CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`APPLICATION NUMBER:
`202514Orig1s000
`
`CLINICAL PHARMACOLOGY AND
`BIOPHARMACEUTICS REVIEW(S)
`
`
`
`
`
`
`

`

`
`
`
`
`OFFICE OF CLINICAL PHARMACOLOGY REVIEW
`
`
`
`NDA:
`Submission Date(s):
`Proposed Brand Name
`Generic Name
`Primary Reviewer
`Team Leader
`OCP Division
`OND Division
`Applicant
`Relevant IND(s)
`Submission Type; Code
`Formulation; Strength(s)
`Indication
`
`Dosage and Administration
`
`202-514
`January 7, 2011
`TBD
`Tafluprost
`Yongheng Zhang, Ph.D.
`Philip M. Colangelo, Pharm.D., Ph.D.
`DCP4
`DTOP
`MERCK & CO., Inc.
`062690
`1S(NME)
`Tafluprost 0.0015% Ophthalmic Solution
`For the reduction of elevated intraocular pressure in open-angle
`glaucoma or ocular hypertension
`One drop of Tafluprost 0.0015% ophthalmic solution in the
`conjunctival sac of the affected eye(s) once daily in the evening
`
`
`
`TABLE OF CONTENTS
`
`1. EXECUTIVE SUMMARY .................................................................................................................. 2
`1.1. RECOMMENDATION ....................................................................................................................... 3
`1.2. PHASE IV COMMITMENTS............................................................................................................. 3
`1.3.
`SUMMARY OF IMPORTANT CLINICAL PHARMACOLOGY AND BIOPHARMACEUTICS FINDINGS.. 3
`2. QUESTION BASED REVIEW ........................................................................................................... 4
`2.1. GENERAL ATTRIBUTES OF THE DRUG .......................................................................................... 4
`2.2. GENERAL CLINICAL PHARMACOLOGY......................................................................................... 5
`2.3.
`INTRINSIC FACTORS .................................................................................................................... 10
`2.4. EXTRINSIC FACTORS ................................................................................................................... 10
`2.5. GENERAL BIOPHARMACEUTICS .................................................................................................. 12
`2.6. ANALYTICAL SECTION ................................................................................................................ 12
`3. LABELING RECOMMENDATIONS ............................................................................................. 14
`4. APPENDICES ........................................................................................................................................ 15
`4.1. PROPOSED PACKAGE INSERT (ORIGINAL AND ANNOTATED) ......................................................... 15
`4.2.
`INDIVIDUAL STUDY REVIEW ....................................................................................................... 25
`4.2.1. Pharmacokinetics of tafluprost in healthy subjects: Study P15005............................................ 25
`4.2.2. PK of tafluprost: preservative-containing vs. preservative-free eye drop (Study P77551) ........ 30
`4.2.3. Evaluation of AFP-172 binding to human serum albumin by ultrafiltration method................. 36
`4.2.4. In Vitro Metabolism Study on Tafluprost and AFP-172 Using Cryopreserved Hepatocytes ..... 38
`4.2.5. Metabolite Profiling and Identification for Tafluprost............................................................... 40
`4.2.6. Reaction Phenotyping for Tafluprost Acid Metabolism Using Human Recombinant CYP450s. 44
`4.2.7. PD comparison of tafluprost 0.0015% ophthalmic solutions: PC vs. PF…………………………47
`
`Page 1 of 48
`
`Reference ID: 2974327
`
`

`

` EXECUTIVE SUMMARY
`
`
`
`1.
`
`Tafluprost (AFP-168, MK-2452) is an ester prodrug of a new synthetic prostaglandin F2α
`(PGF2α) analogue selective for the FP prostanoid receptor. Converting in vivo into the
`pharmacologically active tafluprost acid (AFP-172), tafluprost is a new chemical entity drug
`product developed for the reduction of elevated intraocular pressure (IOP) in open-angle
`glaucoma or ocular hypertension. The proposed product, Tafluprost 0.0015% ophthalmic solution
`(one eye drop once daily), does not contain any preservative agents, such as benzalkonium
`chloride, which is commonly used in the approved prostaglandin analogues (e.g., Xalatan®,
`Travatan®, and Lumigan®) for glaucoma treatment and believed to cause potential toxicity due to
`chronic use. Tafluprost 0.0015% preservative free (PF) and preservative containing (PC) have
`been approved for reducing of elevated IOP in open angle glaucoma and ocular hypertension in
`many countries other than the United States.
`
`In support of the NDA, the Applicant submitted clinical studies including:
`
`
`• Six Phase 1 dose-escalation studies (Studies 74450, 74451, 74452, 74453, 15005, and
`77551) to assess the systemic exposure and tolerability of tafluprost ophthalmic solution
`in healthy subjects.
`
`
`
`
`
`
`
`
`
`• Two Phase 2 dose-ranging studies in patients (Studies P15001 and P15002) to support the
`selection of tafluprost 0.0015% for further development.
`
`• Five Phase 3 studies in patients to assess the efficacy, safety and tolerability of tafluprost
`for the treatment of glaucoma, including a comparison to latanoprost (Study 74458
`[Latanoprost Non-Inferiority Study]), a comparison to timolol (Studies 15003
`[Preservative-containing (PC) Tafluprost vs. PC Timolol Non-Inferiority Study] and 001
`[Preservative-free (PF) Tafluprost vs. PF Timolol Non-Inferiority Study]), a study
`examining tafluprost as adjunctive treatment with timolol (Study 74460 [(Adjunctive
`Treatment to Timolol]), and a bridging study comparing PC and PF formulations of
`tafluprost (Study 77550 [PF/PC Comparison Study]).
`
`•
`
`In addition, an open-label Phase 3b clinical study (77552 [Open label PF tafluprost
`/latanoprost switch study]) to investigate changes in ocular signs and symptoms when
`patients were switched from preservative-containing latanoprost to PF tafluprost.
`
`Page 2 of 48
`
`Reference ID: 2974327
`
`

`

`1.1. Recommendation
`
`
`The Clinical Pharmacology information provided by the Applicant in the NDA submission is
`acceptable.
`
`The reviewer’s proposed label changes in Appendix 4.1 will be forwarded to the sponsor.
`
`
`1.2. Phase IV Commitments
`
`
`
`
`None.
`
`
`1.3. Summary of Important Clinical Pharmacology and Biopharmaceutics Findings
`
`
`Tafluprost is an ester prodrug of tafluprost acid, which is further metabolized in vivo via fatty
`acid β-oxidation and phase II conjugation. The binding of tafluprost acid to human serum
`albumin (4%) was >99%. Tafluprost acid is not metabolized by major human CYP450 enzymes.
`It is unknown if tafluprost or tafluprost acid inhibits or induces any CYP450 enzymes. However,
`given the low systemic exposure (the systemic Cmax is about 1/9th of EC50 value) to tafluprost acid
`following topical ocular administration of tafluprost 0.0015% ophthalmic solution, clinically
`relevant interactions based on inhibition of CYP450 enzymes are not to be expected for tafluprost
`and concomitantly administered drugs.
`
`IOP reduction starts about 2 to 4 hours after topical ocular administration and the maximal effect
`is reached by 12 hours post instillation. The duration of action for tafluprost was greater than 24
`hours, which is consistent with the data obtained on other prostaglandin analogues.
`
`Following topical instillation, tafluprost is absorbed through the cornea and is hydrolyzed to the
`biologically active tafluprost acid (EC50 to the recombinant human FP prostanoid receptor = 217
`pg/mL, or 0.5 nM). Following 8-day q.d. administration of tafluprost 0.0015% Preservative-free
`(PF) ophthalmic solution, mean plasma tafluprost acid Cmax values were 26 pg/mL and 27 pg/mL
`on Day 1 and Day 8, respectively; mean plasma tafluprost acid AUC values were 394 pg*min/mL
`and 432 pg*min/mL on Days 1 and 8, respectively (Study 77551). Mean plasma concentrations of
`tafluprost acid were below the limit of quantification (10 pg/mL) at 30 minutes. Pharmacokinetic
`parameters (AUC and Cmax) of the preservative-containing (PC) and PF formulations of tafluprost
`were comparable.
`
`The effect of the commonly known intrinsic (e.g., renal impairment, hepatic impairment, age
`gender) and extrinsic (e.g., drug-drug interactions) factors on the PK of tafluprost following
`topical administration of tafluprost 0.0015% ophthalmic solution has not been studied. Given the
`low systemic exposure following topical administration, however, dose adjustment is not
`warranted in patients based on the commonly known intrinsic or extrinsic factors.
`
`Page 3 of 48
`
`Reference ID: 2974327
`
`

`

`2. QUESTION BASED REVIEW
`
`2.1.
`
`General Attributes of the Drug
`
`2.1.1. What are the highlights ofthe chemistry andphysical-chemicalproperties ofthe drug
`substance and theformulation ofthe drugproduct?
`
`Tafluprost is a colorless to light yellow viscous liquid. It is practically insoluble in water, very
`soluble in ethanol, diethyl ether, and acetonitrile, sparingly soluble in a mixed solution of
`phosphate bufi‘er/acetonitrile (1:1).
`
`Structural Formula: C95H34F205
`
`Molecular Weight: 452.53 Dalton
`
`CAS Index Name: l—methylethyl (SZ)-7-{(1R, 2R. 3R, SS)-2-[(1E)—3,3-difluoro-4- phenoxy— l-
`butenyl]-3.5-dihydroxycyclopentyl}-5-heptenoate
`
`Chemical Structure:
`
`HO
`
`'1 __\\=/\/\n/O\(Mo 0
`
`HO
`
`F FA
`\ |
`
`Drug Product:
`The drug product, Taflupmst 0.0015% eye drops. is formulated as a sterile. isotonic ophthalmic
`sohltion using common excipients and filled
`“9“) into single-dose containers. The solution
`is clear and colorless with pH of 6.0. The single-dose formulation does not contain benzalkonium
`chloride (BAC), and the amount of polysorbate 80 is
`9"“). Formulations with
`preservative BAC, in multidose containers containing 1 to 50 uglml tafluprost. were used in most
`of the clinical studies. (Table 2.1.1—l)
`
`Table 2.1.1 -1: Com c .
`
`ition of the dru - oduct in sin le-dose and multidose containers
`
`Drug substance
`
`'l‘afluprost 15 microg/ml eye drops in 'l'afluprost 15 microg/ml eye drops
`single-dose container
`in mullidose container
`(mg/ml)
`(mg/ml)
`
`9)“
`
`'l'afluprost
`Excipients
`Glycerol
`Sodium dihydrogcn phosphate
`dihydrate
`Disodium edemle
`(”(0
`
`Polysorbnlc 80
`Sodium hydroxide and/or
`Hydrochloric acid
`”Mater
`
`Page 4 of 48
`
`Reference ID: 2974327
`
`

`

`
`
`Two clinical studies (77550 and 77551) were conducted to bridge the formulation differences
`between the clinical trial formulation (preservative-containing, PC) and the to-be-marketed
`product (preservative free, PF). The results showed that Tafluprost 0.0015% PF eye drops have
`similar pharmacokinetic and pharmacodynamic profiles as Tafluprost 0.0015% PC eye drops.
`
`2.1.2. What is the proposed mechanism of drug action and therapeutic indication?
`
`Tafluprost is a prodrug of a new synthetic prostaglandin F2α (PGF2α) analogue selective for the
`FP prostanoid receptor (EC50 value of 0.5 nM). The prostaglandins comprise a group of naturally
`occurring fatty acids which act as autacoids and exert complex physiologic effects by stimulating
`specific membrane receptors. Like other prostaglandin analogues, tafluprost has also been shown
`to increase the uveoscleral outflow and decrease IOP in monkeys.
`
`The proposed drug product is indicated for the reduction of elevated IOP in open-angle glaucoma
`or ocular hypertension.
`
`2.1.3. What are the proposed dosage(s) and route(s) of administration?
`
`The recommended dose is one drop of Tafluprost 0.0015% ophthalmic solution in the
`conjunctival sac of the affected eye(s) once daily in the evening.
`
`2.2. General Clinical Pharmacology
`
`2.2.1. What are the design features of the clinical pharmacology and clinical studies used to
`support dosing or claims?
`
`
`The clinical pharmacology studies with tafluprost consisted of pharmacokinetic studies as well as
`Phase I and Phase II dose-response studies:
`
`
`• Pharmacokinetics: In four Phase 1 dose-escalation studies (74450, 74451, 74452, and
`74453), neither tafluprost nor tafluprost acid could be detected when using a bioanalytical
`method (HPLC/MS/MS) with LLOQ at 0.2 ng/mL (tafluprost) and 0.1 ng/mL (tafluprost
`acid). One confounding factor is that the plasma samples may have not been stored
`properly in some of these studies to ensure adequate sample stability. In a subsequent
`Study 15005, systemic exposure following topical ocular administration of 0.0015%
`tafluprost ophthalmic solution was successfully assessed using an improved analytical
`method (HPLC/MS/MS)with LLOQ at 10 pg/mL (tafluprost acid). Furthermore, Study
`77551 was conducted to verify if the systemic bioavailability of tafluprost in humans
`after topical ocular q.d. administration of either tafluprost (0.0015%) PF or PC
`ophthalmic solution is similar.
`
`• Two Phase 2 dose-ranging studies in glaucoma patients were conducted to inform dose
`selection for Phase 3. In Study P15001, 0.001%, 0.0025%, and 0.005% concentrations of
`tafluprost were tested. One group of patients received placebo and another received
`latanoprost (positive control). The IOP reduction- time profiles suggested that the optimal
`dose of tafluprost is between 0.001% and 0.0025%. In the second Study P15002, the
`tafluprost concentration was tested at 0.0003%, 0.0015%, and 0.0025%. The study
`showed that 0.0015% of tafluprost offered the best balance between efficacy (IOP
`reduction) and tolerability (measured by eye comfort, conjunctival hyperemia, et al).
`
`Page 5 of 48
`
`
`
`
`
`Reference ID: 2974327
`
`

`

`
`
`• Dose-regimen: The selected 0.0015% concentration of tafluprost was tested in the Phase
`II study 74457 (Pilot Latanoprost Comparison Study). This study showed similar efficacy
`between 0.0015% tafluprost and 0.005% latanoprost. In addition, the duration of action
`for tafluprost was greater than 24 hours, which is in agreement with the data obtained on
`other prostaglandin analogues. Hence, similar to latanoprost, a once daily dose regimen is
`considered appropriate for tafluprost ophthalmic solution.
`
`
`Based on the Phase II dose-finding and efficacy studies, the optimal balance between efficacy and
`tolerability with tafluprost administered once daily appeared to be reached at tafluprost 0.0015%.
`Therefore, this dose regimen was selected for further evaluations in the Phase III clinical studies.
`
`2.2.2. What is the basis for selecting the response endpoints (i.e., clinical or surrogate
`endpoints) or biomarkers (collectively called pharmacodynamics [PD]) and how are they
`measured in clinical pharmacology and clinical studies?
`
`
`IOP is accepted as a surrogate endpoint for assessing the efficacy of treatments for open-angle
`glaucoma and ocular hypertension. The IOP endpoint has served as the basis for approval for all
`IOP-lowering agents for open-angle glaucoma or ocular hypertension.
`
`2.2.3. Are the active moieties in the plasma (or other biological fluid) appropriately identified
`and measured to assess pharmacokinetic parameters and exposure response
`relationships?
`
`
`Yes, the sponsor used a validated LC/MS/MS method to quantitate plasma concentrations of the
`active metabolite, tafluprost acid. (Refer to Section 2.6).
`
`2.2.4. Exposure-response
`
`
`2.2.4.1. What are the characteristics of the exposure-response relationships (dose-
`response, concentration-response) for efficacy? If relevant, indicate the time to
`the onset and offset of the desirable pharmacological response or clinical
`endpoint.
`
`
`The dose-PD response in the eye was studied in Phase 1 dose escalation studies in healthy
`subjects and Phase 2 dose-ranging studies in patients. In Phase 2 Study P15001, 0.001%,
`0.0025%, and 0.005% concentrations of tafluprost were tested. The IOP reduction- time profiles
`suggested that the optimal dose of tafluprost is between 0.001% and 0.0025% as a dose higher
`than 0.0025% did not provide additional IOP reduction (Figure 2.2.4.1-1). In the Phase 2 Study
`P15002, the tafluprost concentrations of 0.0003%, 0.0015%, and 0.0025% were assessed. The
`study showed that 0.0015% of tafluprost offered the best balance between IOP reduction (Figure
`2.2.4.1-2) and tolerability (measured by eye comfort, conjunctival hyperemia, et al).
`
`The IOP reduction starts about 2 to 4 hours after administration and the maximal effect is reached
`12 hours after instillation. The duration of action for tafluprost was greater than 24 hours, which
`is in agreement with the data obtained on other prostaglandin analogues.
`
`
`Page 6 of 48
`
`Reference ID: 2974327
`
`

`

`
`
`Source: Study report P15001
`Note: IOP was measured at 8 am, 12 pm, 4 pm, and 8 pm on baseline (Day 0) and Days 7, 14, and 28.
`Figure 2.2.4.1-1: Percentage Mean Diurnal IOP Reductions During the Treatment Period With
`Tafluprost Treatment at Different Concentrations of in Study P15001
`
`
`
`Source: Study report P15002
`Note: IOP was measured at 8 am, 12 pm, 4 pm, and 8 pm on baseline (Day 0) and Days 7, 14, and 28.
`Figure 2.2.4.1-2: Percentage Mean Diurnal IOP Reductions During the Treatment Period With
`Tafluprost Treatment at Different Concentrations in Study P15002
`
`2.2.4.2. What are the characteristics of the exposure-response relationships (dose-
`response, concentration-response) for safety? If relevant, indicate the time to the
`onset and offset of the undesirable pharmacological response or clinical
`endpoint.
`
`
`In the Phase 2 dose-finding trials with treatment duration of 4 to 6 weeks, the most common
`ocular AEs were: conjunctival hyperemia, eye irritation, and eye pruritus. The conjunctival
`
`Page 7 of 48
`
`Reference ID: 2974327
`
`
`
`
`
`

`

`
`
`hyperemia appeared to be dose related: it occurred more frequently in tafluprost 0.005% and
`0.0025% than in 0.0015%. The degree of conjunctival hyperemia with 0.0015% tafluprost was
`similar to that with latanoprost arm.
`
`2.2.4.3. Does this drug prolong the QT or QTc interval? (You must answer this question,
`unless this is addressed in the question above.)
`
`
`No, Tafluprost 0.0015% ophthalmic solution following topical ocular administration did not
`prolong the QT or QTc interval in the clinical trial population. Due to a low systemic exposure to
`tafluprost and tafluprost acid, a thorough QT study was considered unnecessary and not
`conducted.
`
`
`2.2.4.4. Is the dose and dosing regimen selected by the sponsor consistent with the known
`relationship between dose-concentration-response, and are there any unresolved
`dosing or administration issues?
`
`
`The dosing rationale for Phase 3 pivotal trials was based on the dose-response relationship
`derived from Phase 2 studies (Refer to Section 2.2.4.1). An IOP responder analysis provided by
`the sponsor combining the data from both Phase 2 and 3 trials further supported the selection of
`the 0.0015% as the appropriate dose strength in tafluprost ophthalmic solution (Table 2.2.4.4-1).
`
`Table 2.2.4.4-1: Number (%) of Patients With ≥25% Reduction in Diurnal IOP from Baseline at
`Week 4/Week 6† (Full Analysis Set Population from Phase 2 and 3 Trials; Study Eye)
`
`
`
`
`There is no unresolved dosing or administration issues.
`
`2.2.5. What are the PK characteristics of the drug?
`
`
`2.2.5.1. What are the single dose and multiple dose PK parameters?
`
`Tafluprost PK was studied following 8-day q.d. topical ocular administration of tafluprost
`0.0015% preservative-containing (PC) and preservative-free (PF) ophthalmic solution in healthy
`subjects (Study 77551). The calculated pharmacokinetic parameters are presented in Table
`2.2.5.1-1. For both formulations, the concentrations of tafluprost acid peaked at a median time of
`10 minutes on both Days 1 and 8. Mean plasma concentrations of tafluprost acid were below the
`limit of quantification (10 pg/mL) at 30 minutes. Pharmacokinetic parameters (AUC and Cmax) of
`the PC and PF formulations of tafluprost were comparable (refer to Section 4.2.2).
`
`Following 8-day q.d. administration of tafluprost 0.0015% PF ophthalmic solution to healthy
`subjects, mean plasma tafluprost acid Cmax were 26 pg/mL and 27 pg/mL on Day 1 and Day 8,
`respectively; mean plasma tafluprost acid AUC were 394 pg*min/mL and 432 pg*min/mL on
`Day 1 and 8, respectively, suggesting minimal accumulation. It should be noted that, compared to
`the PF formulation, Cmax or AUC differences between Day 1 and Day 8 appears to be more
`evident for the PC formulation. In fact, the mean tafluprost acid systemic exposure (AUC and
`
`Page 8 of 48
`
`Reference ID: 2974327
`
`

`

`
`
`Cmax) is statistically higher on Day 8 than on Day 1 for the PC formulation. However, the
`difference is not considered to be clinically relevant due to the low exposure.
`
`Table 2.2.2.5-1: Descriptive statistics for pharmacokinetic parameters of tafluprost acid on Days 1
`and 8 (AUC & Cmax: (Mean ± SD); tmax: mean (min-max)) following topical ocular administration
`of tafluprost 0.0015% PF and PC ophthalmic solutions
`
`
`
`
`
`
`2.2.5.2. How does the PK of the drug in healthy volunteers compare to that in patients?
`
`
`Tafluprost PK following topical ocular administration was only evaluated in healthy subjects.
`
`
`2.2.5.3. What are the characteristics of drug absorption?
`
`
`Following topical ocular administration, tafluprost is absorbed through the cornea and is
`hydrolyzed to the biologically active acid metabolite (EC50 to the recombinant human FP
`prostanoid receptor = 217 pg/mL, or 0.5 nM). The plasma concentrations of tafluprost acid
`peaked at a median time of 10 minutes on both Days 1 and 8.
`
`
`2.2.5.4. What are the characteristics of drug distribution?
`
`
`The binding of tafluprost acid to human serum protein (4%) was > 99% (Study PK017, refer to
`Section 4.2.3).
`
`
`2.2.5.5. Does the mass balance study suggest renal or hepatic as the major route of
`elimination? (This may include table with results of mass balance study.)
`
` A
`
`
`
` mass balance study was not performed.
`
`2.2.5.6. What are the characteristics of drug metabolism?
`
`
`Tafluprost, an ester prodrug, is hydrolyzed to its biologically active acid metabolite, tafluprost
`acid, in the eye. Tafluprost acid is further metabolized via fatty acid β-oxidation and phase II
`conjugation (refer to Sections 4.2.4 and 4.2.5).
`
`
`2.2.5.7. What are the characteristics of drug excretion?
`
`
`No studies were submitted that evaluated the major route(s) of drug excretion in humans.
`
`Page 9 of 48
`
`Reference ID: 2974327
`
`

`

`
`
`
`
`2.2.5.8. Based on PK parameters, what is the degree of linearity or nonlinearity in the
`dose-concentration relationship?
`
`
`In four Phase 1 dose-escalation studies (74450, 74451, 74452, and 74453), neither tafluprost nor
`tafluprost acid could be detected when using a bioanalytical method with LLOQ at 0.2 ng/mL (for
`tafluprost) and 0.1 ng/mL (for tafluprost acid). Tafluprost PK was successfully assessed in two
`PK studies (P77551 and P15005) following topical ocular administration of tafluprost ophthalmic
`solution at one dose level (i.e., 0.0015%) when an improved bioanalytical method was used
`(LLOQ = 10 pg/mL for tafluprost acid). Therefore, the degree of linearity or nonlinearity was not
`ascertained.
`
`
`2.2.5.9. How do the PK parameters change with time following chronic dosing?
`
`Refer to Section 2.2.5.1.
`
`
`2.2.5.10. What is the inter- and intra-subject variability of PK parameters in volunteers
`and patients, and what are the major causes of variability?
`
`
`The systemic exposure to tafluprost following topical ocular administration was only evaluated in
`healthy subjects. As shown in Table 2.2.5.1-1, Cmax and AUC values of tafluprost acid were
`variable (CV% >50%). This level of inter-subject variability in systemic exposure is not
`considered unexpected following topical ocular administration.
`
`2.3. Intrinsic Factors
`
`2.3.1. What intrinsic factors (age, gender, race, weight, height, disease, genetic polymorphism,
`pregnancy, and organ dysfunction) influence exposure (PK usually) and/or response, and
`what is the impact of any differences in exposure on efficacy or safety responses?
`
`
`The effect of the commonly known intrinsic factors including race, gender and age on the PK of
`tafluprost following topical administration of tafluprost 0.0015% ophthalmic solution has not
`been studied. Given the low systemic exposure following topical administration, however, dose
`adjustment is not warranted in patients based on the commonly known intrinsic factors.
`
`2.4. Extrinsic Factors
`
`2.4.1. What extrinsic factors (drugs, herbal products, diet, smoking, and alcohol use) influence
`dose-exposure and/or -response and what is the impact of any differences in exposure on
`response?
`Based upon what is known about exposure-response relationships and their variability,
`what dosage regimen adjustments, if any, do you recommend for each of these factors? If
`dosage regimen adjustments across factors are not based on the exposure-response
`relationships, describe the basis for the recommendation.
`
`The impact of the commonly known extrinsic factors on tafluprost dose-exposure and/or –
`response has not been evaluated. Because of the systemic exposure is low, the impact, if any,
`would not be clinically significant. Therefore, no dosage adjustments for extrinsic factors are
`recommended.
`
`2.4.2. Drug-drug interactions
`
`Page 10 of 48
`
`Reference ID: 2974327
`
`

`

`
`
`
`
`2.4.2.1. Is there an in vitro basis to suspect in vivo drug-drug interactions?
`
`
`No. Tafluprost, an ester prodrug, is hydrolyzed to its biologically active acid metabolite,
`tafluprost acid, in the eye. Tafluprost acid is further metabolized via fatty acid β-oxidation and
`phase II conjugation. In vitro metabolism studies suggested that tafluprost acid is not metabolized
`by CYP450 enzymes (Refer to Section 4.2.6).
`
`
`2.4.2.2. Is the drug a substrate of CYP enzymes? Is metabolism influenced by genetics?
`
`Neither tafluprost nor tafluprost acid is a substrate of CYP enzymes (Refer to Section 4.2.6) nor
`has metabolism influenced by genetics.
`
`
`2.4.2.3. Is the drug an inhibitor and/or an inducer of CYP enzymes?
`
`No in vitro inhibition nor in vitro induction studies were performed by the sponsor, thus, it is
`unknown if tafluprost or tafluprost acid is an inhibitor and/or an inducer of CYP enzymes.
`
`
`2.4.2.4. Is the drug a substrate and/or an inhibitor of P-glycoprotein transport
`processes?
`
`
`No transporter studies were performed by the sponsor, thus, it is unknown if tafluprost or
`tafluprost acid is an inhibitor and/or substrate of P-glycoprotein transport process.
`
`
`2.4.2.5. Are there other metabolic/transporter pathways that may be important?
`
`
`No, there are no other metabolic/transporter pathways expected to be of importance.
`
`
`2.4.2.6. Does the label specify co-administration of another drug and, if so, has the
`interaction potential between these drugs been evaluated?
`
`
`No, the label does not specify co-administration of another drug.
`
`
`2.4.2.7. What other co-medications are likely to be administered to the target patient
`population?
`
`
`Tafluprost 0.0015% ophthalmic solution can be used as adjunctive treatment with timolol. No
`other co-administered drugs can be specified.
`
`
`2.4.2.8. Are there any in vivo drug-drug interaction studies that indicate the exposure
`alone and/or exposure-response relationships are different when drugs are co-
`administered?
`
`
`No in vivo drug-drug interaction studies have been conducted.
`
`
`2.4.2.9. Is there a known mechanistic basis for pharmacodynamic drug-drug
`interactions, if any?
`
`
`There is no known mechanistic basis for PD drug-drug interactions.
`
`
`Page 11 of 48
`
`Reference ID: 2974327
`
`

`

`
`
`2.4.2.10. Are there any unresolved questions related to metabolism, active metabolites,
`metabolic drug interactions, or protein binding?
`
`
`There are no unresolved questions related to active metabolites and metabolic drug interactions.
`However, with respect to the assessment of in vitro metabolism of the active tafluprost acid
`metabolite, the validity of the experimental condition in the CYP450 reaction phenotyping
`experiments with the acid metabolite was not confirmed because of the lack of inclusion of
`positive controls (Refer to Section 4.2.6). It should also be noted that plasma protein binding was
`assessed using constituted human albumin solution instead of pooled human plasma (Refer to
`Section 4.2.3).
`
`2.4.3.
`
`What issues related to dose, dosing regimens, or administration are unresolved and
`represent significant omissions?
`
`
`No issues related to dose, dosing regimens, or administration remain unresolved.
`
`2.5.
`
`Not applicable. Tafluprost is formulated as an ophthalmic solution for topical ocular
`administration.
`
`2.6.
`
`2.6.1. How are the active moieties identified and measured in the plasma in the clinical
`pharmacology and biopharmaceutics studies?
`
`General Biopharmaceutics
`
`Analytical Section
`
`
`
`Tafluprost acid (the active metabolite of tafluprost) plasma concentrations were quantified using
`an adequately validated liquid chromatography (LC) assay with tandem mass spectrometric
`detection (MS/MS). Tafluprost acid and the internal standard,
`, were extracted from
`human plasma by liquid-liquid extraction.
`
`2.6.2. Which metabolites have been selected for analysis and why?
`
`Tafluprost acid was selected for analysis because it is the primary and pharmacologically active
`metabolite of tafluprost.
`
`2.6.3. For all moieties measured, is free, bound, or total measured? What is the basis for that
`decision, if any, and is it appropriate?
`
`
`Total tafluprost acid concentrations in the plasma were measured. Free concentrations in the
`plasma are not considered clinically relevant following ocular topical administration.
`
`2.6.4. What bioanalytical methods are used to assess concentrations?
`
`Refer to Section 2.6.1. for further information.
`
`
`2.6.4.1. What is the range of the standard curve? How does it relate to the requirements
`for clinical studies? What curve fitting techniques are used?
`
`
`
`Page 12 of 48
`
`Reference ID: 2974327
`
`(b) (4)
`
`

`

`
`
`The standard curve in plasma ranged from 10 pg/mL to 5000 pg/mL for tafluprost acid. The
`ranges of standard curve are adequate for purposes of determining plasma concentrations of
`tafluprost acid in the clinical studies.
`
`
`2.6.4.2. What are the lower and upper limits of quantification (LLOQ/ULOQ)?
`
`
`The LLOQ and ULOQ are 10 pg/mL and 5000 pg/mL in the undiluted plasma sample,
`respectively.
`
`
`2.6.4.3. What are the accuracy, precision, and selectivity at these limits?
`
`
`The assay accuracy and precision were determined from the assay standards and QCs. The
`accuracy values ranged from 87.8% to 105.8%. The precision values ranged from 0% to 10.3%.
`Assay selectivity was confirmed by analyzing six naïve human plasma samples and none yielded
`above BLQ results.
`
`
`2.6.4.4. What is the sample stability under the conditions used in the study (long-term,
`freeze-thaw, sample-handling, sample transport, autosampler)?
`
`
`Tafluprost acid was stable in stock solution stored at room temperature up to 6 hours and at -10°C
`to -30°C for 32 days, following six freeze/thaw cycles, in processed sample stored in the
`autosampler (15 °C) for 23 hours and at 2°C to 8°C for 126 hours, and in frozen matrix stored at
`-10°C to -30°C for 28 days.
`
`
`2.6.4.5. What is the QC sample plan?
`
`Four QCs prepared in plasma at a concentration of 30, 800, 1500 (diluted QC), and 3500 pg/mL
`of tafluprost acid. Between-run and within-run accuracy and precision were evaluated using
`replicates (n=6) from each of these concentrations were included in each analysis.
`
`
`
`
`Page 13 of 48
`
`Reference ID: 2974327
`
`

`

`
`
`
`3. LABELING RECOMMENDATIONS
`
`See Appendix 4.1. for detail.
`
`Page 14 of 48
`
`Reference ID: 2974327
`
`

`

`
`
`
`
`4. APPENDICES
`
`
`
`4.1. Proposed Package Insert (Original and Annotated) with Clinical
`Pharmacology edits (noted as underline and strikethrough) as of 15July2011
`
`Page 15 of 48
`
`Reference ID: 2974327
`
`9 Page(s) of Draft Labeling have been Withheld in Full as b4 (CCI/TS) immediately
`following this page
`
`

`

`4.2. Individual Study Reviews
`
`4.2.]. Phannacola'netics oftafluprost in healthy subjects: Study P15005
`
`Study Number: P15005
`An Open-Label, Single-Center Study Evaluating the Pharmacokinetics, Safety, and
`Tolerability of Tafluprost 0.0015 % Ophthalmic Solution in Healthy Subjects (Phase 1)
`
`Dates: 26 May, 2005 to 11 June, 2005
`Study Director:
`Analytical site:
`
`OBJECTIVES:
`
`W W
`
`(5)“)
`
`The objective was to investigate the pharmacokinetics, safety and tolerability of tafluprost
`0.0015% ophthalmic solution alter single and repeated dosing in healt