{'fraction_non_alphanumeric': 0.024189526184538655, 'fraction_numerical': 0.0032418952618453864, 'mean_word_length': 4.942222222222222, 'pattern_counts': {'":': 0, '<': 0, '<?xml version=': 0, '>': 0, 'https://': 0, 'lorem ipsum': 0, 'www.': 0, 'xml': 0}, 'pii_count': 0, 'substrings_counts': 0, 'word_list_counts': {'cursed_substrings.json': 0, 'profanity_word_list.json': 0, 'sexual_word_list.json': 0, 'zh_pornsignals.json': 0}}
Measuring oral bioavailability of tacrolimus

In this issue of Pediatric Transplantation, Jacobo-Cabral et al. from Mexico City describe their work comparing the systemic bioavailability of two formulations of tacrolimus – the original Prograf (Astellas Pharma US, Northbrook, IL, USA) – and a Mexican non-innovator formulation, Limustin (1). They conclude that their data prove inferiority of the local Mexican product, as use of this drug results in lower systemic exposure. For a drug such as tacrolimus, which exhibits a narrow therapeutic range, suboptimal bioavailability may lead to serious consequences and even transplant failure (2). Previous studies have shown that impaired bioavailability may raise the risk of therapeutic failure (3). This is potentially an important finding that could directly impact patient care. However, before one accepts the authors’ conclusions, the sampling strategy used by the investigators must be examined carefully. For the benefit of readers unfamiliar with bioavailability studies, we will first briefly review the standard approach. To ensure that a generic compound is similar to the original compound in the systemic levels it produces, measurement of levels over time (so-called the area under the concentration–time curve, or AUC) needs to be within 20% of each other. In other words, the generic product can achieve anywhere between 80–120% of the AUC produced by the original drug. In a typical bioavailability study, the systemic exposure of formulation A and B has to be compared when the subjects serve as their own controls (3). This means that the same subject receives drug A and drug B. By so doing, one eliminates intersubject variability in absorption, distribution, and elimination of drug. Moreover, the subjects have to be randomized to receive first drug A or drug B, and after a washout period to receive the other formulation. These steps aim to ensure that there is no “order effect,” for example, if the first drug given induces the metabolism of the second formulation. None of these conditions were met in the study by Cabral et al. Each formulation was studied in a different group of children, and as the authors pointed out, the two groups differed in age, which may affect drug absorption. Moreover, the two groups differed in height, weight, and proportions of genetic polymorphism relevant to tacrolimus metabolism, all of which may affect the area under the concentration–time curve through differences in clearance rate. Furthermore, while Prograf was studied in 23 children, Limustin was studied in only nine, which increases the chance of error. The authors document that despite relatively similar dose per kg, the AUC and peak levels of tacrolimus achieved by Limustin were only half of what was achieved with Prograf. However, there is a major issue with this result: If this is correct, then the trough steady state levels with Limustin should have been half of the level with Prograf, as steady state trough levels are dependent on the AUC. So how then is it that the steady state trough levels were similar when the two formulations are compared? The answer to this enigma possibly lies in the dissolution data. Limustin dissolves more slowly than Prograf, resulting in a lower AUC over the sampling frame reported in this study, but possibly by the time of the next trough, the drug had the chance to dissolve fully and be absorbed, resulting in an equivalent steady state trough concentration. That is not to say that this study is unimportant, far from it. This study raises a very important question for all of us sharing the common goal of better therapy for children with renal disease. The claim that Limustin has inferior bioavailability is too serious to be determined based on the sampling strategy used in this study. Rather, bioequivalence should be carried out appropriately with children serving as their own controls, or if this cannot be carried out, then one should study this issue in adults where it is