Equivalence and interchangeability of narrow therapeutic index drugs in organ transplantation

Abstract

The calcineurin inhibitors (CNIs), ciclosporin and tacrolimus, are the mainstay of immunosuppression in solid organ transplantation. Generic formulations of these drugs are now available. With increasing pressure on healthcare budgets and the consequent need to match health expectations to available resources, substitution with a generic product appears an attractive option to reduce costs. Approval of generic products differs from innovator drugs, and narrow therapeutic index drugs (NTIs; including CNIs) bring their own particular considerations. With NTIs, small variations in drug exposure could result in reduced immunosuppression or drug toxicity with potentially adverse effects on patient outcomes. NTIs are subject to stricter regulatory approval versus many other generic drugs. However, different generic formulations may still not necessarily be therapeutically equivalent in individuals, raising the possibility of significant differences in exposure between products. Although regional recommendations vary, many guidelines emphasise the need for NTI drug substitution to be initiated by the transplant physician, thus ensuring careful therapeutic monitoring and reduced negative patient impact. The need for therapeutic monitoring during generic substitution has important implications for the overall costs of generic treatment as these costs have to be factored in to the potential savings made from using generic formulations. The reduced acquisition costs of generic products may not necessarily translate into lower overall healthcare costs. This article examines the issue of equivalence and interchangeability of NTI drugs used in organ transplantation, the implications of the approval process for generic drugs on treatment efficacy and safety, and the effective management of substitutions between products.

Keywords: Transplant Medicine.

Figure 1

Variation in individual exposure between generic and branded ciclosporin formulations in a bioequivalence study. Data are shown for individual subjects. The large circles show overall mean ratios for C_max and AUC and encompass the 90% CI of these parameters. AUC, area under the concentration/time curve; C_max, maximum plasma concentration. Based on study Report Number ANA-97-132, submitted by Eon Labs Manufacturing, Inc, Laurelton, New York (USA) to the Illinois (USA) Department of Public Health (n=34).

Figure 2

Bioequivalence and interchangeability. (A) Normal bioequivalence limits (80%–125%). (B) Bioequivalence limits for narrow therapeutic index drugs (90%–111%). Generic A and generic B each show bioequivalence to the branded product, but generic A is not bioequivalent to generic B, as the 90% CIs for the mean ratios lie outside the bioequivalence limits.

Figure 3

Graft survival for kidney transplant patients with low and high within-patient variability for tacrolimus clearance. Reprinted from Borra et al, 2010.

Figure 4

Percentage change in tacrolimus blood trough concentrations following conversion to generic tacrolimus in liver and kidney transplant recipients. Data shown for transplant recipients (kidney, n=30; liver, n=30) whose dosing regimen remained unchanged following 1:1 dose conversion. Adapted from Momper et al, 2011.