Year: 2011
Type: letter
Abstract: To the Editor: We respectfully disagree with some points voiced in Dr. Klintmalm’s editorial regarding generic immunosuppression (1Klintmalm GB Immunosuppression,generic drugs and the FDA.Am J Transplant. 2011; 11: 1765-1766Abstract Full Text Full Text PDF PubMed Scopus (42) Google Scholar). (1)Regardless if a generic or brand immunosuppressant is used, significant variation in calcineurin inhibitors’ trough concentrations must be considered in the context of patient-specific therapeutic ranges. For example, a 25% fluctuation in tacrolimus trough concentrations in a patient whose target is 4–6 ng/mL may not be considered as clinically significant as the same percent change in a patient whose target is 8–12 ng/mL. Moreover, intrasubject variability in exposure to calcineurin inhibitors is commonplace in patients maintained on innovator products. These pharmacokinetic variations are secondary to: impact of food on drug exposure, fluctuations in renal and/or hepatic function, alterations in administration times and timing of trough levels. Although the inception of generic immunosuppressants introduces one additional variable, the clinical significance of this variable is not well defined.(2)Misinformation continues to be disseminated regarding the interpretation of confidence interval (CI) bioequivalence testing (1Klintmalm GB Immunosuppression,generic drugs and the FDA.Am J Transplant. 2011; 11: 1765-1766Abstract Full Text Full Text PDF PubMed Scopus (42) Google Scholar,2Alloway R Isaacs R Lake K et al.Report of the AST conference on immunosuppressive drugs and the use of generic immunosuppressants.Am J Transplant. 2003; 3: 1211-1215Crossref PubMed Scopus (97) Google Scholar). In order for a generic medication to be considered bioequivalent, the 90% CI of the geometric, not arithmetic, mean of the ratio of the generic compared to the innovator product of the maximum concentration and area under the curve (AUC) values must lie between 80% and its reciprocal, 125% (3Center for Drug Evaluation and Research guidance for industry: Statistical approaches for establishing bioequivalence. 2001. Available at: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm070244.pdf. Accessed September 5, 2011.Google Scholar). In contrast to an arithmetic mean, which represents the midpoint of the range of values, a geometric mean mutes the contributing effect of extreme low and high values, respectively. If the true (arithmetic) mean exposure of a generic approaches ±20%, then one or both of the 90% CI is likely to fall outside the bioequivalence limits (4Ensor CR Trofe-Clark J Gabardi S Mc-Devitt-Potter LM Shullo MA Generic maintenance immunosuppression in solid organ transplant recipients.Pharmacotherapy. 2011; 31: 1111-1129Crossref PubMed Scopus (44) Google Scholar). The actual mean differences of four Food and Drug Administration (FDA)-approved tacrolimus generics in healthy volunteers is 4% (range 0–11%) for AUC fasting and 4.5% (2–6%) for AUC fed.(3)The degree of cost savings associated with generic immunosuppressants, and the benefactor of that savings, is multifactorial. For example, a patient’s copay will vary depending on the type of billable insurance they possess (private vs. federally funded Medicare Part B or D vs. state funded Medicaid) and may change throughout the year (5McDevitt-Potter LM Sadaka B Tichy EM Rogers CC Gabardi S A multicenter experience with generic tacrolimus conversion.Transplantation. 2011; 92: 653-657Crossref PubMed Scopus (58) Google Scholar). We agree that savings associated with the use of generic immunosuppressants should be countered by the associated cost of increased laboratory monitoring. We acknowledge that further research is necessary to determine the pharmacoeconomic impact of generic immunosuppressants. Future studies performed in transplant recipients will help answer these questions, as well as provide pharmacokinetic data comparing innovator to generic immunosuppressive products. Currently the FDA is considering potential refinements in bioequivalence criteria for narrow therapeutic index drugs and we expect that selective immunosuppressant agents will be included in this new classification. Transplant clinicians can advocate for policy changes regarding a notification process when a patient is switched from brand-to-generic or generic-to-generic immunosuppressants, but one needs to contemplate what will be done with this information in clinical practice. With consideration of the above parameters, generic immunosuppressants can represent an effective and safe therapeutic alternative for transplant patients that are likely to result in long-term cost savings and potentially improve long-term adherence. This manuscript was not prepared or funded in any part by a commercial organization. The authors of this manuscript have conflicts of interest to disclose as described by the American Journal of Transplantation. Jennifer Trofe-Clark and Steve Gabardi: no conflict of interest to disclose; Lisa McDevitt-Potter-receives research support in the form of salary from Astellas and Novartis; and Rita R. Alloway: clinical research trials funded by Astellas and Novartis to the institution with Rita R. Alloway as Principal Investigator.
Language: English
Subfield: Economics and Econometrics
Domain: Social Sciences
Open Access status: hybrid
Estimated APC paid: $4,300
OpenAlex ID: W1598344561