[ R E V I E W ]
`
`Synergy and Its Clinical Relevance
`in Topical Acne Therapy
`
`LEON H. KIRCIK, MD
`Indiana University School of Medicine, Indianapolis, Indiana; Mount Sinai Medical Center, New York, New York;
`DermResearch, PLLC, Louisville, Kentucky
`
`ABSTRACT
`Biologically active agents generally are thought of either as acting synergistically (they work together) or
`antagonistically (they counteract each other). However, the notion of synergy has a more nuanced meaning in
`pharmacological discussions. Two agents may complement each other, usually by providing a cumulative or additive effect.
`Within pharmacological discourse, “synergy” indicates that the sum of two agents’ combined action is greater than the sum
`of the efficacy of the constituent parts. An example of synergy in dermatological therapy is a novel fixed combination
`formulation of adapalene 0.1% and benzoyl peroxide 2.5%. While the use of both topical benzoyl peroxide and a retinoid
`for the management of mild-to-moderate acne vulgaris has become the standard of care, data show that the two agents in
`the once-daily, fixed combination adapalene/benzoyl peroxide gel formulation confer a synergistic effect, suggesting that
`the formulation can enhance efficacy and improve patient convenience and adherence.
`(J Clin Aesthet Dermatol. 2011;4(11):30–33.)
`
`Multi-agent therapy is common across all medical
`
`specialties and diagnoses, based on the well-
`accepted premise that drugs used in combination
`can provide complementary effects. Within the field of
`dermatology, a majority of patients will be prescribed two or
`more agents to treat their specific condition. Conversely, all
`prescribers recognize that certain drug combinations can
`have detrimental effects. As such, biologically active agents
`are thought of either as acting synergistically or
`antagonistically or, simply, that they either work together or
`they work against each other.1 However, the notion of
`“synergy” has been expanded within the literature and has a
`more nuanced, clearly defined meaning in pharmacological
`discussions. Synergistic combinations would be expected to
`provide improved therapeutic outcomes, better experiences
`for patients, and perhaps even improved adherence, as
`patients may see more rapid and significant benefits of
`treatment.
`
`DEFINING SYNERGY
`Even when two agents complement each other, such as
`by providing distinct mechanisms of action, their combined
`efficacy typically is equivalent to the sum of the efficacy of
`the constituents. Put another way, the two agents provide
`only cumulative efficacy. Certainly, combination therapy
`
`provides benefits over either monotherapy; however, there
`is no apparent increase in efficacy of the constituents by
`virtue of their combined use.
`Rarely, greater than cumulative effect is seen when two or
`more agents are combined, which is true pharmacological
`synergy. Within pharmacological discourse, synergy indicates
`not only that agents are compatible, but that the product of
`their combined action is greater than the sum of the efficacy
`of the constituent parts. In basic terms, a simple summing up
`and comparison of similarly derived variables can be used to
`identify synergy.1 Looking at comparable data, if agent A is
`shown to reduce transepidermal water loss (TEWL) by 12
`percent, agent B reduces it by 15 percent, and the
`combination of agents A+B reduces TEWL by 27 percent,
`then their effect is cumulative. If the combination of A+B
`reduced TEWL by 32 percent, then the combination is said
`to be synergistic.
`While this basic description of synergy is generally true,
`synergy technically is a function of the dose-response curves
`of the individual agents and their combination. There are
`several different approaches to describe synergy. One
`approach can be algebraic. Let us begin with the equation
`for zero interaction, where da and db are the doses of A and
`B, respectively, within the combination, which will be
`termed da,b. Da and Db are the doses of A and B,
`
`DISCLOSURE: Dr. Kircik is a consultant, speaker, investigator, and advisory board member for Galderma.
`ADDRESS CORRESPONDENCE TO: Leon H. Kircik, MD; E-mail: wedoderm@yahoo.com
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`separately, that are isoeffective in combination. Algebraic
`function f(da,b) is the effect of combination. The equation
`for zero interaction line for two agents is: da/Da + db/Db=1.1
`If, instead, the combination is synergistic, then the equation
`will be: da/Da+db/Db<1.
`This demonstrates that, in order to achieve a level of
`efficacy, then the dose of A and/or B in the combination (da
`and/or db) are lower than the dose anticipated based on
`their dose-response curves. Thus A and/or B are more
`effective when used in combination.
`Antagonism results in the formula: da/Da+db/Db>1.
`Here, the required dose of A and/or B (da and/or db) is
`higher than predicted based on dose-response graphs,
`indicating a loss of efficacy when the drugs are combined.1
`Although the equations presented demonstrate the proof
`of synergy based on dose-response data, other endpoint or
`evaluation comparisons can be made. For example, synergy
`could be shown through an analysis of data from a multi-arm
`study that
`involves a combination therapy and
`its
`constituents. Such comparison would be appropriate
`because the data were derived from the same study design
`and under the same investigational scrutiny.2 Unfortunately,
`there is no uniform technique to measure synergy in
`pharmacology. Therefore, different calculation methods will
`end up in different results so that according to one method
`a combination may be synergistic, but by another method, it
`may be antagonistic.1
`An example of synergy in dermatological therapy is seen
`with adapalene 1.0% plus benzoyl peroxide (BPO) 2.5% gel
`formulation (EpiDuo, Galderma, Ft. Worth, Texas), a
`combination acne therapy in which synergy has been
`reported. Analysis of the data for the adapalene 1.0%/BPO
`2.5% combination gel suggests that the combination
`formulation works synergistically to reduce lesion counts
`and improve acne.2
`
`RATIONALE FOR COMBINATION THERAPY
`BPO, one of the first treatments marketed for acne
`vulgaris, remains an important component of the treatment
`regimen for mild-to-moderate acne.3 The agent has received
`renewed interest because its use in combination with oral
`antibiotics is shown to reduce dependence on systemic
`agents and reduce
`the risk of development of
`resistance.4,5 BPO has
`Propionibacterium acnes
`bactericidal activity against P. acnes.3,4 It is also shown to
`confer some degree of comedolytic and anti-inflammatory
`effects.6 One investigation confirmed that the keratolytic
`effects of BPO were similar to those of salicylic acid and
`tretinoin six hours after application to the skin of healthy
`volunteers.7
`In fact, at three hours, BPO actually
`demonstrated more disruption of stratum corneum
`adhesion than did salicylic acid or tretinoin. BPO was also
`found to affect deeper levels of the stratum corneum than
`did salicylic acid, suggesting a role for addressing deeper
`inflammatory lesions. Despite these findings, BPO is
`commonly prescribed by dermatologists8
`in combination
`with other topical therapies to address additional
`multifactorial aspects of the pathogenesis of acne.
`
`Topical retinoids are anticomedolytic agents shown to
`regulate keratinization and provide strong efficacy in the
`management of both inflammatory and noninflammatory
`acne lesions.9 Because they target the microcomedone,
`retinoids are shown to significantly reduce the formation of
`new acne lesions and can significantly interrupt disease
`progression.9 Tretinoin, the first marketed retinoid, has been
`joined by a new generation of retinoids, such as adapalene
`and tazarotene.10 Developed in response to concerns about
`the instability of tretinoin, the naphthoic acid derivative
`adapalene was found in vitro to be photostable and not
`degraded in the presence of BPO.10
`Given its stability, adapalene has been used widely in
`combination with topical antimicrobials, including BPO. The
`agent has been shown to maintain its good tolerability when
`used in combination with other topical agents and to
`produce greater efficacy when used in combination with
`topical BPO, topical clindamycin, or oral antibiotics than any
`of these agents alone.11
`
`EVIDENCE FOR SYNERGY OF ADAPALENE/BPO GEL
`The fixed combination formulation of adapalene 0.1%
`and BPO 2.5% is relatively new to the market. The efficacy,
`safety, and tolerability of the fixed combination formulation
`has been established in multiple controlled trials. One of
`the smaller trials of adapalene/BPO gel involved 517 United
`States subjects randomized 2:2:2:1 to treatment with either
`adapalene/BPO gel, adapalene alone, BPO alone, or vehicle
`once daily for 12 weeks. Evaluation included success rate
`(“clear” or “almost clear” on the Investigator’s Global
`Assessment or IGA) and lesions counts. At the conclusion
`of the trial, the success rate for fixed combination therapy
`was 27.5 percent compared to 15.5 percent for adapelene
`alone, 15.4 percent for BPO alone, and 9.9 percent for
`vehicle.12
`In a North American trial involving 1,429 evaluable
`subjects, adapalene/BPO gel showed a significantly higher
`success rate (P< or = 0.006) and a greater percentage
`reduction in all acne lesion counts (P< or = 0.017) compared
`to adapalene monotherapy, BPO monotherapy, or vehicle
`gel.13 Subjects were randomized in 1:1:1:1 fashion to apply
`either agent once daily for 12 weeks. At conclusion of the
`trial, the success rate for adapalene/BPO gel was 30.1
`percent compared to 19.8 percent with adapalene alone,
`22.2 percent for BPO alone, and 11.3 percent for vehicle. By
`Week 1, adapalene/BPO gel showed a significant early effect
`for reduction of all lesions types compared with adapalene
`alone and vehicle. The reduction
`in
`inflammatory,
`noninflammatory, and total
`lesions was statistically
`significantly greater for adapalene/BPO than for either
`monotherapy or vehicle at study conclusion.
`An international trial involving 1,670 subjects had a
`similar design, with patients randomized 1:1:1:1 to treatment
`with adapalene/BPO, adapalene alone, BPO alone, or
`vehicle.14 Again, adapalene/BPO was rated as more
`successful with a significantly greater reduction in all lesions
`counts compared to any other therapy at the conclusion of
`the trial. A significant early treatment effect, as indicated by
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`TABLE 1. Contribution of synergy to benefit of adapalene/BPO2
`
`Total lesion count
`reductions
`
`Inflammatory lesion
`count reductions
`
`Non-inflammatory lesion
`count reductions
`
`WEEK 1
`
`WEEK 2
`
`WEEK 4
`
`WEEK 8
`
`48.7%
`
`44.4%
`
`20.0%
`
`9.5%
`
`62.5%
`
`33.3%
`
`42.9%
`
`None
`
`40.9%
`
`28.6%
`
`16.7%
`
`13.6%
`
`Success (IGA)
`
`128.6%
`
`13.2%
`
`41.7%
`
`22.2%
`
`that adapalene/BPO
`ratings showed
`IGA
`conferred synergistic success at Weeks 1, 4, 8, and
`12. Contribution of synergy to IGA was 128.6, 13.2,
`41.7, and 22.2 percent, respectively, at Weeks 1, 2, 4,
`and 8.2
`Contribution of synergy to the efficacy of the
`combination of adapalene/BPO is most significant
`early on. For example, contribution of synergy is 48.7
`percent in median percent total lesion reduction at
`Week 1 versus 9.5 percent at Week 8. Similarly,
`contribution of synergy to success rate at Week one
`is 128.6 percent versus 22.2 percent at Week 8.
`There is also no contribution of synergy to any
`parameters at Week 12 (end of study). It is apparent
`that early onset of action for efficacy of the fixed
`combination effect is attributable to synergy.
`
`IGA scores, was identified at Week 2 for combination therapy
`versus any monotherapy and remained throughout the trial
`period. The tolerability profile for the fixed combination gel
`was similar to that for adapalene alone.
`A subgroup analysis of 2,453 international subjects aged
`12 to 17 confirmed previous favorable findings for
`adapalene/BPO.14 The trial design mirrored that of the
`North American and international studies described above.
`By Week 8, success scores (IGA) favored adapalene/BPO
`over either monotherapy or vehicle and the trend
`continued through the 12 weeks of the study. Of note, by
`Week 12, the benefit or combination therapy relative to
`vehicle was 18.7 percent, which was greater than the sum
`of the benefit obtained with the individual components
`(adapalene: 5.7%, BPO: 9.2%). The reduction of
`inflammatory, noninflammatory, and total lesions was
`significantly greater for combination therapy at Week 12
`compared to any other arm.
`Pooled analysis from three double-blind, controlled
`trials of similar design including 3,855 subjects shows that
`adapalene/BPO gel was significantly more efficacious than
`its monotherapies in decreasing total lesion counts as early
`as Week 1 and throughout the study period (p<0.05)
`(Table 1). For up to eight weeks, the combination
`formulation produced a significantly greater synergistic
`reduction in median percent total lesion counts (Table 1).2
`For example, at Week 1, reduction in total lesion counts
`relative to vehicle for adapalene/BPO was 7.4 percent,
`compared to 1.4 percent for adapalene alone and 2.4
`percent for BPO alone. At Week 1, synergy of adapalene/
`BPO contributed 48.7 percent of the efficacy in reducing
`total lesion counts. When the net benefit of combination
`therapy is quantified, it is greater than the sum of the net
`benefits for each component. The contribution of synergy
`to total lesion count reductions was 44.4, 20, and 9.5
`percent, respectively, at Weeks 2, 4, and 8.
`Synergy was also observed for reduction in inflammatory
`lesions through Week 4 and for noninflammatory lesions
`through Week 8. For reduction in inflammatory lesions,
`synergy contributed 62.5 percent to efficacy at Week 1, 33.3
`percent at Week 2, and 42.9 percent at Week 4.2
`
`LIMITATIONS OF AND BASIS FOR SYNERGY
`The data above indicate that the efficacy of fixed
`combination adapalene/BPO gel provides greater efficacy
`than the sum of the efficacy scores for its constituents.2,14
`These studies are limited in that the comparison arms each
`used monotherapy rather
`than applying separate
`formulations of BPO and adapalene in combination.
`However, it does not appear based on these data that
`synergistic effects would be seen if patients applied separate
`formulations of BPO and adapalene in combination. Such
`use could lead to variability in the ratio of drugs applied with
`each application. Furthermore, the two-step regimen may
`contribute to decreased adherence.
`While it is difficult to ascertain definitively why
`adapalene/BPO combination gel confers better efficacy than
`its constituent parts, several possible contributing factors
`have been identified. A synergistic anti-inflammatory effect
`of the combination may be attributed to the anti-P. acnes
`effects of BPO as well as the down-regulation of toll-like
`receptor 2 by adapalene.2,14 In addition to its effects on toll-
`like receptor 2, adapalene is also shown to alter the
`expression of CD1d (cluster of differentiation) and IL-10
`(interleukin), which indicates that it augments the body’s
`innate immunity.2
`Furthermore, it is suggested that the effects of adapalene,
`which alters the follicular microclimate, potentially enhances
`penetration of BPO.2,14 Conversely, since BPO is also
`keratolytic, it may enhance penetration of adapalene.2
`The comedolytic effects of BPO continue to intrigue
`researchers and clinicians. Although BPO has long been
`considered mildly comedolytic, in recent studies of BPO
`monotherapy, 12-week reductions in noninflammatory
`lesions of around 40 percent have been reported. Some
`speculate that the apparently increased comedolytic action
`of BPO may be due to features of novel formulations that
`enhance the bioavailability of BPO and its follicular
`penetration.2
`There is some evidence to suggest that characteristics of
`the vehicle contribute to enhanced efficacy of adapalene
`0.1%/BPO 2.5% gel. Of note, in Tan et al’s analysis, they
`showed that vehicle treatment provided a median 33-
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`TABLE 2. Determining synergy independent of vehicle2
`
`Benefit of treatment = Efficacy of treatment – Efficacy of vehicle
`
`Synergy = Benefit of combination A/B – (Benefit of A + Benefit of B) > 0
`
`Contribution of synergy (%) = (Synergy/Benefit of combination A/B) x 100
`
`percent reduction in total lesions and a median 38-
`percent reduction in inflammatory lesions at 12 weeks.
`Therefore, their data analysis on synergy controlled for
`vehicle effect (Table 2).2 As such, synergy is adjusted as
`the net benefit of the combination as well as its
`components after deducting the vehicle effect from each
`treatment arm.
`The vehicle, which is shown not to be sensitive to
`variations in pH, contains a proprietary gelling agent
`(Simulgel 600 PHA) that does not interfere with the
`pharmacokinetic properties of adapalene. This copolymer
`facilitates a homogenous dispersion of adapalene and BPO in
`the water-based gel. The vehicle also contains humectants,
`such as glycerol and propylene glycol. Additional stabilizing
`excipients include disodium edetate, docusate sodium, and
`poloxamer.
`It is suspected but not proven that the formulation’s
`stability, that is its nonsusceptibility to fluctuations in pH,
`may further protect the active constituents from degradation
`and preserve their efficacy even though adapalene is the only
`retinoid shown to be stable when combined with BPO.
`
`3.
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`9.
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`11.
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`12.
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`13.
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`14.
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`15.
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`16.
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`2011;22(4):197–205. Epub 2010 Jul 28.
`Thiboutot D, Gollnick H, Bettoli V, et al; Global Alliance to
`Improve Outcomes in Acne. New insights into the management
`of acne: an update from the Global Alliance to Improve Outcomes
`in Acne group. J Am Acad Dermatol. 2009;60(5 Suppl):S1–S50.
`Tanghetti E. The evolution of benzoyl peroxide therapy. Cutis.
`2008;82(5 Suppl):5–11.
`Del Rosso JQ, Kim G. Optimizing use of oral antibiotics in acne
`vulgaris. Dermatol Clin. 2009;27(1):33–42.
`Dutil M. Benzoyl peroxide: enhancing antibiotic efficacy in acne
`management. Skin Therapy Lett. 2010;15(10):5–7.
`Waller JM, Dreher F, Behnam S, et al. “Keratolytic” properties of
`benzoyl peroxide and retinoic acid resemble salicylic acid in man.
`Skin Pharmacol Physiol. 2006;19(5):283–289.
`Kinney MA, Yentzer BA, Fleischer AB Jr, Feldman SR. Trends in
`the treatment of acne vulgaris: are measures being taken to avoid
`antimicrobial resistance? J Drugs Dermatol. 2010;9(5):519–524.
`Shalita A. The integral role of topical and oral retinoids in the
`early treatment of acne. J Eur Acad Dermatol Venereol.
`2001;15(Suppl 3):43–49.
`Czernielewski J, Michel S, Bouclier M, Baker M, Hensby JC.
`Adapalene biochemistry and the evolution of a new topical
`retinoid for treatment of acne. J Eur Acad Dermatol Venereol.
`2001;15(Suppl 3):5–12.
`Thiboutot DM, Gollnick HP. Treatment considerations for
`inflammatory acne: clinical evidence for adapalene 0.1% in
`combination therapies. J Drugs Dermatol. 2006;5(8):785–794.
`Thiboutot DM, Weiss J, Bucko A, et al; Adapalene-BPO Study
`Group. Adapalene-benzoyl peroxide, a fixed-dose combination
`for the treatment of acne vulgaris: results of a multicenter,
`randomized double-blind, controlled study. J Am Acad
`Dermatol. 2007;57(5):791–799.
`Gold LS, Tan J, Cruz-Santana A, et al; Adapalene-BPO Study
`Group. A North American study of adapalene-benzoyl peroxide
`combination gel in the treatment of acne. Cutis. 2009;84(2):
`110–116.
`Gollnick HP, Draelos Z, Glenn MJ, et al; Adapalene-BPO Study
`Group. Adapalene-benzoyl peroxide, a unique fixed-dose
`combination topical gel for the treatment of acne vulgaris: a
`transatlantic, randomized, double-blind, controlled study in 1,670
`patients. Br J Dermatol. 2009;161(5):1180–1189.
`Balkrishnan R, Bhosle MJ, Camacho F, Fleischer AB, Feldman
`SR. Prescribing patterns for topical retinoids: analyses of 15 years
`of data from the national ambulatory medical care survey. J
`Dermatolog Treat. 2010;21(3):193–200.
`Gold LS, Cruz A, Eichenfield L, et al. Effective and safe
`combination therapy for severe acne vulgaris: a randomized,
`vehicle-controlled, double-blind study of adapalene 0.1%-benzoyl
`peroxide 2.5% fixed-dose combination gel with doxycycline
`hyclate 100mg. Cutis. 2010;85(2):94–104.
`
`SUMMARY
`Many drugs have complementary actions, but very few
`work synergistically.1 True pharmacological synergy exists
`when the benefits of combination therapy exceed the sum of
`the anticipated benefits of the constituent parts. In
`dermatology, the fixed combination gel formulation of
`adapalene 0.1% and BPO 2.5% is a combination acne
`therapy to have synergy.
`Given current guidelines3 and prescribing trends,15 the
`use of topical BPO—with or without clindamycin—in
`combination with a topical retinoid represents the standard
`of care for patients with mild-to-moderate acne vulgaris.
`Topical combination regimens are also appropriate and
`widely used in conjunction with oral acne therapy, which
`should always be administered with adjunctive topical BPO
`to prevent bacterial resistance. Studies confirm that
`adapalene/BPO gel provides therapeutic benefits when used
`with oral antibiotics.16
`The optimized formulation of adapalene 0.1% and BPO
`2.5% represents a worthwhile option in the topical
`management of acne, providing synergistic benefits early on
`for the reduction of inflammatory, noninflammatory, and
`total acne lesions. By combining two agents into one once-
`daily formulation, the novel fixed combination gel reduces
`the number of product applications. The simplicity and
`convenience of therapy is expected to improve patient
`adherence. The rapid onset of efficacy made possible by the
`synergistic effects of the combination gel formulation may
`further promote adherence.
`
`REFERENCES
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`Berenbaum MC. What is synergy? Pharmacol Rev. 1989;41(2):
`93–41.
`Tan J, Gollnick HP, Loesche C, Ma YM, Gold LS. Synergistic
`efficacy of adapalene 0.1%-benzoyl peroxide 2.5% in the
`treatment of 3,855 acne vulgaris patients. J Dermatolog Treat.
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