes were also present in hepatocyte
`suspensions from rat and monkey. Tafluprost was shown to be metabolized by
`rabbit eye carboxyesterases, but not by any of 12 different recombinant human
`CYP-450 isozymes.
`
`• Repeated-intravenous administration of tafluprost for up to 26 weeks in rats and
`up to 39 weeks in dogs produced species-specific patterns of systemic toxicity. In
`rats, toxicity included dose-related mortality, hyperostosis and myelofibrosis in
`bone marrow of the femur and sternum, increased hematopoesis in the spleen,
`liver, and male femoral bone marrow, and an increase in corticomedullary
`mineralization in the kidney of females. Dose-dependent changes in the
`hematological composition of the blood and bone marrow were also observed.
`Less systemic toxicity occurred in dogs. The most pronounced effects, were
`dose-dependent and transient clinical signs including salivation, emesis, loose
`feces, increased respiration, increased heart rate, and increased blood pressure.
`A prolonged QTc interval was also noted in a 28-day intravenous dose study in
`dogs at a tafluprost dose of 10 μg/kg/day. In the 39-week dog study, one high-
`dose (10 μg/kg/day) male experienced severe hepatotoxicity, and all high-dose
`males demonstrated a slight but significant elevation in serum ALT. Increased
`serum ALT activity was also noted in the 28-day dog study and the change was
`reversible after two weeks recovery. A NOAEL value could not be determined for
`the 26-week rat study, but the plasma Cmax and AUC exposures associated with
`the NOAEL values in the dog studies were more than 30-fold higher than those
`associated with the Cmax and AUC exposures obtained in humans after 8 days of
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`Reference ID: 2975903
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`NDA # 202514
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`Reviewer: James Wild
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`daily topical ocular dosing with the tafluprost dose intended for marketing
`(0.0015%).
`
`• Tafluprost was also administered by the topical ocular route in several repeated-
`dose topical ocular studies in monkeys, and in all of these studies, no systemic
`toxicity was observed. The systemic exposure values for tafluprost acid in these
`studies consistently exceeded the expected clinical exposure by more than 100
`fold. These data strongly suggest that clinical administration of tafluprost by the
`topical ocular route is unlikely to cause systemic toxicity.
`
`• Ocular changes included iridial darkening, sunken eyelids, and blue-gray
`discoloration of the lower eyelid. However, all of the tafluprost-related ocular
`changes are consistent with ocular changes observed with other marketed PGF2α
`analogues including Xalatan® (latanoprost), Lumigan® (bimatoprost), and
`Travatan ® (travoprost). These effects are considered to be mainly cosmetic, not
`associated with loss of function, and not toxicologically significant. Other, more
`serious ocular toxicities including pronounced inflammation or alterations in
`electroretinography were not observed with topical ocular administration of
`tafluprost at any of the administered doses. The NOAEL doses for the topical
`ocular monkey studies provided ocular human equivalent doses that were 67 fold
`higher than the clinical dose intended for marketing.
`
`• Trafluprost was shown to be negative for genotoxicity in an in vitro bacterial
`reverse mutation assay, an in vitro chromosome aberrat