Short Communication

Vasoconstrictor Assay Method for the Bioequivalence Assessment of Topical Corticosteroid Applications: A Complex and Variable Approach

Mastan S1*, Shabana S2
1Department of Pharmacology, Siddhartha Institute of Pharmaceutical Sciences, India
2Department of Pharmacology, Venkatreddy Nagar, Ramalayam Road, India


*Corresponding author: Mastan Shaik, Department of Pharmacology, Siddhartha Institute of Pharmaceutical Sciences, India


Published: 15 Sep, 2017
Cite this article as: Mastan S, Shabana S. Vasoconstrictor Assay Method for the Bioequivalence Assessment of Topical Corticosteroid Applications: A Complex and Variable Approach. Ann Pharmacol Pharm. 2017; 2(17): 1089.

Short Communication

Skin blanching due to topical corticosteroids was initially observed by [1,2] introduced the assessment of bioequivalence (BE) of topical corticosteroids using Vasoconstrictor Assay (VCA)/ Skin Blanching Studies. Eventually, based on these findings, US-FDA issued interim guidance in 1992 and final guidance in 1995 on “Topical Dermatological Glucocorticoids: In vivo Bioequivalence” [3]. From 1995, these guidelines were adapted and recommended by all major regulatory authorities for the BE assessment of topical corticosteroids. In principle, this method relies on the unique ability of topical corticosteroids to produce a blanching response as a result of vasoconstriction of the skin microvasculature. The basis of this approach is the measurement of the pharmacodynamic effect of the drug being assessed as a function of time. The main steps involved in this study includes a) method stabilization and validation, b) pilot study with only reference product, and c) pivotal BE study with both test and reference products as represented in Figure 1. The workflow specified by the regulatory authorities for pilot and pivotal are represented in Figure 2 and Figure 3, respectively. The major difference between pilot and pivotal BE studies are presented in Table 1.
Even though these VCA methods are well adapted by various regulatory authorities, from a practical perspective there are several major limitations/concerns which make this method as a complex and variable. The major limitations/concerns includes – (i) suitable best with fair-skinned subjects who show good blanching response, (ii) works best with medium to high potency formulations and simpler formulations such as gels and ointments, (iii) mostly fail to control intra-subject variability via consistent Chromameter technique, (iv) even with good Chromameter technique , some products’ data do not fit well to a simple Emax model or they have inherent high intra-subject variability that requires sample sizes > 60 (upper limit in US-FDA Guidance), (v) problematic for lower potency products and newer formulations such as sprays, tapes, foam, (vi) expected variability in skin blanching due to several physiological factors, (vii) many fluctuations due to impact of an environmental factors such as hot and humidity. Due to these major limitations/concerns, there is no much BE applications in this segment from Asia based pharmaceutical industries, in fact, which playing major role in the generic production in other therapeutic areas. Hence, there is a remarkable requirement for an alternative approaches in this area which would certainly enhance the overall generic production in an efficient manner in Pharmaceutical Research which intern facilitates pharmacoeconomic benefit to the patients.


Figure 1

Another alt text

Figure 1
Main steps involved in the assessment of bioequivalence of topical corticosteroids using Vasoconstrictor Assay.

Figure 2

Another alt text

Figure 2
Main steps involved in the pilot study of Vasoconstrictor Assay VCA=Vasoconstriction Assay, USFDA= United States Food Drugs Administration; AUEC = Area Under the Effective Curve, PD = Pharmacodynamic; ED50 = Dose Duration at which Effect is Half-maximal.

Figure 3

Another alt text

Figure 3
Main steps involved in the pivotal study of Vasoconstrictor Assay D1 = The shorter dose duration Reference Listed Drug calibrator, D2 = The longer dose duration Reference Listed Drug calibrator, US-FDA=United States Food Drugs Administration; AUEC = Area Under the Effective Curve, CI = Confidence Interval, UNT = Untreated.

Table 1

Another alt text

Table 1
Major differences between pilot and pivotal studies in VCA.

D1 = The shorter dose duration Reference Listed Drug calibrator, D2 = The longer dose duration Reference Listed Drug calibrator, AUEC = Area Under the Effective Curve, CI = Confidence Interval


References

  1. Gupta RK, Patel AK, Shah N, Chaudhary AK, Jha UK, Yadav UC. Oxidative stress and antioxidants in disease and cancer: Asian Pac J Cancer Prev. 2014;15(11):4405-9.
  2. Pham-Huy LA, He H, Pham-Huy C. Free radicals, antioxidants in disease and health. Int J Biomed Sci. 2008;4(2):89-96.
  3. Sciarra J. Infertility an international health problem. Int J Gynaecol Obstet. 1994;46(2):155-63.
  4. Paul C Adamson, Karl Krupp, Alexandra H, Jeffrey D, Klausner, Arthur L. Purnima Population Council. New Delhi: Population Council; 2004. Infertility. Looking Back, Looking Forward: A Sex Heal Ind. 2011;134(4):440-446.
  5. Aitken RJ, Roman SD. Antioxidant systems and oxidative stress in the testes. Oxid Med Cell Longev. 2008;1(1):15-24.
  6. Meistrich ML. Male Gonadal Toxicity. Pediatric blood & cancer. 2009;53(2):261-266.
  7. Esin Yuluğ, Sibel Türedi, Ahmet Alver, Süleyman Türedi, Cemil Kahraman. Effects of Resveratrol on Methotrexate-Induced Testicular Damage in Rats. The Scientific World Journal, 2013.
  8. Lafuente R, González-Comadrán M, Solà I, López G, Brassesco M, Carreras R, et al. Coenzyme Q10 and male infertility: a meta-analysis. J Assist Reprod Genet. 2013;30(9):1147-56.
  9. Heyland DK, Dhaliwal R, Day AG, Muscedere J, Drover J, Suchner U, et al. Reducing Deaths due to Oxidative Stress (The REDOXS Study): rationale and study design for a randomized trial of glutamine and antioxidant supplementation in critically-ill patients. Proc Nutr Soc.2000;65:250-263.
  10. O'Bryan MK, Schlatt S, Gerdprasert O, Phillips DJ, de Kretser DM, Hedger MP. Inducible Nitric Oxide Synthase in the Rat Testis: Evidence for Potential Roles in Both Normal Function and Inflammation-Mediated Infertility. Biol Reprod. 2000;63(5):1285-93.
  11. Aydogan S, Yerer MB, Goktas A. Melatonin and nitric oxide. J Endocrinol Invest. 2006;29(3):281-7.
  12. Pons-Rejraji H, Brugnon F, Sion B. Evaluation of atorvastatin efficacy and toxicity on spermatozoa, accessory glands and gonadal hormones of healthy men: a pilot prospective clinical trial. Reproductive Biology and Endocrinology: RB&E. 2014;12:65.
  13. Shishehbor MH, Brennan ML, Aviles RJ, Fu X, Penn MS, Sprecher DL, et al. Statins promote potent systemic antioxidant effects through specific inflammatory pathways. Circulation. 2003;108(4):426-31.
  14. Sattar N, Preiss D, Murray HM, Welsh P, Buckley BM, de Craen AJ, et al. Statins and risk of incident diabetes: a collaborative meta-analysis of randomised statin trials. Lancet. 2010;375(9716):735-742.
  15. Nakata M, Uto N, Maruyama I, Yada T. Nitric oxide induces apoptosis via Ca2+-dependent processes in the pancreatic beta-cell line MIN6. Cell Struct Funct.1999;24:451-5.
  16. Singh RB, Niaz MA, Rastogi SS. Effect of hydrosoluble coenzyme Q10 on blood pressures and insulin resistance in hypertensive patients with coronary artery disease. J Hum Hypertens. 1999;13:203-8.
  17. Groener JE, van Gent T, van Tol A. Effect of lipid transfer protein on plasma lipids, apolipoproteins and metabolism of high-density lipoprotein cholesteryl ester in the rat. Biochim Biophys Acta.1989;1002:93-100.
  18. Rosenson RS. Current overview of statin-induced myopathy. Am J Med. 2004;116:408-16.
  19. Graham DJ, Staffa JA, Shatin D, Andrade SE, Schech SD, La Grenade L, et al. Incidence of hospitalized rhabdomyolysis in patients treated with lipid-lowering drugs. JAMA. 2004;292:2585-90.
  20. Kalra S. The role of Coenzyme Q10 in statin-associated myopathy. J Am Coll Cardiol. 2009;1:2-8.
  21. Gleeson M. Dosing and efficacy of glutamine supplementation in human exercise and sport training. The J nutr. 2008;138(10):2045S-9S.
  22. Malfertheiner P, Chan FK, McColl KE. Peptic ulcer disease. The Lancet. 2009;374(9699):1449-61.
  23. El-Abhar HS. Coenzyme Q10: A novel gastroprotective effect via modulation of vascular permeability, prostaglandin E 2, nitric oxide and redox status in indomethacin-induced gastric ulcer model. Eur J Pharmacol. 2010;649(1):314-9.
  24. Hsu DZ, Chen KT, Li YH, Chuang YC, Liu MY. Sesamol delays mortality and attenuates hepatic injury after cecal ligation and puncture in rats: role of oxidative stress. Shock. 2006;25(5):528-32.
  25. Silva RO, Lucetti LT, Wong DV, Aragão KS, Junior EM, Soares PM, et al. Alendronate induces gastric damage by reducing nitric oxide synthase expression and NO/cGMP/KATP signaling pathway. Nitric oxide. 2014;40:22-30.