In clinical practice we utilize trough level concentration as a measure of the exposure to tacrolimus. A recent study showed that trough level concentrations can be used as a reliable surrogate measure for area under the curve (AUC) for patients in normal clinical practice receiving generic tacrolimus [7].
Several factors, which may have contributed to the subtherapeutic trough levels upon conversion to generic formulation, were considered. For example, although the outside pharmacy claimed that it prepared the medication in a similar way as the hospital pharmacy, it still remains a possibility that this pharmacy had less experience in compounding narrow therapeutic index drugs (NTI) which may have contributed to the difference in drug levels. Additionally, it’s known that voriconazole can inhibit CYP3A4, decreasing the metabolism of tacrolimus and increasing its blood concentration [8]. As shown in Figure 1, the patient’s dose was reduced from 16.26 mg/kg (therapeutic dosage) to 8.46 mg/kg PO daily (expected prophylactic dosage) that may have resulted in increasing the metabolism of tacrolimus and decreasing its concentration in the plasma. The dose of voriconazole was increased back to 19.5 mg/kg/day at the same time of switching back to the brand name tacrolimus and the rise of blood tacrolimus levels. Therefore the change in voriconazole dose could have contributed to the change in blood tacrolimus levels but because the patient maintained therapeutic drug concentrations after discontinuing voriconazole on day +106, the clinical pharmacology consultation team hypothesized that drug-drug interactions did not fully contribute to the observed drop in tacrolimus levels.
Additionally, it’s unlikely that famotidine administration caused the environment in the stomach to be alkaline and the patient was given it both while in the hospital and after being discharged. Moreover, clinical literature has been inconclusive regarding the impact of antacids on immunosuppresants such as tacrolimus [9]. Moreover, the prevention of tacrolimus absorption due to the concomitant administration of iron or other vitamins is not supported by any clinical literature. In addition to that, the patient received the same iron and vitamins while he was in the hospital. Finally, the other drugs he administered (Acetoaminophen, diphenhydramine, ondansetron, sulfamethoxazole-trimethoprim and valacyclovir) were not reported to interact with tacrolimus. Furthermore, the patient was given these drugs both while he was in the hospital and after being discharged. Finally, he didn’t have any food changes that may have contributed to the changes in bioavailability between the two products when they were given orally.
Pharmacogenetic factors were unlikely to have contributed. The CYP 3A5*1 allele has been implicated in lower tacrolimus trough levels than patients with CYP3A5*3 [10]. This allelic variant, though important, is unlikely to play a critical role for our patient, as he was able to maintain therapeutic trough levels with appropriate dosage of tacrolimus.
The conversion from brand to generic formulation could have contributed to the inability to achieve therapeutic levels of tacrolimus. In general, studying the effect of switching to generic tacrolimus in pediatric patients is not well explored. The only available study that evaluated switching to generic tacrolimus in children was done in renal transplant patients [4]. In that study, both trough and serum creatinine levels were retrospectively analyzed for four patients (with ages range between 8–22 years old). Although trough levels were generally comparable before and after switching from brand name to generic tacrolimus, interindividual differences existed. Serum creatinine levels were identical pre- and post- switch in three of the four patients. The fourth patients suffered from acute rejection immediately after switching to the generic formulation. This was accompanied by a dramatic increase in the patient’s serum creatinine level.
Contradictory results exist regarding the clinical equivalency of brand name tacrolimus formulations to their generic versions in the adult population. Despite the aforementioned study that showed that brand name tacrolimus and generic formulations may not be bioequivalent, other studies have showed that they are bioequivalent. For example, one study examined the efficacy and safety of the generic oral capsules of tacrolimus (TacroBell®) in de novo renal transplantation [11]. The study recruited ninety-six renal transplant recipients from 9 transplantation centers in South Korea. In general, the acute rejection and graft survival rates were comparable to brand name treatment. One unresolved issue with this study is that it was carried out in low risk populations with only short term follow up. Another recent study evaluated seventy conversions, of brand name tacrolimus to the generic tacrolimus (Sandoz), from four centers from patients after kidney, liver or multiorgan transplant [12]. This study showed that trough levels and dosage needed are similar between brand name tacrolimus and its generic formulation. Furthermore, a retrospective analysis of the electronic records and clinical databases for 234 clinically stable adult transplant recipients (renal, liver, and heart) whose tacrolimus was converted from brand name to a generic formulation recently occurred [13]. Trough levels were generally comparable between the two formulations. No deaths or acute rejections were reported but thirty-six patients required dose titration. Another open-label, multicenter pilot study in South Korea evaluated 57 patients receiving generic tacrolimus and corticosteroids after liver transplantation [14]. This group of patients was then compared to another retrospectively matched control group consisting of living donor liver transplant recipients at another center who received brand name tacrolimus. Adverse events were generally comparable between the two patient populations and no patients died during this study. In addition to that, a multicenter crossover pharmacokinetic study in which patients would receive both the generic and brand name formulation for 14 days and then crossover revealed that Sandoz generic tacrolimus has a similar pharmacokinetic profile to Prograf® in kidney transplant patients [15]. Finally, a recent prospective study showed that stable kidney transplant recipients can be converted to Sandoz generic tacrolimus by closely monitoring both plasma creatinine levels and trough concentration of tacrolimus [16].
For our patient, we recommended that the patient return to brand name formulation, after which the patient had therapeutic tacrolimus levels as well as resolution of his GVHD flare.
There are a number of reasons why the current bioequivalence studies may be inadequate for the approval of generic immunosuppressants [17]. First, studies in healthy subjects may not be extrapolated to transplant recipients. Second, steady state conditions may not be represented by single dose studies. Third, the allowance of the confidence interval to be (80%–125%) may be too variable for drugs with a narrow therapeutic index such as immunosuppressants. Finally, children are excluded from these bioequivalence studies. For this reason the American Society of Transplantation strongly supported studies to demonstrate bioequivalence in potentially at risk patients, especially children [18].