Population pharmacokinetics and Bayesian estimation of mycophenolate mofetil in patients with autoimmune hepatitis.

AIMS: Mycophenolate mofetil (MMF) is the most widely used second-line agent in autoimmune hepatitis (AIH). Individual dose adjustment of MMF may avoid adverse outcomes while maximizing efficacy. The aim of the present study was to develop population pharmacokinetic (popPK) models and maximum a posteriori Bayesian estimators (MAP-BEs) to estimate mycophenolic acid interdose area under the curve in AIH patients administered MMF using nonlinear mixed effect modelling. METHODS: We analysed 50 mycophenolic acid PK profiles from 34 different patients, together with some demographic, clinical, and laboratory test data. The median number of plasma samples per profile, immediately preceding and following the morning MMF dose, was 7. PopPK modelling was performed using parametric, top-down, nonlinear mixed effect modelling with NONMEM 7.3. MAP-BEs were developed based on the best popPK model and the best limited sampling strategy selected among several. RESULTS: The pharmacokinetic data were best described by a 2-compartment model, Erlang distribution to describe the absorption phase, and a proportional error. The mean (relative standard error) of popPK parameter estimates of clearance, intercompartmental clearance, central volume and absorption rate with the final model were: 21.6 L h-1 (11%), 22.7 L h-1 (19%), 35.9 L (21%) and 8.7 h-1 (9%), respectively. The peripheral volume was fixed to 300 L. The best MAP-BE relied on the limited sampling strategy at 0.33, 1 and 3 hours after MMF dose administration and was very accurate (bias = 5.6%) and precise (root mean squared prediction error <20%). CONCLUSION: The precise and accurate Bayesian estimator developed in this study for AIH patients on MMF can be used to improve the therapeutic management of these patients.

The PROPKD Score: A New Algorithm to Predict Renal Survival in Autosomal Dominant Polycystic Kidney Disease.

The course of autosomal dominant polycystic kidney disease (ADPKD) varies among individuals, with some reaching ESRD before 40 years of age and others never requiring RRT. In this study, we developed a prognostic model to predict renal outcomes in patients with ADPKD on the basis of genetic and clinical data. We conducted a cross-sectional study of 1341 patients from the Genkyst cohort and evaluated the influence of clinical and genetic factors on renal survival. Multivariate survival analysis identified four variables that were significantly associated with age at ESRD onset, and a scoring system from 0 to 9 was developed as follows: being male: 1 point; hypertension before 35 years of age: 2 points; first urologic event before 35 years of age: 2 points; PKD2 mutation: 0 points; nontruncating PKD1 mutation: 2 points; and truncating PKD1 mutation: 4 points. Three risk categories were subsequently defined as low risk (0-3 points), intermediate risk (4-6 points), and high risk (7-9 points) of progression to ESRD, with corresponding median ages for ESRD onset of 70.6, 56.9, and 49 years, respectively. Whereas a score ≤3 eliminates evolution to ESRD before 60 years of age with a negative predictive value of 81.4%, a score >6 forecasts ESRD onset before 60 years of age with a positive predictive value of 90.9%. This new prognostic score accurately predicts renal outcomes in patients with ADPKD and may enable the personalization of therapeutic management of ADPKD.

Efficiency and Safety of an Early Dose Adjustment of Ribavirin in Patients Infected With Hepatitis C Underexposed to the Drug and Treated With Peginterferon Ribavirin.

BACKGROUND: Ribavirin exposure after the first dose (D0AUC0-4h) >1755 mcg·h·L is predictive of sustained virological response (SVR) in patients with hepatitis C treated with peginterferon and ribavirin. The aim of this study was to test the benefit of ribavirin early dose adjustment based on this target in naïve patients infected with genotype 1. METHODS: A multicenter randomized controlled trial with two parallel groups; fixed-dose (FD) group: standard of care in 2010-2011, ie, peginterferon-α2a 180 mcg·wk and weight-based ribavirin 1000-1200 mg/d during 48 weeks; adapted-dose (AD) group: increase of ribavirin dose if D0AUC0-4h <1755 mcg·h·L. RESULTS: A total of 221 patients were included, 110 in the AD group and 111 in the FD group with similar baseline characteristics. In the perprotocol analysis, SVR was higher in the AD group (55.1% versus 40.4%; P = 0.042), especially in patients with D0AUC0-4h <1755 mcg·h·L (54.3% versus 31.9%; P = 0.029). In the intention-to-treat analysis, the difference was not significant (50% versus 41%; P = 0.197). Ribavirin trough concentrations (C0s) at week 4 of treatment (intention-to-treat analysis) were higher in patients achieving SVR (2.06 versus 1.72 mg/L, P = 0.003). In the subgroup of patients with AUC0-4h <1755 mcg·h·L, 46% of patients with AD achieved a C0 >2.0 mg/L versus 22% of patients with FD (P = 0.013). Grade 1 anemia (but not other grades) was more frequent in the AD group (70% versus 48%, P = 0.001). The number of dose reductions or discontinuation of ribavirin was similar in both groups. CONCLUSIONS: Early ribavirin dose adjustment increases SVR in patients underexposed to ribavirin without increasing grade II-IV anemia. Such a strategy could be useful in patients with no access to new antiviral drugs.

Validation of the psychometrics properties of a French quality of life questionnaire among a cohort of renal transplant recipients less than one year.

BACKGROUND: Renal transplantation is considered as the treatment of choice for patients with end-stage renal disease. Health-related quality of life (HRQoL) of renal transplant recipients (RTR) is very important to assess, especially during the first year after transplantation. To provide new evidence about the suitability of HRQoL measures in RTR during the first post-transplant year, we explored the internal structure, reliability and external validity of a French specific HRQoL instrument, the Renal Transplant Quality of life Questionnaire Second Version (RTQ V2). METHODS: The data were issued from the French multicenter cohort of renal transplant patients followed during 4 years (EPIGREN). The HRQoL of RTR was assessed five times (at 1, 3, 6, 9 and 12 months after transplantation) with the RTQ V2, a specific instrument consisting of 32 items describing five dimensions. Socio-demographic information, clinical characteristics and HRQoL (i.e., RTQ V2 and SF-36) were collected. For the five times, psychometric properties of the RTQ V2 were compared to those reported from the reference population assessed in the validation study. RESULTS: Three hundred and thirty-four patients were enrolled. The proportions of well-projected items, item-internal consistency, item-discriminant validity, floor and ceiling effects, Cronbach's alpha coefficients and item goodness-of-fit statistics were satisfactory for each dimension at the five times of the study. The suitability indices of construct validity were higher than 90 % for each time (minimum-maximum: 90.8-97.4 %). The external validity was less satisfactory, with a suitability indices ranged from 46.7 % at M1 to 66.7 % at M12. However, the discrepancies with the reference population (mainly for the gender) appeared logical considering the scientific literature on HRQoL of RTR during the first post-transplant year and may not compromise the external validity. CONCLUSION: These results support the validity and reliability of the RTQ V2 for evaluating HRQoL in RTR during the first post-transplant year, and confirm that the RTQ V2 is a useful tool to assess the HRQoL precociously after transplant.

eGFR decrease during antiviral C therapy with first generation protease inhibitors: a clinical significance?

BACKGROUND & AIMS: Renal toxicity of first generation protease inhibitors (PIs) was not a safety signal in phase III clinical trials, but was recently reported in recent studies. It appeared important to determine the clinical significance of these findings. METHODS: We retrospectively analysed 101 HCV patients receiving triple therapy with telaprevir (n = 36) or boceprevir (n = 26) or double therapy (n = 39) with peginterferon and ribavirin and having a close monitoring of eGFR (MDRD formula) during and after treatment. EGFR decline over time was assessed by a linear mixed-effects model (LMEM) with search for possible explanatory covariates. RESULTS: Patients treated with telaprevir presented a significant decrease of eGFR with the same kinetics: initial decrease at W (week) 4, nadir at W8 (mean decrease 17.0 ± 18.9 ml/min/1.73 m(2)) and return to baseline at W16. The W8 eGFR was correlated with the D0 eGFR (R(2) = 0.49). The LMEM showed that interindividual variability in the slope of eGFR vs time between D0 and W8 was non-significant and eGFR nadir could be predicted from eGFR obtained at D0. In multivariate analysis, eGFR intercept (i.e. baseline value) was associated with older age and male sex. CONCLUSION: The eGFR significantly varied in telaprevir group only. Our model showed that eGFR nadir mainly depended on initial eGFR. As telaprevir has been shown to inhibit mostly the drug transporter OCT2 which interacts with creatinine transport, the early decrease of eGFR observed could be a benign phenomenon. However, as unpredictable true renal toxicity may occur during therapy, we recommend a thorough follow-up of eGFR.

Association of sirolimus adverse effects with m-TOR, p70S6K or Raptor polymorphisms in kidney transplant recipients.

BACKGROUND: The mammalian target of rapamycin (m-TOR) inhibitor sirolimus is an immunosuppressive drug used in kidney transplantation. m-TOR binds with Raptor and phosphorylates p70S6 kinase, a protein involved in numerous cell signalling pathways. We examined the association of candidate polymorphisms in m-TOR, Raptor and p70S6K, sirolimus dose and exposure, and other time-independent as well as time-dependent covariates, with sirolimus-induced adverse events in kidney transplant recipients. METHODS: This study included a first group of 113 patients, switched from a calcineurin inhibitor to sirolimus, and a validation group of 66 patients from another clinical trial, with the same immunosuppressive regimen. The effects of gene polymorphisms and covariates on the total cholesterol, LDL cholesterol, triglycerides, haemoglobin, cutaneous adverse events, oedemas and infections were studied using multilinear regression, or logistic regression imbedded in linear mixed-effect models. RESULTS: An m-TOR variant haplotype was significantly associated with a decrease in haemoglobin levels in the two populations of patients (discovery group: ß=-0.82 g/dl, P=0.0076; validation group: ß=-1.58 g/dl, P=0.0308). Increased sirolimus trough levels were significantly associated with increased total cholesterol levels (discovery group: ß=0.02 g/l, P<0.0001; validation group: ß=0.02 g/l, P=0.0002) and triglyceride levels (discovery group: ß=0.02 g/l, P=0.0059; validation group: ß=0.05 g/l, P=0.0370). Sirolimus trough levels were also associated with an increased risk for cutaneous adverse events [odds ratio=1.97, 95% confidence interval (1.32-1.94), P=0.0009] and oedemas [odds ratio=1.16, 95% confidence interval (1.03-1.30), P=0.01342] in the discovery group, but this was not confirmed in the validation group. CONCLUSION: These results provide evidence of an association between an m-TOR haplotype and a decrease in haemoglobin in renal transplant recipients.

Post-transplant lymphoproliferative disease (PTLD): Pharmacological, virological and other determinants.

Post-transplant lymphoproliferative disorders (PTLDs) represent a serious complication in solid organ transplantation and are the first cause of cancer related mortality in this population. Pre-transplant Epstein Barr Virus seronegativity and receipt of T cell depleting agents for induction or severe/refractory rejection are known risk factors, but they primarily impact early occurring disease. On the other hand, late occurring disease, which has typically not correlated with the above or other specific risk factors, has recently been shown to be associated with older recipient age and prolonged receipt of calcineurin inhibitors. Furthermore, recent data has contributed to and, in some instances shed light on, previous debate concerning the role of viruses other than EBV and the level of HLA mismatches as risk factors for PTLD. Gene association studies focusing on key cytokines and their receptors have identified several polymorphisms that may prove useful to identify patients at risk, with distinction for early and late occurring disease. Determining the influence of individual maintenance immunosuppressive agents on lymphomagenesis has been limited by the complexity of the multi-drug regimens used and absence of measures of drug exposure and time-dependent covariates in multivariable analyses. Biomarkers that measure the extent of immunosupression may have a role in avoiding PTLD, and other post-transplant complications.

Inhibition of T-cell activation and proliferation by mycophenolic acid in patients awaiting liver transplantation: PK/PD relationships.

Mycophenolic acid (MPA) plasma concentrations were reported to be associated with a decrease in T-cell proliferation, and in both IL-2 α-chain (CD25) and transferin receptor (CD71) expression. The aim of this study was to confirm, quantify and model these PK/PD relationships. Full profiles of MPA plasma concentrations, T-cell proliferation, intracytoplasmic IL-2 and TNF-α expression, and both CD71 and CD25 expression were collected over the 12h after dosing in 10 patients on the waiting list for liver transplantation. Data were analyzed using NONMEM(®). Both CD25 and CD71 expression and T cell proliferation clearly decreased (median of decrease from baseline 62%, 68% and 94%, respectively) with increasing MPA concentrations, in contrast to IL-2 and TNF-α expression. The CD25 and CD71 baseline expression (E(0)) and maximum effect (E(max)) were correlated with the E(0) and E(max) values of T-cell proliferation (r(2)=0.509 and r(2)=0.622, respectively). The CD25, CD71 expression and T-cell proliferation profiles were adequately fitted using a sigmoid inhibitory E(max) model. Low estimated values (≤2 mg/L) for 50% inhibitory MPA concentrations were obtained. This study confirmed a transient MPA concentration-dependent decrease in T-cells expressing CD25 and CD71 and a strong reduction of T-cell proliferation and showed that CD25 and CD71 expression was correlated with T-cell proliferation.

Population pharmacokinetic model and Bayesian estimator for two tacrolimus formulations--twice daily Prograf and once daily Advagraf.

AIM: To investigate the differences in the pharmacokinetics of Prograf and the prolonged release formulation Advagraf and to develop a Bayesian estimator to estimate tacrolimus inter-dose area under the curve (AUC) in renal transplant patients receiving either Prograf or Advagraf. METHODS: Tacrolimus concentration-time profiles were collected, in adult renal transplant recipients, at weeks 1 and 2, and at months 1, 3 and 6 post-transplantation from 32 Prograf treated patients, and one profile was collected from 41 Advagraf patients more than 12 months post-transplantation. Population pharmacokinetic (popPK) parameters were estimated using nonmem. In a second step, the popPK model was used to develop a single Bayesian estimator for the two tacrolimus formulations. RESULTS: A two-compartment model with Erlang absorption (n= 3) and first-order elimination best described the data. In Advagraf patients, a bimodal distribution was observed for the absorption rate constant (K(tr) ): one group with a K(tr) similar to that of Prograf treated patients and the other group with a slower absorption. A mixture model for K(tr) was tested to describe this bimodal distribution. However, the data were best described by the nonmixture model including covariates (cytochrome P450 3A5, haematocrit and drug formulation). Using this model and tacrolimus concentrations measured at 0, 1 and 3h post-dose, the Bayesian estimator could estimate tacrolimus AUC accurately (bias = 0.1%) and with good precision (8.6%). CONCLUSIONS: The single Bayesian estimator developed yields good predictive performance for estimation of individual tacrolimus inter-dose AUC in Prograf and Advagraf treated patients and is suitable for clinical practice.

Large scale analysis of routine dose adjustments of mycophenolate mofetil based on global exposure in renal transplant patients.

BACKGROUND: We report a feasibility study based on our large-scale experience with mycophenolate mofetil dose adjustment based on mycophenolic acid interdose area under the curve (AUC) in renal transplant patients. METHODS: Between 2005 and 2010, 13,930 requests for 7090 different patients (outside any clinical trial) were posted by more than 30 different transplantation centers on a free, secure web site for mycophenolate mofetil dose recommendations using three plasma concentrations and Bayesian estimation. RESULTS: This retrospective study showed that 1) according to a consensually recommended 30- to 60-mg·h/L target, dose adjustment was needed for approximately 35% of the patients, 25% being underexposed with the highest proportion observed in the first weeks after transplantation; 2) when dose adjustment had been previously proposed, the subsequent AUC was significantly more often in the recommended range if the dose was applied than not at all posttransplantation periods (72-80% vs. 43-54%); and 3) the interindividual AUC variability in the "respected-dose" group was systematically lower than that in the "not respected-dose" group (depending on the posttransplantation periods; coefficient of variation %, 31-41% vs 49-70%, respectively). Further analysis suggested that mycophenolic acid AUC should best be monitored at least every 2 weeks during the first month, every 1 to 3 months between months 1 and 12, whereas in the stable phase, the odds to be still in the 30- to 60-mg·h/L range on the following visit was still 75% up to 1 year after the previous dose adjustment. CONCLUSION: This study showed that the monitoring of mycophenolate mofetil on the basis of AUC measurements is a clinically feasible approach, apparently acceptable by the patients, the nurses, and the physicians owing to its large use in routine clinics.

Development and evaluation of a simulation procedure to take into account various assays for the Bayesian dose adjustment of tacrolimus.

BACKGROUND AND OBJECTIVES: Several analytical techniques with different performances are available for the measurement of tacrolimus blood concentrations. The performance of Bayesian estimators (MAP-BEs) allowing dose adjustments of tacrolimus is dependent on the precision of the analytical technique. Hence, any Bayesian estimator should only be used for concentration data obtained with the same assay employed for its development. The present study aimed at evaluating the feasibility of developing Bayesian estimators dedicated to different immunoassays, using the concentrations obtained with the reference high-performance liquid chromatography with mass spectrometric detection (LC-MS/MS) method and a simulation approach. PATIENTS AND METHODS: One hundred thirty-five full pharmacokinetic profiles of tacrolimus were obtained from 45 renal transplant patients using 3 different analytical techniques: 2 immunoassays [enzyme-multiplied immunoassay technique (EMIT) and chemiluminescent microparticle immunoassay (CMIA)] and LC-MS/MS. In a first step, 3 MAP-BEs were developed using the concentrations measured with the 3 techniques. Taking into account the correlation equations between the concentrations obtained with each of the immunoassays and LC-MS/MS, as well as the analytical error of the techniques, 2 hybrid MAP-BEs dedicated to the immunoassays were then developed after simulation of 100 pharmacokinetic profiles. Their performances were compared with those of the respective MAP-BEs developed using the actual immunoassay concentrations. RESULTS: The mean concentrations measured over the dosing interval using EMIT and CMIA were significantly higher than those measured using LC-MS/MS (+15% and +11% in the AUC0₋24 h value, respectively, P < 0.0001), leading to differences in dose recommendations of -0.9 ± 1.1 and -0.7 ± 0.9 mg, respectively. When applying the MAP-BE developed from LC-MS/MS data for the EMIT or CMIA concentrations, tacrolimus AUC0₋24 h was estimated with an imprecision >20% in 33% and 27% of the patients, respectively. In contrast, the "CMIA" and "EMIT" hybrid MAP-BEs provided a good AUC0₋24 h estimation in 85%-93% of the patients. CONCLUSIONS: This study showed the impact of the analytical technique on the performance of Bayesian estimators dedicated to tacrolimus dose adjustment and the feasibility to develop MAP-BE for a specific assay using results from a different assay, based on a limited method comparison study. This methodology could offer clinicians the opportunity to dose adjust tacrolimus whatever the assay used in their center.

Evaluation of Longitudinal Exposure to Tacrolimus as a Risk Factor of Chronic Kidney Disease Occurrence Within the First-year Post-Liver Transplantation.

BACKGROUND: Renal failure is predictive of mortality in the early postliver-transplantation period and calcineurin inhibitors toxicity is a main challenge. Our aim is to assess the impact of longitudinal tacrolimus exposure (TLE) and other variables on chronic kidney disease (CKD)-free 1-year-survival. METHODS: Retrospective data of consecutive patients transplanted between 2011 and 2016 and treated with tacrolimus were collected. TLE and all relevant pre- and post-liver transplantation (LT) predictive factors of CKD were tested and included in a time-to-event model. CKD was defined by repeated estimated glomerular filtration rate (eGFR) values below 60 mL/min/1.73m2 at least for the last 3 months before M12 post-LT. RESULTS: Data from 180 patients were analyzed. CKD-free survival was 74.5% and was not associated with TLE. Pre-LT acute kidney injury (AKI) and eGFR at 1-month post-LT (eGFRM1) <60 mL/min/1.73m2 were significant predictors of CKD. By distinguishing 2 situations within AKI (ie, with or without hepatorenal syndrome [HRS]), only HRS-AKI remained associated to CKD. HRS-AKI and eGFRM1 <60 mL/min/1.73m2 increased the risk of CKD (hazard ratio, 2.5; 95% confidence interval, 1.2-4.9; hazard ratio, 4.8; 95% confidence interval, 2.6-8.8, respectively). CONCLUSIONS: In our study, TLE, unlike HRS-AKI and eGFRM1, was not predictive of CKD-free survival at 1-year post-LT. Our results once again question the reversibility of HRS-AKI.

Polymorphisms in type I and II inosine monophosphate dehydrogenase genes and association with clinical outcome in patients on mycophenolate mofetil.

BACKGROUND: Type I and II inosine monophosphate dehydrogenases (IMPDH) are the targets of mycophenolic acid (MPA), a widely used immunosuppressant. The aims of this study were: to check the presence of controversial polymorphisms in the IMPDH II gene; to look for new ones; and to investigate potential associations between the most frequent SNPs in both IMPDH genes and clinical outcome in renal transplant recipients. METHODS: The DNA and clinical data of 456 patients from two clinical trials were collected. We sequenced the IMPDH II gene in 80 patients and we genotyped the 456 patients' DNA for the IMPDH II rs4974081, rs11706052, 787C>T and the IMPDH I rs2278293 and rs2278294 SNPs, all of which were earlier reported to be potentially involved in MPA treatment related outcome. We investigated the associations of biopsy proven acute rejection (BPAR), leucopenia, cytomegalovirus infections and other infections with these IMPDH polymorphisms, as well as with demographic, biological and treatment data using multivariate analysis. RESULTS: Many IMPDH II variant alleles referenced in Genbank were not detected and no new polymorphisms were identified. In the whole group of 456 patients, the IMPDH I rs2278294 SNP was associated with a lower risk of BPAR and a higher risk of leucopenia over the first year post-transplantation. No other IMPDH I or IMPDH II polymorphism was significantly associated with any clinical outcome. Interestingly, calcineurin inhibitor and MPA exposures below the therapeutic range increased the risk of BPAR. Cytomegalovirus infection was the factor most closely linked with leucopenia, whereas tacrolimus was associated with fewer infections than cyclosporine. CONCLUSION: IMPDH II genotyping may not improve MPA treatment outcome over the first year post-transplantation, in contrast to MPA and calcineurine inhibitor therapeutic drug monitoring and IMPDH I genotyping.

Risk of diarrhoea in a long-term cohort of renal transplant patients given mycophenolate mofetil: the significant role of the UGT1A8 2 variant allele.

AIM: In renal transplant patients given mycophenolate mofetil (MMF), we investigated the relationship between the digestive adverse events and polymorphisms in the UGT genes involved in mycophenolic acid (MPA) intestinal metabolism and biliary excretion of its phase II metabolites. METHODS: Clinical data and DNA from 256 patients transplanted between 1996 and 2006 and given MMF with cyclosporin (CsA, n = 185), tacrolimus (TAC, n = 49) or sirolimus (SIR, n = 22), were retrospectively analysed. The relationships between diarrhoea and polymorphisms in UGT1A8 (2; 518C>G, 3; 830G>A), UGT1A7 (622C>T), UGT1A9 (-275T>A), UGT2B7 (-840G>A) and ABCC2 (-24C>T, 3972C>T) or the co-administered immunosuppressant were investigated using the Cox proportional hazard model. RESULTS: Multivariate analysis showed that patients on TAC or SIR had a 2.8 higher risk of diarrhoea than patients on CsA (HR = 2.809; 95%CI (1.730, 4.545); P < 0.0001) and that non-carriers of the UGT1A8 2 allele (CC518 genotype) had a higher risk of diarrhoea than carriers (C518G and 518GG genotypes) (HR = 1.876; 95%CI (1.109, 3.175); P = 0.0192). When patients were divided according to the immunosuppressive co-treatment, a significant effect of UGT1A8 2 was found in those co-treated with CsA (HR = 2.414; 95%CI (1.089, 5.354); P = 0.0301) but not TAC or SIR (P = 0.4331). CONCLUSION: These results suggest that a possible inhibition of biliary excretion of MPA metabolites by CsA and a decreased intestinal production of these metabolites in UGT1A8 2 carriers may be protective factors against MMF-induced diarrhoea.

Pharmacokinetic modeling and development of Bayesian estimators in kidney transplant patients receiving the tacrolimus once-daily formulation.

BACKGROUND: The once-daily formulation of tacrolimus has been reported to exhibit the same efficacy and safety profile as compared with the immediate-release form administered twice daily. However, as a result of differences in their pharmacokinetic (PK) profile, the PK models or Bayesian estimators (MAP-BE) previously developed for the immediate-release formulation cannot be used for the new once-daily formulation. Using the PK information obtained from a Phase II trial, the aim of this study was to explore the feasibility of developing a PK model and a MAP-BE able to estimate, on the basis of a routinely applicable limited sampling strategy, tacrolimus individual PK parameters and AUC0-24h in de novo renal transplant patients given the once-daily formulation. METHODS: Twelve de novo kidney transplant recipients receiving once-daily tacrolimus as part of their immunosuppressive regimen provided full PK profiles (17 concentration time points over 24 hours) on Days 14 and 42 posttransplantation. On the basis of a one-compartment open model with absorption described as following a double gamma distribution, a classic iterative two-stage method was applied to develop MAP-BEs. All the limited sampling strategies with a maximum of three sampling times within 4 hours postdose were tested for Bayesian forecasting with the aim of accurately estimating the AUC0-24h. RESULTS: Once-daily tacrolimus exhibited a high interpatient PK variability with coefficients of variation of 34.3% and 36.2% for AUC0-24h/dose (mg/kg) on Days 14 and 42, respectively. Regression analysis between C0 and AUC0-24h yielded r = 0.68 and 0.76 at these two periods, respectively. The iterative two-stage approach led to the development of a different MAP-BE for each posttransplantation period, which allowed estimation of once-daily tacrolimus pharmacokinetics and AUC0-24h on the basis of a C0-C1h-C3h sampling schedule. The mean bias of the Bayesian versus reference (trapezoidal) AUCs was 4.2% +/- 6.1% (range, -11.8% to +11.2%; root mean square error = 7.1%) on Day 14 and 0.2% +/- 7.9% (range, -12.9% to +14.1%; root mean square error = 7.8%) on Day 42. CONCLUSION: A PK model and Bayesian estimators allowing estimation of tacrolimus AUC0-24h based on a routinely applicable limited sampling strategy were developed for once-daily tacrolimus in renal transplantation. Further validation in independent groups of patients is required to confirm their applicability for optimizing the monitoring of once-daily tacrolimus in routine clinical practice or to conduct observational or comparative therapeutic drug monitoring clinical trials.

Stability of ribavirin concentrations depending on the type of blood collection tube and preanalytical conditions.

Ribavirin pharmacokinetic and exposure effect trials based on either plasma or serum concentrations have yielded diverging results. This study aimed to compare ribavirin concentrations in serum and plasma and to investigate the influence of blood collection and preanalytical conditions on ribavirin concentration stability. Blood samples from patients with hepatitis virus C and receiving ribavirin were collected in plain (dry) tubes, in tubes containing ethylenediaminetetra-acetic acid or lithium-heparinate, in Type II Serum Separating Tubes with clot activator, or Type II lithium heparinate Plasma Separating Tubes. Different time and temperature conditions were tested before and after blood centrifugation. Ribavirin was determined using liquid chromatography-dual mass spectroscopy. Multiple-way analysis of variance was used for statistical analyses. Ribavirin concentrations showed a higher interlaboratory variability in serum than in plasma. Results were fairly stable over 2 hours in whole blood collected in dry or ethylenediaminetetra-acetic acid tubes and very stable up to 24 hours in serum or plasma kept in gel-containing tubes after immediate centrifugation. When Plasma Separating II gel tubes were kept at +4 degrees C or at ambient temperature for up to 24 hours before centrifugation, ribavirin concentrations decreased by 1% to 8% and 12% to 18%, respectively. These results suggest that blood samples should be collected in gel-containing tubes and centrifuged immediately, after which the tubes can be kept at ambient temperature for the next 24 hours. In case of clinical constraints, Plasma Separating II gel tubes can be kept at +4 degrees C for a maximum of 2 hours before centrifugation with limited impact on the measured concentrations.

Adherence profiles in kidney transplant patients: Causes and consequences.

OBJECTIVE: Adherence is a dynamic phenomenon and a critical determinant of transplant patients outcome. The objective of this longitudinal study was to explore adherence in kidney transplant patients followed-up for up to three years after transplantation. METHODS: Adherence was repeatedly estimated using the Morisky-Green-Levine 4-Item Medication Adherence Scale, in two successive cohorts of 345 (EPIGREN) and 367 (EPHEGREN) kidney transplant recipients. Mixed effect modeling with latent processes and latent classes was used to describe adherence time-profiles. RESULTS: Two latent classes were identified. The adherent class represented 85% of the patients. Patients of the poorer-adherence class displayed a lower adherence at one month (p<10-3), which worsened over time. Good adherence was associated with age >50 years, fewer depression episodes (5% vs. 13%, p = 0.001) and a better mental health component of quality of life (MCS-SF36 47 ±â€¯11 vs. 41 ±â€¯13, p = 0.015). Survival without acute rejection episodes was longer in the adherent class (p = 0.004). CONCLUSIONS: The risk of poor adherence in renal transplant patients can be detected as early as one month post-transplantation, using appropriate and easy tools adapted to routine monitoring. PRACTICE IMPLICATIONS: An early focus on vulnerable patients should allow putting into place actions in order to reduce the risk of poor outcome related to poor adherence.

Ribavirin exposure after the first dose is predictive of sustained virological response in chronic hepatitis C.

UNLABELLED: The impact of ribavirin exposure on sustained virological response (SVR) in patients with chronic hepatitis C is unknown. Preliminary studies showed marked inter-individual variability of ribavirin concentrations despite dose adjustment for body weight (BW) and suggested there was a correlation between single time point concentrations and SVR. None of them evaluated the global exposure to ribavirin. This study was conducted to determine whether early ribavirin global exposure is related with SVR. An exploratory pharmacokinetic-pharmacodynamic (PK-PD) study was conducted in genotype 1 hepatitis C patients treated with peginterferon alfa-2a and ribavirin (dose-adjusted for BW) for 12 weeks, to which amantadine was added for the following 36 weeks. Full and abbreviated ribavirin area under the concentration time curves (AUC(0-12h), AUC(0-4h)) were derived from plasma concentration profiles at day 0 (D0), week 12 (W12), W12 + 1 day, and W24. Virological follow-up was performed at D0 (0, 12, and 24 hours), W2, W4, W6, and monthly until W72 (TaqMan polymerase chain reaction, cut-off 15 international units/mL). Twenty-eight patients were enrolled in the study and 24 completed it. Patients with a SVR had a significantly higher D0 AUC(0-12h) (3695 [1571-6916] versus 2937 [1266-4913] microg/hour/L, P = 0.03) and D0 AUC(0-4h) (2010 [615-3175] versus 1340 [622-2246] microg/hour/L, P = 0.03). Patients with D0 AUCs above the cut-off values defined by receiver operating characteristic curves (3014 microg/hour/L and 1755 microg/hour/L for AUC(0-12h) and AUC(0-4h), respectively) had a significantly better chance of achieving an SVR than patients with AUCs under the thresholds (odds ratio = 16.0, 95% confidence interval 1.54-166.6, P = 0.02 and odds ratio = 8.9, 95% confidence interval, 1.4-56.6; P = 0.02). CONCLUSION: Ribavirin exposure at D0 is significantly related to SVR. To our knowledge, this is the first study to give an early pharmacokinetic predictor of SVR. We propose a minimum AUC(0-4h) threshold of 1755 microg/hour/L at D0 as a target for ribavirin dose adjustment.

A Prognostic Tool for Individualized Prediction of Graft Failure Risk within Ten Years after Kidney Transplantation.

Identification of patients at risk of kidney graft loss relies on early individual prediction of graft failure. Data from 616 kidney transplant recipients with a follow-up of at least one year were retrospectively studied. A joint latent class model investigating the impact of serum creatinine (Scr) time-trajectories and onset of de novo donor-specific anti-HLA antibody (dnDSA) on graft survival was developed. The capacity of the model to calculate individual predicted probabilities of graft failure over time was evaluated in 80 independent patients. The model classified the patients in three latent classes with significantly different Scr time profiles and different graft survivals. Donor age contributed to explaining latent class membership. In addition to the SCr classes, the other variables retained in the survival model were proteinuria measured one-year after transplantation (HR=2.4, p=0.01), pretransplant non-donor-specific antibodies (HR=3.3, p<0.001), and dnDSA in patient who experienced acute rejection (HR=15.9, p=0.02). In the validation dataset, individual predictions of graft failure risk provided good predictive performances (sensitivity, specificity, and overall accuracy of graft failure prediction at ten years were 77.7%, 95.8%, and 85%, resp.) for the 60 patients who had not developed dnDSA. For patients with dnDSA individual risk of graft failure was not predicted with a so good performance.

An adjustable predictive score of graft survival in kidney transplant patients and the levels of risk linked to de novo donor-specific anti-HLA antibodies.

Most predictive models and scores of graft survival in renal transplantation include factors known before transplant or at the end of the first year. They cannot be updated thereafter, even in patients developing donor-specific anti-HLA antibodies and acute rejection.We developed a conditional and adjustable score for prediction of graft failure (AdGFS) up to 10 years post-transplantation in 664 kidney transplant patients. AdGFS was externally validated and calibrated in 896 kidney transplant patients.The final model included five baseline factors (pretransplant non donor-specific anti-HLA antibodies, donor age, serum creatinine measured at 1 year, longitudinal serum creatinine clusters during the first year, proteinuria measured at 1 year), and two predictors updated over time (de novo donor-specific anti-HLA antibodies and first acute rejection). AdGFS was able to stratify patients into four risk-groups, at different post-transplantation times. It showed good discrimination (time-dependent ROC curve at ten years: 0.83 (CI95% 0.76-0.89).