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DRUG THERAPY TOPICS

Clinical Significance of Brand Versus Generic Formulations: Focus on Oral

James Q. Del Rosso, DO

Minocycline is an oral widely pre- lipophilic/hydrophilic partition coefficient of minocy- scribed throughout the world, primarily for the cline appears to correlate with better tissue distribu- treatment of vulgaris; other uses include tion compared with and .3 the treatment of and . Minocycline is well established as an effective In the United States, Propionibacterium acnes oral agent in the management of acne vulgaris; resistance is lowest with minocycline compared minocycline also exhibits the lowest prevalence of with other and with . Propionibacterium acnes resistance compared with The availability of generic formulations of other oral commonly used to treat acne minocycline has created confusion regarding the vulgaris, including tetracycline, doxycycline, and clinical significance of brand versus generic erythromycin.4 In a 4-week comparative trial of minocycline products. This article reviews avail- brand formulations, minocycline (Dynacin®) 100 mg able data on minocycline use for acne vulgaris twice daily produced a log decrease in P acnes almost and discusses a patented brand of minocycline 2-fold greater than tetracycline hydrochloride versus generic formulations, including evalua- 500 mg twice daily and doxycycline monohydrate tions of pharmacologic activity and safety. 100 mg twice daily.5 In a 6-week trial of minocycline Cutis. 2006;77:153-156. (Dynacin), tetracycline, and doxycycline comparing log reductions of P acnes, minocycline exhibited a more rapid onset of effect, the greatest log reduction in P acnes, and the greatest residual reduction in What data support the use of minocycline in the P acnes at 3 weeks after discontinuation of treat- treatment of acne vulgaris? ment.3 In an 8-week, open-label, multicenter trial Minocycline is a semisynthetic, long-acting, oral (n=385), combination therapy using minocycline tetracycline derivative that has been used widely (Dynacin) 100 to 200 mg daily and a brand formula- in dermatology since 1967, predominantly for the tion of benzoyl 6% gel (Triaz®) demon- treatment of acne vulgaris.1 The highly lipophilic strated a rapid onset of clinical effect in patients with property of minocycline is well suited for penetration moderate to severe acne vulgaris that usually was into -rich tissues such as the pilosebaceous noted within the first 2 weeks of treatment; contin- unit.2,3 From a pharmacokinetic perspective, more ued improvement was observed in most patients over than 90% of minocycline is absorbed from the gas- the 8-week study course.6 In this trial, 87% of inves- trointestinal tract; from a physiochemical perspective, tigators rated global response to treatment as marked minocycline is more lipid soluble than tetracycline (57%) or moderate (30%) improvement, and 88% of and doxycycline.3 Additionally, the more favorable patients rated their response as excellent (43%) or good (45%).

Accepted for publication January 27, 2006. From the Department of Dermatology, University of Nevada What are the reported biologic effects of School of , Las Vegas. minocycline that potentially may correlate with Dr. Del Rosso is an advisory board member, consultant, therapeutic activity? and speaker for Doak Dermatologics, a subsidiary of Bradley Pharmaceuticals, Inc; Medicis Pharmaceutical Corporation; In addition to antibiotic activity, a variety of in vitro and Stiefel Laboratories, Inc. and in vivo models have demonstrated multiple Reprints not available from the author. anti-inflammatory and anticollagenolytic effects of

VOLUME 77, MARCH 2006 153 Drug Therapy Topics

Table 1. Oral Minocycline Pharmacologic and Pharmacokinetic Studies*9

Study Minocycline Formulations† Results USP in vitro Brand vs original pelletized Faster drug release with brand vs dissolution rate study10 (100 mg/d) pelletized formulation after 15, 22.5, 30, and 60 min (P≤.05) In vivo Brand vs original brand Higher serum levels seen with brand vs study11 capsule (100 mg/d) capsule formulation over 8 h and after 16, 24, and 36 h (P≤.05) In vivo P acnes log Brand vs original pelletized Approximately 2-fold greater P acnes reduction study12 reduction with brand vs pelletized formulation at week 3 Follicular penetration Brand Result of biopsy using UV light technique study13 confirms presence of minocycline in follicle at day 7

*USP indicates United States Pharmacopeia; P acnes, Propionibacterium acnes. †The brand minocycline was Dynacin®; the original pelletized minocycline and original brand capsules were Minocin®. tetracycline derivatives, including minocycline.5 How do bioavailability and pharmacokinetic These effects include inhibition of proinflammatory profiles of minocycline formulations potentially cytokines (such as interleukin –like cytokine), inhi- correlate with clinical effects? bition of lipase, reduced fatty acids in sebum, suppres- The extent of minocycline bioavailability, which is sion of chemotaxis, decreased granuloma formation, correlated directly with dissolution and active ingre- inhibition of kinase C , suppression dient release from the drug’s oral formulation (tablet, of enzymes (collagenase and capsule), is a factor that may influence clinical effi- gelatinase), free scavenger activity, and sup- cacy because greater drug availability is more likely pression of mitogen-stimulated proliferative lympho- to produce higher follicular drug concentration.9 The cytic activity.1,5,7,8 dissolution rate of minocycline from its oral solid formulation influences how quickly the rise in serum level occurs. A more rapid spike in the serum level How do manufacturing considerations, of minocycline may influence the potential for bioavailability, and pharmacokinetic profiles of vestibular effects (eg, vertigo, dizziness).9 minocycline formulations potentially correlate A summary of pharmacologic and pharmacoki- with clinical activities? netic studies of minocycline, including comparative Because both brand and generic formulations of analyses, are depicted in Table 1.9-13 One minocy- minocycline are available, the question of whether cline brand (Dynacin) has a defined quality assur- clinically meaningful differences are present between ance program that specifies batch-to-batch products has been considered. With regard to phar- consistency using specifications for minocycline maceutical product design and manufacturing, the manufacturing that are more stringent that those use of comparable raw materials does not ensure indicated by the USP.9 The program mandates equivalence of final products, especially from batch to that each minocycline batch meet a 95% potency batch. Specifics related to formulation design and the specification and a dissolution profile of at least manufacturing process directly can affect the potency, 90% release of drug within 45 minutes.9 In addition, dissolution characteristics, and bioavailability of the the brand formulation produces a more favorable formulation.9 Minimum guidelines related to the initial progressive release of minocycline over the manufacturing of minocycline have been established first 15 minutes compared with the rapid release by the US Pharmacopeia (USP); the requirements and quick spiking of minocycline serum level include 90% potency and at least 75% release of observed with some generic formulations.9,10 The minocycline after 45 minutes.9 Figure illustrates the results of USP dissolution

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120

100

80 100 mg capsules (generic) 60 100 mg capsules (generic) 40 100 mg capsules (generic) 100 mg capsules (generic) 20 100 mg tablets (brand) Minocycline Released, % 0 0 2.5 5 7.5 1015 22.5 30 60 Time, min

US Pharmacopeia dissolution studies of minocycline 100 mg using the brand tablets (Dynacin®) vs generic capsule formulations. The area with the green arrow shows (1) a progressive steady rise in minocycline serum level with avoidance of the rapid spike seen with the brand formulation and (2) a correlation with a decrease in vestibular side effects observed with the brand formulation. studies comparing a brand formulation of minocycline No significant differences were noted between (Dynacin) 100-mg tablet with 4 generic formulations the brand and generic minocycline formulations of minocycline 100-mg capsule. The rapid rise in serum for any reported adverse events or symptoms other levels observed within 10 and 15 minutes with some than for vestibular effects. A statistically significant of the generic formulations appears to correlate with (P=.0003) difference was noted with vestibular 9,14 an increase in vestibular effects, as discussed below. symptoms reported on day 5 with the brand for- mulation and on day 20 with the generic formula- tion. The ratio of individual episodes between the What clinical differences have been observed brand and generic formulations was 1:5.4. Five and in studies comparing brand and generic 27 vestibular reaction episodes were noted with the minocycline formulations? brand and generic formulations, respectively. A blinded cross-over study of female patients (n=32) The greater frequency of vestibular effects with aged 21 to 55 years was performed to compare the the minocycline generic formulation compared with incidence of general, vestibular, and gastrointestinal the brand formulation appears to be explained by effects with brand (Dynacin) versus generic formula- the differences in dissolution rate, drug release, and tions of minocycline.9,14 Minocycline was adminis- rate of rise in serum level.9 Based on USP dissolution tered on an mg/kg dose basis at the same time each study parameters, the brand formulation exhibited day over 4 days, with a 14-day intervening washout a progressive dissolution rate of minocycline, with period. The weight-based dosing schedule was: 50 to 90% release within 45 minutes. As a result, initial 69 kg, 100 mg daily (n=20); 70 to 89 kg, 150 mg daily rapid spiking of serum level is obviated while still (n=7); and 90 kg or more, 200 mg daily (n=5). Study achieving complete dissolution and optimal bio- subjects were educated regarding maintenance of a availability. The generic formulation exhibited a side effect diary, specifically noting the severity (mild, rapid release of minocycline, with 100% release in moderate, severe) and duration of reactions. The less than 15 minutes. This probably accounts for the adverse reactions evaluated were general (, significantly higher (P=.0003) reported incidence of malaise), vestibular (vertigo, dizziness, blurred vestibular effects associated with use of the generic vision), and gastrointestinal (nausea, , diar- formulation (Table 2).9 rhea, cramping, flatulence). The study rating system recorded the number of days a subject experienced Conclusion specific adverse events (ie, general vs vestibular vs Minocycline is a semisynthetic oral tetracycline gastrointestinal effects), as well as the number of agent. The high lipophilic properties of minocycline individual episodes for each symptom area. likely correlates with marked follicular penetration

VOLUME 77, MARCH 2006 155 Drug Therapy Topics

Table 2. Oral Minocycline Pharmacodynamic Comparison*9

Study Minocycline Formulations† Results USP in vitro Brand vs generic (100 mg/d) Quick progressive drug release with brand dissolution rate study10 formulation (90% drug release within 45 min); rapid serum level spike with generic formulation (100% drug release within 15 min) Side effect Brand vs generic Ratio of individual episodes of vestibular comparative study15 (100–200 mg/d) effects were 1:5.4 with brand vs generic formulations, respectively; vestibular symptoms reported on day 5 with brand formulation and on day 20 with generic formulation (P=.0003)

*USP indicates US Pharmacopeia. † The brand minocycline was Dynacin®; the generic minocyclines were Barr and Warner-Chilcott formulations.

confirmed by biopsies using UV light techniques 4. DeBenedette V, Cunliffe WJ. Clinical microbial resistance that demonstrate the drug’s presence within follicles to antibiotics now clinically significant in acne. Cosmet after oral ingestion of a brand formulation. Mino- Dermatol. June 1996;6:68-69. cycline is associated with the lowest prevalence of 5. Kligman AM. Comparison of a topical resistant P acnes strains compared with other oral gel, oral minocycline, oral doxycycline and a combination antibiotics used to treat acne vulgaris, including for suppression of P acnes in acne patients. J Dermatol Treat. tetracycline, and is reported to produce the highest 1998;9:187-191. log reduction of P acnes organisms. As with pharma- 6. Gans EH. A multi-centered, open-label evaluation of oral cologic products in general, differences in manufac- Dynacin plus topical Triaz 6% gel for moderate to severe turing standards and specifications may produce a acne. Cosmet Dermatol. August 2000;13:29-32. marked effect on the pharmacokinetic, pharmacody- 7. Golub LM, Ramamurthy EC, McNamara L, et al. Tetracy- namic, and clinical properties of individual minocy- clines inhibit tissue collagenase activity. J Periodont Res. cline formulations. Comparisons of a brand versus 1985;20:12-21. generic formulation of minocycline and original 8. Thung YH, Ferrante A. Inhibition of mitogen-induced comparator pelletized and powder capsule formula- human leukocyte proliferative responses by tetracycline tions demonstrate differences in dissolution rates, analogues. Clin Exp Dermatol. 1987;35:443-448. drug release, serum level profiles, and side effect 9. Del Rosso JQ. Brand versus generic formulations of oral profiles. Dissolution rate and drug release of minocy- minocycline: an update on clinical significance. Poster pre- cline appear to correlate with the reported incidence sented at: American Academy of Dermatology; July 20-24, of vestibular effects. 2005; Chicago, Ill. 10. Data on file. Scottsdale, Ariz: Medicis Pharmaceutical Corporation; 2005. 11. Data on file. Comparative in vivo bioavailability evaluation REFERENCES of minocycline capsules (Phoenix International Studies). 1. Hubbell CG, Hobbs ER, Rist T, et al. Efficacy of minocy- Scottsdale, Ariz: Medicis Pharmaceutical Corporation; cline compared with tetracycline in treatment of acne 1990-1992. vulgaris. Arch Dermatol. 1982;118:989-992. 12. Data on file. Leyden JJ. Comparative in vivo 2. Barringer WC, Schultz W, Sieger GM, et al. Minocycline activity of two minocycline products. Philadelphia, Pa: hydrochloride and its relationship to the pharmaceutical KGL Laboratories; 1997. properties of other . Am J Pharm. 13. Data on file. Follicular absorption of minocycline into the 1974;146:179-191. pilosebaceous follicle (Springhouse Research Study). 3. Leyden JJ, Kaidbey K, Gans EH. The antimicrobial effects Scottsdale, Ariz: Medicis Pharmaceutical Corporation; 1995. in vivo of minocycline, doxycycline and tetracycline in 14. Donachie RJ, Rizer R, Colucci S, et al. Clinical acne humans. J Dermatol Treat. 1996;7:223-225. reports. Stephens Research. 1997;2:1-7.

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