Dataset Information

Model-Informed Precision Dosing of Everolimus: External Validation in Adult Renal Transplant Recipients.

ABSTRACT:

Background and objective

The immunosuppressant everolimus is increasingly applied in renal transplantation. Its extensive pharmacokinetic variability necessitates therapeutic drug monitoring, typically based on whole-blood trough concentrations (C₀). Unfortunately, therapeutic drug monitoring target attainment rates are often unsatisfactory and patients with on-target exposure may still develop organ rejection. As everolimus displays erythrocyte partitioning, haematocrit-normalised whole-blood exposure has been suggested as a more informative therapeutic drug monitoring marker. Furthermore, model-informed precision dosing has introduced options for more sophisticated dose adaptation. We have previously developed a mechanistic population pharmacokinetic model, which described everolimus plasma pharmacokinetics and enabled estimation of haematocrit-normalised whole-blood exposure. Here, we externally evaluated this model for its utility for model-informed precision dosing.

Methods

The retrospective dataset included 4123 pharmacokinetic observations from routine clinical therapeutic drug monitoring in 173 renal transplant recipients. Model appropriateness was confirmed with a visual predictive check. A fit-for-purpose analysis was conducted to evaluate whether the model accurately and precisely predicted a future C₀ or area under the concentration-time curve (AUC) from prior pharmacokinetic observations. Bias and imprecision were expressed as the mean percentage prediction error (MPPE) and mean absolute percentage prediction error (MAPE), stratified on 6 months post-transplant. Additionally, we compared dose adaptation recommendations of conventional C₀-based therapeutic drug monitoring and C₀- or AUC-based model-informed precision dosing, and assessed the percentage of differences between observed and haematocrit-normalised C₀ (?C₀) and AUC (?AUC) exceeding?±?20%.

Results

The model showed adequate accuracy and precision for C₀ and AUC prediction at???6 months (MPPE_C0: 8.1?±?2.5%, MAPE_C0: 26.8?±?2.1%; MPPE_AUC: -?9.7?±?5.1%, MAPE_AUC: 13.3?±?3.9%) and?>?6 months post-transplant (MPPE_C0: 4.7?±?2.0%, MAPE_C0: 25.4?±?1.4%; MPPE_AUC: -?0.13?±?4.8%, MAPE_AUC: 13.3?±?2.8%). On average, dose adaptation recommendations derived from C₀-based and AUC-based model-informed precision dosing were 2.91?±?0.01% and 13.7?±?0.18% lower than for conventional C₀-based therapeutic drug monitoring at???6 months, and 0.93?±?0.01% and 3.14?±?0.04% lower at?>?6 months post-transplant. The ?C₀ and ?AUC exceeded?±?20% on 13.6% and 14.3% of occasions, respectively.

Conclusions

We demonstrated that our population pharmacokinetic model was able to accurately and precisely predict future everolimus exposure from prior pharmacokinetic measurements. In addition, we illustrated the potential added value of performing everolimus therapeutic drug monitoring with haematocrit-normalised whole-blood concentrations. Our results provide reassurance to implement this methodology in clinical practice for further evaluation.

SUBMITTER: Zwart TC

PROVIDER: S-EPMC7862213 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Model-Informed Precision Dosing of Everolimus: External Validation in Adult Renal Transplant Recipients.

Zwart Tom C TC Moes Dirk Jan A R DJAR van der Boog Paul J M PJM van Erp Nielka P NP de Fijter Johan W JW Guchelaar Henk-Jan HJ Keizer Ron J RJ Ter Heine Rob R

Clinical pharmacokinetics 20210201 2

<h4>Background and objective</h4>The immunosuppressant everolimus is increasingly applied in renal transplantation. Its extensive pharmacokinetic variability necessitates therapeutic drug monitoring, typically based on whole-blood trough concentrations (C<sub>0</sub>). Unfortunately, therapeutic drug monitoring target attainment rates are often unsatisfactory and patients with on-target exposure may still develop organ rejection. As everolimus displays erythrocyte partitioning, haematocrit-norma ...[more]

PMID: 32720301

Similar Datasets

Project description:Tacrolimus, an immunosuppressant used in solid organ transplantation, has a narrow therapeutic index and exhibits inter-individual pharmacokinetic variability. Achieving and maintaining a therapeutic level of the drug by giving appropriate doses is crucial for successful immunosuppression, especially during the initial post-transplant period. We studied the effect of CYP3A5, CYP3A4, and ABCB1 gene polymorphisms on tacrolimus trough concentrations in South Indian renal transplant recipients from Kerala to formulate a genotype-based dosing equation to calculate the required starting daily dose of tacrolimus to be given to each patient to attain optimal initial post-transplant period drug level. We also investigated the effect of these genes on drug-induced adverse effects and rejection episodes and looked into the global distribution of allele frequencies of these polymorphisms. One hundred forty-five renal transplant recipients on a triple immunosuppressive regimen of tacrolimus, mycophenolate mofetil, and steroid were included in this study. Clinical data including tacrolimus daily doses, trough levels (C0) and dose-adjusted tacrolimus trough concentration (C0/D) in blood at three time points (day 6, 6 months, and 1-year post-transplantation), adverse drug effects, rejection episodes, serum creatinine levels, etc., were recorded. The patients were genotyped for CYP3A5*3, CYP3A4*1B, CYP3A4*1G, ABCB1 G2677T, and ABCB1 C3435T polymorphisms by the PCR-RFLP method. We found that CYP3A5*3 polymorphism was the single most strongly associated factor determining the tacrolimus C0/D in blood at all three time points (p < 0.001). Using multiple linear regression, we formulated a simple and easy to compute equation that will help the clinician calculate the starting tacrolimus dose per kg body weight to be administered to a patient to attain optimal initial post-transplant period tacrolimus level. CYP3A5 expressors had an increased chance of rejection than non-expressors (p = 0.028), while non-expressors had an increased risk for new-onset diabetes mellitus after transplantation (NODAT) than expressors (p = 0.018). Genotype-guided initial tacrolimus dosing would help transplant recipients achieve optimal initial post-transplant period tacrolimus levels and thus prevent the adverse effects due to overdose and rejection due to inadequate dose. We observed inter-population differences in allele frequencies of drug metabolizer and transporter genes, emphasizing the importance of formulating population-specific dose prediction models to draw results of clinical relevance.

Dataset Information

Model-Informed Precision Dosing of Everolimus: External Validation in Adult Renal Transplant Recipients.

Background and objective

Methods

Results

Conclusions

Publications

Model-Informed Precision Dosing of Everolimus: External Validation in Adult Renal Transplant Recipients.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets