A population pharmacokinetic model to predict the individual starting dose of tacrolimus in adult renal transplant recipients.

AIMS: The aims of this study were to describe the pharmacokinetics of tacrolimus immediately after kidney transplantation, and to develop a clinical tool for selecting the best starting dose for each patient. METHODS: Data on tacrolimus exposure were collected for the first 3 months following renal transplantation. A population pharmacokinetic analysis was conducted using nonlinear mixed-effects modelling. Demographic, clinical and genetic parameters were evaluated as covariates. RESULTS: A total of 4527 tacrolimus blood samples collected from 337 kidney transplant recipients were available. Data were best described using a two-compartment model. The mean absorption rate was 3.6 h-1 , clearance was 23.0 l h-1 (39% interindividual variability, IIV), central volume of distribution was 692 l (49% IIV) and the peripheral volume of distribution 5340 l (53% IIV). Interoccasion variability was added to clearance (14%). Higher body surface area (BSA), lower serum creatinine, younger age, higher albumin and lower haematocrit levels were identified as covariates enhancing tacrolimus clearance. Cytochrome P450 (CYP) 3A5 expressers had a significantly higher tacrolimus clearance (160%), whereas CYP3A4*22 carriers had a significantly lower clearance (80%). From these significant covariates, age, BSA, CYP3A4 and CYP3A5 genotype were incorporated in a second model to individualize the tacrolimus starting dose: [Formula: see text] Both models were successfully internally and externally validated. A clinical trial was simulated to demonstrate the added value of the starting dose model. CONCLUSIONS: For a good prediction of tacrolimus pharmacokinetics, age, BSA, CYP3A4 and CYP3A5 genotype are important covariates. These covariates explained 30% of the variability in CL/F. The model proved effective in calculating the optimal tacrolimus dose based on these parameters and can be used to individualize the tacrolimus dose in the early period after transplantation.

Personalized immunosuppression in elderly renal transplant recipients.

The number of elderly people has increased considerably over the last decades, due to a rising life expectancy and ageing populations. As a result, an increased number of elderly with end-stage-renal-disease are diagnosed, for which the preferred treatment is renal transplantation. Over the past years the awareness of the elderly as a specific patient population has grown, which increases the importance of research in this group. Elderly patients often receive kidneys from elderly donors while younger donor kidneys are preferentially reserved for younger recipients. Although the rate of acute rejection after transplantation is lower in the elderly, these rejections may lead to graft loss more frequently, as kidneys from elderly donors have marginal reserve capacity. To prevent acute rejection, immunosuppressive therapy is needed. On the other hand, elderly patients have a higher risk to die from infectious complications, and thus less immunosuppression would be preferable. Immunosuppressive treatment in the elderly is complicated further by changes in the pharmacokinetics and pharmacodynamics, with increasing age. Adjustments in standard immunosuppressive regimes are therefore suggested for this population. An unmet need in transplantation medicine is a tool to guide a personalized approach to immunosuppression. Recently several promising biomarkers that identify injury to the graft at an early stage or predict acute rejection have been identified. Unfortunately, none of these biomarkers were tested specifically in the elderly. We believe there is an urgent need to perform clinical trials investigating novel immunosuppressive regimens in conjunction with biomarker studies in this specific population.

Pharmacogenetic aspects of the use of tacrolimus in renal transplantation: recent developments and ethnic considerations.

INTRODUCTION: Tacrolimus (Tac) is effective in preventing acute rejection but has considerable toxicity and inter-individual variability in pharmacokinetics and pharmacodynamics. Part of this is explained by polymorphisms in genes encoding Tac-metabolizing enzymes and transporters. A better understanding of Tac pharmacokinetics and pharmacodynamics may help to minimize different outcomes amongst transplant recipients by personalizing immunosuppression. AREAS COVERED: The pharmacogenetic contribution of Tac metabolism will be examined, with a focus on recent discoveries, new developments and ethnic considerations. EXPERT OPINION: The strongest and most consistent association in pharmacogenetics is between the CYP3A5 genotype and Tac dose requirement, with CYP3A5 expressers having a ~ 40-50% higher dose requirement compared to non-expressers. Two recent randomized-controlled clinical trials using CYP3A5 genotype, however, did not show a decrease in acute rejections nor reduced toxicity. CYP3A4*22, CYP3A4*26, and POR*28 are also associated with Tac dose requirements and may be included to provide the expected improvement of Tac therapy. Studies focusing on the intracellular drug concentrations and on calcineurin inhibitor-induced nephrotoxicity also seem promising. For all studies, however, the ethnic prevalence of genotypes should be taken into account, as this may significantly impact the effect of pre-emptive genotyping.

Economic burden of gouty arthritis attacks for employees with frequent and infrequent attacks.

The objective of this study was to compare episode-related and annual costs and work absence days for employees with <3 versus ≥ 3 annual gout attacks. Human Capital Management Services data (2009-2010) from adult employees with gout (International Classification of Diseases, Ninth Revision code 274.x) and ≥ 12 months of medical and pharmacy benefits were studied. Outcomes of interest included medical and drug costs, number of emergency department and urgent care visits, number of inpatient days, short- and long-term disability, sick leave, workers' compensation costs, and work absence days. An algorithm based on diagnosis code and antigout medication use identified acute gout treatment episodes. Multivariate analysis compared annual and pre-episode vs. during-episode outcomes for employees with ≥ 3 vs. <3 gout annual attacks. Of 3361 employees with gout, 76 had ≥ 3 attacks; these employees had higher short-term disability costs ($1663 vs. $643, P=0.06) and days (11.68 versus 4.61, P<0.05), more emergency room visits (0.55 vs. 0.23, P<0.0001), and urgent care visits (0.07 vs. 0.04, P<0.01), and lower pharmacy costs ($1677 vs. $1108, P<0.0001) than those with <3 attacks. Medical costs both before ($203 higher) and during attacks ($136 higher) were significantly higher for those with ≥ 3 attacks than for those with <3 attacks. Additionally, a quadratic increasing relationship was found between number of attacks and cost. Frequency of acute gout attacks (≥ 3 episodes per year) among employees with gout was associated with greater short-term disability cost, absence days, and emergency department and urgent care visits, and trends toward higher overall costs.

Life-threatening complications of ibogaine: three case reports.

Ibogaine is a naturally occurring psychoactive alkaloid extracted from the roots of the Tabernanthe iboga plant, which in alternative medicine is used to treat drug dependency. However, this upcoming, online advocated therapy can be dangerous due to its potentially lethal adverse effects. We present three cases in which toxic side effects were noted. We used the Naranjo scale to estimate the probability of a causal relationship between these effects and ibogaine. Findings in these three cases are suggestive of a causal relationship between the use of ibogaine and serious respiratory and cardiac problems (including lengthening of the QT interval). In our opinion it is of great importance that clinicians are aware of these potentially serious side effects and realise that widespread online marketing practices will give many more people access to ibogaine.

Comparison of real-world adherence, healthcare resource utilization and costs for newly initiated valsartan/amlodipine single-pill combination versus angiotensin receptor blocker/calcium channel blocker free-combination therapy.

OBJECTIVE: To compare adherence, healthcare costs and utilization of valsartan/amlodipine single-pill combination (SPC) and angiotensin-receptor blocker/calcium-channel blocker multiple-pill free-combination (ARB + CCB FC) therapy using real-world data. METHODS: A retrospective study (January 1, 2007 to April 30, 2009) was conducted using US commercial healthcare insurance claims. Patients were assigned to two cohorts: 'valsartan/amlodipine SPC cohort' and 'ARB + CCB FC therapy cohort'. The primary endpoints were adherence and persistence. The secondary endpoints were 1-year healthcare costs and utilization. RESULTS: Out of 12,628 eligible patients 3259 (26%) were included in the valsartan/amlodipine SPC cohort and 9369 (%74) in the ARB + CCB FC cohort. Risk-adjusted adherence rates were higher for valsartan/amlodipine SPC patients [OR: 1.38, 95% CI: (1.24, 1.53)]. The Cox proportional hazard model showed that valsartan/amlodipine SPC cohort patients were less likely to discontinue medication (HR: 0.87, p < 0.001). Comparison between the groups also yielded that total healthcare costs of valsartan/amlodipine SPC patients were 16-20% lower than ARB + CCB FC therapy patients (p < 0.0001). LIMITATIONS: Since claims data are collected for payment purposes rather than research purposes, the study is bound by limitations for the retrospective analysis. For example, the presence of a claim for a filled prescription does not indicate that the medication was consumed or taken as prescribed. Data on health behaviors and patient lifestyle were not available. Over-the-counter medications and clinical disease severity were not available in the dataset. Incorrect coding is also a possibility. However, we have used previously validated datasets where these effects are minimal. Heterogeneity of the sample may create bias in our estimates, however, we have used advanced statistical methods to control for observed and unobserved bias. CONCLUSION: The real-world use of valsartan/amlodipine SPC was associated with better adherence and persistence relative to ARB + CCB FC therapy among patients with hypertension. Moreover, patients taking single-pill combination therapy had lower healthcare costs and utilization.

Progression to type 2 diabetes, healthcare utilization, and cost among pre-diabetic patients with or without comorbid hypertension.

OBJECTIVE: This study examined progression to type 2 diabetes and compared healthcare utilization and costs among patients with pre-diabetes, with or without comorbid hypertension. RESEARCH DESIGN AND METHODS: This study drew from a large national claims database (2003-2008). Patients were ≥18 years of age with a medical claim or lab value indicating the presence of pre-diabetes. The index date was the first pre-diabetes diagnosis (ICD-9 codes 790.21, 790.22, 790.29) or qualifying lab value of fasting plasma glucose or impaired glucose intolerance. All patients had ≥12-month data pre- and post- index date. Multivariate analysis was conducted to identify risk factors affecting progression to type 2 diabetes, and to estimate the impact of hypertension status and diabetes progression on healthcare utilization and cost. RESULTS: 144,410 patients met study criteria, with an average follow-up of 802 (SD 344) days. Among participants, 30.7% progressed to diabetes, with a mean 288 (SD 340) days from pre-diabetes identification to diabetes diagnosis. Compared with patients who did not progress, the total adjusted medical costs for patients who developed diabetes increased by $1429 in 1 year, $2451 in 2 years, and $3621 in 3 years (p < 0.001). Patients with concomitant hypertension were significantly more likely to progress to type 2 diabetes, and had higher total medical costs compared to patients without hypertension ($476 higher in 1 year, $949 in 2 years, $1378 in 3 years). CONCLUSIONS: Patients with pre-diabetes who progressed to type 2 diabetes had higher healthcare utilization and costs compared with patients who did not. The presence of hypertension substantially increased costs and was associated with higher likelihood of diabetes progression. Blood pressure, lifestyle intervention, body mass index, and other factors cannot be examined due to the limitations of the data. Results may not be generalizable to patients with insurance other than commercial or Medicare.

Recovery of CD3+ and CD5- lymphocyte subpopulation after autologous bone marrow transplantation and chemotherapy.

Although most circulating T cells in normal subjects express both CD3 and CD5 antigens on the cell surface, a small number lack the CD5 antigen. Recipients of allogeneic bone marrow transplants develop increased numbers of CD3+ CD5- cells, particularly those who develop graft versus host disease (GVHD). This CD3+ CD5- population may rise transiently in patients who have received an autologous bone marrow transplant (BMT) and in patients following completion of intensive chemotherapy for acute myeloid leukaemia (AML). These findings suggest that these CD3+ CD5- cells are a normal component of the regenerating lymphoid system after BMT or chemotherapy.