Nationwide conversion to generic tacrolimus in pediatric kidney transplant recipients

Naicker, Derisha; Reed, Peter; Ronaldson, Jane; Kara, Tonya; Wong, William; Prestidge, Chanel

doi:10.1007/s00467-017-3707-3

Cited by 9 publications

(5 citation statements)

References 14 publications

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“…One of the studies already highlighted recruited small sample sizes (n = 2-10) due to the nature of study population, for example, patients with organ transplant (59). Risk factors of poor study design from the studies already identified include: non-randomized study design (44,62,67,103); parallel study arms (35); retrospective study design (104); methodology used in statistical results (e.g., partial AUC calculations were not considered for complex release methylphenidate formulations) (104), or baseline errors for endogenous molecules (e.g., levothyroxine ( 105)).…”

Section: Poor Study Design Including Small Sample Sizementioning

confidence: 99%

Development of a Pediatric Relative Bioavailability/Bioequivalence Database and Identification of Putative Risk Factors Associated With Evaluation of Pediatric Oral Products

Pawar

Zhao

et al. 2021

AAPS J

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Generally, bioequivalence (BE) studies of drug products for pediatric patients are conducted in adults due to ethical reasons. Given the lack of direct BE assessment in pediatric populations, the aim of this work is to develop a database of BE and relative bioavailability (relative BA) studies conducted in pediatric populations and to enable the identification of risk factors associated with certain drug substances or products that may lead to failed BE or different pharmacokinetic (PK) parameters in relative BA studies in pediatrics. A literature search from 1965 to 2020 was conducted in PubMed, Cochrane Library, and Google Scholar to identify BE studies conducted in pediatric populations and relative BA studies conducted in pediatric populations. Overall, 79 studies covering 37 active pharmaceutical ingredients (APIs) were included in the database: 4 bioequivalence studies with data that passed BE evaluations; 2 studies showed bioinequivalence results; 34 relative BA studies showing comparable PK parameters, and 39 relative BA studies showing differences in PK parameters between test and reference products. Based on the above studies, common putative risk factors associated with differences in relative bioavailability (DRBA) in pediatric populations include age-related absorption effects, high inter-individual variability, and poor study design. A database containing 79 clinical studies on BE or relative BA in pediatrics has been developed. Putative risk factors associated with DRBA in pediatric populations are summarized.

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Section: Poor Study Design Including Small Sample Sizementioning

confidence: 99%

Development of a Pediatric Relative Bioavailability/Bioequivalence Database and Identification of Putative Risk Factors Associated With Evaluation of Pediatric Oral Products

Pawar

Zhao

et al. 2021

AAPS J

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“…However, a lot of studies have been published in recent years about the successful use of generic tacrolimus by switching from the original product or de novo use after transplantation (3)(4)(5). It has also been reported that conversion to generic tacrolimus is safe in the pediatric kidney transplant patients (6).…”

Section: Introductionmentioning

confidence: 99%

Clinical and Safety Outcomes of Conversion Original Tacrolimus to Generic Tacrolimus in Turkish Kidney Transplant Recipients

Günay

2020

Preprint

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Background After the United States, The Food and Drug Administration approved the use of the first generic of the original tacrolimus in 2009, generic tacrolimus was preferred in many countries for cost-reducing reasons. This is the first study on the conversion of original tacrolimus to the generic tacrolimus, reported from Turkey. Methods The inclusion criteria of this single-center, retrospective study were 1) being ≥18 years old, 2) passing at least three months after kidney transplantation, 3) conversion from reference tacrolimus (Prograf®) to generic tacrolimus (Adoport®). The primary endpoints were acute rejection, an increase in serum creatinine, decreases in e-GFR, tacrolimus level, tacrolimus concentration/dose ratio. We applied the paired T-test to analyze the pre-conversion and final visit laboratory values. Results Thirty-six patients who agreed to use generic tacrolimus evaluated. The mean age was 39.8 years (± 11.6), % 52,7 were female, % 86,1 were living donor transplants. The patients followed up for 12 months (3-41). There was no increase in serum creatinine value, no decreases in e-GFR and tacrolimus concentration/dose ratio. We observed a decrease in tacrolimus level (p=0,037). Decreasing the target value may have caused this result, as there are 9 patients with positive BK-DNA. None of the patients needed a biopsy. Conclusion Based on the results of our study, renal outcomes are safe and the drugs could be changed safely. Whether Prograf® or Adoport®, whichever is used, it is important to continue taking the drug at the recommended dose and time. The physician should be careful in dose adjustment after conversion, especially for those who are in the first year of transplantation.

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“…Monitoring of immunosuppressive therapy is most often performed on immunosuppressant blood levels that mirror the pharmacokinetics but not the pharmacodynamics. 8 Therefore, other potential methods to determine immune function and grade of immunosuppression, such as analysis of the Torque-Teno virus load 9 or virus-specific T cells (Tvis), 10 are currently evaluated. Tvis control virus replication and have been shown to correlate with virus-specific as well as general cellular immune defense, which represents the individual's susceptibility to infections.…”

mentioning

confidence: 99%

Steering Transplant Immunosuppression by Measuring Virus-Specific T Cell Levels: The Randomized, Controlled IVIST Trial

Ahlenstiel-Grunow

Liu

Schild

et al. 2020

JASN

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Background Pharmacokinetic monitoring is insufficient to estimate the intensity of immunosuppression after transplantation. Virus-specific T cells correlate with both virus-specific and general cellular immune defense. Additional steering of immunosuppressive therapy by virus-specific T cell levels might optimize dosing of immunosuppressants. Methods In a multicenter, randomized, controlled trial, we randomized 64 pediatric kidney recipients to a control group with trough-level monitoring of immunosuppressants or to an intervention group with additional steering of immunosuppressive therapy by levels of virus-specific T cells (quantified by cytokine flow cytometry). Both groups received immunosuppression with cyclosporin A and everolimus in the same target range of trough levels. Primary end point was eGFR 2 years after transplantation. Results In the primary analysis, we detected no difference in eGFR for the intervention and control groups 2 years after transplantation, although baseline eGFR 1 month after transplantation was lower in the intervention group versus the control group. Compared with controls, patients in the intervention group received significantly lower daily doses of everolimus and nonsignificantly lower doses of cyclosporin A, resulting in significantly lower trough levels of everolimus (3.5 versus 4.5 µg/L, P<0.001) and cyclosporin A (47.4 versus 64.1 µg/L, P<0.001). Only 20% of patients in the intervention group versus 47% in the control group received glucocorticoids 2 years after transplantation (P=0.04). The groups had similar numbers of donor-specific antibodies and serious adverse events. Conclusions Steering immunosuppressive therapy by virus-specific T cell levels in addition to pharmacokinetic monitoring seems safe, results in a similar eGFR, and personalizes immunosuppressive therapy by lowering exposure to immunosuppressive drugs, likely resulting in lower drug costs. Clinical Trial registry name and registration number: IVIST trial, https://www.clinicaltrialsregister.eu/ctr-search/search?query=2009-012436-32 and ISRNCT89806912

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Nationwide conversion to generic tacrolimus in pediatric kidney transplant recipients

Cited by 9 publications

References 14 publications

Development of a Pediatric Relative Bioavailability/Bioequivalence Database and Identification of Putative Risk Factors Associated With Evaluation of Pediatric Oral Products

Development of a Pediatric Relative Bioavailability/Bioequivalence Database and Identification of Putative Risk Factors Associated With Evaluation of Pediatric Oral Products

Clinical and Safety Outcomes of Conversion Original Tacrolimus to Generic Tacrolimus in Turkish Kidney Transplant Recipients

Steering Transplant Immunosuppression by Measuring Virus-Specific T Cell Levels: The Randomized, Controlled IVIST Trial

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