Abstract
Dosing requires consideration of diverse patient-specific factors affecting drug pharmacokinetics and pharmacodynamics. The available pharmacometric methods have limited capacity for modeling the inter-relationships and patterns of variability among physiological determinants of drug dosing (PDODD). To investigate whether generative adversarial networks (GANs) can learn a generative model from real-world data that recapitulates PDODD distributions. A GAN architecture was developed for modeling a PDODD panel comprised of: age, sex, race/ethnicity, body weight, body surface area, total body fat, lean body weight, albumin concentration, glomerular filtration rate (EGFR), urine flow rate, urinary albumin-to-creatinine ratio, alanine aminotransferase to alkaline phosphatase R-value, total bilirubin, active hepatitis B infection status, active hepatitis C infection status, red blood cell, white blood cell, and platelet counts. The panel variables were derived from National Health and Nutrition Examination Survey (NHANES) data sets. The dependence of GAN-generated PDODD on age, race, and active hepatitis infections was assessed. The continuous PDODD biomarkers had diverse non-normal univariate distributions and bivariate trend patterns. The univariate distributions of PDODD biomarkers from GAN simulations satisfactorily approximated those in test data. The joint distribution of the continuous variables was visualized using three 2-dimensional projection methods; for all three methods, the points from the GAN simulation random variate vectors were well dispersed amongst the test data. The age dependence trend patterns in GAN data were similar to those in test data. The histograms for R-values and EGFR from GAN simulations overlapped extensively with test data histograms for the Hispanic, White, African American, and Other race/ethnicity groups. The GAN-simulated data also mirrored the R-values and EGFR changes in active hepatitis C and hepatitis B infection. GANs are a promising approach for simulating the age, race/ethnicity and disease state dependencies of PDODD.
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RN–Conducted experiments, data analysis, manuscript preparation. DDM–Assisted with experiments, data analysis, manuscript preparation. SS–Study concept and design, data analysis, manuscript preparation. VG–Study oversight, manuscript review. MR–Study concept and design, data analysis, manuscript preparation.
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Rahul Nair and Deen Dayal Mohan have no conflicts. Srirangaraj Setlur and Dr. Venu Govindaraju received unrelated research funding from the National Science Foundation, United States Postal Service, and the Intelligence Advanced Research Projects Activity agencies. Dr. Murali Ramanathan received research funding from the National Science Foundation, Department of Defense, and the National Institutes of Health.
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Nair, R., Mohan, D.D., Setlur, S. et al. Generative models for age, race/ethnicity, and disease state dependence of physiological determinants of drug dosing. J Pharmacokinet Pharmacodyn 50, 111–122 (2023). https://doi.org/10.1007/s10928-022-09838-4
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DOI: https://doi.org/10.1007/s10928-022-09838-4