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Pharmaceutics
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Artificial Intelligence Enabled Pharmacometrics
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Artificial Intelligence Enabled Pharmacometrics

A special issue of Pharmaceutics (ISSN 1999-4923). This special issue belongs to the section "Pharmacokinetics and Pharmacodynamics".

Deadline for manuscript submissions: closed (28 February 2023) | Viewed by 32663

Special Issue Editor

Prof. Dr. Ulrika Simonsson

E-Mail Website
Guest Editor
Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden
Interests: antibiotic resistance; e-health; pharmacokinetics; pharmacometrics; pharmacodynamics; therapeutic drug monitoring; tuberculosis; translational medicine; nonlinear mixed effect modeling; modeling and simulation; infectious diseases; artificial intelligence; machine learning

Special Issue Information

Dear Colleagues,

The goal of this Special Issue is to present the latest advances in the field of pharmacometrics enhanced by artificial intelligence (AI), with the ultimate aim to further improve drug discovery and development as well as personalized medicine.

Pharmacometrics and quantitative systems pharmacology plays a vital role in the development of new drugs and personalized medicine. With the current scientific advancements, increasingly vast amounts of medical data become available, which we believe creates attractive opportunities for computationally more efficient methods such as AI technologies.

AI can support pharmacometric approaches and can be integrated in, e.g., model building and selection of predictive covariates; therapy optimization; or selection and inclusion of innovative biomarkers through, e.g., imaging. AI technologies can add value to modeling and simulation workflows through higher computationally efficiency, faster analysis of big data such as imaging and -omics data, and improvement of complex model performance, whereas classical modeling and simulation methods can be used to improve interpretability of AI approaches in the context of clinical pharmacology and provide hypothesis testing, which is crucial for regulatory interactions. To utilize the great potential of both methods, we propose pharmacometrics and AI to join forces in order to improve model performance, predictivity, and confidence in clinical pharmacological models compared with either approach alone.

For this research topic, we welcome original research, reviews, and opinion letters on AI-enabled pharmacometrics. Both technical and clinical implementation research falls within the scope.

Prof. Dr. Ulrika Simonsson
Guest Editor

Manuscript Submission Information

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Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Artificial intelligence
  • Pharmacometrics
  • Machine learning
  • Model-informed drug discovery and development (MID3)
  • Drug discovery and development
  • Modeling and simulation
  • Deep learning
  • Quantitative systems pharmacology
  • Nonlinear mixed effects modeling
  • Personalized medicine

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Published Papers (8 papers)

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Research

17 pages, 4271 KiB  
Article
Machine Learning for Exposure-Response Analysis: Methodological Considerations and Confirmation of Their Importance via Computational Experimentations
by Rashed Harun, Eric Yang, Nastya Kassir, Wenhui Zhang and James Lu
Pharmaceutics 2023, 15(5), 1381; https://doi.org/10.3390/pharmaceutics15051381 - 30 Apr 2023
Cited by 6 | Viewed by 2704
Abstract
Exposure-response (E-R) is a key aspect of pharmacometrics analysis that supports drug dose selection. Currently, there is a lack of understanding of the technical considerations necessary for drawing unbiased estimates from data. Due to recent advances in machine learning (ML) explainability methods, ML [...] Read more.
Exposure-response (E-R) is a key aspect of pharmacometrics analysis that supports drug dose selection. Currently, there is a lack of understanding of the technical considerations necessary for drawing unbiased estimates from data. Due to recent advances in machine learning (ML) explainability methods, ML has garnered significant interest for causal inference. To this end, we used simulated datasets with known E-R “ground truth” to generate a set of good practices for the development of ML models required to avoid introducing biases when performing causal inference. These practices include the use of causal diagrams to enable the careful consideration of model variables by which to obtain desired E-R relationship insights, keeping a strict separation of data for model-training and for inference generation to avoid biases, hyperparameter tuning to improve the reliability of models, and estimating proper confidence intervals around inferences using a bootstrap sampling with replacement strategy. We computationally confirm the benefits of the proposed ML workflow by using a simulated dataset with nonlinear and non-monotonic exposure–response relationships. Full article
(This article belongs to the Special Issue Artificial Intelligence Enabled Pharmacometrics)
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15 pages, 1373 KiB  
Article
Deep Learning Methods Applied to Drug Concentration Prediction of Olanzapine
by Richard Khusial, Robert R. Bies and Ayman Akil
Pharmaceutics 2023, 15(4), 1139; https://doi.org/10.3390/pharmaceutics15041139 - 4 Apr 2023
Cited by 7 | Viewed by 2896
Abstract
Pharmacometrics and the utilization of population pharmacokinetics play an integral role in model-informed drug discovery and development (MIDD). Recently, there has been a growth in the application of deep learning approaches to aid in areas within MIDD. In this study, a deep learning [...] Read more.
Pharmacometrics and the utilization of population pharmacokinetics play an integral role in model-informed drug discovery and development (MIDD). Recently, there has been a growth in the application of deep learning approaches to aid in areas within MIDD. In this study, a deep learning model, LSTM-ANN, was developed to predict olanzapine drug concentrations from the CATIE study. A total of 1527 olanzapine drug concentrations from 523 individuals along with 11 patient-specific covariates were used in model development. The hyperparameters of the LSTM-ANN model were optimized through a Bayesian optimization algorithm. A population pharmacokinetic model using the NONMEM model was constructed as a reference to compare to the performance of the LSTM-ANN model. The RMSE of the LSTM-ANN model was 29.566 in the validation set, while the RMSE of the NONMEM model was 31.129. Permutation importance revealed that age, sex, and smoking were highly influential covariates in the LSTM-ANN model. The LSTM-ANN model showed potential in the application of drug concentration predictions as it was able to capture the relationships within a sparsely sampled pharmacokinetic dataset and perform comparably to the NONMEM model. Full article
(This article belongs to the Special Issue Artificial Intelligence Enabled Pharmacometrics)
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26 pages, 591 KiB  
Article
Adoption of Machine Learning in Pharmacometrics: An Overview of Recent Implementations and Their Considerations
by Alexander Janssen, Frank C. Bennis and Ron A. A. Mathôt
Pharmaceutics 2022, 14(9), 1814; https://doi.org/10.3390/pharmaceutics14091814 - 29 Aug 2022
Cited by 22 | Viewed by 4337
Abstract
Pharmacometrics is a multidisciplinary field utilizing mathematical models of physiology, pharmacology, and disease to describe and quantify the interactions between medication and patient. As these models become more and more advanced, the need for advanced data analysis tools grows. Recently, there has been [...] Read more.
Pharmacometrics is a multidisciplinary field utilizing mathematical models of physiology, pharmacology, and disease to describe and quantify the interactions between medication and patient. As these models become more and more advanced, the need for advanced data analysis tools grows. Recently, there has been much interest in the adoption of machine learning (ML) algorithms. These algorithms offer strong function approximation capabilities and might reduce the time spent on model development. However, ML tools are not yet an integral part of the pharmacometrics workflow. The goal of this work is to discuss how ML algorithms have been applied in four stages of the pharmacometrics pipeline: data preparation, hypothesis generation, predictive modelling, and model validation. We will also discuss considerations before the use of ML algorithms with respect to each topic. We conclude by summarizing applications that hold potential for adoption by pharmacometricians. Full article
(This article belongs to the Special Issue Artificial Intelligence Enabled Pharmacometrics)
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29 pages, 9861 KiB  
Article
Machine Learning and Pharmacometrics for Prediction of Pharmacokinetic Data: Differences, Similarities and Challenges Illustrated with Rifampicin
by Lina Keutzer, Huifang You, Ali Farnoud, Joakim Nyberg, Sebastian G. Wicha, Gareth Maher-Edwards, Georgios Vlasakakis, Gita Khalili Moghaddam, Elin M. Svensson, Michael P. Menden, Ulrika S. H. Simonsson and on behalf of the UNITE4TB Consortium
Pharmaceutics 2022, 14(8), 1530; https://doi.org/10.3390/pharmaceutics14081530 - 22 Jul 2022
Cited by 35 | Viewed by 7473
Abstract
Pharmacometrics (PM) and machine learning (ML) are both valuable for drug development to characterize pharmacokinetics (PK) and pharmacodynamics (PD). Pharmacokinetic/pharmacodynamic (PKPD) analysis using PM provides mechanistic insight into biological processes but is time- and labor-intensive. In contrast, ML models are much quicker trained, [...] Read more.
Pharmacometrics (PM) and machine learning (ML) are both valuable for drug development to characterize pharmacokinetics (PK) and pharmacodynamics (PD). Pharmacokinetic/pharmacodynamic (PKPD) analysis using PM provides mechanistic insight into biological processes but is time- and labor-intensive. In contrast, ML models are much quicker trained, but offer less mechanistic insights. The opportunity of using ML predictions of drug PK as input for a PKPD model could strongly accelerate analysis efforts. Here exemplified by rifampicin, a widely used antibiotic, we explore the ability of different ML algorithms to predict drug PK. Based on simulated data, we trained linear regressions (LASSO), Gradient Boosting Machines, XGBoost and Random Forest to predict the plasma concentration-time series and rifampicin area under the concentration-versus-time curve from 0–24 h (AUC0–24h) after repeated dosing. XGBoost performed best for prediction of the entire PK series (R2: 0.84, root mean square error (RMSE): 6.9 mg/L, mean absolute error (MAE): 4.0 mg/L) for the scenario with the largest data size. For AUC0–24h prediction, LASSO showed the highest performance (R2: 0.97, RMSE: 29.1 h·mg/L, MAE: 18.8 h·mg/L). Increasing the number of plasma concentrations per patient (0, 2 or 6 concentrations per occasion) improved model performance. For example, for AUC0–24h prediction using LASSO, the R2 was 0.41, 0.69 and 0.97 when using predictors only (no plasma concentrations), 2 or 6 plasma concentrations per occasion as input, respectively. Run times for the ML models ranged from 1.0 s to 8 min, while the run time for the PM model was more than 3 h. Furthermore, building a PM model is more time- and labor-intensive compared with ML. ML predictions of drug PK could thus be used as input into a PKPD model, enabling time-efficient analysis. Full article
(This article belongs to the Special Issue Artificial Intelligence Enabled Pharmacometrics)
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12 pages, 783 KiB  
Article
Identification of miRNA-Small Molecule Associations by Continuous Feature Representation Using Auto-Encoders
by Ibrahim Abdelbaky, Hilal Tayara and Kil To Chong
Pharmaceutics 2022, 14(1), 3; https://doi.org/10.3390/pharmaceutics14010003 - 21 Dec 2021
Cited by 3 | Viewed by 3239
Abstract
MicroRNAs (miRNAs) are short non-coding RNAs that play important roles in the body and affect various diseases, including cancers. Controlling miRNAs with small molecules is studied herein to provide new drug repurposing perspectives for miRNA-related diseases. Experimental methods are time- and effort-consuming, so [...] Read more.
MicroRNAs (miRNAs) are short non-coding RNAs that play important roles in the body and affect various diseases, including cancers. Controlling miRNAs with small molecules is studied herein to provide new drug repurposing perspectives for miRNA-related diseases. Experimental methods are time- and effort-consuming, so computational techniques have been applied, relying mostly on biological feature similarities and a network-based scheme to infer new miRNA–small molecule associations. Collecting such features is time-consuming and may be impractical. Here we suggest an alternative method of similarity calculation, representing miRNAs and small molecules through continuous feature representation. This representation is learned by the proposed deep learning auto-encoder architecture. Our suggested representation was compared to previous works and achieved comparable results using 5-fold cross validation (92% identified within top 25% predictions), and better predictions for most of the case studies (avg. of 31% vs. 25% identified within the top 25% of predictions). The results proved the effectiveness of our proposed method to replace previous time- and effort-consuming methods. Full article
(This article belongs to the Special Issue Artificial Intelligence Enabled Pharmacometrics)
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22 pages, 1965 KiB  
Article
Drug Therapeutic-Use Class Prediction and Repurposing Using Graph Convolutional Networks
by Mapopa Chipofya, Hilal Tayara and Kil To Chong
Pharmaceutics 2021, 13(11), 1906; https://doi.org/10.3390/pharmaceutics13111906 - 10 Nov 2021
Cited by 4 | Viewed by 2595
Abstract
An important stage in the process of discovering new drugs is when candidate molecules are tested of their efficacy. It is reported that testing drug efficacy empirically costs billions of dollars in the drug discovery pipeline. As a mechanism of expediting this process, [...] Read more.
An important stage in the process of discovering new drugs is when candidate molecules are tested of their efficacy. It is reported that testing drug efficacy empirically costs billions of dollars in the drug discovery pipeline. As a mechanism of expediting this process, researchers have resorted to using computational methods to predict the action of molecules in silico. Here, we present a way of predicting the therapeutic-use class of drugs from chemical structures only using graph convolutional networks. In comparison with existing methods which use fingerprints or images as training samples, our approach has yielded better results in all metrics under consideration. In particular, validation accuracy increased from 83–88% to 86–90% for single label tasks. Similarly, the model achieved an accuracy of over 88% on new test data. Finally, our multi-label classification model made new predictions which indicated that some of the drugs could have other therapeutic uses other than those indicated in the dataset. We performed a literature-based evaluation of these predictions and found evidence that validates them. This renders the model a potential tool to be used in search of drugs that are candidates for repurposing. Full article
(This article belongs to the Special Issue Artificial Intelligence Enabled Pharmacometrics)
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14 pages, 1308 KiB  
Article
Population Pharmacokinetic Modelling of the Complex Release Kinetics of Octreotide LAR: Defining Sub-Populations by Cluster Analysis
by Iasonas Kapralos and Aristides Dokoumetzidis
Pharmaceutics 2021, 13(10), 1578; https://doi.org/10.3390/pharmaceutics13101578 - 28 Sep 2021
Cited by 3 | Viewed by 2710
Abstract
The aim of the study is to develop a population pharmacokinetic (PPK) model, of Octreotide long acting repeatable (LAR) formulation in healthy volunteers, which describes the highly variable, multiple peak absorption pattern of the pharmacokinetics of the drug, in individual and population levels. [...] Read more.
The aim of the study is to develop a population pharmacokinetic (PPK) model, of Octreotide long acting repeatable (LAR) formulation in healthy volunteers, which describes the highly variable, multiple peak absorption pattern of the pharmacokinetics of the drug, in individual and population levels. An empirical absorption model, coupled with a one-compartment distribution model with linear elimination was found to describe the data well. Absorption was modelled as a weighted sum of a first order and three transit compartment absorption processes, with delays and appropriately constrained model parameters. Identifiability analysis verified that all twelve parameters of the structural model are identifiable. A machine learning method, i.e., cluster analysis, was performed as pre-processing of the PK profiles, to define subpopulations, before PPK modelling. It revealed that 13% of the patients deviated considerably from the typical absorption pattern and allowed better characterization of the observed heterogeneity and variability of the study, while the approach may have wider applicability in building PPK models. The final model was evaluated by goodness of fit plots, Visual Predictive Check plots and bootstrap. The present model is the first to describe the multiple-peak absorption pattern observed after octreotide LAR administration and may be useful to provide insights and validate hypotheses regarding release from PLGA-based formulations. Full article
(This article belongs to the Special Issue Artificial Intelligence Enabled Pharmacometrics)
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10 pages, 792 KiB  
Article
Application of Deep Neural Networks as a Prescreening Tool to Assign Individualized Absorption Models in Pharmacokinetic Analysis
by Mutaz M. Jaber, Burhaneddin Yaman, Kyriakie Sarafoglou and Richard C. Brundage
Pharmaceutics 2021, 13(6), 797; https://doi.org/10.3390/pharmaceutics13060797 - 26 May 2021
Cited by 4 | Viewed by 3130
Abstract
A specific model for drug absorption is necessarily assumed in pharmacokinetic (PK) analyses following extravascular dosing. Unfortunately, an inappropriate absorption model may force other model parameters to be poorly estimated. An added complexity arises in population PK analyses when different individuals appear to [...] Read more.
A specific model for drug absorption is necessarily assumed in pharmacokinetic (PK) analyses following extravascular dosing. Unfortunately, an inappropriate absorption model may force other model parameters to be poorly estimated. An added complexity arises in population PK analyses when different individuals appear to have different absorption patterns. The aim of this study is to demonstrate that a deep neural network (DNN) can be used to prescreen data and assign an individualized absorption model consistent with either a first-order, Erlang, or split-peak process. Ten thousand profiles were simulated for each of the three aforementioned shapes and used for training the DNN algorithm with a 30% hold-out validation set. During the training phase, a 99.7% accuracy was attained, with 99.4% accuracy during in the validation process. In testing the algorithm classification performance with external patient data, a 93.7% accuracy was reached. This algorithm was developed to prescreen individual data and assign a particular absorption model prior to a population PK analysis. We envision it being used as an efficient prescreening tool in other situations that involve a model component that appears to be variable across subjects. It has the potential to reduce the time needed to perform a manual visual assignment and eliminate inter-assessor variability and bias in assigning a sub-model. Full article
(This article belongs to the Special Issue Artificial Intelligence Enabled Pharmacometrics)
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