Cost-effectiveness analysis of CYP3A5 genotype-guided tacrolimus dosing in solid organ transplantation using real-world data.

The objective of this study was to estimate the cost-effectiveness of CYP3A5 genotype-guided tacrolimus dosing in kidney, liver, heart, and lung transplant recipients relative to standard of care (SOC) tacrolimus dosing, from a US healthcare payer perspective. We developed decision-tree models to compare economic and clinical outcomes between CYP3A5 genotype-guided and SOC tacrolimus therapy in the first six months post-transplant. We derived inputs for CYP3A5 phenotype frequencies and physician use of genotype test results to inform clinical care from literature; tacrolimus exposure [high vs low tacrolimus time in therapeutic range using the Rosendaal algorithm (TAC TTR-Rosendaal)] and outcomes (incidences of acute tacrolimus nephrotoxicity, acute cellular rejection, and death) from real-world data; and costs from the Medicare Fee Schedule and literature. We calculated cost per avoided event and performed sensitivity analyses to evaluate the robustness of the results to changes in inputs. Incremental costs per avoided event for CYP3A5 genotype-guided vs SOC tacrolimus dosing were $176,667 for kidney recipients, $364,000 for liver recipients, $12,982 for heart recipients, and $93,333 for lung recipients. The likelihood of CYP3A5 genotype-guided tacrolimus dosing leading to cost-savings was 19.8% in kidney, 32.3% in liver, 51.8% in heart, and 54.1% in lung transplant recipients. Physician use of genotype results to guide clinical care and the proportion of patients with a high TAC TTR-Rosendaal were key parameters driving the cost-effectiveness of CYP3A5 genotype-guided tacrolimus therapy. Relative to SOC, CYP3A5 genotype-guided tacrolimus dosing resulted in a slightly greater benefit at a higher cost. Further economic evaluations examining intermediary outcomes (e.g., dose modifications) are needed, particularly in populations with higher frequencies of CYP3A5 expressers.

Cost-effectiveness of once-daily vs twice-daily tacrolimus among Hispanic and Black kidney transplant recipients.

BACKGROUND: Tacrolimus is a first-line immunosuppressive therapy to prevent rejection and graft failure in kidney transplant recipients. Once-daily extended-release tacrolimus tablets (LCPT) have been shown to be efficacious, particularly for Hispanic and Black patient subpopulations who are rapid metabolizers, but is more costly than twice-daily immediate-release tacrolimus (IR-Tac). OBJECTIVE: To evaluate the cost-effectiveness of LCPT during the first year of treatment vs IR-Tac in kidney transplant recipients who are Hispanic or Black. METHODS: A decision analytic model from a US payer perspective was developed using (1) subgroup outcomes data pooled from two phase 3 clinical trials that compared LCPT and IR-Tac, and (2) direct costs from real-world data sources (ie, costs of LCPT and IR-Tac treatments, biopsy-proven acute rejection, treatment-related serious adverse events [SAEs], graft failure, and consequent dialysis). The primary outcome was cost per successfully treated patient, defined as having a functioning graft after 1 year and without treatment-related SAEs. Probabilistic sensitivity analyses established distributions for cost and outcomes estimates, and a series of one-way sensitivity analyses identified parameters that had the most effect on results. RESULTS: Total overall cost for the Hispanic group was $14,765 for LCPT and $12,416 for IR-Tac, and total cost in the Black group was $16,626 for LCPT and $9,871 for IR-Tac. Total overall effectiveness of LCPT and IR-Tac was 88.32% and 84.75% in the Hispanic group and 93.24% and 85.78% in the Black group, respectively. The incremental cost-effectiveness ratio (ICER) for using LCPT over IR-Tac during the first year of treatment in the Hispanic group was $65,643 per additional successfully treated patient. The ICER for the Black group was $90,458. The single parameter having the most impact on results in both groups was the probability of a treatment-related SAE in IR-Tac, which accounted for 49% of variation in results in the Hispanic group and 46% in the Black group. CONCLUSIONS: Overall results for both groups show that LCPT is incrementally more costly and more effective compared with IR-Tac, indicating a trade-off scenario. LCPT is a cost-effective strategy if a decision makers' willingness to pay for 1 additional successfully treated patient exceeds the ICER and must be weighed against the costs of graft loss, continuing dialysis, and potential retransplant. This study provides a foundation for further research to update and expand inputs as more data become available to improve real-world relevance and decision making. DISCLOSURES: This study was funded by Veloxis Pharmaceuticals, Inc., which provided clinical trial file data and nonbinding feedback on the model structure, data interpretation, clinical expertise, manuscript review, and areas of publication interest (ie, managed care). Hurwitz, Grizzle, Villa Zapata, and Malone received grant funding from Veloxis Pharmaceuticals, Inc., through University of Arizona to conduct research and analysis for this study. Tyler is employed by Veloxis Pharmaceuticals, Inc. Some of the data reported and used in this research were available from the US Renal Data System, the US Bureau of Labor Statistics, and the Agency for Healthcare Research and Quality's Healthcare Cost and Utility Project. The interpretation and reporting of these data are the responsibility of the authors and in no way should be seen as an official policy or interpretation of the US government.

Population pharmacokinetic analysis and dosing guidelines for tacrolimus co-administration with Wuzhi capsule in Chinese renal transplant recipients.

WHAT IS KNOWN AND OBJECTIVES: Tacrolimus (TAC) is a first-line immunosuppressant which is used to prevent transplant rejection after solid organ transplantation (SOT). However, it has a narrow therapeutic index and high individual variability in pharmacokinetics (PK) and pharmacogenomics (PG). It has been reported that the metabolism of TAC can be affected by genetic factors, leading to different rates of metabolism in different subjects. Wuzhi Capsule (WZC) is a commonly used TAC-sparing agent in Chinese SOT to reduce TAC dosing due to its inhibitory effect on TAC metabolism by enzymes of the CYP3A subfamily. The aims of this study were to assess the effect of TAC+WZC co-administration and genetic polymorphism on the pharmacokinetics of TAC, by using a population pharmacokinetic (PPK) model. A dosing guideline for individualized TAC dosing is proposed based on the PPK study. METHODS: The medical records of 165 adult patients with kidney transplant and their 824 TAC concentrations from two kidney transplantation centres were reviewed. The genotypes of four single-nucleotide polymorphisms (SNPs) in CYP3A5*3 and ABCB1 (rs1128503, rs2032582 and rs1045642) were tested by MASSARRAY. A PPK model was constructed by nonlinear mixed effect model (NONMEM® , Version 7.3). Finally, Monte Carlo simulations were employed to design initial dosing regimens based on the final model. RESULTS AND DISCUSSION: The one-compartmental PPK model with first-order absorption and elimination of TAC was established in kidney transplant recipients (KTRs). CYP3A5*3 had significant impact on the PPK model. The haematocrit (HCT), postoperative time (POD) and CYP3A5*3 genotypes had a significant influence on TAC clearance when combined with WZC. The model was expressed as 23.4 × (HCT/0.3)-0.729  × 0.837 (combination with WZC) × e-0.0875(POD/12.6) ×1.18 (CYP3A5 expressors). For patients carrying the CYP3A5*3/*3 allele and with 30% HCT, the required TAC dose to achieve target trough concentrations of 10-15 ng/ml was 4 mg twice daily (q12h). For patients with the CYP3A5*3/*3 allele, the required dose was 3 mg TAC q12h when combined with WZC, and for patients with the CYP3A5*1/*1 or *1/*3 allele, the required dose was 4 mg of TAC q12h when co-administered with WZC. WHAT IS NEW AND CONCLUSION: Wuzhi Capsule co-administration and CYP3A5 variants affect the PK of TAC Dosing guidelines are made based on the PPK model to allow individualized administration of TAC, especially when co-administered with WZC.

Initial Dosage Optimization of Tacrolimus in Pediatric Patients With Thalassemia Major Undergoing Hematopoietic Stem Cell Transplantation Based on Population Pharmacokinetics.

BACKGROUND: Hematopoietic stem cell transplantation (HSCT) is an effective treatment for hematological disorders. Tacrolimus is widely used after HSCT, but it has highly interindividual variable pharmacokinetics. Population pharmacokinetics (PPK) researches of tacrolimus in children with ß-thalassemia major (ß-TM) undergoing HSCT are insufficient. OBJECTIVE: To establish a PPK model of tacrolimus in children with ß-TM and optimize initial dosing regimen for achieving target concentration of 5 to 15 ng/mL. METHODS: Data on patients aged <18 years were retrospectively collected from January 2017 to December 2018. PPK analysis and Monte Carlo simulations were performed using nonlinear mixed-effects modeling. RESULTS: A data set of 55 patients with 332 concentrations was included. A 2-compartment model could best describe the pharmacokinetics of tacrolimus. The body surface area and gender were significant covariates in the final model. The typical value of clearance, the distribution volume of the central room, the distribution volume of the peripheral room, and the intercompartmental clearance were 5.05L/h, 4.33L, 155L, and 6.22L/h, respectively. The optimal initial dosing regimen of 0.03, 0.04, 0.05, 0.06, and 0.10 mg/kg were appropriate for female children with a weight (WT) of 50 to 10 kg. The regimen of 0.04, 0.05, 0.06, 0.07, and 0.12 mg/kg is suitable for male children with a WT of 50 to 10 kg. The probability of target attainment (PTA) of each regimen reached 91%. CONCLUSION AND RELEVANCE: A stable PPK model of tacrolimus was established. The proposed dosage regimen reached a good PTA, which could provide a reference for tacrolimus therapy.

Assessment of Clinically Relevant Drug Interactions by Online Programs in Renal Transplant Recipients.

BACKGROUND: Potential drug-drug interactions (pDDIs) with immunosuppressive drugs are frequently observed in renal transplant recipients. Drug interaction programs are acknowledged as a fundamental tool to alert physicians to pDDIs, but there is a high concern about variation among different programs in terms of quality and reliability of information. OBJECTIVES: To (a) characterize the difference in severity levels of pDDIs with tacrolimus and cyclosporine provided by 3 drug interaction programs and (b) identify clinically relevant DDIs with these immunosuppressive drugs in renal transplant recipients. METHODS: This study was conducted in a nephrology outpatient clinic at the University Research & Training Hospital between November 2017 and February 2018. A clinical pharmacist attended clinic visits with physicians and evaluated drug interactions. Micromedex, Medscape, and Lexicomp drug interaction programs were used to identify pDDIs and their severities. Furthermore, Drug Interaction Probability Scale (DIPS) criteria were applied to identify clinically relevant drug interactions seen in clinic patients. Finally, a clinical pharmacist intervened to manage clinically relevant drug interactions identified by DIPS. RESULTS: 80 patients (54 under tacrolimus; 26 under cyclosporine treatment) were included in this study. The 3 drug interaction programs generated 648 pDDIs, 63 of which were different drug interaction pairs. Ninety-eight pDDIs were common to all 3 drug interaction programs. Sixty-three different drug interaction pairs were evaluated according to severity level, and 3 drug interaction pairs were at the same level (moderate) among the programs. The Fleiss' kappa overall interrater agreement was poor. The kappa revealed a moderate agreement for interaction pairs with a "severe" rating and a slight agreement for interaction pairs with a "major" rating. According to the DIPS evaluation, 11 pDDIs were classified as "possible," and the percentage of clinically relevant drug-drug interactions was 4.0% (10/248), 4.2% (11/265), and 8.2% (11/135) for Medscape, Lexicomp, and Micromedex, respectively. Although daily doses of immunosuppressive drugs were not changed, the blood concentrations of these drugs increased after administration of an interacting drug. As a result, in order to maintain normal therapeutic range of concentrations, dose reduction or drug change was applied where appropriate. CONCLUSIONS: Interaction checker programs are commonly used by health institutions, since they provide quick and summarized information on mechanism and management of drug interactions, when no clinical pharmacist is present to interpret. However, the likelihood of detecting clinically relevant DDIs by interaction checker programs is relatively low, and there are inconsistencies among different programs. Individualized patient monitoring should be maintained by a multidisciplinary health care team that includes a clinical pharmacist, and decision making should be based on professional assessment of the renal transplant patient. DISCLOSURES: No outside funding supported this study. The authors have no conflicts of interest to disclose.

Model-based assessment of pharmacokinetic changes of sunitinib, tacrolimus, and everolimus in a patient with metastatic renal cell carcinoma after renal transplantation.

The safety of the coadministration of sunitinib with tacrolimus and everolimus with regard to therapeutic drug monitoring has not been demonstrated. Here, we report a patient who showed high sunitinib concentrations, in addition to pharmacokinetic changes in tacrolimus and everolimus after sunitinib therapy. A living-donor renal transplant patient treated with tacrolimus and everolimus was diagnosed with pulmonary and pleural metastases of renal cell carcinoma. The patient received sunitinib therapy (37.5 mg/day, 2 weeks on and 1 week off). This patient exhibited a high total sunitinib concentration (sunitinib, 105.8 ng/mL; N-desethyl sunitinib, 27.9 ng/mL) on day 10 postinitiation and experienced grade 3 diarrhea. The observed sunitinib concentrations were a little higher than those reported in the 421C>A polymorphism of the ATP-binding cassette subfamily G member 2 gene carrier. The observed concentrations of both tacrolimus and everolimus gradually decreased compared with the Bayesian-predicted values after the onset of sunitinib therapy, and the doses of tacrolimus and everolimus were increased. Careful therapeutic drug monitoring of sunitinib, tacrolimus, and everolimus concentrations is necessary during combination therapy, especially after episodes of diarrhea.

Initial dosage optimization of tacrolimus in Chinese pediatric patients undergoing kidney transplantation based on population pharmacokinetics and pharmacogenetics.

BACKGROUND: The purpose of our research was to recommend the initial tacrolimus dosage for Chinese pediatric patients undergoing kidney transplantation based on population pharmacokinetics and pharmacogenetics. METHODS: Demographic data, laboratory results, drug combinations, and pharmacogenetics from Chinese pediatric patients undergoing kidney transplantation were analyzed using non-linear mixed-effects modeling. A Monte Carlo simulation was performed to evaluate the optimal initial dose of tacrolimus. RESULTS: Body weight and post-transplant days, combined with wuzhi-capsule (WZ, extracted from schisandra sphenanthera, whose primary efficient constituents are schisantherin A, schisandrol B, schisandrin, etc., and often used to treat drug-induced hepatitis in Chinese organ transplant patients) and CYP3A5 polymorphisms, influenced the clearance of tacrolimus in these patients. With same weight and post-transplant days, tacrolimus clearance rates from patients carrying CYP3A5*3/*3 and without WZ, carrying CYP3A5*1 allele and without WZ, carrying CYP3A5*3/*3 and with WZ, carrying CYP3A5*1 allele and with WZ were 1, 1.6, 0.72, and 1.152, respectively. In addition, the initial dose for each condition is recommended. CONCLUSIONS: The initial dosage recommendations in the tacrolimus instructions were not individualized, and we have developed more accurate initial doses based on weight and the CYP3A5 genotype. In addition, lower initial doses are recommended with concurrent use of WZ.

[Clinical Pharmacometrics for Rational Drug Treatment].

Pharmacometrics is the mathematical study of pharmacokinetics, disease progression, and clinical outcomes. One objective of pharmacometrics is to facilitate rational drug treatment in patients, also termed clinical pharmacometrics. In this review, our clinical pharmacometric studies conducted over the last 10 years are discussed. Population pharmacokinetic analysis using therapeutic monitoring data for levetiracetam revealed that oral clearance allometrically scaled to both body weight and estimated glomerular filtration rate can accurately predict clinical data from patients of various ages (pediatric to elderly) with varying renal function. Dosage adjustments based on renal function in the package information are effective in controlling the trough and peak concentrations in similar ranges. In addition, a retrospective pharmacokinetic and pharmacodynamic study revealed that the efficacy of low-dose clobazam therapy was significantly influenced by CYP2C19 polymorphisms. Pharmacokinetic and pharmacodynamic models were successfully built using electronic medical information to explain retrospective international normalized ratio values of prothrombin time before and after catheter ablation in warfarin-treated patients. Simulation studies suggest that more than 20 mg of vitamin K2 is unnecessary in the preoperative period of catheter ablation. A physiologically based pharmacokinetic model adapted to tacrolimus pharmacokinetic data in patients who underwent living-donor liver transplantation was constructed, and clarified that oral clearance of this drug was affected by CYP3A5 genotypes in both the liver and intestine to the same extent. In conclusion, pharmacometrics is a useful methodology for individualized and optimized drug therapy.

Tacrolimus-loaded lecithin-based nanostructured lipid carrier and nanoemulsion with propylene glycol monocaprylate as a liquid lipid: Formulation characterization and assessment of dermal delivery compared to referent ointment.

Nanostructured lipid carriers (NLC) and nanoemulsions (NE) are colloid carriers which could improve dermal delivery of tacrolimus. The aims of this study were to evaluate effects of different formulation and process parameters on physicochemical characteristics and stability of lecithin-based NLC with glyceryl palmitostearate as solid and propylene glycol monocaprylate as liquid lipid and to compare the influence of different inner structure of tacrolimus-loaded NLC and corresponding NE on physicochemical characteristics, stability, entrapment efficiency, in vitro drug release and overall skin performance. Solid/liquid lipid ratio, total amount of lipids, homogenization pressure and cooling after the preparation were identified as critical variables in NLC development. Moreover, tacrolimus-loaded NLC emerged as more stabile carrier than NE. Differential stripping performed on porcine ear skin revealed significantly higher tacrolimus amount in stratum corneum from nanocarriers compared to referent ointment (Protopic®). Similarly the highest amount of tacrolimus in hair follicles was obtained using NLC (268.54 ±â€¯92.38 ng/cm2), followed by NE (128.17 ±â€¯48.87 ng/cm2) and Protopic® (77.61 ±â€¯43.25 ng/cm2). Contrary, the highest permeation rate through full-thickness porcine ear skin was observed for Protopic®, implying that the selection of experimental setup is critical for reliable skin performance assessment. Overall, developed NLC could be suggested as promising carrier in a form of lotion for tacrolimus dermal delivery.

Comparison of a time-varying covariate model and a joint model of time-to-event outcomes in the presence of measurement error and interval censoring: application to kidney transplantation.

BACKGROUND: Tacrolimus (TAC) is an immunosuppressant drug given to kidney transplant recipients post-transplant to prevent antibody formation and kidney rejection. The optimal therapeutic dose for TAC is poorly defined and therapy requires frequent monitoring of drug trough levels. Analyzing the association between TAC levels over time and the development of potentially harmful de novo donor specific antibodies (dnDSA) is complex because TAC levels are subject to measurement error and dnDSA is assessed at discrete times, so it is an interval censored time-to-event outcome. METHODS: Using data from the University of Colorado Transplant Center, we investigated the association between TAC and dnDSA using a shared random effects (intercept and slope) model with longitudinal and interval censored survival sub-models (JM) and compared it with the more traditional interval censored survival model with a time-varying covariate (TVC). We carried out simulations to compare bias, level and power for the association parameter in the TVC and JM under varying conditions of measurement error and interval censoring. In addition, using Markov Chain Monte Carlo (MCMC) methods allowed us to calculate clinically relevant quantities along with credible intervals (CrI). RESULTS: The shared random effects model was a better fit and showed both the average TAC and the slope of TAC were associated with risk of dnDSA. The simulation studies demonstrated that, in the presence of heavy interval censoring and high measurement error, the TVC survival model underestimates the association between the survival and longitudinal measurement and has inflated type I error and considerably less power to detect associations. CONCLUSIONS: To avoid underestimating associations, shared random effects models should be used in analyses of data with interval censoring and measurement error.

Comparative assessment of efficacy and safety potential of multifarious lipid based Tacrolimus loaded nanoformulations.

The present work reports the development, optimization and characterization of novel lipid based nanoformulations viz., Liquid crystalline nanoparticles (LCNP), solid lipid nanoparticles (SLN) and nanostructured lipid carriers (NLC) and liposomes loaded with Tacrolimus (Tac) for topical delivery. Different nanoformulations were developed after screening lipids and suitable surfactants depending upon emulsification ability. The various nanoformulations were then optimized (to achieve higher entrapment efficacy, lower particle size, PDI and zeta potential), characterized and loaded into gel. The gels loaded with nanoformulations were also characterized depending upon rheology and viscosity. The gels were analyzed for in vitro drug release, HaCaT cell lines studies and skin permeation studies. The in vivo efficacy studies were carried out using mouse tail model and skin irritation studies using Draize patch test and measurement of TEWL. The developed nanoformulations showed optimum particle size (<200 nm), polydispersity index (PDI < 0.3), zeta potential (≥-10 mV) and higher entrapment efficiency (>85%). The nanoformulations showed higher penetration of Tac into skin. Tac-LCNP, Tac-SLN, Tac-NLC and Tac-liposomes loaded gels showed 14, 11.5, 12.5 and 3.7 folds increment in dermal bioavailability respectively, in comparison to free Tac loaded gel and 2.5, 2 and ∼2 folds augmentation in dermal bioavailability respectively as compared to Tacroz™ Forte. In case of Tac-liposomes, the dermal bioavailability was lower as compared with the marketed formulation, Tacroz™ Forte. Despite, the increased bioavailability into the skin, the developed nanoformulations showed no significant skin irritation. The above mentioned nanoformulations were able to achieve greater penetration of Tac into the skin as compared to marketed ointment of Tac, Tacroz™ Forte.

Effect of CYP3A5 genotype on hospitalization cost for kidney transplantation.

Background Dosage quantities of tacrolimus (TAC) vary according to cytochrome P450 3A5 (CYP3A5) genotype. Genotyping is expected to optimize the response to TAC response and to minimize adverse effects. In Thailand, kidney transplantation is reimbursable with the same diagnosis-related group payment regardless of patient's CYP3A5 genotype. Objective This study aimed to determine the costs of TAC administration, therapeutic drug monitoring (TDM), and hospitalization for kidney transplantation across CYP3A5*1/*1, *1/*3, and *3/*3 genotypes. Setting A single transplant center in a university hospital. Method This is an observational study that collected data from patients pooled from both arms of a randomized controlled trial that tested initial doses of TAC. Main outcome measure TAC and TDM cost and hospitalization cost for transplantation were compared between genotypes. Results The CYP3A5*1/*1 patients had the highest median combined TAC-TDM cost and hospitalization cost ($1062 and $9097), followed by CYP3A5*1/*3 ($859 and $6467) and CYP3A5*3/*3 patients ($761 and $5604). The CYP3A5*1/*1 patients had a higher hospitalization cost by $2787 over the CYP3A5*1/*3 patients, despite marginal significance. The CYP3A5*1/*1 patients had a significantly higher cost of TAC plus TDM (by $309) and hospitalization cost (by $3275) than the CYP3A5*3/*3 patients. Both study costs were significantly higher in patients with delayed graft functioning than in patients with instant or slow graft functioning. Conclusion The benefits of genotype detection in patients with CYP3A5*1/*1 should be considered for a higher reimbursement rate because of the substantial differences in total hospitalization cost for kidney transplantation among patients with different CYP3A5 genotypes.

Tacrolimo de liberação prolongada para profilaxia de rejeição de transplante renal / Prolonged release tacrolimus for renal transplant rejection prophylaxis

CONTEXTO: O transplante renal é a terapia de substituição renal mais custo-efetiva, como evidencia estudo realizado em nosso país, sendo seu grande limitador a rejeição mediada por reação celular ou humoral. A rejeição aguda de enxerto renal é, em geral, definida como uma deterioração aguda da função do enxerto associada às alterações histopatológicas. A prevenção de rejeição aguda com imunossupressão eficaz representa um fator decisivo no aparecimento tardio da nefropatia crônica e espera-se que, dessa forma, reduza as taxas de rejeição aguda e crônica, aumente a sobrevida do enxerto (sem necessidade de diálise) e do paciente. A profilaxia de rejeição ao transplante consiste na terapia de indução ou inicial, que pode se estender por 07 a 10 dias em âmbito hospitalar e terapia de manutenção que se refere ao esquema imunossupressor utilizado posteriormente a este período. É comum que se utilize tacrolimo em ambas as etapas de imunossupressão em associação a outros medicamentos imunossupressores como azatioprina ou micofenolato de mofetila e corticosteroides. A posologia do tacrolimo disponível no SUS, forma de liberação imediata, é de duas tomadas em um dia, entretanto, está registrada no Brasil a forma de liberação prolongada desse medicamento para o qual se preconiza a utilização de uma dose diária. Nesse parecer avalia-se a proposta de incorporação da forma de liberação prolongada ao SUS submetida pela empresa produtora do medicamento. TECNOLOGIA: Tacrolimo na forma de cápsulas de liberação prolongada com 1 mg e 5 mg. PERGUNTA: O uso de tacrolimo na forma de liberação prolongada é eficaz, seguro e custo-efetivo na imunossupressão de pacientes receptores de transplante renal, quando comparado à terapia com tacrolimo de liberação imediata? EVIDÊNCIAS CIENTÍFICAS: A evidência disponível sobre a utilização de tacrolimo de liberação prolongada na prevenção de rejeição aguda de transplante renal em relação à forma de liberação imediata se baseia principalmente em metanálise de alta qualidade metodológica de estudos controlados randomizados. De acordo com essa evidência o medicamento em associação a micofenolato de mofetila e corticoides não tem efeito diferente do tacrolimo de liberação imediata em associação aos mesmos medicamentos quando se avaliam os seguintes desfechos em adultos recém transplantados: mortalidade em seis meses e um ano, rejeição aguda comprovada por biópsia em seis meses e um ano, perda do enxerto em seis meses e um ano e funcionalidade do enxerto em seis meses e um ano após o início do tratamento. Também não se identificaram diferenças em relação à segurança dos medicamentos, mas de forma isolada em um estudo controlado randomizado, um pequeno aumento na frequência de infecção por citomegalovírus em indivíduos tratados com a forma de liberação prolongada. AVALIAÇÃO ECONÔMICA: O demandante considerou o estudo de Kuypers e colaboradores (2013) para subsidiar a escolha do estudo de custo-efetividade como modelo de avaliação econômica. Nesse estudo, controlado randomizado aberto, os pacientes foram alocados a tratamentos com tacrolimo de libração prolongada ou de liberação imediata. O desfecho primário do estudo é a aderência ao tratamento avaliada pela persistência dos pacientes em relação ao tratamento (manutenção no tratamento) e pela implementação do regime de doses em cada tratamento. A persistência dos pacientes ao tratamento reflete a porcentagem dos participantes que permanecem em tratamento durante o tempo de seguimento do estudo e a implementação do tratamento reflete, entre os que persistem no tratamento, a porcentagem de pacientes que permanecem seguindo o esquema posológico corretamente. Para o primeiro elemento do desfecho, a persistência no tratamento, que traduz de fato a aderência não houve diferença significativa entre os grupos (81,5% para o regime de liberação prolongada e 71,9% para o regime de liberação imediata, sem diferença estatística, p=0,0824). Para o segundo desfecho, avaliado somente para os que permanecem em tratamento, ou seja, os aderentes, observou-se diferença significativa, que representa um benefício da forma de liberação prolongada quando se avalia a porcentagem de pacientes que seguem corretamente o esquema posológico (88,2% vs. 78,8%, p=0,0009). Dessa forma, foi equivocada a interpretação do demandante pressupondo uma superioridade do medicamento de liberação prolongada em relação ao de imediata no que diz respeito à aderência. Para os desfechos de efetividade que utiliza no modelo o demandante apresenta a diferença entre as porcentagens de participantes que seguem corretamente o esquema posológico, entre os aderentes (88,2% vs. 78,8%), como uma diferença na aderência, quando não se observa diferença significativa entre as porcentagens de indivíduos que permanecem em tratamento, medida pela persistência ao tratamento. No estudo não se avaliam desfechos clínicos como a porcentagem de rejeição aguda ao enxerto, perda e viabilidade do enxerto ou mortalidade, dessa foram não é possível inferir que a dificuldade de seguir a posologia de tratamento, da forma como avaliada no estudo, traria consequências relevantes aos pacientes. O modelo mais adequado para a avaliação econômica nesse cenário seria um estudo de custo-minimização por não existirem diferenças na efetividade entre esses dois medicamentos. AVALIAÇÃO DE IMPACTO ORÇAMENTÁRIO: Considerando os custos somente dos medicamentos calculados com base em população de peso médio de 69 Kg e dose média de 0,075 m/Kg/dia (forma de liberação prolongada aproximadamente R$ 2.593,00 por paciente e de R$ 925,20 por paciente para a forma de liberação imediata), a velocidade de difusão da tecnologia no SUS (market share) entre 10% e 39% no período de cinco anos e a frequência de transplantes renais projetada para o período de 2018 a 2022, o impacto orçamentário incremental na perspectiva do SUS foi de R$ 882 mil para o primeiro ano e de R$ 42 milhões para os cinco anos da projeção. RECOMENDAÇÃO INICIAL DA CONITEC: Os membros presentes na 71ª reunião ordinária da CONITEC de 03/10/2018 decidiram por unanimidade recomendar de forma preliminar a não incorporação de tacrolimo de liberação prolongada como imunossupressor em transplante renal no SUS. A Comissão entendeu que não se demonstra a superioridade desse medicamento em relação à forma de liberação imediata já incorporada e que, dessa forma, não se justifica a proposta de preço superior submetida pelo demandante. CONSULTA PÚBLICA: O relatório de recomendação da CONITEC foi disponibilizado por meio da Consulta Pública nº 58/2018 entre os dias 16/10/2018 e 05/11/2018. Foram recebidas 01 contribuição técnico-científica e 03 contribuições de experiência ou opinião de pacientes, familiares, amigos ou cuidadores de pacientes, profissionais de saúde ou pessoas interessadas no tema. Após apreciação das contribuições encaminhadas pela Consulta Pública, destaca-se a ausência de novas evidências que pudessem modificar o entendimento firmado no relatório, de que não se demonstra uma correlação entre uma melhoria de 9,8% na implementação do regime terapêutico observada no estudo de Kuypers e colaboradores (2013) e a diminuição na frequência de desfechos clínicos como rejeição aguda comprovada por biópsia, perda do enxerto, mortalidade, frequência de diagnóstico de diabetes, incidência de câncer ou doenças linfoproliferativas e frequência de infecções, após um ano de uso. DELIBERAÇÃO FINAL: Os membros da CONITEC presentes na 73ª Reunião do plenário do dia 06/12/2018 deliberaram, por unanimidade, por não recomendar o tacrolimo de liberação prolongada para a profilaxia de rejeição em transplante renal. Foi assinado o Registro de Deliberação nº 410/2018. DECISÃO: Não incorporar o tacrolimo de liberação prolongada para profilaxia de rejeição em transplante renal, no âmbito do Sistema Único de Saúde - SUS. Dada pela Portaria nº 81, publicada no DOU nº 241, seção 1, página 77, em 17 de dezembro de 2018.

Tacrolimo de liberação prolongada para profilaxia de rejeição de transplante hepático / Prolonged release tacrolimus for prophylaxis of liver transplant rejection

CONTEXTO: O transplante de fígado é indicado para o tratamento da insuficiência hepática aguda, da insuficiência hepática crônica, da cirrose hepática, de distúrbios metabólicos que possam ser corrigidos com o transplante hepático e de carcinoma hepatocelular (CHC). A sobrevida dos receptores de transplante hepático é 69% em 5 anos e tem melhorado devido ao aprimoramento de técnicas cirúrgicas e da logística de captação e alocação dos órgãos ofertados e surgimento de novos imunossupressores. Tacrolimo (TAC) foi introduzido como agente imunossupressor no início da década de 1990, dez anos depois de ciclosporina (CsA) e foi inicialmente desenvolvido para o transplante de fígado. A eficácia do TAC por via oral é maior do que a da CsA, o que tornou o TAC o mais utilizado nos protocolos de imunossupressão, geralmente em combinação com corticoide. A posologia do tacrolimo disponível no SUS, forma de liberação imediata, é de duas tomadas em um dia, entretanto, está registrada no Brasil a forma de liberação prolongada desse medicamento para o qual se preconiza a utilização de uma dose diária. Nesse parecer avalia-se a proposta de incorporação da forma de liberação prolongada ao SUS submetida pela empresa produtora do medicamento. TECNOLOGIA: Tacrolimo na forma de cápsulas de liberação prolongada com 1 mg e 5 mg. PERGUNTA: O uso de tacrolimo na forma de liberação prolongada é eficaz, seguro e custo-efetivo na imunossupressão de pacientes receptores de transplante hepático, quando comparado à terapia com tacrolimo de liberação imediata? EVIDÊNCIAS CIENTÍFICAS: A evidência disponível sobre a utilização de tacrolimo de liberação prolongada na prevenção de rejeição aguda de transplante hepático é de alta qualidade baseando-se em estudos controlados randomizados duplo-cegos de boa qualidade metodológica. De acordo com essa evidência o medicamento em associação a corticoides é nãoinferior ao tacrolimo de liberação imediata quando se avalia o efeito na diminuição de rejeição aguda somente em adultos recém transplantados ou já em fase de manutenção com a forma de liberação imediata, após conversão para a forma de liberação prolongada. Além disso, é possível, mas com um grau maior de incerteza, que em longo prazo (até três anos) o medicamento tenha um efeito marginal no aumento da sobrevida de indivíduos transplantados. AVALIAÇÃO ECONÔMICA: O demandante considerou um estudo observacional retrospectivo elaborado com informações provenientes do registro de transplantes europeu para a fundamentação da escolha do estudo de custo-efetividade como modelo para a avaliação econômica. De acordo com o estudo a utilização durante três anos de tacrolimo de liberação prolongada está relacionado a aumentos na viabilidade do enxerto (8%) e na sobrevida global (7%) quando se avaliaram os dados ajustados por fatores de risco conhecidamente interferentes nos desfechos avaliados. O estudo foi elaborado na perspectiva do SUS com horizontes temporais de 3 e 30 anos. Os desfechos de efetividade utilizados foram a taxa de perda do enxerto e anos de vida salvos. Foram utilizadas taxas de desconto anuais de 5% para os custos e desfechos. Foi apresentado um modelo de Markov que compreende três estados de saúde: "vivo com enxerto"; "vivo sem enxerto" e "morto". Foram calculados os custos associados a cada estado por meio de microcusteio. Os resultados da análise para o horizonte temporal de 3 anos apontam para uma dominância da tecnologia em análise, o tacrolimo de liberação prolongada, em relação ao medicamento já incorporado ao SUS, de liberação imediata. Na simulação o uso da forma de liberação imediata causou um gasto total adicional de R$ 3 mil reais em média por paciente e um pior desempenho, ocasionando mais perdas de enxerto e mortes. Em uma simulação de 30 anos essa dominância não se mantém e os resultados apontam para um cenário de maior efetividade associada a um maior gasto para a tecnologia de liberação prolongada em relação à de liberação imediata. Quando se avaliam os anos de vida salvos, a relação de custo-efetividade incremental é de R$ 13.722,00 por ano de vida salvo. AVALIAÇÃO DE IMPACTO ORÇAMENTÁRIO: Considerando os custos somente dos medicamentos calculados com base em população de peso médio de 70 Kg e dose média de 0,075 m/Kg/dia (forma de liberação prolongada de R$ 2.593,00 por paciente e de R$ 925,20 por paciente para a forma de liberação imediata), a velocidade de difusão da tecnologia no SUS (market share) entre 10% e 39% no período de cinco anos e a frequência de transplantes de fígado projetada para o período de 2018 a 2022, o impacto orçamentário incremental na perspectiva do SUS foi de R$ 284 mil para o primeiro ano e de R$ 14 milhões para os cinco anos da projeção. RECOMENDAÇÃO INICIAL DA CONITEC: Os membros presentes na 71ª reunião ordinária da CONITEC de 03/10/2018 decidiram por unanimidade recomendar de forma preliminar a não incorporação de tacrolimo de liberação prolongada como imunossupressor em transplante hepático no SUS. A Comissão entendeu que o medicamento é não-inferior à forma de liberação imediata já incorporada, não se demonstrando a superioridade, e que, dessa forma, não se justifica a proposta de preço superior submetida pelo demandante. CONSULTA PÚBLICA: O Relatório de Recomendação da CONITEC foi disponibilizado por meio da Consulta Pública nº 56/2018 entre os dias 16/10/2018 e 05/11/2018. Não foram recebidas contribuições técnico-científicas e 05 contribuições de experiência ou opinião. Todas as cinco opiniões recebidas foram contrárias à recomendação inicial da CONITEC, pelos seguintes motivos: o uso do medicamento de liberação prolongada além proporcionar uma maior comodidade posológica e aumentar a adesão ao tratamento, estaria relacionado a uma menor taxa de rejeição do transplante e a uma menor frequência de utilização de corticoides para controlar esses casos de rejeição. Após apreciação das contribuições destaca-se a ausência de novas evidências que pudessem modificar o entendimento firmado no relatório, de que não se demonstra pelas evidências mais robustas uma diferença entre os dois medicamentos avaliados em relação ao efeito em importantes desfechos clínicos relacionados à imunossupressão em transplante hepático, como rejeição aguda comprovada por biópsia após seis meses de uso e de mortalidade após um ano de uso. Dessa forma, o pressuposto de superioridade utilizado nos estudos econômicos não se sustentaria, questionando-se também a validade da proposta de maior preço para a forma de liberação prolongada. DELIBERAÇÃO FINAL DA CONITEC: Os membros da CONITEC presentes na 73ª Reunião do plenário do dia 06/12/2018 deliberaram, por unanimidade, por não recomendar o tacrolimo de liberação prolongada para a profilaxia de rejeição em transplante hepático. Foi assinado o Registro de Deliberação nº 411/2018. DECISÃO: Não incorporar o tacrolimo de liberação prolongada para profilaxia de rejeição em transplante hepático, no âmbito do Sistema Único de Saúde - SUS. Dada pela Portaria nº 80, publicada no DOU nº 241, seção 1, página 77, em 17 de dezembro de 2018.

Assessment of corneal and conjunctival metaplasia by impression cytology during the treatment of canine keratoconjunctivitis sicca.

The purpose of this study was to assess the condition of cells in the conjunctiva and corneal epithelium prior to and during cyclosporine- or tacrolimusbased treatment of keratoconjunctivitis sicca (KCS). The study was performed on 40 dogs with KCS. The dogs were divided into two groups of 20 animals each. In Group I, 0.75% cyclosporine eye drops were administered three times a day, while in Group II 0.02% tacrolimus eye drops were administered twice daily. Additionally, each group was subdivided into three subgroups based on the results of the Schirmer I tear test (STT I). Evaluation of cellular metaplasia in the cornea and the palpebral and bulbar conjunctiva based on the Nelson-Adams scale was performed by impression cytology using Millipore round filters (Millipore VSWP 01300 DA) of 25 µm pore diameter applied to the studied area. Ophthalmological and cytological examinations were performed prior to the treatment as well as after one and two months of therapy. In both groups, a decrease in Nelson-Adams values was observed, corresponding to the increasing STT values [Rxy Spearman statistically significant correlation coefficient values between -0.75 (P < 0.001) and -0.45 (P < 0.01)]. The absence of goblet cells was observed in all dogs, regardless of the KCS stage. Goblet cells reappeared following both tacrolimus- and cyclosporine-based treatment in impression cytology specimens classified as 0 in the Nelson-Adams scale. The extent of corneal and conjunctival metaplasia in the course of tacrolimus- and cyclosporine-based treatment of KCS decreases with increasing STT values.

Angiolymphoid hyperplasia with eosinophilia: a case report.

BACKGROUND: Angiolymphoid hyperplasia with eosinophilia is a benign neoplasm that includes blood vessel proliferation and a dense eosinophilic inflammatory infiltrate. Mostly, it affects middle-aged adults manifesting as flesh/plum-colored pruritic nodules and papules, most commonly affecting the ear and the periauricular area. CASE PRESENTATION: In this case, we report a 13-year-old Caucasian girl with bilateral, huge, protruding, and yellowish nostril masses which were peculiar in location and of gross appearance. At first, the disease proved to be a diagnostic dilemma. After making a diagnosis of angiolymphoid hyperplasia with eosinophilia, the disease also proved to be a therapeutic dilemma. It did not respond to oral prednisolone or to oral indomethacin, and it proved to be resistant to topical steroids. Although surgery is the standard therapeutic approach, it recurred despite multiple surgical attempts. However, the only regimen that seemed to partially control the lesion was intralesional steroids combined with topical tacrolimus ointment. CONCLUSIONS: Angiolymphoid hyperplasia with eosinophilia proves a therapeutic dilemma, because there is a large variety of proposed treatments, yet there is not enough data on most of them. Although the disease is not deadly by itself, it usually presents with disfiguring lesions that grimly affect the patient's quality of life. This warrants further research and efforts to find an effective cure and a unified therapeutic approach.

Conversion From Once-Daily Prolonged-Release Tacrolimus to Once-Daily Extended-Release Tacrolimus in Stable Liver Transplant Recipients.

OBJECTIVES: After organ transplant, strategies to simplify the therapeutic regimen may improve adherence and prevent rejection and/or graft loss. The aim of the present study was to evaluate the safety of conversion from once-daily prolonged-release tacrolimus (Advagraf; Astellas Pharma Europe Limited, Middlesex, UK) to once-daily extended-release tacrolimus (Envarsus; Chiesi SAS, Nanterre, France) in stable adult liver transplant recipients. MATERIALS AND METHODS: This observational study inclu-ded 44 liver transplant patients (median age of 59 y; 63.6% men; median delay after transplant of 72.5 mo). Conversion was based on a 1:0.70 proportion. RESULTS: Mean dose of tacrolimus was 2.65 ± 1.24 mg/day before conversion and 2.09 ± 1.68 mg/day after conversion (P < .05), with ratio of 1:0.79. Mean serum tacrolimus trough level increased after conversion (4.92 ± 1.65 vs 5.60 ± 2.89 ng/mL; P < .05), with ratio of 1:1.14. Six months after conversion, mean dose of tacrolimus was 1.65 ± 0.93 mg/day (ratio of 1:0.62) and mean serum tacrolimus trough level was 4.82 ± 1.85 ng/mL, similar to the initial level before conversion. At the end of follow-up, 2 patients had returned to once-daily prolonged-release tacrolimus because of adverse effects (allergy, digestive trouble), which resolved thereafter. The mean cost of tacrolimus therapy was 5.54 ± 2.29 Euros/patient/day before conversion and 4.11 ± 2.32 Euros/patient/day after conversion (P < .05). CONCLUSIONS: Conversion from prolonged-release to extended-release tacrolimus in stable liver transplant patients is safe and cost-effective; however, initially, dose adaptations and careful monitoring are required.

Pharmacokinetics and Clinical Outcomes of Generic Tacrolimus (Hexal) Versus Branded Tacrolimus in De Novo Kidney Transplant Patients: A Multicenter, Randomized Trial.

BACKGROUND: Scrupulous comparison of the pharmacokinetic and clinical characteristics of generic tacrolimus formulations versus the reference drug (Prograf) is essential. The pharmacokinetics of the Tacrolimus Hexal (TacHexal) formulation is similar to Prograf in stable renal transplant patients, but data in de novo patients are lacking. METHODS: De novo kidney transplant patients were randomized to generic tacrolimus (TacHexal) or Prograf in a 6-month open-label study. RESULTS: The primary end point, the dose-normalized area under the curve0-12h at month 1 posttransplant, was similar with TacHexal or Prograf; back-transformed geometric means of adjusted log-transformed values (analysis of variance) were 18.99 ng·h·L (TacHexal) and 20.48 ng·h·L (Prograf) (ratio, 1.08; 90% confidence interval, 0.84-1.38; P = 0.605). The dose-normalized peak concentration geometric means at month 1 was also comparable between treatments (ratio, 1.16; 90% confidence interval, 0.88-1.54; P = 0.377). There were no relevant differences in other pharmacokinetic parameters at month 1 or in area under the curve0-4h and trough concentration when measured at months 3 and 6. The adjusted change in mean estimated glomerular filtration rate from baseline to month 6 (Nankivell) was noninferior for TacHexal versus Prograf using observed values (47.7 vs 38.6 mL/min per 1.73 m, P < 0.001) and was superior based on observed values (P = 0.044) but not using last observation-carried forward method. Rates of biopsy-proven acute rejection (5.7% vs 7.9%), adverse events, and serious adverse events were similar with TacHexal or Prograf. CONCLUSION: Tacrolimus pharmacokinetics is similar with TacHexal and Prograf early after kidney transplantation. Efficacy and safety in this limited data set were comparable, with at least equivalent graft function under TacHexal.

Therapeutic monitoring of pediatric transplant patients with conversion to generic tacrolimus.

OBJECTIVE: Therapeutic 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. METHOD: Pediatric 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. RESULTS: In 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. CONCLUSION: In 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.

Objetivo: La monitorización terapéutica durante el intercambio de marcas comerciales de inmunosupresores es esencial para mantener una similar exposición al fármaco en pacientes trasplantados. Sin embargo, la información disponible en trasplante pediátrico es limitada. El objetivo del trabajo fue evaluar la exposición, seguridad y eficacia en pacientes pediátricos trasplantados en etapa de mantenimiento, sujetos a intercambio entre el producto innovador y el genérico de tacrolimus. Método: El Área de Farmacia del hospital detectó aquellos pacientes sujetos a intercambio de formulaciones según la disponibilidad de medicamentos. Se obtuvieron las concentraciones de tacrolimus en el valle (C0), parámetros de laboratorio y características clínicas antes y después del intercambio. El análisis estadístico se realizó mediante el test de muestras pareadas de Wilcoxon. Resultados: Se incluyeron 10 pacientes con trasplante renal, hepático, cardíaco y de células hematopoyéticas. La mediana (rango) del C0 normalizado por la dosis pre y post intercambio fue 74,8[(ng/ml)/(mg/kg)](13,8-518,4) y 65,1[(ng/ml)/(mg/kg)] (13,5-723,5), respectivamente (p>0,05). La dosis de tacrolimus fue 0,070(mg/kg) (0,024-0,461) y 0,069(mg/kg) (0,017-0,571) para el innovador y el genérico, respectivamente (p>0,05). Los parámetros de laboratorio de funcionalidad renal y hepática no cambiaron con la conversión de marcas (p>0,05). No se observaron eventos adversos, rechazo agudo, muerte o pérdida del injerto durante el periodo analizado. Conclusiones: En la población estudiada, no se observaron diferencias significativas en los parámetros de laboratorio, exposición al tacrolimus o dosis en el intercambio de marcas comerciales. Destacamos el rol de la monitorización terapéutica a la hora de garantizar una sustitución segura, especialmente en poblaciones vulnerables.

Evaluación de la efectividad y seguridad de tacrolimus forma farmacéutica de liberación prolongada en comparación con tacrolimus forma farmacéutica de liberación inmediata / Evaluation of the effectiveness and safety of tacrolimus prolonged-release dosage form compared to tacrolimus immediate release dosage form

CONTEXTO: Se recibe el expediente 2002-8946-16-9 el día 22 de Agosto de 2016, en donde se solicita evaluar el impacto económico de la incorporación del tacrolimus en su forma farmacéutica de liberación prolongada (FFLP) en comparación con la forma farmacéutica de liberación inmediata (FFLI). En dicho expediente consta que se realizaron en ANMAT e INCUCAI evaluaciones de eficacia comparativa entre el tacrolimus en ambas formas farmacéuticas encontrándose equivalencia en la eficacia. En consonancia con el informe presentado el día 26 de Setiembre de 2016 y debido a que no fue posible obtener los resultados de las evaluaciones mencionadas, se decide realizar la evaluación de la efectividad de la forma farmacéutica de liberación prolongada (FFLP) en comparación con la efectividad de la forma farmacéutica de liberación inmediata (FFLI). TECNOLOGÍA: El tratamiento inmunosupresor representa un pilar fundamental en la sobrevida de los pacientes trasplantados. El tacrolimus, agente inmunosupresor de la familia de los inhibidores de la calcineurina, es uno de los dos agentes más usados en todo el mundo para la prevención de rechazo de injertos. La no adherencia al tratamiento es uno de los principales factores de riesgo para desarrollar malos resultados a largo plazo luego de un trasplante, y constituye la causa prevenible más importante de pérdida del injerto. Se postula que las intervenciones que mejoren la adherencia al tratamiento inmunosupresor podrían mejorar la sobrevida del injerto. En este sentido, se ha desarrollado una forma farmacéutica de tacrolimus de liberación prolongada (FFLP) que permite la administración una sola vez al día, en contraste con la forma farmacéutica tradicional, de liberación inmediata (FFLI). CARACTERÍSTICAS DE LA TECNOLOGÍA: El tacrolimus es un agente inmunosupresor cuya actividad se ha demostrado en experimentos tanto in vivo como in vitro. Pertenece al grupo farmacoterapéutico de los inmunosupresores inhibidores de la alcineurina. Su acción se ejerce mediante la inhibición de la formación de linfocitos citotóxicos, principales responsables del rechazo del injerto. BÚSQUEDA Y ANÁLISIS DE LA EVIDENCIA CIENTÍFICA: Se realizó una amplia búsqueda de evidencia científica en diversas bases de datos bibliográficas mediante distintas estrategias definidas para responder a la pregunta de investigación. No se utilizaron filtros temporales, por grupo etáreo o por status de publicación. Se incluyeron Estudios Controlados Aleatorizados (ECA). La búsqueda y selección se realizó de manera independiente por dos investigadoras. Se realizó valoración crítica de la evidencia mediante la Herramienta Cochrane para la valoración de sesgos de ensayos clínicos. En caso de desacuerdo se consultó a una tercera profesional. Se definieron como desenlaces de interés: 1. sobrevida global al final del seguimiento, 2. sobrevida del injerto al final del seguimiento, 3. rechazo agudo documentado por biopsia o Enfermedad de Injerto contra Huésped, 4. diabetes de diagnóstico posterior al trasplante, 5. hipertensión arterial de novo, 6. calidad de vida y 7. enfermedad renal crónica al final del seguimiento. Se realizaron análisis cualitativos y cuantitativos de los puntos finales de interés, utilizándose el software de la Colaboración Cochrane, disponible on line: Review Manager- versión 5.3 (RevMan 5.3). RESULTADOS DE LOS ESTUDIOS SELECCIONADOS: Fueron incluidos 15 ECAs, los cuales reportaron información proveniente de 4.131 pacientes receptores de trasplante de órganos sólidos. Los hallazgos de los estudios fueron sintetizados a través de metanálisis en los desenlaces 1 a 5, arrojando las siguientes estimaciones en la comparación de FFLP y FFLI: sobrevida global al final del seguimiento OR 0,95 (IC95% de 0,67 a 1,36; p 0,79); sobrevida del injerto OR 1 (IC95% de 0,77 a 1,29; p 0,99); rechazo agudo documentado por biopsia OR 1,04 (IC95% de 0,86 a 1,24; p 0,71); diabetes de diagnóstico posterior al trasplante OR 1,05 (IC95% de 0,87 a 1,26; p 0,61); hipertensión arterial de novo OR 0,94 (IC95% 0,75 a 1,18; p 0,61). En el caso de enfermedad renal crónica, el desenlace se reportó en 13 de los estudios incluidos, no detectándose diferencias significativas en ninguno de los trabajos. CONCLUSIONES DEL ANÁLISIS: Este informe se basa en una revisión no sistemática de la literatura y las recomendaciones que pueda contener deben interpretarse en el contexto en que fue realizada la evaluación. Dichas recomendaciones son de carácter no vinculante. Su adopción dependerá del critério de quien deba implementarla. En cuanto a calidad de vida y adherencia al tratamiento, se evaluó en 3 de los estudios incluidos, que no reportaron diferencias entre en tratamiento con FFLP vs FFLI. La efectividad y la seguridad de tacrolimus en su forma farmacéutica de liberación prolongada resultaron, de acuerdo a la evidencia encontrada y al análisis efectuado, equivalentes a las de la forma farmacéutica de liberación inmediata para todos los resultados de salud considerados. La indicación de una u otra forma farmacéutica deberá basarse en las preferencias de los pacientes y los costos derivados de una u otra estrategia.