Evaluation of the performance of a prior tacrolimus population pharmacokinetic kidney transplant model among adult allogeneic hematopoietic stem cell transplant patients.
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ABSTRACT:
SUBMITTER: Zhu J
PROVIDER: S-EPMC8212733 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Tacrolimus exhibits high inter-patient pharmacokinetics (PK) variability, as well as a narrow therapeutic index, and therefore requires therapeutic drug monitoring. Germline mutations in cytochrome P450 isoforms 4 and 5 genes (CYP3A4/5) and the ATP-binding cassette B1 gene (ABCB1) may contribute to interindividual tacrolimus PK variability, which may impact clinical outcomes among allogeneic hematopoietic stem cell transplantation (HSCT) patients. In this study, 252 adult patients who received tacrolimus for acute graft versus host disease (aGVHD) prophylaxis after allogeneic HSCT were genotyped to evaluate if germline genetic variants associated with tacrolimus PK and pharmacodynamic (PD) variability. Significant associations were detected between germline variants in CYP3A4/5 and ABCB1 and PK endpoints (e.g., median steady-state tacrolimus concentrations and time to goal tacrolimus concentration). However, significant associations were not observed between CYP3A4/5 or ABCB1 germline variants and PD endpoints (e.g., aGVHD and treatment-emergent nephrotoxicity). Decreased age and CYP3A5*1/*1 genotype were independently associated with subtherapeutic tacrolimus trough concentrations while CYP3A5*1*3 or CYP3A5*3/*3 genotypes, myeloablative allogeneic HSCT conditioning regimen (MAC) and increased weight were independently associated with supratherapeutic tacrolimus trough concentrations. Future lines of prospective research inquiry are warranted to use both germline genetic and clinical data to develop precision dosing tools that will optimize both tacrolimus dosing and clinical outcomes among adult HSCT patients.
| S-EPMC7037631 | biostudies-literature
Project description:Pharmacokinetic analyses comparing generic tacrolimus preparations versus the reference drug in kidney transplant patients are lacking. A prospective, multicenter, open-label, randomized, two-period (14 days per period), two-sequence, crossover and steady-state pharmacokinetic study was undertaken to compare twice-daily generic tacrolimus (Sandoz) versus reference tacrolimus (Prograf®) in stable renal transplant patients. AUC(0-12h) and peak concentration (C(max) ) were calculated from 12 h pharmacokinetic profiles at the end of each period (days 14 and 28). Of 71 patients enrolled, 68 provided evaluable pharmacokinetic data. The ratios of geometric means were 1.02 (90% CI 97-108%, p = 0.486) for AUC(0-12h) and 1.09 (90% CI 101-118%, p = 0.057) for C(max) . Mean (SD) C(0) was 7.3(1.8) ng/mL for generic tacrolimus versus 7.0(2.1) ng/mL for reference tacrolimus based on data from days 14 and 28. Correlations between 12 h trough levels and AUC were r = 0.917 for generic tacrolimus and r = 0.887 for reference drug at day 28. These data indicate that generic tacrolimus (Sandoz) has a similar pharmacokinetic profile to the reference drug and is bioequivalent in kidney transplant recipients according to US Food and Drug Administration and European Medicines Agency guidelines.
| S-EPMC3472020 | biostudies-literature
Project description:BK virus (BKV) is associated with kidney and bladder disease after hematopoietic cell transplantation (HCT) but less is known about the seroprevalence of pre-transplant antibodies to BKV in children. We measured BKV IgG antibody titers in 36 children before HCT. BKV IgG antibodies were detected in all 36 patients, with 28/36 (77.8%) developing BK viremia in the first 100 days. Pre-HCT BKV IgG antibody titers >1:40,960 were protective against later BK viremia ≥10,000 copies/ml. The seroprevalence of antibodies to BKV is high in children undergoing HCT and post-transplant BK viremia, which is associated with bladder and kidney injury, is common.
| S-EPMC4515143 | biostudies-literature
Project description:Introduction: Polymorphisms in genes responsible for the metabolism and transport of tacrolimus have been demonstrated to influence clinical outcomes for patients following allogeneic hematologic stem cell transplant (allo-HSCT). However, the clinical impact of germline polymorphisms specifically for oral formulations of tacrolimus is not fully described. Methods: To investigate the clinical impact of genetic polymorphisms in CYP3A4, CYP3A5, and ABCB1 on oral tacrolimus pharmacokinetics and clinical outcomes, we prospectively enrolled 103 adult patients receiving oral tacrolimus for the prevention of graft-versus-host disease (GVHD) following allo-HSCT. Patients were followed in the inpatient and outpatient phase of care for the first 100 days of tacrolimus therapy. Patients were genotyped for CYP3A5 *3 (rs776746), CYP3A4 *1B (rs2740574), ABCB1 exon 12 (rs1128503), ABCB1 exon 21 (rs2032582), ABCB1 exon 26 (rs1045642). Results: Expression of CYP3A5 *1 was highly correlated with tacrolimus pharmacokinetics in the inpatient phase of care (p < 0.001) and throughout the entirety of the study period (p < 0.001). Additionally, Expression of CYP3A5 *1 was associated with decreased risk of developing AKI as an inpatient (p = 0.06). Variants in ABCB1 were not associated with tacrolimus pharmacokinetics in this study. We were unable to discern an independent effect of CYP3A4 *1B or *22 in this population. Conclusion: Expression of CYP3A5 *1 is highly influential on the pharmacokinetics and clinical outcomes for patients receiving oral tacrolimus as GVHD prophylaxis following allo-HSCT.
| S-EPMC10800424 | biostudies-literature
Project description:AimsVarious mycophenolate mofetil (MMF) population pharmacokinetic (popPK) models have been developed to describe its PK characteristics and facilitate its optimal dosing in adult kidney transplant recipients co-administered with tacrolimus. However, the external predictive performance has been unclear. Thus, this study aimed to comprehensively evaluate the external predictability of published MMF popPK models in such populations and investigate the potential influencing factors.MethodsThe external predictability of qualified popPK models was evaluated using an independent dataset. The evaluation included prediction- and simulation-based diagnostics, and Bayesian forecasting. In addition, factors influencing model predictability, especially the impact of structural models, were investigated.ResultsFifty full PK profiles from 45 patients were included in the evaluation dataset and 11 published popPK models were identified and evaluated. In prediction-based diagnostics, the prediction error within ±30% was less than 50% in most published models. The prediction- and variability-corrected visual predictive check and posterior predictive check showed large discrepancies between the observations and simulations in most models. Moreover, the normalized prediction distribution errors of all models did not follow a normal distribution. Bayesian forecasting demonstrated an improvement in the model predictability. Furthermore, the predictive performance of two-compartment (2CMT) models incorporating the enterohepatic circulation (EHC) process was not superior to that of conventional 2CMT models.ConclusionsThe published models showed large variability and unsatisfactory predictive performance, which indicated that therapeutic drug monitoring was necessary for MMF clinical application. Further studies incorporating potential covariates need to be conducted to investigate the key factors influencing model predictability of MMF.
| S-EPMC6422729 | biostudies-literature
Project description:We aimed to characterize the population pharmacokinetics (PK) of vedolizumab for acute graft-versus-host disease prophylaxis in adults undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT) and assess potential clinically relevant covariates. Dosing, patient characteristics, and PK from a phase 1b, open-label, dose-finding study of vedolizumab 75 mg initial dose escalated to 300 mg and a phase 3 study of vedolizumab 300 mg in patients receiving allo-HSCT were analyzed using a two-compartment population PK model with linear elimination. Covariates included age, race, weight, sex, albumin, lymphocyte count, GvHD type, and concomitant medications. Weight, albumin, and lymphocyte count were time-varying covariates. Model selection was driven by goodness-of-fit criteria, precision of parameter estimates, and visual predictive checks. In 193 patients undergoing allo-HSCT, vedolizumab PK were well described by a two-compartment, linear PK model. Using reference covariate values, final parameter estimates (95% confidence intervals [CI]) were: clearance, 0.148 (0.136, 0.162) L/day; central volume of distribution, 3.12 (3.03, 3.21) L; intercompartmental clearance, 0.500 (0.408, 0.612) L/day; and peripheral volume of distribution, 3.95 (3.52, 4.44) L. Weight and albumin were the most important predictors of vedolizumab PK, with clearance decreasing by ≈20% for low body weight/high albumin and increasing by ≈30% for high body weight/low albumin. There was an inverse relationship between vedolizumab clearance and age, but no detectable effect for lymphocyte count or GvHD type. Post hoc analyses did not detect any relationship between vedolizumab PK and concomitant medications. In summary, the covariates studied did not have a clinically meaningful effect on the PK of vedolizumab.
| S-EPMC11374527 | biostudies-literature
Project description:As survival rates in allogeneic hematopoietic stem cell transplantation (HSCT) continue to improve, attention to long-term complications, including cardiovascular disease, becomes a major concern. Cardiovascular disease and dyslipidemia are a common, yet often overlooked occurrence post-HSCT that results in significant morbidity and mortality. Also, increasing evidence shows that several anti-hyperlipidemia medications, the 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors in particular, may have a role in modulating graft-versus-host disease (GVHD). However, factors such as drug-drug interactions, adverse effect profiles, and the relative efficacy in lowering cholesterol and triglyceride levels must be taken into account when choosing safe and effective lipid-lowering therapy in this setting. This review seeks to provide guidance to the clinician in the management of dyslipidemia in the allogeneic HSCT population, taking into account the recently published American College of Cardiology/American Heart Association guidelines on hyperlipidemia management, special considerations in this challenging population, and the evidence for each agent's potential role in modulating GVHD.
| S-EPMC4408224 | biostudies-literature
Project description:AimSeveral tacrolimus population pharmacokinetic models in adult renal transplant recipients have been established to facilitate dose individualization. However, their applicability when extrapolated to other clinical centres is not clear. This study aimed to (1) evaluate model external predictability and (2) analyze potential influencing factors.MethodsPublished models were screened from the literature and were evaluated using an external dataset with 52 patients (609 trough samples) collected by postoperative day 90 via methods that included (1) prediction-based prediction error (PE%), (2) simulation-based prediction- and variability-corrected visual predictive check (pvcVPC) and normalized prediction distribution error (NPDE) tests and (3) Bayesian forecasting to assess the influence of prior observations on model predictability. The factors influencing model predictability, particularly the impact of structural models, were evaluated.ResultsSixteen published models were evaluated. In prediction-based diagnostics, the PE% within ±30% was less than 50% in all models, indicating unsatisfactory predictability. In simulation-based diagnostics, both the pvcVPC and the NPDE indicated model misspecification. Bayesian forecasting improved model predictability significantly with prior 2-3 observations. The various factors influencing model extrapolation included bioassays, the covariates involved (CYP3A5*3 polymorphism, postoperative time and haematocrit) and whether non-linear kinetics were used.ConclusionsThe published models were unsatisfactory in prediction- and simulation-based diagnostics, thus inappropriate for direct extrapolation correspondingly. However Bayesian forecasting could improve the predictability considerably with priors. The incorporation of non-linear pharmacokinetics in modelling might be a promising approach to improving model predictability.
| S-EPMC4834594 | biostudies-literature
Project description:Post bone marrow transplant patients are susceptible to atypical infections, especially viral pathogens. The risk increases many folds in cases of allogeneic transplantation, which also receive GVHD prophylaxis. Viral pathogens like cytomegalovirus and herpes are the common ones encountered during follow-up period. However, in recent times there have been reports of a variety of disease manifestations of rare viruses like polyoma virus and adenovirus. These viral infections may play a crucial role in morbidity and mortality in immunocompromised patients. We hereby elaborate the follow-up course of a 36-year-old post allogeneic transplant patient of acute myeloid leukemia who developed adenovirus related haemorrhagic cystitis. Treatment with oral ribavirin lead to dramatic improvement in symptomatology within a week. This cases re-emphasizes the fact that after ruling out the commoner pathogens, it's of utmost importance to strongly consider the atypical pathogens in such cases.
| S-EPMC4925499 | biostudies-other
Project description:PurposeCognitive impairment is common and consequential in patients with cancer who undergo allogeneic hematopoietic stem cell transplantation (HSCT). However, there is no standard of care for evaluating cognition in patients prior to or after receiving HSCT, and it is not known which patients are at highest risk for cognitive impairment. The objectives of this study were to describe cognitive function in patients prior to allogeneic HSCT and identify demographic, disease-related, and psychosocial factors associated with cognitive function.MethodsPrior to HSCT, participants completed the Montreal Cognitive Assessment (MoCA). We assessed bivariable associations between continuous MoCA scores and demographic, disease-related, and psychosocial variables using linear regression. Variables significant at the p < 0.2 level were adjusted for age, sex, and years of education in multiple linear regression analyses.ResultsOver 50% of participants demonstrated evidence of cognitive impairment (MoCA < 26) prior to transplantation. When adjusted for demographic variables, two characteristics were significantly associated with worse cognitive function: the hematopoietic cell transplantation-comorbidity index score (p = 0.01) and history of alcohol or substance abuse (p = 0.02). Pre-HSCT cancer and cancer treatment-specific variables were not associated with cognitive function.ConclusionCognitive impairment is common in patients scheduled to receive HSCT. Pre-transplantation evaluation of medical comorbidities and history of substance abuse may be important in identifying patients at risk for cognitive impairment. Further research characterizing the trajectory and impact of cognitive impairment on patient symptom burden and function may help improve outcomes.
| S-EPMC7897215 | biostudies-literature