Generic Tacrolimus Research Articles

Changes in drug crystallinity in a commercial tacrolimus amorphous formulation result in variable pharmacokinetics

Tacrolimus capsules contain the drug as the amorphous form. It is well known that drug crystallinity is a risk factor for the performance of amorphous formulations. This study investigated the impact of varying levels of crystalline drug on the pharmacokinetics of tacrolimus following oral dosing of a 5 mg capsule under fasting conditions. Two treatments with percent crystallinity of 20% and 50% were achieved by exposing a marketed generic tacrolimus product to open dish storage conditions of 35 °C and 75% relative humidity (RH) for up to 20 days. Crystallinity was monitored with X-ray powder diffraction. Prograf®, the reference listed drug (RLD), an amorphous generic drug product, and generic drug products containing 20% and 50% crystalline tacrolimus were evaluated. All four treatments were administered to healthy participants in a randomized, single-dose, four-treatment, four-period, four-way crossover study. Blood sampling occurred over 24 h. The amorphous generic tacrolimus product was determined not to be bioequivalent to the RLD. The capsules containing both 20% and 50% crystalline tacrolimus also failed the bioequivalence recommendations when compared to the amorphous generic or to the RLD. Both levels of crystalline tacrolimus resulted in BE failure for both Cmax and AUC parameters. The impact of tacrolimus crystallization was greater for maximum blood concentration (Cmax) values relative to the area-under-the-curve (AUC) values. This study demonstrates that crystalline tacrolimus formed in a marketed generic product and these changes resulted in variable pharmacokinetics which could be of significant clinical concern.

De-novo use of generic tacrolimus (Adoport) in renal transplant recipients: A single center experience from Türkiye

Objective: Renal transplantation is the best treatment for end-stage kidney disease, and tacrolimus has become an important immunosuppressive treatment for kidney transplant patients since it was introduced. After the first generic tacrolimus has been approved by the FDA, studies have begun to compare the effectiveness and safety of generic tacrolimus with the original tacrolimus. When using generic immunosuppressive therapies, it is also necessary to ensure that it provides adequate immunosuppression and does not cause severe toxicity. This study aims to compare clinical outcomes, including acute rejection, graft loss and adverse reactions, in patients receiving brand tacrolimus (Prograf, Astellas Pharma, U.S.) or generic tacrolimus (Adoport, Sandoz, UK) from the start of kidney transplant therapy. Study Design: Renal transplant recipients between 1 January 2015-1 March 2020 were screened retrospectively. All patients receiving de novo generic tacrolimus (n:51) and randomly selected 102 control renal transplant recipients receiving original tacrolimus were included in this study. Materials and Methods: We evaluated and recorded demographic, clinical and laboratory data including age, gender, primary kidney disease, donor type (live or dead), induction and death regimen, tacrolimus dose, tacrolimus through levels, serum creatinine, biopsy-confirmed acute rejection episodes, delayed transplant function, positive BK polyomavirus in the urine, BK polyomavirus-related nephropathy, cytomegalovirus infection in 1-year follow-up. Results: Most of the patients were male (64.1%) with a mean age of 38.3 years. There was no significant difference in demographic characteristics between the original and generic tacrolimus groups. No differences were found in terms of creatinine levels, total daily dose of tacrolimus and tacrolimus trough levels at discharge and the first year. Additionally, biopsy-confirmed acute rejection in the following year after transplantation, BKPyV positivity in urine, BKPyVAN, CMV viremia and adverse reactions related to tacrolimus were similar between the two groups. Conclusion: With this study, we aimed to contribute to the literature with our experience on the use of generic tacrolimus from our country. As a result of our study, we noted that generic tacrolimus can be safely preferred for de-novo use with close drug-level monitoring because it is an immunosuppressant agent with a narrow therapeutic index. There is a continuing need for randomized prospective-designed and multi-centric studies with a wide range of patients.

Clinical Utilization of Generic Drugs and Biosimilars for Ulcerative Colitis Treatment: Insights from a Nationwide Database Study in Japan

Introduction: Limited data exist regarding the prevalence and clinical practice involving generic drugs and biosimilars for treating ulcerative colitis (UC) in Japan. We aimed to clarify the clinical usage of these generic drugs and biosimilars for UC treatment in Japan using a nationwide database. Methods: We collected data from 30,675 UC cases, along with their prescriptions for both generic drugs or biosimilars and their original counterparts, using a medical claim database provided by DeSC Healthcare, Inc. We calculated the prescription and penetration rates of generic drugs and biosimilars and demonstrated the transition of these rates. Additionally, the cumulative retention rates between infliximab originator and biosimilar were compared using the Kaplan-Meier method. Results: The prescription rate of generic mesalazine increased from approximately 10% in 2015 to over 30% in 2021. Although the prescription rate of generic molecular targeting drugs (MTDs) also increased from approximately 0.15% in 2014 to 2.5% in 2021, the increment was lower than that of generic mesalazine. The penetration rates of generic 5-aminosalicylic acid and tacrolimus ranged from over 30% to approximately 50%. Infliximab biosimilar achieved an approximate 20% penetration rate, whereas adalimumab achieved <5%. The cumulative retention rates did not differ between infliximab originator and biosimilar. Conclusions: The penetration rates of generics and biosimilars for UC treatment are relatively low compared with those for treatment in other fields and the goal of the Ministry of Health, Labor, and Welfare. Several countermeasures are necessary for the widespread use of generics and biosimilars, ultimately contributing to cost-effective and sustainable healthcare delivery.

Efficacy and safety of generic once-daily prolonged release tacrolimus (TacroBell SR cap.) in de novo kidney transplant recipients: a multicenter, non-comparative, phase IV study

Efficacy and safety of generic once-daily prolonged release tacrolimus (TacroBell SR cap.) in <i>de novo</i> kidney transplant recipients: a multicenter, non-comparative, phase IV study

Therapeutic monitoring of pediatric transplant patients with conversion to generic tacrolimus

ObjectiveTherapeutic monitoring during interchange of tacrolimus commercial formulations is essential to ensure similar exposure in transplant patients. However, there are limited data in the pediatric transplant population. This study aims to evaluate exposure, safety and efficacy in maintenance pediatric transplant patients under generic tacrolimus substitution. MethodPediatric patients who underwent interchange of tacrolimus formulations were detected by the Service of Pharmacy and included in this study. Tacrolimus trough levels (C0), laboratory parameters and clinical characteristics were recorded before and after the switch. Statistical analysis was performed using Wilcoxon matched pair t-test. ResultsIn total, 10 patients with kidney, liver, heart and hematopoietic stem cell transplantation received the innovator and switched to the generic product. The median (range) of the C0 normalized by the dose before and after switch was 74.8 [(ng/ml)/(mg/kg)] (13.8-518.4) and 65.1 [(ng/ml)/(mg/kg)] (13.5-723.5), respectively (p>0.05). Tacrolimus dose was 0.070(mg/kg) (0.024-0.461) and 0.069(mg/kg) (0.017-0.571) for the innovator and generic formulation, respectively, with no difference when comparing both values (p>0.05). Laboratory parameters did not change after conversion (p>0.05). Adverse events, acute rejection, death and graft loss were not observed. ConclusionsIn our study population, no significant differences in terms of laboratory parameters, drug exposure and dose were observed. We emphasize the need of close monitoring to ensure a safe interchange, especially in vulnerable populations such as the pediatric.

Bioequivalence evaluation and blood concentration estimation of generic and branded tacrolimus in healthy subjects under fasting: A randomized, four-periods, two-sequences, complete repeated, crossover study

ObjectiveThe demand for generic tacrolimus is enormous. Our randomized trial was an open-label single-dose testing with four-periods and two-sequences; we aimed to evaluate the bioequivalence between a generic and branded tacrolimus by establishing their area under concentration-time curve (AUC) predictive equations. For better comparison, each tacrolimus served either as test vs. reference in sequence 1 or vice versa as reference vs. test in sequence 2. MethodsForty healthy subjects were randomized into two groups, namely a sequence 1 group (N = 20 in test-reference-test-reference) or sequence 2 (N = 20, reference-test-reference-test) received a test tacrolimus (Ruibeirong®; Chengdu Shengdi Medicine Co., Ltd.) and a reference tacrolimus (Astagraf XL®, Astellas Ireland Co., Ltd.) under the fasting condition with a wash-out period of ≥14 days between every two phases. Blood samples were collected sequentially until 120 h after oral administration of tacrolimus. ResultsA 95% upper confidence bound was −0.05% for the peak concentration (Cmax), −0.02% for the AUC from 0 to the last time point (AUC0-t), and − 0.02% for the AUC from 0 to infinity (AUC0-∞). The geometric least square means ratio (test/reference) with 90% of confidence interval (CI)) was 96.10% (90.58%–101.95%) for Cmax, 93.80% (88.52%–99.39%) for AUC0-t, and 94.34% (89.20%–99.77%) for AUC0-∞. Meanwhile, the ratio of within-subject standard deviation of test/reference (σWT/WR) with 90% CI was 0.66 (0.50–0.86) for Cmax, 0.73 (0.55–0.96) for AUC0-t, and 0.75 (0.57–0.98) for AUC0-∞. These results fulfilled the bioequivalence criteria by the Food and Drug Administration. Both products showed acceptable safety. Moreover, the AUC predictive equations (by linear regression plus limited sampling strategy) with 2–5 sampling time point showed the high performance (all R > 0.970, predictive error (PE) >0.5%, absolute PE <5.1%, which were interchangeable between test and reference products. ConclusionGeneric tacrolimus (Ruibeirong®) is bioequivalent to branded tacrolimus (Astagraf XL®) with tolerable safety, which AUC predictive equations work well and are interchangeable between the two products.

Generic Tacrolimus in Kidney Transplant Patients at Jordan University Hospital

Background: Tacrolimus is the immunosuppressive drug of choice for kidney transplant patients, but its cost is very high in the total drug cost for patients with renal disease. Lower drug costs can be achieved with generic tacrolimus. For this reason, the Ministry of Health mandated to implementation of a switch to generic form and so we wanted to evaluate whether a switch could be safely performed and to observe the effect of this on kidney function. Subjects and Methods: In this observational study, 28 stable kidney transplant patients taking Prograf®(Astellas) were switched to a generic Pangraf®(Pancea) in a 1:1 dose ratio and were followed up for 6 months. Plasma creatinine levels and trough concentrations of tacrolimus were recorded three times on Prograf® and weekly for 4 weeks, then monthly after conversion to Pangraf®. Results: Tacrolimus mean C0 levels were 6.97 ± 0.92 ng/mL before and 7.4 ± 1.23 ng/mL after conversion (P = 0.22). Mean serum creatinine values were 1.13 ± 0.53 mg/dL and 1.15 ± 0.54 mg/dL before and after conversion, respectively (P = 0.27). Conclusion: Switching from branded tacrolimus to generic tacrolimus seems possible and safe, but close monitoring is essential.

EE288 Economic Evaluation of Generic Tacrolimus and Innovator in Renal Transplant Recipients in Egypt

Both brand and generic tacrolimus proved to have the same quality, efficacy, safety and pharmacokinetics properties. We conducted a cost minimization analysis to estimate the direct medical costs of adopting the generic tacrolimus compared to the innovator from a payer perspective in the Egyptian renal transplant recipients over one year.

Cost-Utility of Immunosuppressive Therapy Post-Renal Transplantation in Saudi Arabia: The Saudi Ministry of Health Perspective

ObjectivesChronic kidney disease is ranked fourth among the top 10 causes of death in Saudi Arabia. Renal transplantation has been recognized as the treatment of choice compared with long-term dialysis to maintain graft survival and prolong a patient’s healthy living. Immunosuppressants (ISs) must be administered lifelong. The choice between IS therapies can be challenging because of the similarity in efficacy with some differences in adverse events profile. The objective of this study was to assess the cost-effectiveness of different IS regimens in Saudi Arabia. MethodsA 25-year Markov model was developed based on a previously published study from the Saudi Ministry of Health payer perspective. Efficacy parameters were driven from the literature, whereas cost data were estimated from the Ministry of Health database. A Monte Carlo simulation was conducted to test the base-case model results’ robustness. ResultsAll comparators resulted in 6.2 quality-adjusted life-years (QALYs) except for Advagraf® treatment (5.5 QALYs). Generic tacrolimus plus mycophenolate mofetil (MMF) will cost 70 701.45 US dollars ($) (Saudi riyal 265 130.44) per patient to gain 6.2 QALYs over 25 years’ time horizon. In the improved adherence scenario, Envarsus® plus generic MMF generated 9.6 QALYs with a cost of $59 849 per patient. Monte Carlo simulation results have shown that generic tacrolimus is still the cheapest treatment option compared with other treatment arms. ConclusionsThe current analysis suggested that all IS options are not cost-effective strategies relative to the willingness-to-pay threshold of $20 000. Nevertheless, Envarsus plus generic MMF regimen could become the most cost-effective regimen at different willingness-to-pay thresholds.

Outcomes of De Novo Use of Generic Tacrolimus (Adoport®) in Living-Related Kidney Transplantation: A Single-Center, Real-Life Experience of 5 Years

Outcomes of De Novo Use of Generic Tacrolimus (Adoport®) in Living-Related Kidney Transplantation: A Single-Center, Real-Life Experience of 5 Years

Efficacy and safety of a switch from twice-daily tacrolimus to once-daily generic tacrolimus in stable liver transplant patients.

BackgroundOnce-daily tacrolimus reduces non-compliance relative to twice-daily tacrolimus. However, little is known about the safety and efficacy of conversion from twice-daily tacrolimus to generic once-daily tacrolimus in liver transplantation (LT). Herein, we investigated the efficacy and safety of a switch from twice-daily tacrolimus to generic once-daily tacrolimus in patients with stable liver graft function.MethodsThis prospective, multicenter, open-label, single-arm study was conducted in 17 medical centers for 1 year from July 2019 to July 2020 (NCT04069065). Primary endpoint was the incidence of biopsy-proven acute rejection (BPAR) for 24 weeks after conversion. Secondary endpoints were graft failure, patient death, and adverse events (AEs).ResultsOf 151 screened LT patients, 144 patients were enrolled. BPAR, graft failure, and patient death did not occur in this patient population. There were no statistical differences in blood tests, liver function tests, or biochemical tests between visits in any of the patients. Median tacrolimus trough level decreased abruptly from 4.7 ng/mL to 3.2 ng/mL after generic once-daily tacrolimus conversion, but median tacrolimus dose increased due to low tacrolimus trough level. Ninety-two adverse events occurred in 54 patients. Liver enzyme levels increased in seven patients (4.9%) after the switch to generic once-daily tacrolimus, but the liver function tests of these patients normalized thereafter. There were three cases of severe AEs not related to investigational drug.ConclusionsPresent study suggests that conversion from twice-daily tacrolimus to generic once-daily tacrolimus is effective and safe in stable LT patients.

P-85 USE OF LOW DOSES OF GENERIC TACROLIMUS AND THERAPEUTIC LEVELS IN LIVER TRANSPLANT PATIENTS: RESULTS FROM A SINGLE CENTER IN PERU

Tacrolimus is the basis of immunosuppressive treatment in liver transplantation, with dosages of blood levels to ensure adequate graft function. In Peru, since 2005 generic tacrolimus has been used exclusively in all transplant centers due to lower costs. There are no presentations (0.5 mg), necessary for its use in a group of transplanted patients who require low doses of the drug. To show the results of the use of low doses (<2 mg/day) of generic tacrolimus, using 0.5 mg capsules and measure tacrolimus blood levels in correlation to the time of transplantation and the frequency of liver graft rejection, toxicity, or infections in this group of patients. Observational, descriptive, cross-sectional, and retrospective study. Demographic data, transplant time, dose and blood levels of tacrolimus, rejection, and adverse effects were obtained from electronic medical records from October to December 2020. Inclusion criteria: adults, doses: <2 mg/day, > 3 months use of generic tacrolimus (NORGRAF: The Madras Pharmaceuticals, India) using 0.5 mg capsules, prepared by the Pharmacy Service at the Guillermo Almenara Hospital. Exclusion criteria: Pediatrics, retransplant, combined transplant. Statistical analysis and processing was using SPSS 23. Eleven of 246 patients (4.52%) were identified. All patients had blood levels within the therapeutic range in relation to transplantation time and graft function. Average daily dose: 1.3 mg (0.5-1.5 mg /d). Average blood levels: 5.82 ng/L (3.57-10.3 ng / ml). Average transplant time: 73 months (3-120 months). There were no rejection episodes or adverse effects of nephrotoxicity, neurotoxicity, or infections. The use of low doses of generic tacrolimus (<2 mg/d), using 0.5 mg capsules prepared by the Pharmacy service, allows for the proper adjustment of the daily dose of immunosuppression, obtaining therapeutic success in the prevention of cellular graft rejection, especially in long-standing liver transplant patients without presenting toxicity.

MO920TRANSITION FROM GENERIC TO BRAND TACROLIMUS IN TUNISIAN RENAL TRANSPLANT RECIPIENTS

Abstract Background and Aims Due to unavailability of the generic tacrolimus, commonly used in renal transplant patients in Tunisia, all renal transplant switched to the Brand. No previous studies have assessed the pharmacokinetic differences of this generic tacrolimus compared to the brand. The aim of the present study was to evaluate the effect of this switch on the tacrolimus dose (D) and on the dose-adjusted tacrolimus trough blood concentrations (C0/D) in Tunisian renal transplant recipients. Method For the 255 renal transplant monitored in biochemestry department of Sahloul University hospital, 808tacrolimus trough concentration (C0) were collected from october 2018 to February 2020 and were divided to 406 C0 determination before switch and 402 after switch. The dose and the post-transplantation period was recorded for each C0. Results The generic tacrolimus doses used were significantly higher compared to the brand: 0,12 mg/kg [0,02-0,6] vs 0,11 mg/kg [0,02-0,22] p&amp;lt;0,001 and this was reported in different post graft periods: 0,17 [0,03-0,22] vs 0,13 [0,06-0,22] p&amp;lt;0,001in the 3 first months after the transplantation and 0,11 [0,02-0,48] vs 0,08 [0,02-0,22] p&amp;lt;0,001 above.The C0/D were significantly lowe runder the the generic tacrolimus compared to the brand 48,34ng/ml per mg/kg/day [11,58-210,00] vs77,35ng/ml per mg/kg/day[19,38-221,67]; p&amp;lt;0,001 and this was reported in different post graft periods: 71,12ng/ml per mg/kg/day [6,80, 451,56] vs80,9750ng/ml per mg/kg/day [17,33-458,80] p=0,017 in the 3 first months after the transplantation and 71,12ng/ml per mg/kg/day [6,80, 451,56] vs80,9750ng/ml per mg/kg/day [17,33-458,80] p=0,017 above. Dose needed to reach target tacrolimus C0 seems to be higher with the generic tacrolimus compared to the brand. Conclusion Approval of a generic is dependent on bioequivalence testing in healthy adult volunteers after a single dose, however studies on renal graft recipient populations after chronic use are needed to assed bioequivalence in this special population.

Kinetics of generic tacrolimus in heart transplantation: A cautionary note

Tacrolimus is a core component of immunosuppressive regimens. This study compared active pharmaceutical ingredient (API) and dissolution kinetics of branded tacrolimus and formulations from three generic manufacturers (Mylan, Dr. Reddy's, Intas) including samples from patients who suffered acute cardiac allograft rejection. Generic samples showed similar API content compared to branded samples with no major impurities. Capsules that underwent uniformity testing had consistent capsule-to-capsule API. Dissolution testing showed similar profiles between branded tacrolimus and Mylan, but notable differences with Dr. Reddy's and Intas. The approximate maximal inhibitory concentration (IC50) was highest in branded tacrolimus (29 minutes), followed by Mylan (26 minutes), Dr. Reddy's (19 minutes), and Intas (14 minutes) (Student-Newman-Keuls Multiple Comparisons Test; overall ANOVA: p = 0.0199, F = 6.469). This study suggests that the bioavailability of certain generic tacrolimus formulations peak significantly earlier than branded tacrolimus. Further study is needed to determine whether these differences are clinically relevant.

STABIL-study: The Course of Therapy, Safety and Pharmacokinetic Parameters of Conversion of Prograf® to Tacrolimus HEXAL®/Crilomus® in Renal Transplant Recipients - an Observational Study in Germany.

Tacrolimus HEXAL®/Crilomus® is an approved generic immunosuppressant for the prevention and treatment of rejection following renal transplantation. For safe and socioeconomically efficient conversion of the innovator into a generic formulation, high- -quality data are necessary, in view of the different and country-specific comorbidities and pharmacokinetics in kidney transplant recipients. From 2014 to 2017, we enrolled 32 kidney transplant recipients, receiving newly prescribed Tacrolimus HEXAL®/Crilomus® in 5 German centers. Efficacy and safety data were collected over 6-8 months and retrospectively compared to the period prior to conversion. The mean tacrolimus trough level was 4.91 ng/mL Standard Deviation (SD) (SD ±1.7) before and 5.06 ng/mL (SD ±1.97) after conversion. Mean tacrolimus trough concentration-dose-ratio (+/- SD) was 187.1 ng/mL/mg/kg/day (SD 99.2) for the reference and 205.1 ng/mL/mg/kg/day (SD 133) for the generic product, resulting in a non-significant difference of 18.0 ng/mL/mg/kg/day (SD 71.8) (p=0.84, Wilcoxon V=180). Overall, dosing had to be changed in 4 (14.8%) patients. Graft function remained stable and no rejections occurred. In conclusion, conversion to the generic tacrolimus formulation can be considered safe and feasible in long-term kidney transplant recipients in Germany. As suggested by guidelines, vigilant therapeutic drug monitoring is recommended to account for possible tacrolimus concentration variability on the individual patient level.

Clinical Pharmacokinetics and Bayesian Estimators for the Individual Dose Adjustment of a Generic Formulation of Tacrolimus in Adult Kidney Transplant Recipients.

Tacrolimus has a narrow therapeutic range and requires dose adjustment, usually based on the trough blood concentration but preferably on the area under the concentration-time curve over 12 h post-dose (AUC0-12h). The single-arm, multicentre, clinical study IMPAKT aimed: (i) to develop, in de novo kidney transplant recipients, pharmacokinetic models and maximum a-posteriori Bayesian estimators for a generic, immediate-release, oral formulation of tacrolimus to estimate tacrolimus AUC0-12h at different post-transplant periods using a limited sampling strategy, and considering the CYP3A5*3 polymorphism as a covariate and (ii) to compare the performance of these Bayesian estimators to those previously developed for the original formulation. Thirty patients were enrolled and 29 provided nine blood samples over 9 h at day 7 and months 1 and 3 post-transplant. Tacrolimus blood profiles measured with liquid chromatography-tandem mass spectrometrywere modelled using one-compartment, double gamma absorption, linear elimination models developed in-house. Different limited sampling strategies of three time-points within 4 h post-dose were tested for the maximum a-posteriori Bayesian estimator of tacrolimus AUC0-12h. The models and estimators were validated internally and their performance compared to that of models previously developed for the original formulation. The concentration-time curves, AUC0-12h/dose and trough blood concentration/dose exhibited wide inter-individual variability. The covariate-free pharmacokinetic models developed for the three post-transplant periods closely fitted the individual profiles. Maximum a-posteriori Bayesian estimators based on three different limited sampling strategies and no covariate yielded accurate AUC0-12h estimates, including for the five cytochrome P450 3A5 expressers and for the four patients without corticosteroids. The 0-1 h-3 h strategy finally chosen had very low bias (-4.0 to -2.5%) and imprecision (root mean square error 5.5-9.2%). The maximum a-posteriori Bayesian estimators previously developed for the reference product fitted the generic profiles with similar performance. We developed original pharmacokinetic models and accurate maximum a-posteriori Bayesian estimators to estimate patient exposure and adjust the dose of generic tacrolimus, and confirmed that the robust tools previously developed for the original formulation can be applied to this generic.

Relevant Issues of Planning Bioequivalence Studies of Drugs with a Narrow Therapeutic Range

In order to be registered, generic drugs with a narrow therapeutic range have to undergo bioequivalence or therapeutic equivalence studies. In most cases, comparative pharmacokinetic studies and demonstration of bioequivalence between the test and the reference products are sufficient for this group of drugs. However, there is no established official definition in Russia for the group of drugs that are regarded as having a narrow therapeutic range. Evaluation of bioequivalence of such drugs has to be performed providing for narrower confidence intervals, which entails certain problems at the stage of bioequivalence study planning. Finding solutions to the problems stated above is of great importance. The aim of the study was to develop approaches to planning bioequivalence studies of drugs with a narrow therapeutic range. Materials and methods: the paper analyses the results of 33 bioequivalence studies of drugs with a narrow therapeutic range, in which Cmax, AUC0-t, and tmax were calculated. Intra-individual variation and weighted mean intra-individual variation of Cmax and AUC0-t were estimated in the study. Statistical processing was performed using IBM SSPS Statistics v.25. and Microsoft Office Excel 2016. Results: the paper summarises criteria for categorising drugs as having a narrow therapeutic range and describes general requirements for assessing their bioequivalence. A number of bioequivalence studies of generic valproic acid, carbamazepine, levothyroxine, tacrolimus, and cyclosporine products which meet the criteria for drugs with a narrow therapeutic range, were analysed retrospectively. The data on their pharmacokinetics and intra-individual variation were calculated. It also summarises requirements for bioequivalence evaluation of drugs with a narrow therapeutic range. The paper gives product-specific recommendations for performing bioequivalence studies. Conclusion: the study helped to formulate approaches to the planning of bioequivalence studies of generic drugs with a narrow therapeutic range using the examples of valproic acid, carbamazepine, levothyroxine, tacrolimus, and cyclosporine.

Oral generic tacrolimus initiation and substitution in the Medicaid population: a new user cohort study

Objective Although existing studies have compared clinical efficacy and pharmacokinetics of generic with brand tacrolimus, little is known about generic tacrolimus utilization patterns or factors predicting generic substitution. This study examines associations between patient-level factors and generic tacrolimus initiation or substitution among new users of oral generic or brand-name tacrolimus. Methods This new user retrospective cohort study identified 374 beneficiaries who initiated generic or brand tacrolimus treatment, using 100% Medicaid administrative claims data from 11 states in 2011–2012. Outcomes were generic tacrolimus initiation and substitution within 12 months of treatment initiation. Multivariable logistic regression and Cox proportional hazards models were used to identify factors associated with generic tacrolimus initiation and substitution. Results Two-thirds of oral tacrolimus new users initiated generic tacrolimus. Patients who were older age and black were significantly more likely to initiate generic tacrolimus (adjusted odds ratio [AOR] = 1.02, 95% confidence interval [CI] = 1.001–1.03; AOR = 2.54, 95% CI = 1.40–4.62; respectively). Patients with more concomitant prescriptions, more comorbidities, or higher initial daily dosage had significantly lower likelihoods of initiating generic tacrolimus (AOR = 0.93, 95% CI = 0.87–0.99; AOR = 0.87, 95% CI = 0.77–0.99; AOR = 0.96, 95% CI = 0.93–0.993). Among brand tacrolimus new users, 23.6% substituted with generics within 12 months, and an addition of prior hospitalization or unit of initial daily dosage increment was associated with 35% (subdistribution hazard ratio [SHR] = 1.35, 95% CI = 1.02–1.76) or 2% (SHR = 1.02, 95% CI = 1.00–1.04) increase in likelihood of generic substitution, respectively. Conclusions Understanding associations between patient-level factors with generic tacrolimus initiation and substitution could help practitioners and policymakers monitor treatment effect and facilitate generic tacrolimus utilization.

Clinical and safety outcomes of conversion original tacrolimus to generic tacrolimus in Turkish kidney transplant recipients

IntroductionAfter 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 about the conversion of original to generic tacrolimus, reported from Turkey. MethodsThe 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 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. ResultsThirty-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). There were 9 patients with positive BK-DNA. None of the patients needed a biopsy. ConclusionsBased on the results of our study, renal outcomes are safe and the drugs could be changed safely. Whether AdoportⓇ or PrografⓇ, whichever is used, it is important to take 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.

Real-life Bioequivalence of Tacrolimus in Patients With Living-Related Donor De Novo Renal Transplantation: An Observational Study

Tacrolimus is a narrow therapeutic index drug. As a result, regulatory agencies worldwide recommend stringent bioequivalence evaluation criteria for approval of generics. Despite this, the professional transplantation societies have raised concerns over the safety and efficacy of generic substitutions. We conducted this pragmatic real-life bioequivalence study to assess the effect of generic substitutions of tacrolimus. This was an observational study including recipients of renal transplantation who were considered for generic medication substitution. Transplanted organs were from living-related donors and were performed at least 1 month before the study. Time of administration of the drug, time of dosing with respect to meals, and time of blood sample collection were controlled; however, the lot number of the generic drugs was not controlled. The participants were allowed to use their usual supplies irrespective of the lot number. Concentration (C0) was quantified by liquid chromatography with tandem mass spectrometry after the generic substitution from ABC brand to XYZ brand. The average C0 ± SD with generic ABC was 11.09 ± 4.26 ng/mL and generic ABC was 9.7 ± 4.12 ng/mL. Though there was no statistically significant difference observed between the concentrations, when the individual patient data was examined, 2 patients were found to have a very high concentration of tacrolimus and at least 7 patients fell below the therapeutic range. These derangements called for retitration with the new generic tacrolimus (40%). The results of our study suggest that generic-to-generic substitutions should be carried out very carefully in a closely observed setting in patients with renal transplants. The strength of our study is that it matched the real clinical practice setting as much as possible unlike a bioequivalence study. Therefore, we recommend repeating C0 at least 3 times over a period of 7 to 10 days with a generic substitution to prevent untoward consequences.