Limited Sampling Models and Bayesian Estimation for Mycophenolic Acid Area under the Curve Prediction in Stable Renal Transplant Patients Co-Medicated with Ciclosporin or Sirolimus

Musuamba, Flora T.; Rousseau, Annick; Bosmans, Jean‐Louis; Senessael, Jean-Jacques; Cumps, Jean; Marquet, Pierre; Wallemacq, Pierre; Verbeeck, Roger K.

doi:10.2165/11318060-000000000-00000

Cited by 50 publications

(61 citation statements)

References 36 publications

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“…The initial pharmacokinetic model of Li et al (6), which was developed in 402 HCT recipients, was modified to include total MPAG (as described by Musuamba et al (15)) and unbound MPA concentrations. Briefly, total MPA pharmacokinetics was described using a two-compartmental model with first-order elimination and first-order absorption with a lag time (Fig.…”

Section: Methodsmentioning

confidence: 99%

Pharmacokinetic and Pharmacodynamic Analysis of Inosine Monophosphate Dehydrogenase Activity in Hematopoietic Cell Transplantation Recipients Treated with Mycophenolate Mofetil

Hong

Mager

Sandmaier

et al. 2014

Biology of Blood and Marrow Transplantation

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A novel approach to personalizing postgrafting immunosuppression in hematopoietic cell transplant (HCT) recipients is evaluating inosine monophosphate dehydrogenase (IMPDH) activity as a drug-specific biomarker of mycophenolic acid (MPA)-induced immunosuppression. This prospective study evaluated total MPA, unbound MPA, and total MPA glucuronide plasma concentrations and IMPDH activity in peripheral blood mononuclear cells (PMNC) at five time points after the morning dose of oral mycophenolate mofetil (MMF) on day +21 in 56 nonmyeloablative HCT recipients. Substantial interpatient variability in the pharmacokinetics and pharmacodynamics was observed and accurately characterized by the population pharmacokinetic/dynamic model. IMPDH activity decreased with increasing MPA plasma concentration, with maximum inhibition coinciding with maximum MPA concentration in most patients. The overall relationship between MPA concentration and IMPDH activity was described by a direct inhibitory Emax model with an IC50 = 3.23 mg/L total MPA and 57.3 ng/mL unbound MPA. The day +21 IMPDH area under the effect curve (AUEC) was associated with cytomegalovirus reactivation, non-relapse mortality, and overall mortality. In conclusion, a pharmacokinetic/dynamic model was developed that relates plasma MPA concentrations with PMNC IMPDH activity after an MMF dose in HCT recipients. Future studies should validate this model and confirm that day +21 IMPDH AUEC is a predictive biomarker.

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Section: Methodsmentioning

confidence: 99%

Pharmacokinetic and Pharmacodynamic Analysis of Inosine Monophosphate Dehydrogenase Activity in Hematopoietic Cell Transplantation Recipients Treated with Mycophenolate Mofetil

Hong

Mager

Sandmaier

et al. 2014

Biology of Blood and Marrow Transplantation

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“…The latest published studies investigating population pharmacokinetics of MPA and including a mechanism-based model for EHC are those by Musuamba et al [91] and de Winter et al [92] Musuamba et al [91] developed a model with a compartment to describe EHC in stable renal transplant recipients who were co-medicated with sirolimus (tables I and II). The application of Bayesian estimation allowed for accurate prediction of MPA AUC from 0 to 12 hours (AUC 12 ) and individualized dosing.…”

Section: Outline Of Population Pharmacokinetic Modelling Of Mpa Pumentioning

confidence: 99%

“…In summary, the review of the published papers found 12 studies [26,42,67,68,70,71,83–89,91,92] using NONMEM to describe the pharmacokinetics of MPA in renal transplant patients. Only one study included children [68] and one study used Win-NonLin.…”

Section: Outline Of Population Pharmacokinetic Modelling Of Mpa Pumentioning

confidence: 99%

The Evolution of Population Pharmacokinetic Models to Describe the Enterohepatic Recycling of Mycophenolic Acid in Solid Organ Transplantation and Autoimmune Disease

Sherwin

Fukuda

Brunner

et al. 2011

Clinical Pharmacokinetics

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With the increasing use of mycophenolic acid (MPA) as an immunosuppressant in solid organ transplantation and in treating autoimmune diseases such as systemic lupus erythematosus, the need for strategies to optimize therapy with this agent has become increasingly apparent. This need is largely based on MPA’s significant between-subject and between-occasion (within-subject) pharmacokinetic variability. While there is a strong relationship between MPA exposure and effect, the relationship between drug dose, plasma concentration and exposure (area under the concentration-time curve [AUC]) is very complex and remains to be completely defined. Population pharmacokinetic models using various approaches have been proposed over the past 10 years to further evaluate the pharmacokinetic and pharmacodynamic behaviour of MPA. These models have evolved from simple one-compartment linear iterations to complex multi-compartment versions that try to include various factors, which may influence MPA’s pharmacokinetic variability, such as enterohepatic recycling and pharmacogenetic polymorphisms. There have been major advances in the understanding of the roles transport mechanisms, metabolizing and other enzymes, drug-drug interactions and pharmacogenetic polymorphisms play in MPA’s pharmacokinetic variability. Given these advances, the usefulness of empirical-based models and the limitations of nonlinear mixed-effects modelling in developing mechanism-based models need to be considered and discussed. If the goal is to individualize MPA dosing, it needs to be determined whether factors which may contribute significantly to variability can be utilized in the population pharmacokinetic models. Some pharmacokinetic models developed to date show promise in being able to describe the impact of physiological processes such as enterohepatic recycling. Most studies have historically been based on retrospective data or poorly designed studies which do not take these factors into consideration. Modelling typically has been undertaken using non-controlled therapeutic drug monitoring data, which do not have the information content to support the development of complex mechanistic models. Only a few recent modelling approaches have moved away from empiricism and have included mechanisms considered important, such as enterohepatic recycling. It is recognized that well thought-out sampling schedules allow for better evaluation of the pharmacokinetic data. It is not possible to undertake complex absorption modelling with very few samples being obtained during the absorption phase (which has often been the case). It is important to utilize robust AUC monitoring which is now being propagated in the latest consensus guideline on MPA therapeutic drug monitoring. This review aims to explore the biological factors that contribute to the clinical pharmacokinetics of MPA and how these have been introduced in the development of population pharmacokinetic models. An overview of the processes involved in the enterohepatic recycling of MPA will be provided. ...

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“…A number of studies have tested Bayesian procedures for estimation of MPA AUC and shown satisfactory predictive power. [50][51][52][53] Disadvantages of Bayesian methods include a more complex calculation requiring specialist software and user training and reliance on the existence of an appropriate pharmacokinetic model and knowledge of covariates. 16 Thus, it is less easily applicable on a routine basis in the clinical setting, although web-based services are available to assist (http//pharmaco.chu-limoges.fr/abis.htm).…”

Section: Discussionmentioning

confidence: 99%

Evaluation of Limited Sampling Strategies for Mycophenolic Acid After Mycophenolate Mofetil Intake in Adult Kidney Transplant Recipients

Barraclough

Isbel²,

Franklin³

et al. 2010

Therapeutic Drug Monitoring

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Multiple limited sampling strategies (LSSs) have been proposed for estimation of mycophenolic acid (MPA) area under the concentration-time curve from 0 to 12 hours postdose (AUC 0-12) after mycophenolate mofetil intake. The aim of this study was to provide summary information on all published LSSs for MPA and to evaluate their predictive performance in an independent population of kidney transplant recipients. Seventy-eight LSSs for MPA were identified. Sixty-nine full AUC profiles were collected from 45 subjects (25 cotreated with cyclosporine and 20 with tacrolimus). Predicted MPA AUC 0-12, calculated by applying the relevant concentration measurements within the LSS equations, was compared with full AUC calculated by using all concentration measurements in the linear trapezoidal rule. Four error indices (median prediction error, median percentage prediction error [MPPE], root median squared prediction error, and median absolute percentage prediction error [MAPE]) were used to evaluate bias and imprecision. Twelve of the 25 LSSs for cyclosporine-cotreated recipients and one of the 53 LSSs for tacrolimus-cotreated recipients displayed acceptable (less than 15%) bias and imprecision. In the cyclosporine group, two equations demonstrated the highest predictive power, one that used four time points in the first 6 hours postdose (r2 = 0.84, MPPE 1.6%, MAPE 7.8%) and one that used four time points in the first 4 hours postdose (r2 = 0.76, MPPE -0.8%, MAPE 10.2%). In the tacrolimus group, an equation that used two time points in the first 4 hours postdose was superior (r2 = 0.80, MPPE -3.0%, MAPE 13.6%). Application of the LSSs most appropriate for cyclosporine-cotreated patients to the tacrolimus-cotreated group resulted in clinically unacceptable bias and imprecision and vice versa. High variability in performance of LSSs highlights the importance of validating any LSS before applying it to an alternative population. Attention to comedication use is of particular relevance when choosing a LSS.

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Limited Sampling Models and Bayesian Estimation for Mycophenolic Acid Area under the Curve Prediction in Stable Renal Transplant Patients Co-Medicated with Ciclosporin or Sirolimus

Cited by 50 publications

References 36 publications

Pharmacokinetic and Pharmacodynamic Analysis of Inosine Monophosphate Dehydrogenase Activity in Hematopoietic Cell Transplantation Recipients Treated with Mycophenolate Mofetil

Pharmacokinetic and Pharmacodynamic Analysis of Inosine Monophosphate Dehydrogenase Activity in Hematopoietic Cell Transplantation Recipients Treated with Mycophenolate Mofetil

The Evolution of Population Pharmacokinetic Models to Describe the Enterohepatic Recycling of Mycophenolic Acid in Solid Organ Transplantation and Autoimmune Disease

Evaluation of Limited Sampling Strategies for Mycophenolic Acid After Mycophenolate Mofetil Intake in Adult Kidney Transplant Recipients

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