Easy and reliable maximum a posteriori Bayesian estimation of pharmacokinetic parameters with the open‐source R package mapbayr

Pharmacokinetic (PK) parameter estimation is a critical and complex step in the model‐informed precision dosing (MIPD) approach. The mapbayr package was developed to perform maximum a posteriori Bayesian estimation (MAP‐BE) in R from any population PK model coded in mrgsolve. The performances of mapbayr were assessed using two approaches. First, “test” models with different features were coded, for example, first‐order and zero‐order absorption, lag time, time‐varying covariates, Michaelis–Menten elimination, combined and exponential residual error, parent drug and metabolite, and small or large inter‐individual variability (IIV). A total of 4000 PK profiles (combining single/multiple dosing and rich/sparse sampling) were simulated from each test model, and MAP‐BE of parameters was performed in both mapbayr and NONMEM. Second, a similar procedure was conducted with seven “real” previously published models to compare mapbayr and NONMEM on a PK outcome used in MIPD. For the test models, 98% of mapbayr estimations were identical to those given by NONMEM. Some discordances could be observed when dose‐related parameters were estimated or when models with large IIV were used. The exploration of objective function values suggested that mapbayr might outdo NONMEM in specific cases. For the real models, a concordance close to 100% on PK outcomes was observed. The mapbayr package provides a reliable solution to perform MAP‐BE of PK parameters in R. It also includes functions dedicated to data formatting and reporting and enables the creation of standalone Shiny web applications dedicated to MIPD, whatever the model or the clinical protocol and without additional software other than R.

[1]  D. Tosi,et al.  Therapeutic Bayesian monitoring of sunitinib in two patients with impaired absorption or elimination , 2021, Journal of clinical pharmacy and therapeutics.

[2]  S. Wicha,et al.  From Therapeutic Drug Monitoring to Model‐Informed Precision Dosing for Antibiotics , 2021, Clinical pharmacology and therapeutics.

[3]  L. Ysebaert,et al.  Limited Sampling Strategy for Determination of Ibrutinib Plasma Exposure: Joint Analyses with Metabolite Data , 2021, Pharmaceuticals.

[4]  W. Huisinga,et al.  Perspectives on Model‐Informed Precision Dosing in the Digital Health Era: Challenges, Opportunities, and Recommendations , 2020, Clinical pharmacology and therapeutics.

[5]  Malek Okour,et al.  DosePredict: A Shiny Application for Generalized Pharmacokinetics‐Based Dose Predictions , 2020, Journal of clinical pharmacology.

[6]  Isabel Spriet,et al.  Software Tools for Model-Informed Precision Dosing: How Well Do They Satisfy the Needs? , 2020, Frontiers in Pharmacology.

[7]  L. Dupré,et al.  Population Pharmacokinetics of Ibrutinib and Its Dihydrodiol Metabolite in Patients with Lymphoid Malignancies , 2020, Clinical Pharmacokinetics.

[8]  Mirjam N Trame,et al.  Performance of the SAEM and FOCEI Algorithms in the Open‐Source, Nonlinear Mixed Effect Modeling Tool nlmixr , 2019, CPT: pharmacometrics & systems pharmacology.

[9]  M. Riggs,et al.  Quantitative Systems Pharmacology and Physiologically‐Based Pharmacokinetic Modeling With mrgsolve: A Hands‐On Tutorial , 2019, CPT: pharmacometrics & systems pharmacology.

[10]  Niklas Hartung,et al.  Bayesian Data Assimilation to Support Informed Decision Making in Individualized Chemotherapy , 2019, CPT: pharmacometrics & systems pharmacology.

[11]  Wenping Wang,et al.  Nonlinear Mixed‐Effects Model Development and Simulation Using nlmixr and Related R Open‐Source Packages , 2019, CPT: pharmacometrics & systems pharmacology.

[12]  Robert J Bauer,et al.  NONMEM Tutorial Part I: Description of Commands and Options, With Simple Examples of Population Analysis , 2019, CPT: pharmacometrics & systems pharmacology.

[13]  S. Chapel,et al.  Updated Population Pharmacokinetic Model of Cabozantinib Integrating Various Cancer Types Including Hepatocellular Carcinoma , 2019, Journal of clinical pharmacology.

[14]  M. Danhof,et al.  Individualized Dosing Algorithms and Therapeutic Monitoring for Antiepileptic Drugs , 2018, Clinical pharmacology and therapeutics.

[15]  France Mentré,et al.  PFIM 4.0, an extended R program for design evaluation and optimization in nonlinear mixed-effect models , 2018, Comput. Methods Programs Biomed..

[16]  S. Broutin,et al.  Therapeutic Drug Monitoring of Carboplatin in High-Dose Protocol (TI-CE) for Advanced Germ Cell Tumors: Pharmacokinetic Results of a Phase II Multicenter Study , 2017, Clinical Cancer Research.

[17]  Marc Lavielle,et al.  Parameter Estimation in Nonlinear Mixed Effect Models Using saemix, an R Implementation of the SAEM Algorithm , 2017 .

[18]  J. Schellens,et al.  Development of a Pharmacokinetic Model to Describe the Complex Pharmacokinetics of Pazopanib in Cancer Patients , 2017, Clinical Pharmacokinetics.

[19]  W Wang,et al.  A Tutorial on RxODE: Simulating Differential Equation Pharmacometric Models in R , 2015, CPT: pharmacometrics & systems pharmacology.

[20]  Kyun-Seop Bae,et al.  R-based reproduction of the estimation process hidden behind NONMEM(R) Part 1: first-order approximation method , 2015 .

[21]  J. Schellens,et al.  Integrated semi-physiological pharmacokinetic model for both sunitinib and its active metabolite SU12662. , 2015, British journal of clinical pharmacology.

[22]  S. Wicha,et al.  TDMx: a novel web-based open-access support tool for optimising antimicrobial dosing regimens in clinical routine. , 2015, International journal of antimicrobial agents.

[23]  J Wojciechowski,et al.  Interactive Pharmacometric Applications Using R and the Shiny Package , 2015, CPT: pharmacometrics & systems pharmacology.

[24]  Andrew C. Hooker,et al.  PopED: An extended, parallelized, nonlinear mixed effects models optimal design tool , 2012, Comput. Methods Programs Biomed..

[25]  J. Proost,et al.  Evaluation of 5-Fluorouracil Pharmacokinetics in Cancer Patients with a C.1905+1G>A Mutation in DPYD by Means of a Bayesian Limited Sampling Strategy , 2012, Clinical Pharmacokinetics.

[26]  Mats O. Karlsson,et al.  Standard Error of Empirical Bayes Estimate in NONMEM® VI , 2012, The Korean journal of physiology & pharmacology : official journal of the Korean Physiological Society and the Korean Society of Pharmacology.

[27]  M. Karlsson,et al.  Integrated Population Pharmacokinetic Analysis of Voriconazole in Children, Adolescents, and Adults , 2012, Antimicrobial Agents and Chemotherapy.

[28]  Cees Neef,et al.  Optimal Sampling Strategy Development Methodology Using Maximum A Posteriori Bayesian Estimation , 2011, Therapeutic drug monitoring.

[29]  R. Savic,et al.  Importance of Shrinkage in Empirical Bayes Estimates for Diagnostics: Problems and Solutions , 2009, The AAPS Journal.

[30]  Ju‐Seop Kang,et al.  Overview of Therapeutic Drug Monitoring , 2009, The Korean journal of internal medicine.

[31]  Mary H. H. Ensom,et al.  Beyond Cyclosporine: A Systematic Review of Limited Sampling Strategies for Other Immunosuppressants , 2006, Therapeutic drug monitoring.

[32]  S. Urien,et al.  Population pharmacokinetic study of methotrexate in patients with lymphoid malignancy , 2006, Cancer Chemotherapy and Pharmacology.

[33]  P. Marquet,et al.  Adaptive Control Methods for the Dose Individualisation of Anticancer Agents , 2000, Clinical pharmacokinetics.

[34]  L. Sheiner,et al.  Modelling of individual pharmacokinetics for computer-aided drug dosage. , 1972, Computers and biomedical research, an international journal.

[35]  D. Yim,et al.  R-based reproduction of the estimation process hidden behind NONMEM ® Part 2 : First-order conditional estimation , 2016 .

[36]  R Core Team,et al.  R: A language and environment for statistical computing. , 2014 .

[37]  X. Pivot,et al.  A limited sampling strategy for determining carboplatin AUC and monitoring drug dosage. , 2000, European journal of cancer.

[38]  A. Iliadis,et al.  A limited-sampling strategy for estimation of etoposide pharmacokinetics in cancer patients , 1999, Cancer Chemotherapy and Pharmacology.