Annick Rousseau

Individualized mycophenolate mofetil dosing based on drug exposure significantly improves patient outcomes after renal transplantation.

Efficacy and safety of mycophenolate mofetil (MMF) may be optimized with individualized doses based on therapeutic monitoring of its active metabolite, mycophenolic acid (MPA). In this 12‐month study, 137 renal allograft recipients from 11 French centers receiving basiliximab, cyclosporine A, MMF and corticosteroids were randomized to receive either concentration‐controlled doses or fixed‐dose MMF. A novel Bayesian estimator of MPA AUC based on three‐point sampling was used to individualize doses on posttransplant days 7 and 14 and months 1, 3 and 6. The primary endpoint was treatment failure (death, graft loss, acute rejection and MMF discontinuation). Data from 65 patients/group were analyzed. At month 12, the concentration‐controlled group had fewer treatment failures (p = 0.03) and acute rejection episodes (p = 0.01) with no differences in adverse event frequency. The MMF dose was higher in the concentration‐controlled group at day 14 (p < 0.0001), month 1 (p < 0.0001) and month 3 (p < 0.01), as were median AUCs on day 14 (33.7 vs. 27.1 mg•h/L; p = 0.0001) and at month 1 (45.0 vs. 30.9 mg•h/L; p < 0.0001). Therapeutic MPA monitoring using a limited sampling strategy can reduce the risk of treatment failure and acute rejection in renal allograft recipients 12 months posttransplant with no increase in adverse events.

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

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 (AUC0–12h, AUC0–4h) 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 AUC0–12h (3695 [1571–6916] versus 2937 [1266–4913] μg/hour/L, P = 0.03) and D0 AUC0–4h (2010 [615–3175] versus 1340 [622–2246] μg/hour/L, P = 0.03). Patients with D0 AUCs above the cut‐off values defined by receiver operating characteristic curves (3014 μg/hour/L and 1755 μg/hour/L for AUC0–12h and AUC0–4h, 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 AUC0–4h threshold of 1755 μg/hour/L at D0 as a target for ribavirin dose adjustment. (HEPATOLOGY 2008;47:1453–1461.)

Population pharmacokinetic modeling of oral cyclosporin using NONMEM: comparison of absorption pharmacokinetic models and design of a Bayesian estimator.

There have been very few population pharmacokinetic (PopPK) studies and Bayesian forecasting methods dealing with cyclosporin (CsA) so far, probably because of the difficulty of modeling the particular absorption profiles of CsA. The present study was conducted in stable renal transplant patients treated with Neoral® and employed the NONMEM program. Its goals were (1) to develop a population pharmacokinetic model for CsA based on an Erlang frequency distribution (which describes asymmetric S-shaped absorption profiles) combined with a 2-compartment model; (2) to compare this model with models combining a time-lag parameter and either a zero-order or first-order rate constant and with a model based on a Weibull distribution; and (3) to develop a PK Bayesian estimator for full AUC estimation based on that “Erlang model.” The PopPK model was developed in an index set of 70 patients, and then individual PK parameters and AUC were estimated in 10 other patients using Bayesian estimation. The “Erlang” model best described the data, with mean absorption time (MAT), apparent clearance (CL/F), and apparent volume of the central compartment (Vc/F) of 0.78 hours, 26.3 L/h, and 76 L, respectively (interindividual variability CV = 33, 30, and 48%). Bayesian estimation allowed accurate prediction of systemic exposure using only 3 samples collected at 0, 1, and 3 hours. Regression analysis found no significant difference between the predicted and observed concentrations (10 per patient), and AUC0–12 were estimated with a nonsignificant bias (0.6 to 8.7%) and good precision (RMSE = 5.3%). In conclusion, the Erlang distribution best described CsA absorption profiles, and a Bayesian estimator developed using this model and a mixed-effect PK modeling program provided accurate estimates of CsA systemic exposure using only 3 blood samples.

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.

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.

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.

Population pharmacokinetics of mycophenolic acid in pediatric renal transplant patients using parametric and nonparametric approaches.

Mycophenolic acid (MPA) is an immunosuppressive drug widely used in the prevention of acute rejection in pediatric renal transplant recipients and is characterized by a wide inter-individual variability in its pharmacokinetics. The aim of this study was to compare population pharmacokinetic modeling of MPA in pediatric renal transplant recipients given mycophenolate mofetil, the ester prodrug of MPA, using parametric and nonparametric population methods. The data from 34 pediatric renal transplants (73 full pharmacokinetic profiles obtained on day 21, months 3, 6 and 9 post-transplant) were analyzed using both the nonlinear mixed-effect modeling (NONMEM) and nonparametric adaptive grid (NPAG) approaches, based on a two-compartment model with first order lagged time absorption and first order elimination. The predictive performance of the two models was evaluated in a separate group of 32 patients. Higher mean population parameter values and ranges of individual pharmacokinetic parameters were obtained with NPAG, especially for the elimination constant ke: mean 1.16 h(-1) (0.26-4.33 h(-1)) and 0.78 h(-1) (0.66-1.15 h(-1)) with NPAG and NONMEM, respectively. With NPAG, the skewness and kurtosis values for ke (2.03 and 7.80, respectively) were far from the theoretical values expected for normal distributions. Such a non-normal distribution could explain the high value of shrinkage (35%) obtained for this parameter with the parametric NONMEM method. Bayesian forecasting of mycophenolic acid exposure using the NPAG population pharmacokinetic parameters as priors yielded a better predictive performance, with a significantly smaller bias than with the NONMEM model (-1.68% vs -9.53%, p<0.0001). In conclusion, in the present study, NPAG was found to be the most adequate population pharmacokinetic method to describe the pharmacokinetics of MPA in pediatric 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.

Impact of longitudinal exposure to mycophenolic acid on acute rejection in renal-transplant recipients using a joint modeling approach.

This study aimed to investigate the association between longitudinal exposure to mycophenolic acid (MPA) and acute rejection (AR) risk in the first year after renal transplantation, and to propose MPA exposure targets conditionally to this association. A joint model, adjusted for monitoring strategy (fixed-dose versus concentration-controlled) and recipient age, was developed; it combined a mixed-effects model to describe the whole pattern of MPA exposure (i.e. area under the concentration-time curve (AUC)) and a survival model. MPA AUC thresholds were determined using time-dependent receiver-operating characteristics (ROC) curves. Data from 490 adult renal-transplant recipients, representative of the general population of adult renal-transplant patients (i.e. including patients considered at low immunological risk-enrolled in the OPERA trial as well as second renal transplant and patients co-treated by either cyclosporine or tacrolimus), were analyzed. A significant association was found between the longitudinal exposure to MPA (MPA AUCs=f(t)) and AR (p=0.0081), and validated by bootstrapping. A significant positive correlation was observed between time post-transplantation and ROC thresholds which increased in average from 35 mg h/L in the first days to 41 mg h/L beyond six months post-transplantation (p<0.001). Using a new modeling approach which recognizes the repeated measures in a same patient, this study supports the association between MPA exposure and AR.