CENTER FOR DRUG EVALUATION AND RESEARCH
`
`APPLICA TI0N NUMBER:
`
`50-805
`
`CLINICAL PHARMACOLOGY AND
`BIOPHARMACEUTICS REVIEW! S Q
`
`

`

`Clinical Pharmacology and Biopharmaceutics Review
`
`NDA Number
`
`50-805
`
`Letter Date(s)
`Brand Name
`
`-
`
`Generic Name
`
`Reviewer
`
`Team Leader
`
`OCPB Division
`
`0ND Division
`
`Applicant
`
`Related IND(s)
`
`July 29th, 2005, February 10‘“, 2006 and April 7th, 2006
`OraceaTM
`
`Doxycycline
`
`\____ :-0 mg
`
`._..—-‘-‘— '
`
`Abimbola Adebowale Ph.D.
`
`Dennis Bashaw Pharm.D.
`
`DCP3
`
`OND—540
`
`Collagenex Pharmaceuticals, PA
`
`67,833 and _~.,\,
`
`Submission Type; Code
`
`Original NDA
`
`Formulation
`
`Indication
`
`Capsules
`
`Tc \ : inflammatory lesions in patients with rosacea
`
`Mum
`
`Table of Contents
`
`1
`
`Executive Summary ....................................................................................................... 1
`1 . 1
`Recommendation ...................................................................................................... 2
`1.2
`Phase IV Commitment ............................................................................................. 2
`1.3
`Summary of CPB Findings ....................................................................................... 2
`2 QBR................................................................................................................................ 5
`2.1
`General Attributes .................................................................................................... 5
`2.2 General Clinical Pharmacology ................................................................................ 6
`2.3
`Intrinsic Factors ........................................................................................................ 12
`2.4
`Extrinsic Factors ....................................................................................................... 14
`2.5 General Biopharmaceutics ........................................................................................ 14
`2.6 Analytical ................................................................................................................. 1 9
`Labeling Recommendations ........................................................................................... 20
`3
`4 Appendix ........................................................................................................................ 21
`4.1
`Proposed Labeling .................................................................................................... 21
`4.2
`Pharmacometrics Consult ......................................................................................... 21
`4.3
`Individual Study Review .......................................................................................... 31
`4.4 OCPB Filing Form ................................................................................................... 52
`
`Executive Summary
`1
`The applicant has submitted a 505 (b) (1) application for OraceaTM (doxycycline *f
`40 mg capsules.
`It is intended to be taken once daily in the morning tOK—Anflammatory
`lesions in patients with rosacea. Oracea capsules consists of immediate release (IR) beads (75
`%) and delayed-release (DR) beads (25 %) containing 30 mg and 10 mg of doxycycline,
`_ monohydrate, respectively. The applicant stated that the DR beads are formed by coating the IR
`
`

`

`7Wu The IR and DR beads are then filled into a
`beads with a ..
`hard gelatin capsule shell.
`
`Although doxycycline is classified as an antimicrobial agent, the applicant stated that at the
`systemic concentrations provided by OraceaTM 40 mg, doxycycline is not effective as an
`antimicrobial agent and appears to exert its beneficial actions on inflammatory lesions of rosacea
`by mechanisms independent of antimicrobial activity.
`In light of this,
`the goal of their
`formulation development was to achieve bioequivalence to Periostat ® (doxycycline hyclate
`tablets) 20 mg in terms of area under the concentration time curve (AUC) while keeping the
`maximum plasma level (Cmax) below 1.0 ug/mL so as not
`to exceed the threshold for
`antimicrobial
`activity in vitro, which may increase the risk of developing resistant
`microorganisms. Periostat ® (NDA 50-783) is an approved drug product that was previously
`developed by the applicant, for use twice daily, as an adjunct to scaling and root planning to
`promote attachment level gain and to reduce pocket depth in patients with adult periodontitis.
`
`1.1
`
`Recommendation (3):
`
`The clinical pharmacology and biopharmaceutics data submitted for OraceaTM capsules
`adequately characterized its pharrnacokinetics following single and multiple dose administration.
`The data also demonstrated that the rate and extent of doxycycline from OraceaTM was
`equivalent to that of Periostat®, the imtnediate release drug product, at steady state, but not
`following a single dose. The rate and extent of absorption of doxycycline obtained following a
`single dose of Oracea capsules was hi
`er than that obtained following administration of
`Periostat® tablets BID. Since OraceaT is intended for chronic dosing in patients with rosacea,
`this may not be a safety concern in actual use since the systemic exposure following multiple
`dosing was found to be equivalent. In addition the applicant included safety data obtained from
`their Phase 3 trials for Oracea in this application. This data is currently being reviewed by the
`medical reviewer.
`
`Therefore, from a clinical pharmacology and biopharmaceutics perspective the applicant has met
`the requirement outlined in 21 CFR 320 and, their application is acceptable provided that the
`applicant agrees to tighten the dissolution specifications as proposed below. We also
`recommend that the applicant incorporate our labeling changes as outlined in Section 3 of this
`review in their final label.
`
`Comment to be conveyed to the Applicant:
`The dissolution specifications are not acceptable because the proposed specifications at the 2—hr
`time point are too wide to ensure batch to batch quality. Based on the dissolution data generated
`with the clinical/bioavailability batches, it is recommended that the 2 hr specification be revised
`from'éé—v’
`dissolved to A and “" %) dissolved.
`
`1.2
`
`Phase IV Commitments: None
`
`1.3
`
`Summary of Clinical Pharmacology and Biopharmaceutics (CPB) Findings:
`The pharrnacokinetics of doxycycline following administration of single or multiple
`doses of Oracea 40 mg have been evaluated in four studies. All four pharmacokinetic studies
`
`

`

`were conducted in healthy adult volunteers of both genders and used an open—label, randomized,
`crossover study design. Two initial studies (PERIO—DOXYSR—103 and 104) and two subsequent
`studies (COL-101-SDPK-105 and COL-101-SSPK-106) were conducted. These studies will be
`labeled as 103, 104, 105 and 106 for the most part of this review. All of these studies used the
`same formulation of the drug product as that proposed for marketing. A dissolution method and
`specifications were also proposed.
`The in vivo PK studies primarily evaluated the following:
`o The pharmacokinetics after single and multiple dosing of Oracea in healthy subjects
`0 The effect of food on Oracea after a single dose
`0 The relative bioavailability of Oracea ® capsules (40 mg) once daily to Periostat 20 mg
`immediate release (IR) tablets BID after single and multiple dosing in healthy subjects
`0 The effect of gender on the pharmacokinetics of doxycycline
`
`In addition to these four PK studies, a pilot clinical study performed during the development of
`Oracea that showed doxycycline is absorbed mainly in the upper part of the gastrointestinal tract
`and, a published study by Grahnen et a1 (1994)
`that showed that
`the bioavailability of
`doxycycline monohydrate is reduced after pre—treatment with omeprazole were summarized in
`the NDA.
`'
`‘
`
`Please note that the following names have been used interchangeably during the development of
`Oracea and were used in this application in various source documents: “Oracea,” “Doxycycline’___'—
`v»
`./
`J
`u!
`.4
`v
`-,
`-
`
`Single Dose Pharmacokinetics
`
`Absorption:
`The pharrnacokinetics of doxycycline following single dose administration of Oracea was
`evaluated in three pharrnacokinetic studies (#’s 103, 104 and 105). The rate (Cmax) and extent
`(AUC 0-24 orAUC 0—72) of absorption of doxycycline obtained in all three studies were
`comparable. The median Tmax of doxycycline ranged from about 1 hour to 4 hours in- all three
`studies.
`
`In contrast, the rate and extent of absorption of doxycycline from Oracea was not similar to that
`of Periostat BID following single dose administration.
`In studies 103 and 104, the applicant
`compared the relative bioavailability of doxycycline after a single dose of Oracea to currently
`marketed Periostat 20 mg administered BID (12 hours apart) in healthy volunteers. The results
`of both studies indicated that Oracea had a higher rate and extent of absorption. This was further
`demonstrated by the 90 % CI for Cmax (125 to 172 % for Study # 103 and 147 to 203 % for
`study # 104) and AUC 0—24 (97.7 to 128 % for study # 103 and 114 to 144 % % for study # 104)
`being outside the 80 to 125 % range.
`
`Excretion:
`Following a single dose of Oracea 40 mg capsules the mean (SD) half life of doxycycline in
`healthy volunteers (aged ~18—45 years old) was 15.1 (5.49), and 21.2 (7.64) hrs respectively
`(Study # 103 and 105).
`
`

`

`Food Efiect
`The applicant evaluated the effect of food on the pharmacokinetics of a single dose of Oracea (40
`mg) capsules in study # 105, a randomized, tWo-way crossover study in 30 male and female
`subjects. The concomitant administration of Oracea with a high-fat meal resulted in a decrease
`in the rate and extent of absorption (Cmax and AUC) by about 45 % and 22 %, respectively,
`compared to dosing under fasting conditions. There was a delay of about 1 hour for the mean
`Tmax in the fed state compared to the fasted state. In addition the Tmax was much more
`variable (range of:
`nrs) in the fed state compared to the fasted state (range of
`hrs). Consistent with the current labeling of approved Periostat 20 mg tablets, the applicant
`recommends that if Oracea should be taken close to meal times, it is recommend that it be taken
`at least one hour prior to or two hours after meals.
`
`Multiple Dose Pharmacokinetics:
`Absorgtion:
`The pharmacokinetics of doxycycline following multiple dose administration of Oracea was
`evaluated in two pharmacokinetic studies (#’s 104 and 106). The rate (Cmax) and extent (AUG
`0-24 or AUG 0-72) of absorption of doxycycline obtained1n both studies were comparable. The
`median Tmax of doxycycline ranged from about 0.5 hours to 4 hours1n both studies, comparable
`to that obtained following a single dose.
`'
`
`In addition, the rate and extent of absorption of Oracea was found to be equivalent to that of
`Periostat BID following multiple dose administration for 7 days1n study # 106 (N= 30). This
`was further demonstrated by the 90 % CI for Cmax (101.73 to 113.20 %) and AUG (90.9 to
`100. 83 %) being within the 80 to 125 % range.
`
`.
`Excretion:
`Following multiple dosing of Oracea 40 mg capsules for 7 days the mean (SD) half life of
`doxycycline in healthy volunteers (aged ~18-45 years old) was 23.2 (6.2) hrs in Study # 106
`which is comparable to that obtained following a single dose.
`
`Intrinsic Factors:
`
`Gender: The effect of gender on the pharmacokinetics of doxycycline following a single dose of
`Oracea was evaluated in study # 105 in 16 males and 14 female subjects under fed and fasted
`conditions. Female subjects had both a higher rate and extent of absorption than males. These
`differences are thought to be due to differences in body weight/lean body mass and are consistent
`with historical doxycycline PK data. The applicant has proposed to include this information in
`their label.
`
`Gastric Insufficiency: The applicant included a published report by Grahnen et al (1994) in
`which the authors evaluate the effect of increased pH (obtained by pre-treatment with
`omeprazole) on the bioavailability of doxycycline monohydrate and doxycycline carrageenate in
`24 healthy volunteers using an open-label, crossover, 2x2 factorial design. Following prior
`administration of omeprazole,'doxycycline monohydrate showed a decrease in bioavailability
`(38 % for AUC and 45 % for Cmax) compared to carrageenate formulation which did not show
`changes in bioavailability. The authors recommended that in patients with high gastric pH (e.g.
`
`

`

`due to frequent use of H2-blockers as well as physiological achlohydria, this decreased
`absorption of doxycycline monohydrate may well have a clinical impact. The applicant has
`proposed to include this information in their label.
`
`Dissolution:
`
`t
`
`
`
`”‘4
`l
`
`Abimbola Adebowale, Ph.D.
`Clinical Pharmacology Reviewer
`Division of Clinical Pharmacology 3
`Office of Clinical Pharmacology
`
`
`Dennis Bashaw, Pharm.D.
`Team Leader
`
`Division of Clinical Pharmacology 3
`Office of Clinical Pharmacology
`
`2.
`
`QBR
`
`2.1
`
`General Attributes
`
`Physicochemical Properties ofthe Drug Substance:
`
`The active pharmaceutical ingredient in Oracea is doxycycline monohydrate. The active
`ingredient, doxycycline monohydrate is synthetically derived from oxytetracycline. The
`molecular formula of doxycycline monohydrate is C22H24N208.H20, the molecular weight is
`462.46, and the structural formula is as follows:
`
`
`
`

`

`DoxycyCline monohydrate is a light yellow to pale yellow crystalline powder that dissolves in
`dilute solutions of mineral acids and in solutions of alkali hydroxides and carbonates.
`It is
`slightly soluble in methanol 1 % 1M HCl, very slightly soluble in water and in alcohol, and
`practically insoluble in chloroform and in ether.
`
`Therapeutic Indication (s):
`
`.
`
`The proposed indication for Oracea is tr ‘9,— inflammatory lesions in patients with rosacea.
`
`Mechanism ofAction:
`Rosacea is an inflammatory condition of the skin, classically presenting with flushing and/or
`blushing along with erythema, edema, telangiectasia, papules, pustules, and nodules of the face.
`The inflammatory lesions observed in patients with rosacea are, in part, manifestations of a
`neutrophil-mediated process. Activation of neutrophils is associated with the production of
`inflammatory mediators, including reactive oxygen species and nitric oxide that contribute to the
`inflammatory lesions. The applicant stated that research has shown that doxycycline inhibits
`these mediators, thereby down-regulating the pro—inflammatory response.
`
`Proposed Dosage and Route ofAdministration
`
`Oracea is intended to be taken orally, once daily in the morning.
`
`2.2
`
`General Clinical Pharmacology
`
`What were the design features of the clinical pharmacology and clinical studies used to
`Q.
`support efficacy and safety?
`
`Efficacy: Two similar Phase 3 trials, labeled COL—101—ROSE—301 (N = 251) and COL-101—
`ROSE—302 (N = 286), respectively, were conducted to evaluate the efficacy and safety of
`Oracea. The study design for both trials was identical except that a 4-week extension period
`without treatment was added to study 302 to assess longevity of treatment effects. Both studies
`were outpatient, multi—center, randomized, double—blind, placebo—controlled, parallel-group trials
`to evaluate the safety and efficacy of Oracea for reducing total inflammatory lesions compared
`with placebo. The patients were to take one capsule of study medication once daily every
`morning for 16 weeks. Study visits were at baseline and Weeks 3, 6, 12, 16, and in Study 302
`also at week 20 (patients stopped treatment at Week 16). Patients were randomized 1:1 to Oracea
`or placebo.
`'
`
`Safety: Safety was evaluated from data obtained from the following studies that were conducted
`with Oracea:
`,
`
`0 The two Phase 3 studies: COL—lOl—ROSE—301 and COL—lOl—ROSE-302 (already
`discussed under efficacy)
`'
`_
`0 Four pharmacokinetic (PK)
`studies: PERIO—DOXYSR—103, PERIO-DOXYSR—104,
`COL-101-SDPK-105, and COL-lOl—SSPK—106 (also refereed to as 103, 104, 105 and
`106). A brief description of the PK studies is provided in the table below:
`
`'
`
`

`

`Sub ects
`
` . PERIO-
`
`healthy
`To compare the bioavailability of one 40 Open—label,
`
`DOXYSR—103 mg capsule of Oracea QD vs Two 20 mg randomized, three—way volunteers
`
`
`
`Periostat® tablets BID vs. Two 20 mg single-dose, crossover
`9 males and
`
`
`
`
`study with a 7 day 9 females washout
`Periostat® tablets QD
`
`
`between
`
`
`_. eriods
`
`
`
`
`
`, PERIO-
`To compare the bioavailability of one 40 Open-label,
`14
`healthy
`
`DOXYSR—104 mg capsule of Oracea QD vs. two 20 mg randomized,
`two-way volunteers
`
`
`
`
`‘
`Periostat ® tablets BID
`crossover,
`7—day
`7 males and
`
`
`
`
`7 females
`treatment study with a
`
`
`
`96—hour
`washout
`
`between .eriods
`
`
`
`
`
`
`
`
`
`
`
`30
`healthy
`on Open—label,
`COL—101-
`To
`evaluate
`the
`effect of
`food
`randomized,‘ two—way volunteers
`SDPK—lOS
`doxycycline BA after administration of
`
`
`
`
`
` 16 males and
`Oracea
`crossover, single—dose,
`
`
`
`
`14 females
`
`food—effect study with
`
`
`a
`7-day
`washout
`
`
`
`
`between _-eriods.
`
`
`
`
`
`
`
`32
`healthy
`Open-label
`and
`the pharmacokinetics
`To compare
`
`g COL-101-
`volunteers
`‘ SSPK—106
`two-way
`randomized,
`bioequivalence between one 40 mg capsule
`
`
`
`
`
`23 males and
`7
`day
`crossover,
`of Oracea QD and one 20 mg Periostat®
`
`
`
`
`9 females
`tablet BID.
`multiple—
`treatment,
`
`
`
`
`dose study with a 7—
`
`day washout between
`
`periods
`
`Reviewer ’s Comments: The PK studies in the table above will be referred to as 103, 104, 105
`and I 06for brevity in the rest ofthis QBR.
`
`What is the basis ofselecting the response endpoints, i.e. clinical or pharmacodynamic
`Q.
`endpoints and how were they measured in the clinical studies?
`
`The primary efficacy endpoint identified in the protocols for the two pivotal trials was the
`change in total inflammatory lesion count (papules + pustules + nodules) from baseline to
`endpoint (Week 16) The applicant stated that this end-point was chosen because it was the most
`directly relevant measure to support the proposed indication for Oracea‘‘to 5'- inflammatory
`lesions in patients with rosacea”. There were no pharmacodynamic endpoints evaluated1n this
`NDA.
`
`Q.
`
`Were the active moieties in plasma appropriately identified and measured to assess the
`pharmacokinetic parameters?
`
`Yes, (See section 2.6 for details of the analytical method validation)
`
`

`

`What are the characteristics of the exposure-response relationships for efficacy or
`
`Q.
`safety?
`
`There were no exposure—response relationships evaluated in this NDA, since only one strength of
`Oracea is being proposed for marketing.
`
`Q.
`
`What are the PK characteristics ofthe drug?
`
`Single-Dose PK parameters
`The PK of doxycycline following administration of a single dose of Oracea was evaluated in
`three Pharmacokinetic studies (# 103, 104 and 105). The results of these studies are reproduced
`in the table below:
`
`
`
`(ng/mL)
`
`(ng.hr/mL)
`
`(n.hr/mL)
`
`(ng.hr/mL)
`
`
`.
`(204.0)
`
`
`= 13)
`510
`3.0
`1 105'
`(220.7) /
`(N 30)
`median (range) shown for Tmax; ND = not determined
`fasted treatment leg only
`
`(1921.9)
`
`(1290.5)
`ND
`
`(2495.8)
`
`(2721.6)
`
`8189
`(2999.1)
`
`9227
`(3212.8)
`
`
`
`a b
`
`
`
`
`
`
`
`(N = 17
`
`T
`
`‘1“)
`
`
`
`(5.49)
`
`
`
`21.2
`(7.64)
`
`
`
`Reviewer’s Comments:
`studies were comparable.
`
`The single dose pharmacokinetic parameters obtained in all three
`
`Multiple—Dose PK Parameters:
`The PK of Oracea capsules following administration of multiple doses for 7 days were evaluated
`in two Pharmacokinetic studies (#104 and 106). The results of these studies are reproduced in the
`table below:
`
`;
`
`
`
`
`
`
`“—
`
`
`,1
`
`
`(2443.9)
`(N = 30)
`
`a
`median (range) shown for Tmax; ND = not determined
`
`n/mL
`
`n,.hr/mL)
`
`(n_.hr/mL)
`
`(N = 13)
`
`(177.6)
`
`(1963.9)
`
`(6.2)
`
`Reviewer ’5' Comments: Cmax and Tmax are comparable for both studies and AUC is somewhat
`comparable. The PK parameters obtained after multiple dosing are somewhat comparable to
`that obtainedfollowing single dosing ifone takes the variability into account.
`
`

`

`Q.
`
`Is the single dose pharmacokinetics of Oracea comparable to that of a currently
`marketed immediate release drug product (Periostat 20 mg tablets) that contains
`doxycycline?
`
`No it is not. The data from study # 103 and 104 indicated that following a single dose, the systemic
`exposure of doxyxcycline from Oracea is higher than that of Periostat BID. In study #-PERIO—
`DOXYSR-103 (N=17),
`the applicant compared the pharmacokinetics of doxycycline after a
`single dose administration of Oracea, to currently marketed Periostat 20 mg BID and 40 mg QB
`in healthy volunteers. Inserted below is a graph showing the plasma concentration time profiles
`for the three treatments:
`
`7""
`
`600 ’
`
`+ Treatmwl A (Single 40 mg $5225 1mm capsule)
`+ heatment B (20—mg Periostat tablet given BID}
`“on Treatment C ('1‘we 20mg Whom! mbtcts)
`
`'
`
`
`
`400
`
`
`
`
`
`500
`
`DoxycyclineConcentration{nglmL}
`
`0
`
`4 812[62024283236404448525660646872
`
`TichLrs)
`
`Figure 14.2.‘1-1. Mean Plasma Doxycycline Concentration versus Time
`i’rofile in the Normal Scale.
`
`Reviewer '3 Comments: The graphs above indicate that Treatment A (Oracea 40 mg) had a systemic
`exposure that was higher than that obtainedfor Treatment B (Periostat ® Ix 20 mg) and lower
`than that obtainedfor Treatment C (Periostat ® 2x 20 mg). Graph above demonstrates that
`Oracea shows some extended release but not delayed release properties.
`
`
`
`PERIO-DOXYSR—103: Pharmacokinetic Results for DoxycyclineTable 2.7.1-2
`
`Pharmacokinetic Parameters for Doxycycline
`
`
`
`
`Cm
`AUCtH
`AUCM
`tmax'l
`AUC 5.14
`
`
`
`Treatment
`(nglmL)
`(hr)
`(ng-hr/mL)
`
`(ng' hr) (ng'hr/mL)
`
`
`
`A (OraceaTM)
`
`Mean
`SD
`
`
`B ('Pcdostat‘” BID)
`Mean
`
`SD
`
`
`C (2 Periostat“, once)
`
`.
`623
`Mean
`245.9 ’
`SD
`
`
`
`Source: Table 1 1.4.1.1-1 (Module 5, volume 1.1, page 52)
`
`
`8. Median (range) shown for tmx.
`
`9 n-
`
`-
`
`

`

`Reviewer ’s Comments: The PKparameters show that Treatment C U’eriostat 2 x 20 mg at once)
`had the highest valuefor mean Cmax and A UC infin comparison to Treatments A (Oracea) and B
`(Periostat 1 x 20 mg). TreatmentA had a higher Cmax and A UC 0—24, but lowerAUC 0—t and A UC 0-oo
`than treatment B. Therefore the results for A UC were not consistent. The Tmax was comparablefor
`Treatment A and C. Applicant stated that the relatively high median Tmax valuefor treatment B could be
`attributed to the Tmax occurring during the PM dose of the 12—hour BID dosing regimen. Mean T 1/2
`values were similar across treatments.
`
`Table 2.7.1-3 PERIO~DOXYSR~103: Statistical Results of Relative Bioavailabillty for
`anycycline
`*
`
`.
`
`90% Confidence
`Interval”
`
`Comparison of
`{
`
`
`
`Treatments
`
`
`A (Oraceant) to
`(125, 172)
`
`
`' B (periosm’ BID)
`(97.7, 123)
`
`(76.2, 106)
`
`.
`.
`.,
`(75.7, 102)
`
`A (Oraceam‘) to
`1n(c,,.,,)
`(75.3, 103)
`
`c (2 Periostat” once) MAUCW)
`(79.6, 104)
`
`
`mama-1)
`(77.3, 108)
`I
`
`
`
`
`
`..
`, .magg‘gm
`.
`"iii?
`77 0, 104)
`1
`
`
`c (2 Periostat“ once) mom)
`545
`(142, 195) —]
`m B (Rename 13m) MAUCW)
`5678
`(107. 141)
`
`
`MAUCM)
`'
`7620
`(33.4, :16)
`l
`. r-u 4.4,
`niacin.)
`g
`1:44
`anwn- "Pnkl. 11 A 1 a 1 nu...a..1. c .._L._.. .
`u
`.
`
`(.8
`114) ,
`
`t
`.
`
`I
`
`the statistical comparisons
`Reviewer ’s Comments: Consistent with the PK results above,
`indicated that the rate and extent of absorption of doxycycline from Oracea (Treatment A) was
`not equivalent to that ofPeriostat ® BID (Treatment B) or Periostat 40 mg at once (Treatment
`C). The 90% CIfor In Cmax and In AUC (except AUC 0—t and AUC 0—inffor comparison of
`Treatment B and C) were all outside the 80% to 125 % range.
`The applicant stated that the relatively small sample size of 17 subjects should be taken into
`consideration in evaluatingthese results. This reviewer believes that another source of error
`could have been due to that fact that a large number of samples had to be re—assayed because
`they yielded concentration levels that were above the range of the calibration curve. Although
`the dilution was validated, however, diluting the samples to bring them within the range of the
`standard curve could have introduced another source oferror.
`
`In study # PERIO—DOXYSR—104 (N = 13) the applicant compared the systemic exposure of
`doxycycline after a multiple dose (7 days) administration of Oracea,
`to currently marketed
`Periostat 20 mg BID in healthy volunteers.
`In this study the relative bioavailability of
`doxycycline on Day 1 and Day 7 were evaluated. Reproduced in the table below are the Day 1
`pharmacokinetic results.
`
`
`
`
`
`
`
`Cmax n_/mL)
`AUC (0—24)
`n_.hr/mL
`
`
`Table: PERIO-DOXYSR-104: PK and Statistical Results for Dox c cline
`PK Parameter
`Treatment A (Oracea)
`Treatment B (Periostat BID
`
`
`
`
`
`
`
`343 (129.2)
`586 (159.4)
`(147, 203)
`
`
`5588 (1290.5)
`4399 (1358.7)
`(1 14, 144)
`
`
`
`
`
`
`15.0 (0.5, 23.9)
`2.50 (1.0, 4.0)
`a Tmax = median (range); * 90_ % CI on natural log transformed parameters; NA = not applicable
`
`90%
`Interval
`
`Confidence"
`
`10
`
`

`

`Reviewer ’s Comments: Following a single dose, the data obtained was consistent with that of
`study # 103 in that the rate and extent of absorption of doxycycline was higher from Oracea
`when compared to Periostat BID. The 90% C1 for In Cmax and In AUC were also outside the
`80% to 125 % range. Applicant stated that the relatively high median Tmax value for treatment B
`could be attributed to the Tmax occurring during the PM dose ofthe 12—hour BID dosing regimen.
`
`the systemic exposure of
`The data from study # 103 and 104 indicate that following a single dose,
`doxyxcycline from Oracea is higher than that of Periostat BID, indicating that safety may be a concern
`from a clinical perspective (preliminary review of the safety data indicated that there were no serious
`adverse events reported in these two studies, however this is currently under review by the medical
`reviewer). Since this medication is intendedfor chronic dosing this may not be a concern if the systemic
`exposure following multiple dose administration is similar.
`
`' Q.
`
`Is the steady-state pharmacokinetics of Oracea comparable to that of a currently
`marketed immediate release drug product (Periostat 20 mg tablets) that contains
`doxycycline?
`
`Yes it is. In study # COL-lOl—SSPK-106 (N= 30),®the rate and eXtent of absorption of Oracea
`40 mg QD administered for 7 days versus Periostat® tablets 20 mg BID administered for 7 days
`in healthy volunteers was evaluated Inserted below is a graph showing the Day 7 plasma
`concentration-time profiles of both treatments.
`
`50,,
`
`500
`
`m 135::333333325as“ mans”)
`
`]
`
`‘2
`
`100
`
`
`'DoxycyclineConcentration(HE/Hi) §
`
`§
`
`9...
`
` I
`
`4
`8
`12
`l 6
`20
`24
`23
`32
`
`0
`
`.
`36
`‘imc (hr)
`Figure 14.2. 1 —1 Mean Plasma Doxycycline Concentration on Day 7 versus Time
`Profile in the Normal Scale
`
`40
`
`44
`
`48
`
`52
`
`56
`
`60
`
`64
`
`.
`68
`
`72
`
`The arithmetic mean PK parameters on day 7 are summarized in the table below:
`
`Table 2.7.1_-9
`
`COL-1 01-SSPK—106: Arithmetic Mean (SD) Pharmacokinetic
`
`-
`Parameters for Doxycycline
`
`
`Doxycycline PK Parametera
`
`._ A (Oraceam QD)
`, B (Periostat‘ BID)
`600 (194.2)
`565 (233.3)
`c.mx (ng/mL)
`
`
`
`
`tm (hr)
`2.00 (1.0, 4.0)
`2.25 (1.00, 12.0)
`
`
`
`7543 (2443.9) 8040 (3288.8)
`
`AUC” (ng-hr/mL)
`
`
`
`
`a: values are mean (SD) except for median (range) for Tmax
`
`11
`
`

`

`Reviewer ’s Comments: Doxycycline had a median Tmax value of approximately 2 hours after
`both treatments A and B. Treatment A (Oracea) had a higher arithmetic mean for Cmax and a
`lower mean AUC value for doxycycline relative to Treatment B (Periostat® tablets) which is
`consistent with the graphical representation above.
`Table 2.7.1410
`COL-IOI-SSPKAOG: Statistical Analysis of Pharmacokinetic Data
`
`'
`I
`Test Least
`Reference Least
`S
`
`quam Mean
`Squares Mean
`
`
`
`90% Confidence
`Doxycycline PK
`(Treatment A,
`(Treatment 3,
`
`
`
`
`
`rarameter
`Oraceam)
`Pentium" 311))
`Test! Reference
`Interval
`
`
`AUC“ (ng-hr/mL)
`(90.90. 106.83)
`
`
`
`Cm (DE/mm
`(101.73, 113.20)
`
`
`
`(70.78, 80.87}
`Cnin (WM)
`
`
`
`
`Reviewer ’5 Comments: The data in the table above indicates that Treatment A and Treatment B
`
`were equivalent at steaajz state because the 90% confidence intervals for In (Cmax) and In
`(A UCss) were contained within the 80 % to 125 % range. The Cmin for Treatment A was less
`than that of Treatment B. The clinical relevance ofthisfinding in terms ofefi‘icacy is unknown.
`
`2.3
`
`Intrinsic Factors
`
`How does the systemic exposure change with various intrinsic factors?
`
`Gender Effect: The applicant evaluated the effect of gender on the pharmacokinetics of
`doxycycline after a single dose administration of Oracea in study # COL—101-SDPK—105 in 16
`males and 14 females under fed and fasted conditions. Inserted below is a table showing the
`results of the gender analysis:
`
`COL—101—SDPK—105: Statistical Analysis of Pharmacokinetlc Data -—
`Table 2.7.1-8
`Gender Effect
`
`
`' _airwiseP-value'
`
`
`Gender—by-
`Treatment ‘
`P—value‘
`.
`
`A-
`Male
`
`Gender
`P—value':
`
`.
`
`Doxycycline
`PK
`Parameter
`
`‘ ..
`
`.
`
`.
`
`'
`
`13—
`B:-
`Female Male
`<0.0001
`<0.0001
`0.3210
`<0.0001
`0.0010
`
`A (fasted)
`NA
`NA
`
`B (fed)
`
`B (fed)
`A (fasted)
`
`_ NA
`
`
`
` Qruw-nn- TnLIn 1A '3 a n l1!_..I.—l_ : “.1... 1 —
`
`Consistent with historical doxycycline PK data (and as reflected in the product labeling for
`Periostat®), a significant gender effect was observed on the rate (Cmax) and extent (AUC) of
`doxycycline absorption from Oracea. Female subjects had both a higher rate and extent of
`absorption than males. Further, for the rate of doxycycline absorption, a gender—by—treatment
`
`12
`
`

`

`effect was observed, with a significantly higher Cmax for fasted female subjects compared with
`fed female subjects and, fasted or fed male subjects. These differences are thought to be due to
`differences in body weight/lean body mass.
`
`Reviewer ’s Comments:
`
`The applicant has proposed to include this data in the label under ”special populations ” after
`clinical studies ” as follows
`Gender: The pharmacokinetics of ORACEA was compared1n 16 males and 14 females
`under fed and fasted conditions. WM._MW"
`
`,MWM.,M-.-~m~~-<-~m_~__w\~_. 5‘--. mam—“N,“
`
`However, this revieWer is proposing some revision to the label to be consistent with the approved
`label in Periostat tablets (see section 3 for labeling recommendations)
`
`The published report by Grahnen et a1 (1994) evaluated the effect of increased gastric pH
`(obtained by pre—treatment with omeprazole) on the bioavailability of doxycycline monohydrate
`and doxycycline carrageenate in 24 healthy volunteers, using an open, randomized, four-
`treatment, four-period, crossover, 2 x 2 factorial design. Each subject received a single dose of
`100 mg of each of the doxycycline formulations with and without pre—treatmentwith omeprazole
`(40 mg daily for 7 days). There was a one week wash-out period between sessions. Blood
`samples were obtained after dosing at 0, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36, and 48 h. The
`plasma concentrations of doxycycline were determined by a modified HPLC method with UV
`detection. The limit of quantitation was 0.05 mcg/mL.
`
`
`Results:
`
`The authors concluded that a statistically significant difference in kinetics was observed between
`the two formulations of doxycycline, as the doxycycline formulation was shown to have
`decreased bioavailability at high gastric pH, and the new formulation doxycycline carragenate
`had unchanged bioavailability at high pH. Basically, the two formulations had a comparable rate
`and extent of absorption without omeprazole pre—treatment. After omeprazole, the monohydrate
`showed a decrease in bioavailability (38% for AUC and 45% for Cmax) compared to the
`carrageenate formulation, which was not affected by prior administration of omeprazole. Many
`of the subjects (about 40 %) did not reach a therapeutic plasma level of doxycycline (0.6
`mcg/mL) during the combination of omeprazole and doxycycline monohydrate, and most
`adverse events (mainly gastrointestinal) were reported after this combination. The authors stated
`that although pH was not monitored during the study, the effect of 1 week of pre-treatment with
`omeprazole is very probably related to achlorhydria.
`
`1 Grahnen A, Olsson B, Johansson G, et a1. Doxycycline carrageenate—an improved formulation providing more
`reliable absorption and plasma concentrations at high gastric pH than doxycycline monohydrate. Eur J Clin
`Pharmacol 1994; 46: 143-146.
`
`13
`
`

`

`Based on the aforementioned, the authors recommended that, as large populations of patients
`have a high gastric pH due to frequent use of HZ-blockers, proton pump inhibitors and antacids,
`as well as to physiological achlorhydria, the decreased absorption of doxycycline monohydrate
`may well have a clinical impact, for example when the patients are treated with tetracyclines for
`0
`an infection.
`
`Reviewer ’5 Comments: Although the study was not actually conducted in patients with gastric
`insufiiciency and the formulation used in this study is not the same as the proposedformulation
`the doxycycl