Modeling Metformin and Dapagliflozin Pharmacokinetics in Chronic Kidney Disease.

Chronic kidney disease (CKD) is a complication of diabetes that affects circulating drug concentrations and elimination of drugs from the body. Multiple drugs may be prescribed for treatment of diabetes and co-morbidities, and CKD complicates the pharmacotherapy selection and dosing regimen. Characterizing variations in renal drug clearance using models requires large clinical datasets that are costly and time-consuming to collect. We propose a flexible approach to incorporate impaired renal clearance in pharmacokinetic (PK) models using descriptive statistics and secondary data with mechanistic models and PK first principles. Probability density functions were generated for various drug clearance mechanisms based on the degree of renal impairment and used to estimate the total clearance starting from glomerular filtration for metformin (MET) and dapagliflozin (DAPA). These estimates were integrated with PK models of MET and DAPA for simulations. MET renal clearance decreased proportionally with a reduction in estimated glomerular filtration rate (eGFR) and estimated net tubular transport rates. DAPA total clearance varied little with renal impairment and decreased proportionally to reported non-renal clearance rates. Net tubular transport rates were negative to partially account for low renal clearance compared with eGFR. The estimated clearance values and trends were consistent with MET and DAPA PK characteristics in the literature. Dose adjustment based on reduced clearance levels estimated correspondingly lower doses for MET and DAPA while maintaining desired dose exposure. Estimation of drug clearance rates using descriptive statistics and secondary data with mechanistic models and PK first principles improves modeling of CKD in diabetes and can guide treatment selection.

Multivariable Automated Insulin Delivery System for Handling Planned and Spontaneous Physical Activities.

BACKGROUND: Hybrid closed-loop control of glucose levels in people with type 1 diabetes mellitus (T1D) is limited by the requirements on users to manually announce physical activity (PA) and meals to the artificial pancreas system. Multivariable automated insulin delivery (mvAID) systems that can handle unannounced PAs and meals without any manual announcements by the user can improve glycemic control by modulating insulin dosing in response to the occurrence and intensity of spontaneous physical activities. METHODS: An mvAID system is developed to supplement the glucose measurements with additional physiological signals from a wristband device, with the signals analyzed using artificial intelligence algorithms to automatically detect the occurrence of PA and estimate its intensity. This additional information gained from the physiological signals enables more proactive insulin dosing adjustments in response to both planned exercise and spontaneous unanticipated physical activities. RESULTS: In silico studies of the mvAID illustrate the safety and efficacy of the system. The mvAID is translated to pilot clinical studies to assess its performance, and the clinical experiments demonstrate an increased time in range and reduced risk of hypoglycemia following unannounced PA and meals. CONCLUSIONS: The mvAID systems can increase the safety and efficacy of insulin delivery in the presence of unannounced physical activities and meals, leading to improved lives and less burden on people with T1D.

Detection of Meals and Physical Activity Events From Free-Living Data of People With Diabetes.

BACKGROUND: Predicting carbohydrate intake and physical activity in people with diabetes is crucial for improving blood glucose concentration regulation. Patterns of individual behavior can be detected from historical free-living data to predict meal and exercise times. Data collected in free-living may have missing values and forgotten manual entries. While machine learning (ML) can capture meal and exercise times, missing values, noise, and errors in data can reduce the accuracy of ML algorithms. METHODS: Two recurrent neural networks (RNNs) are developed with original and imputed data sets to assess detection accuracy of meal and exercise events. Continuous glucose monitoring (CGM) data, insulin infused from pump data, and manual meal and exercise entries from free-living data are used to predict meals, exercise, and their concurrent occurrence. They contain missing values of various lengths in time, noise, and outliers. RESULTS: The accuracy of RNN models range from 89.9% to 95.7% for identifying the state of event (meal, exercise, both, or neither) for various users. "No meal or exercise" state is determined with 94.58% accuracy by using the best RNN (long short-term memory [LSTM] with 1D Convolution). Detection accuracy with this RNN is 98.05% for meals, 93.42% for exercise, and 55.56% for concurrent meal-exercise events. CONCLUSIONS: The meal and exercise times detected by the RNN models can be used to warn people for entering meal and exercise information to hybrid closed-loop automated insulin delivery systems. Reliable accuracy for event detection necessitates powerful ML and large data sets. The use of additional sensors and algorithms for detecting these events and their characteristics provides a more accurate alternative.

A physical activity-intensity driven glycemic model for type 1 diabetes.

BACKGROUND AND OBJECTIVE: The glucose response to physical activity for a person with type 1 diabetes (T1D) depends upon the intensity and duration of the physical activity, plasma insulin concentrations, and the individual physical fitness level. To accurately model the glycemic response to physical activity, these factors must be considered. METHODS: Several physiological models describing the glycemic response to physical activity are proposed by incorporating model terms proportional to the physical activity intensity and duration describing endogenous glucose production (EGP), glucose utilization, and glucose transfer from the plasma to tissues. Leveraging clinical data of T1D during physical activity, each model fit is assessed. RESULTS: The proposed model with terms accommodating EGP, glucose transfer, and insulin-independent glucose utilization allow for an improved simulation of physical activity glycemic responses with the greatest reduction in model error (mean absolute percentage error: 16.11 ± 4.82 vs. 19.49 ± 5.87, p = 0.002). CONCLUSIONS: The development of a physiologically plausible model with model terms representing each major contributor to glucose metabolism during physical activity can outperform traditional models with physical activity described through glucose utilization alone. This model accurately describes the relation of plasma insulin and physical activity intensity on glucose production and glucose utilization to generate the appropriately increasing, decreasing or stable glucose response for each physical activity condition. The proposed model will enable the in silico evaluation of automated insulin dosing algorithms designed to mitigate the effects of physical activity with the appropriate relationship between the reduction in basal insulin and the corresponding glycemic excursion.

Meal and Physical Activity Detection from Free-living Data for Discovering Disturbance Patterns to Glucose Levels in People with Diabetes.

Objective: Interpretation of time series data collected in free-living has gained importance in chronic disease management. Some data are collected objectively from sensors and some are estimated and entered by the individual. In type 1 diabetes (T1D), blood glucose concentration (BGC) data measured by continuous glucose monitoring (CGM) systems and insulin doses administered can be used to detect the occurrences of meals and physical activities and generate the personal daily living patterns for use in automated insulin delivery (AID). Methods: Two challenges in time-series data collected in daily living are addressed: data quality improvement and detection of unannounced disturbances to BGC. CGM data have missing values for varying periods of time and outliers. People may neglect reporting their meal and physical activity information. In this work, novel methods for preprocessing real-world data collected from people with T1D and detection of meal and exercise events are presented. Four recurrent neural network (RNN) models are investigated to detect the occurrences of meals and physical activities disjointly or concurrently. Results: RNNs with long short-term memory (LSTM) with 1D convolution layers and bidirectional LSTM with 1D convolution layers have average accuracy scores of 92.32% and 92.29%, and outper-form other RNN models. The F1 scores for each individual range from 96.06% to 91.41% for these two RNNs. Conclusions: RNNs with LSTM and 1D convolution layers and bidirectional LSTM with 1D convolution layers provide accurate personalized information about the daily routines of individuals. Significance: Capturing daily behavior patterns enables more accurate future BGC predictions in AID systems and improves BGC regulation.

Prior Informed Regularization of Recursively Updated Latent-Variables-Based Models with Missing Observations.

Many data-driven modeling techniques identify locally valid, linear representations of time-varying or nonlinear systems, and thus the model parameters must be adaptively updated as the operating conditions of the system vary, though the model identification typically does not consider prior knowledge. In this work, we propose a new regularized partial least squares (rPLS) algorithm that incorporates prior knowledge in the model identification and can handle missing data in the independent covariates. This latent variable (LV) based modeling technique consists of three steps. First, a LV-based model is developed on the historical time series data. In the second step, the missing observations in the new incomplete data sample are estimated. Finally, the future values of the outputs are predicted as a linear combination of estimated scores and loadings. The model is recursively updated as new data are obtained from the system. The performance of the proposed rPLS and rPLS with exogenous inputs (rPLSX) algorithms are evaluated by modeling variations in glucose concentration (GC) of people with Type 1 diabetes (T1D) in response to meals and physical activities for prediction windows up to one hour, or 12 sampling instances, into the future. The proposed rPLS family of GC prediction models are evaluated with both in-silico and clinical experiment data and compared with the performance of recursive time series and kernel-based models. The root mean squared error (RMSE) with simulated subjects in the multivariable T1D simulator where physical activity effects are incorporated in GC variations are 2.52 and 5.81 mg/dL for 30 and 60 mins ahead predictions (respectively) when information for all meals and physical activities are used, increasing to 2.70 and 6.54 mg/dL (respectively) when meals and activities occurred, but the information is with-held from the modeling algorithms. The RMSE is 10.45 and 14.48 mg/dL for clinical study with prediction horizons of 30 and 60 mins, respectively. The low RMSE values demonstrate the effectiveness of the proposed rPLS approach compared to the conventional recursive modeling algorithms.