ORIGINAL RESEARCH ARTICLE
`
`Clin Pharmacokinet 2007; 46 (8): 697-712
`0312-5963/07/0008-0697/$44.95/0
`
`© 2007 Adis Data Information BV. All rights reserved.
`
`Pharmacokinetics of Dapsone Gel, 5%
`for the Treatment of Acne Vulgaris
`Diane M. Thiboutot,1 Jonathan Willmer,2 Harry Sharata,3 Rebat Halder4 and
`Steven Garrett5
`
`1 Pennsylvania State University College of Medicine, Hershey, Pennsylvania, USA
`2 Cantest Clinical Research Ltd, Vancouver, British Columbia, Canada
`3 Madison Skin and Research, Inc., Madison, Wisconsin, USA
`4 Howard University College of Medicine, Washington, District of Columbia, USA
`5 QLT USA, Inc., Fort Collins, Colorado, USA
`
`Abstract
`
`Background: Oral dapsone has been available for over 60 years and has been
`used to treat severe acne vulgaris; however, the oral formulation is known to cause
`dose-dependent haematological reactions and is currently indicated only for
`diseases such as dermatitis herpetiformis and Hansen’s disease. A gel formulation
`of dapsone was recently developed to treat acne vulgaris. As dapsone is adminis-
`tered topically, it was expected that systemic absorption would be considerably
`lower than that observed with oral dapsone therapy, thereby avoiding any adverse
`haematological effects.
`Objective: To report the pharmacokinetic profile of topically applied dapsone gel,
`5% in the treatment of acne vulgaris.
`Study participants and methods: Three prospective, open-label studies enrolled
`a total of 548 subjects with acne vulgaris: two phase I pharmacokinetic studies
`(crossover and drug interaction) and one phase III long-term safety study. In the
`crossover study (n = 18), topical dapsone gel applied twice daily for a total of 14
`days to 22.5% of the body surface area was compared with a single dose of oral
`dapsone 100mg (the typical clinical dose). In the drug-interaction study (n = 24),
`oral trimethoprim/sulfamethoxazole monotherapy, topical dapsone gel monother-
`apy and the two in combination were used twice daily for 7, 21 and 7 days,
`respectively. In the long-term safety study (n = 506), topical dapsone gel was
`applied twice daily to acne-affected areas for up to 12 months. Blood samples
`were drawn at various timepoints in each study to assess drug and metabolite
`concentrations. Systemic concentrations of dapsone, N-acetyl dapsone, dapsone
`hydroxylamine, trimethoprim and sulfamethoxazole were determined, according
`to the study design.
`Results: In the crossover study, the mean area under the plasma concentration-
`time curve (AUC) from 0 to 24 hours for dapsone was 417.5 ng • h/mL after 2
`weeks of dapsone gel therapy (n = 10), compared with an AUC from time zero to
`
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`infinity of 52 641 ng • h/mL after a single dose of oral dapsone; this represents a
`126-fold lower systemic exposure for dapsone gel at typical therapeutic doses.
`In the drug-interaction study, the AUC from 0 to 12 hours for dapsone
`was 221.52 ng • h/mL after 3 weeks of dapsone gel monotherapy compared
`with 320.3 ng • h/mL after 1 week of coadministration with trimethoprim/sul-
`famethoxazole. In the long-term safety study, the mean plasma dapsone concen-
`trations ranged from 7.5 to 11 ng/mL over 12 months. Overall, total systemic
`exposures to dapsone and its metabolites were approximately 100-fold less for
`dapsone gel than for oral dapsone, even in the presence of trimethoprim/
`sulfamethoxazole. There were no reports of any haematological adverse events.
`Conclusions: Topical application of dapsone gel in various settings ranging from
`2 weeks to 12 months resulted in systemic exposures to dapsone and its metabo-
`lites that were approximately 100-fold less than those after oral dapsone at a
`therapeutic dose level. The concentrations of dapsone and its metabolites reached
`steady state and did not increase during prolonged treatment.
`
`Background
`
`currently indicated only for the treatment of derma-
`titis herpetiformis and Hansen’s disease in doses
`ranging from 100 to 300mg,[10] but historically, oral
`Acne vulgaris is the most common reason indi-
`viduals visit a dermatology office[1] and, increasing-
`dapsone was also used for the treatment of severe
`ly, more patients are seeking treatment for acne from acne in doses ranging from 25 mg/day to 300 mg/
`non-dermatologists.[1,2] Acne has both inflammatory week.[11-13] The most notable adverse effects of oral
`and bacterial components[2,3] but, until recently, the
`dapsone are haematological reactions, including
`inflammatory events were considered secondary oc-
`dose-dependent haemolysis and methaemoglobi-
`currences in the sequence of lesion development.[4]
`naemia, which result from the increased oxidative
`Newer data now suggest that inflammatory events
`stress produced by the hydroxylamine metabo-
`lite.[8,9,13] Individuals with glucose-6-phosphate
`occur before, and possibly initiate, the hyper-
`proliferation observed in acne lesions.[5] These find-
`dehydrogenase (G6PD) deficiency are sensitive to
`ings support the classification of acne vulgaris as an
`these effects, since the absence of functional G6PD
`inflammatory skin disease as opposed to a keratino-
`can
`lead
`to haemolysis and denaturation of
`cyte/hyperproliferative disorder.[5] Proinflammatory
`haemoglobin.
`cytokines play a role in the formation of acne le-
`Oral dapsone was usually most effective for pa-
`sions, and it has recently been suggested that the
`tients with severe acne; however, some improve-
`bacterium Propionibacterium acnes, one of the key ment was also noted in patients with mild acne.[13] It
`pathogenic factors linked to the development of was hypothesised that topical application of dapsone
`acne, releases proinflammatory cytokines.[6,7]
`in a gel formulation for the treatment of acne vul-
`Dapsone (4,4′-diaminodiphenyl sulfone) is a syn-
`garis would greatly minimise the systemic exposure
`thetic sulfone with both anti-inflammatory and an-
`to dapsone, while delivering an effective clinical
`tibacterial actions.[8,9] Its primary metabolites are N-
`dose of dapsone to the affected area and avoiding the
`acetyl dapsone and dapsone hydroxylamine. Oral
`adverse haematological effects observed with oral
`dapsone has been available for over 60 years and is
`dapsone therapy.
`
`© 2007 Adis Data Information BV. All rights reserved.
`
`Clin Pharmacokinet 2007; 46 (8)
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`Pharmacokinetics of Dapsone Gel, 5%
`
`699
`
`Dapsone gel, 5% (Aczone™, QLT USA, Inc.,
`Fort Collins, CO, USA)1 was approved in the US for
`the treatment of acne vulgaris, based on two
`randomised controlled studies that demonstrated
`statistically and clinically significant improvements
`in both acne lesion counts and treatment success
`over 12 weeks.[14] This article reports the pharma-
`cokinetic results of three additional studies that in-
`vestigated the systemic absorption and safety of
`dapsone gel in the treatment of acne vulgaris.
`
`Study Participants and Methods
`
`shoulders and/or upper chest, representing up to
`approximately 22.5% of the total body surface area.
`Following application of dapsone gel in all studies,
`swimming and bathing were prohibited for 2 hours;
`the use of moisturisers, sunscreens and cosmetics on
`the treatment areas was prohibited for 1 hour. In the
`pharmacokinetic studies, to represent maximum ex-
`posure, dapsone gel was applied to all of these body
`areas regardless of whether acne was present at the
`particular site. In the long-term safety study, it was
`applied only to acne-involved parts of these body
`areas and could be discontinued where the acne had
`cleared; likewise, it was to be restarted if acne
`Two phase I pharmacokinetic studies and a phase
`lesions reappeared in these parts.
`III long-term safety study were conducted between
`The studies were conducted in accordance with
`24 January 2002 and 14 April 2004. The crossover
`the ethical principles of the Declaration of Helsinki
`study compared 15-day administration of dapsone
`and in compliance with the US FDA Good Clinical
`gel with a single dose of oral dapsone 100mg to
`Practice Guidelines, and the protocol for each study
`evaluate the relative systemic concentrations of oral was reviewed and approved by an institutional re-
`and topical administration. The drug-interaction
`view board or ethics committee. All subjects and
`study of dapsone gel and oral trimethoprim/
`their parents or guardians, as appropriate, gave writ-
`sulfamethoxazole was conducted to explore possible
`ten informed consent before the start of study proce-
`interactions between dapsone gel and trimethoprim/
`dures.
`sulfamethoxazole; coadministration of oral dapsone
`and oral trimethoprim/sulfamethoxazole is known to
`increase the plasma concentrations of both drugs by
`approximately 1.5 times compared with monother-
`apy.[10] The long-term safety study of dapsone gel
`examined the safety and efficacy of dapsone gel
`over 12 months in a setting more closely aligned to
`clinical practice;[15] the dapsone plasma concentra-
`tion results from that study are reported here.
`All three studies were open-label trials conducted
`in subjects with a clear diagnosis of acne vulgaris,
`defined as at least 20 inflammatory lesions at base-
`line (ten or more inflammatory lesions on the face,
`with the remaining lesions on the back, shoulders
`and chest). Dapsone gel was applied twice daily
`(once in the morning and once in the evening at least
`1 hour before bedtime) to the face, upper back,
`
`Crossover Study of Dapsone Gel, 5%
`Followed by Oral Dapsone
`
`Study Design and Subjects
`The crossover study was a single-centre, open-
`label, two-period, pharmacokinetic and safety study
`(figure 1). The primary objective was to evaluate the
`pharmacokinetic profile of dapsone gel and the rela-
`tive systemic drug concentrations following oral and
`topical dapsone administration at typical therapeutic
`doses. Subjects applied dapsone gel for 15 days to
`the maximum expected skin area (approximately
`22.5% of body surface area). A subset of subjects
`then underwent a 14-day washout period and re-
`turned to the clinic for administration of a single
`dose of oral dapsone, given at the recommended
`
`1 The use of trade names is for product identification purposes only and does not imply endorsement.
`
`© 2007 Adis Data Information BV. All rights reserved.
`
`Clin Pharmacokinet 2007; 46 (8)
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`700
`
`Thiboutot et al.
`
`Crossover
`study
`
`Drug-interaction
`study
`
`Long-term safety
`study
`
`Study design
`phase I; open-label;
`2-period crossover
`
`Duration
`2 weeks
`
`Number of centres
`1
`
`Application area
`22.5% of BSA
`
`Study design
`phase I; open-label
`
`Study design
`phase III; open-label
`
`Duration
`42 days
`
`Number of centres
`1
`
`Application area
`20.0% of BSA
`
`Duration
`12 months
`
`Number of centres
`18
`
`Application area
`22.5% of BSA
`
`Number enrolled
`18
`
`Number enrolled
`24
`
`Number enrolled
`506
`
`Voluntary withdrawal
`1
`
`Discontinued due to AE
`3
`
`Discontinued due to AE
`11
`
`Completed study
`17
`
`Lost to follow-up
`2
`
`Lost to follow-up
`79
`
`Number enrolled
`10
`
`Completed study
`10
`
`Completed study
`19*
`
`Voluntary withdrawal
`59
`
`* Of these 19 subjects,
`17 were included in
`the modified
`pharmacokinetic cohort
`
`Discontinued – other
`17
`
`Completed study
`340
`
`Period 1
`
`Period 2
`
`Fig. 1. Summary of trials. AE = adverse event; BSA = body surface area.
`
`Blood Sampling
`
`administration of a single dose of oral dapsone
`therapeutic dose of 100mg. Pharmacokinetic evalua-
`100mg (Jacobus Pharmaceutical, Princeton, NJ,
`tions of plasma dapsone and N-acetyl dapsone con-
`centrations were performed in both periods of the USA).
`study. Eligible subjects were men or women be-
`tween the ages of 18 and 40 years with acne vul-
`garis. Subjects with G6PD deficiency were not eligi-
`ble for participation in the oral dapsone period of the
`trial.
`
`Dapsone Gel, 5%
`On all treatment days that coincided with
`pharmacokinetic sampling (days 0, 1, 2, 3, 5, 7 and
`14), the first blood sample was drawn prior to the
`Treatment
`morning application of topical dapsone to yield
`trough samples. On days 0 and 14, blood samples for
`Dapsone gel was applied twice daily to all of the
`the topical dapsone pharmacokinetic analysis were
`face, upper back, shoulders and upper chest. How-
`collected before dapsone application (hour 0), and at
`ever, on the first and last topical treatment days
`1, 2, 3, 4, 6, 8, 10 and 12 hours following the
`(days 0 and 14, respectively), dapsone was applied
`only in the morning. After the 14-day washout peri- morning application (which was the only applica-
`od, a subset of ten subjects returned to the clinic for
`tion on those days). Trough blood samples were also
`
`© 2007 Adis Data Information BV. All rights reserved.
`
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`Pharmacokinetics of Dapsone Gel, 5%
`
`701
`
`obtained on days 1, 2 and 3 (hours 24, 48 and 72)
`and on days 5 and 7. In addition, blood samples were
`drawn 24, 48 and 72 hours after the last application
`of topical dapsone. A total of 26 blood samples were
`collected from each subject in this period of the
`study.
`
`rule. For oral dapsone, the AUC from 0 to infinity
`(AUC∞) was estimated as AUC0–t + Ct/ke, where Ct
`is the last measurable concentration (at time t) and
`ke is the elimination rate constant calculated by
`linear regression of the terminal phase data. The t1/2
`was calculated as ln(2)/ke. Concentrations below the
`LLQ were assigned a value of zero for all
`Single-Dose Oral Dapsone 100mg
`pharmacokinetic calculations. Relative exposures
`Baseline blood samples for the oral dapsone were estimated by comparing the AUC24 for dap-
`pharmacokinetic analysis were obtained on day 28
`sone gel with the AUC∞ for oral dapsone.
`after the 14-day washout period. After administra-
`tion of oral dapsone 100mg, blood samples were
`drawn over 3 days at hours 1, 2, 3, 4, 6, 8, 10, 12, 24,
`48 and 72. A total of 12 blood samples were collect-
`ed from each subject in this period of the study.
`
`Bioanalytical Methods
`Plasma concentrations of dapsone and N-acetyl
`dapsone were assayed in a central laboratory (MDS
`Pharma Services, Saint-Laurent, QC, Canada) using
`a validated high-performance liquid chromatogra-
`phy-tandem mass spectrometry (HPLC-MS/MS)
`method. The lower limit of quantitation (LLQ) for
`dapsone and N-acetyl dapsone was 0.05 ng/mL.
`
`Pharmacokinetic Analyses
`The following pharmacokinetic parameters were
`assessed: the area under the plasma concentration-
`time curve (AUC), maximum plasma concentration
`(Cmax), time to reach Cmax (tmax) and elimination
`half-life (t1/2). For oral dapsone, the terminal elimina-
`tion half-life was determined. For dapsone gel, the
`apparent elimination half-life of dapsone after the
`last treatment was determined. Non-compartmental
`methods were used to calculate the pharmacokinetic
`parameters using WinNonlin® version 4.0.1 (Phar-
`sight Corporation, Mountain View, CA, USA). The
`linear trapezoidal rule was used in conjunction with
`the extravascular input model 200. Both the Cmax
`and the tmax were determined directly from the
`plasma concentration data without interpolation.
`The AUC from 0 to 24 hours (AUC24) was calculat-
`ed by numerical integration using the trapezoidal
`
`Statistical Methods
`The sample size was based on having a reason-
`able number of subjects for computing descriptive
`statistics. Twenty subjects were planned and it was
`estimated that ten subjects would cross over to the
`oral dapsone subset. A total of 18 subjects were
`enrolled in the study (the all-subjects dataset). The
`pharmacokinetic evaluable dataset also included all
`18 subjects, except for determination of the ke,
`which included 17 subjects (one subject had volun-
`tarily discontinued after day 15). Descriptive statis-
`tics for the pharmacokinetic analysis (mean, medi-
`an, standard deviation, minimum, maximum) were
`determined using data from all subjects who com-
`pleted the sampling sequence (the pharmacokinetic
`evaluable set). Laboratory data were summarised by
`timepoints at screening and on days 5 and 14 and,
`for the subset of ten subjects only, on days 28 and
`31. Shift tables were constructed for change from
`baseline. The pharmacokinetic parameters of basic
`interest were the Cmax and AUC24.
`
`Drug-Interaction Study of Dapsone Gel, 5%
`with Trimethoprim/Sulfamethoxazole
`
`Study Design and Subjects
`The drug-interaction study was an open-label,
`single-centre study to evaluate the steady-state
`pharmacokinetics of
`trimethoprim/sulfamethoxa-
`zole alone, dapsone gel alone and the two agents
`in combination (figure 1). Oral trimethoprim/sul-
`
`© 2007 Adis Data Information BV. All rights reserved.
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`702
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`Thiboutot et al.
`
`famethoxazole was administered twice daily for 7
`days (days 1–7). Following a 7-day washout period
`(days 8–14), dapsone gel was applied twice daily for
`3 weeks (days 15–35). Immediately afterwards (i.e.
`there was no washout period), the two agents were
`used concomitantly for 1 week (days 36–42). Eligi-
`ble subjects were men or women between the ages
`of 18 and 50 years with acne vulgaris. Trimetho-
`prim/sulfamethoxazole must be used with caution in
`individuals with G6PD deficiency,[10] and so sub-
`jects with this condition were not eligible for study
`enrolment.
`
`Bioanalytical Methods
`The systemic concentrations of trimethoprim,
`sulfamethoxazole, dapsone, N-acetyl dapsone and
`dapsone hydroxylamine were determined from plas-
`ma analysis (Cantest BioPharma Services, Burna-
`by, BC, Canada). The plasma concentrations of
`trimethoprim and sulfamethoxazole were assayed
`using an HPLC-MS method. The LLQ for trimetho-
`prim was 0.10 μg/mL and the LLQ for sulfamethox-
`azole was 1 μg/mL. The plasma concentrations of
`dapsone, N-acetyl dapsone and dapsone hydroxyl-
`amine were assayed using HPLC-MS/MS. The LLQ
`for dapsone, N-acetyl dapsone and dapsone
`hydroxylamine was 0.30 ng/mL.
`
`Treatment
`The subjects took one oral dose of double-
`Pharmacokinetic Analysis
`strength
`trimethoprim/sulfamethoxazole 160mg/
`The following pharmacokinetic parameters were
`800mg (Apotex Inc., Weston, ON, Canada) twice
`assessed using non-compartmental methods and
`daily with a full glass of water 1 hour before or 2 WinNonlin® version 4.0.1: the AUC from 0 to 12
`hours after meals. Dapsone gel was applied twice
`hours (AUC12), Cmax, minimum plasma concentra-
`daily to all of the face, upper back, shoulders and
`tion (Cmin) and tmax. The linear trapezoidal rule was
`upper chest, regardless of the presence of acne le-
`used in conjunction with the extravascular input
`sions.
`model 200. Samples below the LLQ were assigned a
`concentration of zero for all pharmacokinetic calcu-
`lations.
`
`Blood Sampling
`
`Trimethoprim/Sulfamethoxazole
`A total of 26 serial blood samples were collected
`from each subject for determination of trimethoprim
`and sulfamethoxazole plasma concentrations ac-
`cording to the following sampling schedule: trough
`samples (pre-dose) on days 1, 5, 6, 7, 36, 40, 41 and
`42, and post-dose samples on days 7 and 42 (hours
`1, 2, 3, 4, 6, 8, 10, 12 and 24).
`
`Dapsone Gel, 5%
`A total of 25 serial blood samples were collected
`from each subject for determination of dapsone, N-
`acetyl dapsone and dapsone hydroxylamine plasma
`concentrations according to the following sampling
`schedule: trough samples on days 15, 22, 29, 35, 36,
`40, 41 and 42, and post-dose samples on days 35 and
`42 (hours 1, 2, 3, 4, 6, 8, 10, 12 and 24).
`
`Statistical Methods
`The full analysis set comprised 24 subjects who
`received at least one dose of trimethoprim/sul-
`famethoxazole beginning on day 1. The pharma-
`cokinetic evaluable set (n = 19) included all subjects
`who completed the pharmacokinetic profiles on
`days 7, 35 and 42 and had adequate plasma concen-
`tration data from which to calculate the pharmacoki-
`netic parameters. The modified pharmacokinetic
`evaluable set (n = 17) consisted of all subjects in the
`pharmacokinetic evaluable set, except for two sub-
`jects who had trimethoprim and sulfamethoxazole
`concentration values of zero or nearly zero on day
`42. The primary analysis for drug interaction was
`performed on the modified pharmacokinetic evalu-
`able set. The pharmacokinetic evaluable set was
`used for secondary analyses.
`
`© 2007 Adis Data Information BV. All rights reserved.
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`Pharmacokinetics of Dapsone Gel, 5%
`
`703
`
`The primary pharmacokinetic parameters for as-
`sessment of a drug-drug interaction were the AUC12
`and Cmax for trimethoprim/sulfamethoxazole, dap-
`sone and the metabolites N-acetyl dapsone and dap-
`sone hydroxylamine. The secondary pharmacoki-
`netic parameters were the Cmin and tmax of each
`drug and metabolite.
`For evaluation of the difference in the AUC12
`and Cmax between trimethoprim/sulfamethoxazole
`alone (day 7) and in combination with dapsone gel
`(day 42), the data were natural log transformed.
`Using ANOVA, with treatment as a factor and sub-
`ject as a random effect, a 90% confidence interval
`was constructed. In a similar manner, day 35 (dap-
`sone gel alone) was compared with day 42 (dapsone
`gel and trimethoprim/sulfamethoxazole together). If
`the 90% confidence intervals for the AUC12 and
`Cmax ratios of the geometric means fell within the
`range of 80–125%, it was concluded that there was
`no interaction. Trough concentration comparisons
`were performed using a repeated measures ANOVA
`model, and the Wilcoxon signed rank test was used
`for tmax comparisons.
`Statistical analyses to identify a potential drug
`interaction were consistent with those described in
`the November 1999 Guidance for Industry.[16]
`
`Long-Term Safety Study of Dapsone Gel,
`5% Monotherapy
`
`Study Design and Subjects
`
`ations, were conducted at prespecified intervals
`throughout the trial. A full description of the long-
`term safety study has been presented and is pub-
`lished in detail elsewhere.[15]
`
`Treatment
`Dapsone gel was applied twice daily to only the
`acne-involved areas of the face, upper back, shoul-
`ders and upper chest. The applications of dapsone
`gel could be stopped in those areas where acne had
`cleared; however, it had to be re-applied to those
`areas if the acne lesions reappeared.
`
`Blood Sampling
`Plasma concentrations of dapsone and N-acetyl
`dapsone were evaluated in the full study population
`at baseline and at months 1, 3, 6, 9 and 12. A subset
`of subjects (the first 35 who enrolled in the trial) also
`had blood samples drawn for haematology and dap-
`sone concentration analyses at weeks 1 and 2. All
`available subjects were screened for G6PD deficien-
`cy at month 6. Due to the flat concentration versus
`time profile of topical dapsone, trough concentra-
`tions were not required.
`
`Bioanalytical Methods
`Plasma dapsone and N-acetyl dapsone concentra-
`tions were assayed in a central laboratory (MDS
`Pharma Services, Saint-Laurent, QC, Canada) using
`HPLC-MS. The LLQ was 0.05 ng/mL for dapsone
`and N-acetyl dapsone. Concentrations below the
`LLQ were assigned a value of 0.049999 ng/mL for
`all dapsone and N-acetyl dapsone concentration cal-
`culations.
`
`The long-term safety study was a 12-month, mul-
`ticentre, open-label study of dapsone gel (figure 1).
`Statistical Methods
`The primary objective was to evaluate the long-term
`Analyses were performed on the all-subjects
`safety of dapsone gel, 5% when used for up to 12
`dataset, defined as any subject to whom the study
`months in subjects with acne vulgaris. Dapsone gel
`drug was dispensed. Descriptive statistics (i.e. the
`was applied twice daily to acne-involved areas on
`the face, back, shoulders and chest, as needed, for 12 mean, median, standard deviations and maximum)
`months. Plasma concentrations of dapsone and N- were used to summarise plasma concentration re-
`acetyl dapsone, as well as safety and efficacy evalu-
`sults.
`
`© 2007 Adis Data Information BV. All rights reserved.
`
`Clin Pharmacokinet 2007; 46 (8)
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`704
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`Table I. Baseline demographic characteristics of participants in three studies
`
`Characteristic
`
`Sex (n)
`Male
`Female
`
`Age (y)
`Mean (range)
`12–15y (n)
`≥16y (n)
`
`Crossover studya
`dapsone gel, 5%
`period 1; n = 18
`
`oral dapsone subset,
`period 2; n = 10
`
`Drug-interaction studyb
`modified pharmacokinetic
`evaluable dataset; n = 17
`
`Long-term safety studyc
`n = 506
`
`9
`9
`
`22 (18–32)
`0
`18
`
`4
`6
`
`22 (18–32)
`0
`10
`
`10
`7
`
`28 (18–44)
`0
`17
`
`231
`275
`
`20 (12–77)
`181
`325
`
`Ethnicity (n)
`403
`15
`9
`17
`Caucasian
`48
`0
`0
`0
`African American
`36
`0
`0
`0
`Hispanic
`19d
`2
`1
`1
`Other
`a Dapsone gel, 5% for 2wk; a subset (n = 10) of the original 18 subjects then received a single dose of oral dapsone 100mg.
`b Oral trimethoprim/sulfamethoxazole for 1wk, followed by dapsone gel, 5% monotherapy for 3wk, followed by both therapies in
`combination for 1wk.
`c Dapsone gel, 5% monotherapy over 12mo.
`d
`Included nine Asian participants.
`
`ure 1). The baseline demographics of the full dataset
`and the subset are summarised in table I.
`
`Pharmacokinetic Profile for Dapsone Gel, 5%
`The plasma concentration of dapsone was mea-
`surable within the first 2 hours following the first
`application of dapsone gel on day 0 and continued to
`increase throughout the day in most subjects (figure
`
`Day 0
`Day 14
`
`35
`
`30
`
`25
`
`20
`
`15
`
`10
`
`Plasma dapsone concentration (ng/mL)
`
`5 0
`
`0
`
`4
`
`8
`
`16
`
`20
`
`24
`
`12
`Time (h)
`Fig. 2. Mean ± SD plasma dapsone concentration-time profiles
`over 24 hours following the first application of dapsone gel (day 0)
`and at steady state following 15 days of therapy (day 14) in the
`crossover study of dapsone gel, 5% followed by oral dapsone (n =
`18).
`
`Results
`
`Crossover Study of Dapsone Gel, 5%
`Followed by Oral Dapsone
`
`Eighteen subjects enrolled in the study received
`at least one dose of dapsone gel and completed 15
`days of dapsone gel therapy (figure 1). The mean
`quantity of dapsone applied per day was 110 ±
`61mg. All but two subjects applied dapsone gel as
`required; these two subjects missed one application
`each. One of the 18 subjects tested positive for
`G6PD deficiency, the degree of which was severe.
`This subject was not eligible for the oral dapsone
`period of the study but was included in the dataset
`for the dapsone gel period of the study. Another
`subject voluntarily withdrew from the study after
`day 15. A subset of ten of the remaining 16 partici-
`pants (defined as the first ten subjects who volun-
`teered for the oral dapsone period of the trial and
`who did not have G6PD deficiency) underwent a
`14-day washout period and then returned to the
`clinic for the oral dapsone period of the trial (fig-
`
`© 2007 Adis Data Information BV. All rights reserved.
`
`Clin Pharmacokinet 2007; 46 (8)
`
`8
`
`Mylan (IPR2019-01095) MYLAN1023, p. 008
`
`

`

`Pharmacokinetics of Dapsone Gel, 5%
`
`705
`
`2). The pharmacokinetic parameters measured for with a harmonic mean t1/2 of 20.6 hours. The mean
`dapsone and N-acetyl dapsone for the 18 subjects
`Cmax was 1375 ng/mL (median 1342 ng/mL) and
`the mean AUC∞ was 52 641 ng • h/mL (median
`who received dapsone gel and for the subset of ten
`43 340 ng • h/mL) [table II, figure 3].
`subjects who also received oral dapsone are sum-
`marised in table II. Upon entering the crossover
`portion of the trial after 15 days of dapsone gel
`therapy, the subset of ten subjects had a mean Cmax
`for dapsone of 19.4 ng/mL (median 13.9 ng/mL),
`a mean AUC24 of 417.5 ng • h/mL (median
`298.2 ng • h/mL) and a median tmax of 9 hours. The
`harmonic mean t1/2 of dapsone after the last dose of
`dapsone gel was estimated at 48 hours (median 53.5
`hours). These same ten subjects had a mean Cmax of
`7.1 ng/mL for N-acetyl dapsone and a mean AUC24
`of 148 ng • h/mL.
`
`Comparison of Oral Dapsone to Topical Dapsone
`Relative exposures to dapsone were determined
`by comparing the AUC24 after repeated administra-
`tion with dapsone gel with the AUC∞ for oral dap-
`sone (an estimate of the steady-state AUC for daily
`oral dapsone 100mg). The steady-state exposure
`after a total of 14 days of topical treatment with
`dapsone gel was 126-fold (median 145-fold) lower
`than the steady-state exposure for oral dapsone. The
`mean peak plasma concentrations were also lower
`after
`topical administration by approximately
`70-fold (median 96-fold) [table II]. Similar results
`were observed for N-acetyl dapsone plasma concen-
`trations [table II]. The mean dapsone plasma con-
`centrations over 24 hours for oral dapsone (single
`
`Pharmacokinetic Profile for Single-Dose Oral
`Dapsone 100mg
`
`Following a single dose of oral dapsone 100mg,
`the median tmax occurred at 3.8 hours and declined
`
`Table II. Crossover study: dapsone and N-acetyl dapsone plasma pharmacokinetic parameters following topical application of dapsone gel,
`5% (day 0 and steady state) and a single dose of oral dapsone 100mga,b
`
`Parameter
`
`Dapsone
`AUC24 (ng • h/mL)
`AUC∞ (ng • h/mL)
`Cmax (ng/mL)
`tmax (h)d
`t1/2 (h)e
`
`Period one
`dapsone gel, 5%
`(day 0); n = 18
`
`dapsone gel, 5%
`(day 14); n = 18
`
`Period two – comparison of oral extension subset
`dapsone gel, 5%
`oral dapsone 100mg
`ratio of oral to
`(day 14); n = 10
`(day 28); n = 10
`topical; n = 10
`
`88.7 ± 51
`NA
`5.4 ± 3.2
`25.2
`NA
`
`415 ± 224.4
`NA
`19.7 ± 10.2
`6
`42
`
`417.5 ± 292.9
`NA
`19.4 ± 13.1
`9
`48
`
`22 783 ± 7734.7
`52 641 ± 36 223.8
`1375 ± 517.3
`3.8
`20.6
`
`NA
`126.1c
`70.9
`0.4
`0.4
`
`N-acetyl dapsone
`AUC24 (ng • h/mL)
`8095 ± 6232.6
`148 ± 162
`167.8 ± 134.5
`40.1 ± 37.6
`NA
`AUC∞ (ng • h/mL)
`18 047 ± 18 128.3
`121.9c
`NA
`NA
`NA
`553 ± 568.7
`7.1 ± 7.3
`8.2 ± 6.3
`2.5 ± 2.2
`77.9
`Cmax (ng/mL)
`tmax (h)d
`0.5
`3.8
`7
`5
`24.9
`t1/2 (h)e
`0.6
`21.1
`38.3
`37.4
`NA
`a Dapsone gel, 5% for 2wk; a subset (n = 10) of the original 18 subjects then received a single dose of oral dapsone 100mg.
`b Values are expressed as the mean ± SD unless specified otherwise.
`c AUC over a dosing interval τ (AUCτ) at steady state with repeated oral administration is expected to be equal to the single dose
`AUC∞. Therefore, the ratio of the oral to topical AUC compares the AUC∞ for oral to the steady-state AUC24 for topical.
`d Median.
`e Harmonic mean.
`AUC = area under the plasma concentration-time curve; AUC∞ = AUC from time zero to infinity; AUC24 = AUC from 0 to 24 hours; Cmax =
`maximum plasma concentration; tmax = time to reach Cmax; t1/2 = elimination half-life.
`
`© 2007 Adis Data Information BV. All rights reserved.
`
`Clin Pharmacokinet 2007; 46 (8)
`
`9
`
`Mylan (IPR2019-01095) MYLAN1023, p. 009
`
`

`

`706
`
`Thiboutot et al.
`
`b
`
`10 000
`
`1000
`
`100
`
`10
`
`12
`
`24
`
`36
`
`48
`
`60
`
`72
`
`0
`
`12
`
`24
`
`36
`
`48
`
`60
`
`72
`
`a
`
`1750
`
`1500
`
`1250
`
`1000
`
`750
`
`500
`
`250
`
`0
`
`0
`
`Plasma dapsone concentration (ng/mL)
`
`Time (h)
`Fig. 3. Mean ± SD plasma dapsone concentration over 72 hours following a single oral dose of dapsone 100mg represented in (a) linear
`form and (b) semi-log form in the crossover study of dapsone gel, 5% followed by oral dapsone (n = 10). The peak plasma concentration
`occurred at approximately 4 hours post-administration.
`
`Plasma dapsone concentration (ng/mL)
`
`dose) and for dapsone gel (steady state) for the ten
`subjects participating in both periods of the study
`are shown in figure 4.
`
`Drug-Interaction Study of Dapsone Gel, 5%
`with Trimethoprim/Sulfamethoxazole
`
`Twenty-four subjects enrolled in the study and
`received at least one dose of trimethoprim/sul-
`famethoxazole. Three subjects discontinued due to
`adverse events attributed
`to
`trimethoprim/sul-
`famethoxazole, and two subjects moved from the
`area and withdrew consent (figure 1). The remaining
`19 subjects completed the study and had pharma-
`cokinetic profiles performed on days 7, 35 and 42.
`Two of the 19 subjects were excluded from the
`pharmacokinetic analysis because of inadequate ex-
`posures to trimethoprim/sulfamethoxazole (zero or
`near-zero levels on day 42), possibly due to vomit-
`ing and/or noncompliance. Neither subject reported
`missing any doses of trimethoprim/sulfamethoxa-
`zole or dapsone gel. As a result of these zero values,
`the pharmacokinetic data of these two subjects were
`not considered adequate. The data from the remain-
`ing 17 subjects, who constituted the modified
`pharmacokinetic evaluable dataset, were used for
`the primary analysis for determining a drug interac-
`tion. The baseline demographics of these 17 subjects
`
`are summarised in table I. The mean quantity of
`dapsone applied per day was 337mg ± 176mg.
`Seven subjects missed a total of 13 applications of
`dapsone gel and 13 doses of trimethoprim/sul-
`famethoxazole over the course of the study.
`
`Pharmacokinetic Profile for Trimethoprim/
`Sulfamethoxazole
`Table III summarises the results for the individu-
`al pharmacokinetic parameters evaluated for the
`modified pharmacokinetic evaluable dataset (n =
`17). The steady state of both trimethoprim and sul-
`famethoxazole was reached by day 5, and the
`
`1
`After 15 days of DG 5%
`2
`After 21 days of DG 5%
`2
`After 7 days of DG 5% + TMP/SMX
`
`80
`
`70
`
`60
`
`50
`
`40
`
`30
`
`20
`
`10
`
`0
`
`0
`
`4
`
`8
`
`1