CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`APPLICATION NUMBER:
`204427Orig1s000
`
`CLINICAL PHARMACOLOGY AND
`BIOPHARMACEUTICS REVIEW(S)
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` OFFICE OF CLINICAL PHARMACOLOGY REVIEW
`NDA: 204427
`Submission Date(s): 7/29/2013
`Brand Name
`Kerydin
`Generic Name
`Tavaborole Topical Solution, 5%
`Primary Reviewer
`An-Chi Lu, M.S., Pharm.D.
`Doanh Tran, Ph.D.
`Team Leader
`Division of Clinical Pharmacology 3
`OCP Division
`Division of Dermatology and Dental Products
`OND division
`Sponsor
`Anacor Pharmaceuticals Inc.
`Submission Type
`Original NDA
`Formulation; Strength(s)
`Topical Solution, 5%
`Indication
`For the topical treatment of onychomycosis
`
`
`
`
`
`Table of Contents
`
`1  EXECUTIVE SUMMARY ..................................................................................................... 2 
`
`1.1 
`
`1.2 
`
`1.3 
`
`Recommendation ............................................................................................................................................... 2 
`
`Phase IV Commitments/Requirements ............................................................................................................ 2 
`
`Summary of Important Clinical Pharmacology and Biopharmaceutics Findings ....................................... 2 
`
`2  QUESTION‐BASED REVIEW ............................................................................................ 3 
`
`2.1 
`
`2.2 
`
`2.3 
`
`2.4 
`
`2.5 
`
`2.6 
`
`General Attributes ............................................................................................................................................. 3 
`
`General Clinical Pharmacology ........................................................................................................................ 5 
`
`Intrinsic Factors ............................................................................................................................................... 10 
`
`Extrinsic Factors .............................................................................................................................................. 11 
`
`General Biopharmaceutics .............................................................................................................................. 13 
`
`Analytical .......................................................................................................................................................... 13 
`
`3  DETAILED LABELING RECOMMENDATIONS .......................................................... 16 
`
`4  APPENDIX .......................................................................................................................... 17 
`
`Individual Trial Reviews ................................................................................................................................. 17 
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`1
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`4.1 
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`Reference ID: 3464157
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`1 Executive Summary
`This application is for Kerydin (tavaborole) Topical Solution, 5%. Tavaborole is a new
`molecular entity (NME). The Sponsor has submitted this NDA via 505(b)(1) regulatory
`pathway, and the proposed indication for Kerydin (tavaborole) Topical Solution is for the
`treatment of onychomycosis. It is intended to be applied to the entire nail surface and
`under the tip of each nail being treated once daily for 48 weeks.
`
`1.1 Recommendation
`The Office of Clinical Pharmacology/Division of Clinical Pharmacology III finds NDA
`204427 acceptable from a Clinical Pharmacology perspective, pending agreement on
`recommended labeling changes.
`
`1.2 Phase IV Commitments/Requirements
`Post Marketing Requirement (PMR) for a pharmacokinetic/safety trial of tavaborole
`topical solution, 5% in pediatric subjects age 12-17 years and 11 months with
`onychomycosis of toenails
`
`
`1.3 Summary of Important Clinical Pharmacology and Biopharmaceutics
`Findings
`Systemic bioavailability:
`Trial P06118 was a maximal use PK trial to determine the PK of tavaborole 5% solution
`in subjects with toenail onychomycosis following topical administration. A total of 24
`subjects diagnosed with distal subungual onychomycosis involving at least 4 toenails,
`including at least 1 great toenail were treated with a single dose of tavaborole 5%
`solution (approximately 200 μL) on all 10 toenails, including up to 2 mm of the
`surrounding skin on Day 1. All subjects received once daily dosing for 14 consecutive
`days on Days 5 to 18.
`
`After a single topical application on Day 1, the mean Cmax (± standard deviation) in
`plasma was 3.54± 2.26 ng/mL, the mean AUClast was 44.4 ± 25.5 ng*hr/mL, and the
`median Tmax was 12 hours (range 4.03-23.9 hours). After 14 days of repeated daily
`applications, the mean Cmax was 5.17±3.47 ng/mL, the mean AUCτ was 75.8 ± 44.5
`ng*hr/mL, and the median Tmax was 8.03 hours (range 0.47-24.0 hours).
`
`Both the mean Cmax and AUC increased from Day 1 to Day 18, with values of Cmax
`increased from 3.54 ng/mL to 5.17 ng/mL and AUC from 44.4 ng*hr/mL to 75.8
`ng*hr/mL. The accumulation ratio based on AUC was 2.2. Based on the plasma trough
`concentrations, it appears that steady state was reached on Day 11 after 6 days of daily
`dosing.
`
`Based on the NOAEL level of 3% tavaborole solution determined in the 9-month dermal
`minipig toxicity study, the safety margin is 10.1 based on mean human AUCτ and 4.4
`based on maximum human AUCτ.
`
`Effects on QT interval:
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`Reference ID: 3464157
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`From the review of Interdisciplinary Review Team for QT Studies Consultation, Dr.Moh
`Jee Ng has concluded that no significant QTc prolongation effects of tavaborole (doses of
`topical solution, 5% q.d. and topical solution, 5% b.i.d.) were detected. For the
`supratherapeutic dose group, tavaborole topical solution, 5% was applied twice daily on
`all 10 toenails and 10 fingernails and approximately 5 mm of skin surrounding all nails
`for 14 days to healthy subjects. Following the supratherapeutic dose, the mean Cmax was
`22.4 ± 14.3 ng/mL. Compared to the Cmax of 5.17 ng/mL in the maximal use PK trial
`P06118 after 14 continuous days of once-daily dosing, the Cmax obtained from
`supratherapeutic dose of this TQT trial was 4.3-times higher (range: 3.3-times to 6.5-
`times). With the supratherapeutic dose (applied to healthy subjects) achieving a Cmax 4.3-
`times higher than the Cmax observed in the maximal use PK trial, tavaborole does not
`prolong QTc to any clinically relevant extent.
`
`Drug-Drug Interaction:
`The drug-drug interaction potential of tavaborole was assessed in the in vitro inhibition
`and induction studies. The results indicated that tavaborole is not likely to induce the
`activity of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, and CYP3A4/5 or inhibit
`the activity of CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6,
`CYP2E1, and CYP3A4/5. The I/Ki ratio is calculated to be < 0.00068.
`
`Pediatrics:
`The sponsor did not provide any PK data for tavaborole topical solution, 5% in pediatrics.
`The sponsor is requesting a waiver of pediatric trials in pediatrics less than 12 years of
`age and deferral of pediatric trials in age range of 12-17 years and 11 months to be
`conducted post approval. The Division of Dermatology and Dental Products (DDDP)
`agrees with the waiver and deferral of pediatric trials. DDDP proposed a
`pharmacokinetic/safety trial in 40 pediatric subjects age 12-17 years and 11 months with
`onychomycosis of toenails
`. This reviewer recommends that the trial
`includes assessment of PK under maximal use conditions in a subgroup of at least 16
`evaluable subjects.
`
`Clinical Pharmacology Briefing:
`An optional intra-division level Clinical Pharmacology briefing was conducted on
`February 24, 2014 with the following in attendance: Hae-Young Ahn, Yow-Ming Wang,
`Doanh Tran, Chinmay Shukla, and An-Chi Lu.
`
`
` 2
`
` Question-Based Review
`
`2.1 General Attributes
`
`2.1.1 What is the proposed indication for Tavaborole Topical Solution, 5%?
`Tavaborole Topical Solution, 5% is proposed for the topical treatment of onychomycosis
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`Reference ID: 3464157
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`2.1.2 What is onychomycosis?
`Onychomycosis is a fungal infection of the nail plate and other parts of the nail unit
`including the nail matrix. Dermatophytes are responsible for most finger and toenail
`infections, and Dermatophytic onychomycosis (tinea unguium) occurs in three distinct
`forms: distal and lateral subungual, proximal subungual, and superficial white. The vast
`majority of distal and proximal subungual onychomycosis results from Trichophyton
`rubrum. Superficial white onychomycosis is usually caused by T. mentagrophytes,
`although cases caused by T. rubrum have also been reported.
`The prevalence in the United and States and Europe is up to 10% of adult population, and
`is related to occlusive footwear. The disease is very common in adults, but may also
`occur in children.
`
`
`2.1.3 What are the highlights of the physicochemical properties of Tavaborole?
`Chemically, tavaborole is 5-fluoro-1,3-dihydro-1-hydroxy-2,1-benzoxaborole, or
`5-fluoro-2,1-benzoxaborol-1(3H)-ol. Tavaborole has a molecular weight of 151.93
`Daltons, and is a white to off-white powder.
`
`The molecular formula of tavaborole is C7 H6 B F O2. The structural formula is as
`follows:
`
`
`
`
`Formulation properties:
`based solution
`Tavaborole Topical Solution, 5% is an alcohol/
`containing 5% tavaborole (w/w). The solution is filled to a minimum label amount of 10
`mL in a 12 mL, amber USP
` glass bottle with an 18-400 neck finish and an 18-400
`black
` closure with a
` foam liner. Each
`milliliter of Kerydin contains 43.5 mg of tavaborole (5% w/w). For details of product
`composition see section 2.5.2.
`
`Dosage and Route of Administration:
`Apply to affected nails once daily for 48 weeks. It should be applied to the entire nail
`surface and under the tip of each nail being treated.
`
`Mechanism of Action:
`The mechanism of action of tavaborole is inhibition of fungal protein synthesis.
`Tavaborole inhibits protein synthesis by inhibition of an aminoacyl-transfer ribonucleic
`acid (tRNA) synthetase (AARS). Tavaborole has been shown to be active against most
`strains of Trichophyton mentagrophytes and Trichophyton rubrum, both in vitro and in
`clinical infections.
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`2.2 General Clinical Pharmacology
`
`2.2.1 How was the dose/duration selected for Tavaborole Topical Solution, 5%?
`Dose selection for pivotal clinical trials and commercialization was chosen based on
`safety and efficacy results from Phase 2 trials.
`
`In the Phase 2 double-blind, vehicle-controlled trial AN2690-ONYC-200/200A, three
`strengths of tavaborole solution, 2.5%, 5%, and 7.5%, were compared to vehicle control
`in subjects with onychomycosis (n=187). It was reported that patients treated with 5%
`achieved the highest proportion of clear nails and complete responses (clear nail plus
`negative fungal culture and negative KOH) at the Day 360 assessment. The 7.5%
`treatment group had more application site reactions (ASRs), drug holidays / dosing
`modifications due to ASRs, and discontinuations due to ASRs compared to the 5%
`treatment group.
`
`2.2.2 What are the design features of the clinical pharmacology and clinical trials
`used to support Tavaborole Topical Solution, 5%?
`The applicant has sponsored the following 12 clinical trials in support of the development
`of Tavaborole Topical Solution, 5%:
`
`Clinical Pharmacology Trials:
`AN2690-ONYC-101: 21 day cumulative irritation test, n =37. The medical reviewer is
`reviewing this trial.
`AN2690-ONYC-103: Definitive repeat insult patch test (RIPT) and cumulative irritation
`trial of Tavaborole Topical Solution, 5% in healthy volunteers, n=279. The medical
`reviewer is reviewing this trial.
`P05577: Absorption, metabolism, and excretion of 14C-tavaborole as a topical solution in
`adult males, n=6.
`P06118: Maximal use Pharmacokinetic (PK) trial of Tavaborole Topical Solution, 5% in
`subjects with onychomycosis (14 days of dosing), n=24.
`AN2690-ONYC-102: Thorough QT/QTc safety and PK trial of Tavaborole Topical
`Solution, 5% in healthy subjects (14 days of dosing), n=55. This reviewer has reviewed
`the PK portion of the result.
`AN2690-ONYC-202: Open-label multiple-dose trial of safety and PK of tavaborole
`solution 7.5% (29 days of dosing), n=15. This PK trial was not reviewed, as tavaborole
`solution 7.5% is not the to-be-marketed formulation.
`AN2690-ONYC-205: Open-label multiple-dose trial of safety and PK of tavaborole
`solution 7.5% (29 days of dosing), n=20. This PK trial was not reviewed, as tavaborole
`solution 7.5% is not the to-be-marketed formulation.
`
`Phase II trials:
`Uncontrolled:
`AN2690-ONYC-201: Open-label rising multiple-dose multi-center trial to evaluate safety
`and efficacy of tavaborole solutions 5% and 7.5% in subjects with onychomycosis (180
`or 360 days of dosing), n=89.
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`AN2690-ONYC-203: Open-label rising multiple-dose multi-center trial to evaluate safety
`and efficacy of tavaborole solutions 1% and 5% in subjects with onychomycosis (180
`days of dosing), n=60.
`Controlled:
`AN2690-ONYC-200/200A: Randomized, double-blind, vehicle-controlled, multi-center
`trial to evaluate the safety and efficacy of topically applied tavaborole 2.5%, 5% and
`7.5% solution vs. vehicle for the treatment of adult subjects with onychomycosis of the
`great toenail (180 days of dosing), n=187. The medical reviewer is reviewing this trial.
`
`Phase III trials:
`AN2690-ONYC-301: Randomized, double-blind, vehicle-controlled, multi-center trial to
`evaluate the efficacy and safety of Tavaborole Topical Solution, 5%, vs. vehicle in the
`treatment of onychomycosis of the toenail in adults (48 weeks of dosing), n=594. The
`medical reviewer is reviewing this trial.
`AN2690-ONYC-302: Randomized, double-blind, vehicle-controlled, multi-center trial to
`evaluate the efficacy and safety of Tavaborole Topical Solution, 5%, vs. vehicle in the
`treatment of onychomycosis of the toenail in adults (48 weeks of dosing), n=604. The
`medical reviewer is reviewing this trial.
`
`2.2.3 What trials have been conducted for bioavailability evaluation of the drug
`product? What is the systemic bioavailability of tavaborole topical solution, 5%?
`The systemic exposure of tavaborole topical solution, 5% was evaluated in trial 18143.
`Trial 18143 was a maximal use PK trial to determine the pharmacokinetics of tavaborole
`5% solution in subjects with toenail onychomycosis following topical administration.
`
` A
`
` total of 24 subjects diagnosed with distal subungual onychomycosis involving at least
`4 toenails, including at least 1 great toenail were treated with a single dose of tavaborole
`5% solution (approximately 200 μL) on all 10 toenails, including up to 2 mm of the
`surrounding skin on Day 1. All subjects received once daily dosing for 14 consecutive
`days on Days 5 to 18.
`
`After a single topical application on Day 1, out of the 24 subjects, 3 subjects had all
`plasma tavaborole concentrations below the LLOQ (0.5 ng/mL) at the timepoints
`assessed (predose, 0.5, 1, 2, 4, 8, 12, 16, and 24 hours postdose), and 16 subjects had
`measurable concentrations at the 8-hour time point. The mean Cmax in plasma was 3.54
`ng/mL, and the median Tmax was 12 hours.
`
`After 14 days of repeated daily applications, on Day 18, most subjects (n=20) had
`measurable concentrations pre-dose, and all subjects had measurable concentrations at 12
`hours post-dose. At 72 hours, about half of subjects (n=13) had measurable
`concentrations; at 96 hours, 6 subjects still had measurable concentrations. The mean
`Cmax was 5.17 ng/mL, and the median Tmax was 8.03 hours.
`
`Both of the mean Cmax and ACU increased from Day 1 to Day 18, with values of Cmax
`from 3.54 ng/mL to 5.17 ng/mL and AUC from 44.4 ng*hr/mL to 75.8 ng*hr/mL. The
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`accumulation ratio based on AUC was 2.22. Based on the plasma trough concentrations,
`it appears that steady state was reached on Day 11 after 6 days of daily dosing.
`Table 1 shows the mean pharmacokinetic parameters of tavaborole following single dose
`and at steady state.
`
`Table 1: Mean (CV, %) Plasma Pharmacokinetic Parameters of Tavaborole (SCH 900340)
`Following Single (Day 1) and Multiple (Day 18) Once-Daily Topical Applications of 200 µL
`of 5% Solution of Tavaborole to All Ten Toenails and 2 mm of Skin Surrounding Each
`Toenail of Onychomycosis Patients
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`2.2.4 What is the metabolic pathway for Tavaborole Topical Solution, 5%?
`The proposed biotransformation pathway for tavaborole is depicted below in Figure 1:
`
`Figure 1: Proposed Biotransformation Pathway for Tavaborole
`
`
`
`The proposed metabolic pathways for tavaborole were established from the results of
`topical administration to the skin of mice. Not all metabolites were confirmed in humans;
`those metabolites confirmed in humans are shown in circles in Figure 1. For humans,
`tavaborole metabolism was studied in the radiolabeled AME (P05577) and maximal use
`PK trial (P06118). In summary, tavaborole undergoes extensive metabolism. By
`qualitative assessment, trace levels of a sulfate conjugate (M5) and a benzoic acid
`metabolite (M6a) were detected at steady-state in plasma. In urine, M5 was the only
`metabolite identified in the radiolabeled AME (P05577) trial, and both M5 and M6a were
`identified after single dose and at steady state in the maximal use PK trial (P06118).
`Below are more details for the two trials on the metabolism of tavaborole.
`
`In Trial P05577, six healthy adult male volunteers (19-35 years of age) were applied with
`a single topical application of 14C-tavaborole (a total of ~200 µL containing a total of
`~100 µCi radioactivity) to all 10 toenails and 5 mm of the surrounding skin of each toe.
`The ratio of Cmax for plasma tavaborole/plasma total radioactivity was approximately
`0.146, indicating extensive metabolism and that the systemic exposure to tavaborole was
`approximately 15% of the exposure to plasma total radioactivity. The mean cumulative
`total radioactivity excreted in urine over a 10 day period was 17.9% of the applied dose,
`suggesting there is systemic absorption of this topical product. The total radioactivity
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`levels in all the fecal samples were less than the LLOQ (2.58 ng equiv/mL) in all the
`subjects, indicating excretion was primarily via the renal pathway. For metabolite
`profiling, there was not enough radiocarbon present in plasma or fecal samples for
`profiling of metabolites using liquid chromatography-mass spectrometry (LC-MS) with
`in-line flow scintillation analysis (FSA) or off-line microplate scintillation counter
`detection. In urine, M5, the sulfate conjugate metabolite of the benzyl alcohol metabolite
`(M6; AN3019) was the only metabolite identified. The amount of M5 excreted during 0-
`120 hr post-dose represented 14.6% of the administered dose applied topically. From the
`radiochromatogram of 0-120 hr pooled urine, three minor metabolites representing less
`than 1% of the dose were also observed, but could not be detected by LC-MS and thus
`were not identified. For further details, see Appendix for individual trial review.
`
`In the maximal use PK trial P06118 (see above Section 2.2.3 for study design), plasma
`samples were pooled (0-24 hours) across all subjects on Day 1 (single dose) and Day 18
`(14 days of multiple dose). Urine was collected at predose on Day 1, and at 0-24 hours as
`blocks post dose on Days 1 and 18.
`
`In pooled plasma by qualitative assessment, no metabolites were detected on Day 1, and
`trace levels of a sulfate conjugate (M5) and a benzoic acid metabolite (M6a) were
`detected at steady-state on Day 18. In urine, M5 and M6a were the only metabolites
`detected on Day 1 and Day 18.
`
`2.2.5 Does Tavaborole Topical Solution, 5% prolong QT intervals?
`From the review of Interdisciplinary Review Team for QT Studies Consultation, Dr.Moh
`Jee Ng has concluded that no significant QTc prolongation effects of tavaborole (doses of
`topical solution, 5% q.d. and topical solution, 5% b.i.d.) were detected in the Thorough
`QTc Trial AN2690-ONYC-102.
`
`In the Thorough QTc Trial AN2690-ONYC-102, a total of 55 healthy volunteers were
`randomized to one of eight sequences with the following four study treatments:
` Vehicle (V): Solution vehicle for tavaborole QD on all 10 toenails for 14 days
` Positive Control (PC): Solution vehicle for tavaborole QD on all 10 toenails for
`14 days, plus a single dose of unblinded moxifloxacin 400 mg administered orally
`in the morning on Day 14 under fasted conditions
` Therapeutic Dose (DT): tavaborole Topical Solution, 5% QD on all 10 toenails
`for 14 days (nail plates only)
` Supratherapeutic Dose (DS): tavaborole Topical Solution, 5% twice daily (BID,
`defined as every 12 hours) on all 10 toenails and 10 fingernails and approximately
`5 mm of skin surrounding all nails for 14 days
`
`
`Because the TQT trials was conducted in healthy volunteers instead of subjects with
`onychomycosis, it is important to evaluate the tavaborole systemic exposure to ensure
`that the exposure achieved in the TQT trial was similar or higher than that expected
`following clinical use. Following the supratherapeutic dose, the mean Cmax was 22.4 ±
`14.3 ng/mL. Compared to the Cmax of 5.17 ng/mL in the maximal use PK trial P06118
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`Reference ID: 3464157
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`after 14 continuous days of once-daily dosing, the Cmax obtained from supratherapeutic
`dose of this TQT trial was 4.33-times higher (range: 3.3-times to 6.5-times).
`
`From the review of Dr.Moh Jee Ng, as shown in
`Figure 2, there is a positive and significant relationship between tavaborole plasma
`concentrations and ΔΔQTcF with a positive slope of 0.23 ms per ng/mL (95% CI: 0.036
`– 0.41, p-value =0.05). Dr. Ng noted that at the supratherapeutic concentrations assessed
`in this trial, tavaborole does not prolong QTc to any clinically relevant extent.
`
`Figure 2: Observed Median-Quantile Tavaborole (AN2690) Concentrations and Associated
`Mean (90% CI) ∆QTcF (color dots) Together with the Mean (90% CI) Predicted
`∆QTcF (black line with shaded grey area)
`
`
`
`2.3
`
`Intrinsic Factors
`
`
`
`2.3.1 What is the systemic drug exposure in pediatrics?
`In this submission, the applicant did not provide information in pediatrics. The applicant
`requested a waiver of pediatric trials of subjects aged 0 to 11 years and 11 months for the
`reason that studies are impossible or highly impractical (e.g. the number of pediatric
`patients is so small or is geographically dispersed) and requested a deferral of studies in
`pediatrics 12 years of age and older.
`
` is not prevalent in population younger than 12
`Onychomycosis
`years of age. The Division of Dermatology and Dental Products (DDDP) concludes that
`the product may not be used in a substantial number of patients in this age group and that
`the studies are not feasible.
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`DDDP recommends the applicant to conduct a pharmacokinetic/safety trial of Tavaborole
`topical solution, 5% in pediatric subjects age 12-17 years and 11 months with
`onychomycosis of toenails
`. There should be 40 male or female
`subjects 12–17 years 11 month of age with at least of 16 evaluable subjects under
`maximal use conditions to adequately characterize the pharmacokinetics in this age
`group. Subjects must have a clinical diagnosis of distal subungual onychomycosis
`affecting at least one great toenail (20% to 60% of the nail after the nail had been
`trimmed), confirmed by a central mycology laboratory to be positive for KOH wet mount
`and fungal culture for a dermatophyte. Subjects included in the PK subgroup should be
`under maximal use conditions (i.e., subjects with ≥50% involvement of both great
`toenails and 4 additional affected toenails). Serial PK assessments should be performed
`after single dose and at steady state. Several trough samples should be obtained to assess
`the attainment of steady state.
`
`2.4 Extrinsic Factors
`
`2.4.1 What is the effect of tavaborole on the PK of other drugs?
`In vitro studies for inhibition and induction indicated that tavaborole is not likely to
`induce the activity of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, and CYP3A4/5
`or inhibit the activity of CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19,
`CYP2D6, CYP2E1, and CYP3A4/5. The I/Ki ratio is calculated to be < 0.00068.
`
`In the in vitro inhibition study, 002-NCL PK-053-01, the ability of tavaborole to inhibit
`CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1 and
`CYP3A4/5 was evaluated at concentrations from 0.1 to 100 μM in human liver
`microsomes. The human liver microsomes from a pool of 16 individuals were incubated
`with marker substrates at concentrations approximately equal to their apparent Km, in the
`presence or absence of tavaborole, to evaluate tavaborole as a direct and time-dependent
`inhibitor of CYP activity.
`
`Tavaborole caused 42% direct inhibition of CYP2E1 with an IC50 value of >100 μM,
`and caused time-dependent and partial NADPH-dependent inhibition of CYP2A6 activity
`at a concentration of tavaborole >30 μM, but no IC50 value was calculated due to
`insufficient inhibition across the range of concentrations examined.
`
`With the estimate of the Ki value of CYP enzymes by tavaborole >50 μM, and the mean
`Cmax at steady state of 5.17 ng/mL (0.034 μM) in the maximal use PK trial P06118, the
`I/Ki ratio is calculated to be < 0.00068.
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`Reference ID: 3464157
`
`11
`
`COPYRIGHT
`MATERIAL
`
`FlatWing Ex. 1041, p. 12
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`

`

`Table 2: In vitro evaluation of tavaborole as an inhibitor results
`Time-Dependent Inhibmon
`Direct Inhibition
`ZercMinute Preincubation
`7
`30-Minute Preincubation
`
`'
`
`'
`
`'
`
`MaXImum Inhibflion at 11201101
`MaXIlTlUI'n Inhibition al 100 tiM
`(ii/.1”
`le (iiMi‘
`(«1.1”
`le: (pMi'
`cvp Reaction
`Enzyme
`5.5
`>100
`15
`>100
`Pnenacetin O—dealkylation
`CYP1A2
`41
`>100
`4.3
`>100
`Coumann 7-hydroxylation
`CYP2A6
`0.5
`>100
`NA
`>100
`Etavrrenz 8-hydroxylation
`CYP286
`7.1
`>100
`9.5
`>100
`Amodiequine N-deelkylation
`CYP2CB
`NA
`>100
`NA
`>100
`Diclofenac 4'-hydroxylahon
`CYPZCS
`5.5
`>100
`11
`>100
`S-Mephenytorn 4'-hydioxylation
`CYPZC19
`8.5
`>100
`14
`>100
`Dextromethorphan O-demethylation
`CYP2D6
`73
`57
`42
`>100
`Chlorzorazone 6onydroxytation
`CYP2E1
`4 .3
`>100
`5.7
`>100
`Testosterone GBrhydroxylation
`CYP3A4l5
`1.2
`>100
`NA
`>100
`Midazolam 1 ’-hydroxylation
`CYP3A4/5
`a: Average data (re. percent of control activrty) obtained from duplicate samples for each test article concentration were used to calculate lcso values.
`value: were calculated With XLFit.
`b: Maxtmum inhibition (96) is wlculated with the tollowrno formula and data for the highest concentration 01 test article evaluaed (results are rounded to two
`significant figures): MaXImum inhibition (°/o) = 100% ‘ Percent solvent control.
`c. Time-dependent inhibition was deterrnineo by comparison of ICso values With and without preincuoau‘on. by comparison or the maximum inhibition (°/c] with
`and without preincubation and by Visual inspection at the leo plot.
`Time—dependent inhibition was found to be at least partialty dependent upon the presence of NADPH—generating system.
`11‘
`NA = Not applicable. No value was obtained as the rates at the highest concentration of SCH 900340 evaluated (100 uM) were higher than the control rates.
`
`Potential
`for Time-
`Dependent
`Inhibition:
`No
`Yes"
`No
`No
`No
`No
`No
`Yes“
`No
`No
`ICso
`
`In the in vitro induction study, DM27769, the induction potential of tavaborole on
`CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, and CYP3A4/5 was evaluated.
`Human hepatocytes from 3 donors were incubated and treated once daily for three
`consecutive days with tavaborole (0.126, 1.26, and 12.6 11M), vehicle controls ODMSO
`0.1% v/v), or positive controls (omeprazole 100 11M, phenobarbital 750 11M, and rifampin
`10 11M). The metabolite analysis by Liquid Chromatography-Mass Spectrometry (LC-
`MS) was performed on the supernatant fractions (CYP1A2: Acetaminophen; CYP2B6:
`Hydroxybupropion; CYP2C8: N—Desethylamodiaquine; CYP2C9: 4’-Hydroxydiclofenac;
`CYP2C19: 4'-Hydroxymephenytoin; CYP3A4/5: 6B-Hydroxytestosterone).
`
`Table 3 shows the induction ratios relative to vehicle control (DMSO). Using a cut-off
`ratio of 1.5 for presence of induction, treatment of cultured human hepatocytes with
`tavaborole up to 12.6 uM caused little or no change in CYP1A2, CYP2B6, CYP2C8,
`CYP2C9, and CYP3A4/5 enzyme activity compared with the vehicle control.
`
`Table 3: The effects of treating cultured human hepatocytes with tavaborole or
`prototypical inducers on microsomal cytochrome P450 (CYP) enzyme activity as fold
`increase
`
`Fold Increase‘
`S-Mepnenytorn
`Amodiaquine
`Diclolenac
`Eupropion
`Phenaoetin
`4‘-hydroxylation
`N-deelkylation
`4‘-hydroxy1ation
`hydroxytation
`O-dealkytation
`[CYP2019)
`(CYP208)
`(CYP2C9)
`(CYPZBG)
`(CYP1A2)
`Concentration
`Treatment
`1.00: 1.28
`1.00 z 0.19
`1.00 : 0.25
`1 00 z 0.69
`1.00 z 0.43
`0.1% (v/v)
`Dimetnyi suitoxioe
`10910.10
`1.06: 0.15
`1.012015
`0.944 20.044
`1.06 $0.14
`0.126 “M
`SCH 900340
`1.06: 0.15
`0.981 1 0.273
`0.899 2 0.084
`0.940 t 0.175
`0.926 1 0.183
`1 26 0M
`SCH 900340
`1.06: 0.13
`1.00 2 0.20
`0.972 1 0.182
`0.855 2 0.144
`1.06 t 0.21
`12.6 11M
`SCH 900340
`1.59: 1.31
`2.98:0.15
`1.572020
`79011.84
`4381 19.8
`100 0M
`Omeprazole
`2.301122
`4.34 1_ 0.43
`1.83 1 0.41
`11.1 ; 2.7
`2.13 .v 0.39
`750 pM
`Phenobarbital
`3.67 i 0.50
`5.04 t 0.26
`2.33 t 0.31
`5 42 1 2.41
`1.97 1 0.76
`10 uM
`Ritamon
`a: Values are the mean : standard deviation of three determinations (human hepatocyte preparations H920, H921 and H923).
`Data are shown graphically in Figure 10.
`
`V
`
`l
`
`V
`
`V
`
`Testosterone
`Eli-hydroxylation
`(CYP3A4/5)
`1.00 r 0.45
`10910.10
`0.932 1 0.167
`1.04 t 0.14
`3.27: 1.91
`9.14 L 4.71
`9.42 t 4.45
`
`Reference ID: 3464157
`
`FlatWing EX- 1041, P- 13
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`FlatWing Ex. 1041, p. 13
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`2.4.2 H’hat other extrinsicfactors (food, herbalproducts, smoking, alcohol use)
`influence the PK of Tavaborole Topical Solution, 5%?
`
`Effects of extrinsic factors, such as herbal products, smoking, and alcohol use on the PK
`of Tavaborole Topical Solution, 5% were not evaluated. Since this is a topical product, an
`effect of food is not anticipated.
`
`2.5 General Biopharmaceutics
`
`2.5.1
`
`Is the to-be-marketedformulation identical to the one used in Phase 3 efficacy
`and safety trials?
`
`The to-be-marketed formulation was used in the Phase 3 safety and efficacy trials
`(AN2690-ONYC-301 and AN2690-ONYC-302), the Repeat Insult Patch Test
`(RIPT)/cumulative irritation trial (AN2690—ONYC-103), the Thorough QTc trial
`(AN2690—0NYC—102), and the maximal use PK trial (PO6118). Including the to—be-
`marketed formulation, a total of three tavaborole topical solution formulations were used
`in the clinical trials. The second formulation was only used in one Phase 1 trial (P05577),
`and the third formulation was used in all other Phase 1 and Phase 2 trials. The only
`difference between these formulations was in the
`M“)
`
`2.5.2 What is thefinalproduct composition?
`
`Table 4 shows the components and composition of Tavaborole Topical Solution, 5%.
`
`Table 4: Composition of Tavaborole Topical Solution, 5%
`
`Components
`
`'l'avaborole
`Alcohol
`
`Propylene Glycol
`Edetme Calcium Disodium
`
`Quality Standard
`
`ln-house
`USP
`
`USP
`USP
`
`2.6 Analytical
`
`Function
`
`Active
`
`Concentration
`
`(% w/w)
`
`5.00
`
`OX0
`
`OX0
`
`2.6.1 What bioanalytical methods were used to assess drug concentrations?
`
`Two bioanalytical methods used in two trials (Maximal use PK trial P06118 and
`Thorough QTc Trial AN2690—ONYC—102) were assessed by this reviewer.
`
`Maximal use PK Trial P06118:
`
`Tavaborole concentrations in human citrate plasma were determined using a liquid
`chromatographic assay with mass spectrometric detection (LC-MS) after application of
`supported liquid-liquid extraction (SLLE).
`
`In summary, plasma samples to determine tavaborole concentrations are centrifuged for 4
`minutes at 14000 RPM. Supernatant is transferred and applied on SLLE cartridge. Elute
`samples by using 1-Chlorobutane/Ethanol=95:5 (v/V) and collect the eluates in glass
`
`13
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`Reference ID: 3464157
`
`FIatWing EX- 1041, p. 14
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`FlatWing Ex. 1041, p. 14
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`

`

`laboratory tubes. The eluates are then evaporated, dissolved by Milli-Q water, transferred
`to the wells of a tapered masterblock, and submitted for analysis.
`
`Thorough QTc Trial AN2690-ONYC-102:
`Human plasma samples containing tavaborole, tavaborole-d2