Standardization of lithium concentration to the 12-hour level using SimpLi: a simulation study and model validation

BackgroundLithium is one of the key medications for the treatment of bipolar disorder, but it requires therapeutic drug monitoring because of its narrow therapeutic window. In routine clinical practice, blood sampling is often performed outside the recommended 10-14 hour interval after the last evening dose, which distorts interpretation of the measured concentration (overestimation with early sampling and underestimation with late sampling) and may lead to inappropriate dose adjustment. ObjectiveTo develop and validate, using synthetic data, a multiplicative model (SimpLi) that standardizes a measured lithium concentration to the 12-hour level while accounting for sampling time and daily dose. Materials and MethodsA simulation study was conducted in accordance with ADEMP recommendations. A synthetic cross-sectional dataset (n = 1000) was generated with distributions of time since the last lithium dose, serum concentrations, and doses derived from the Bipolar CHOICE study, with a median sampling time of 12 hours (IQR 11-14) and a time-concentration correlation of r {approx} -0.30. The dataset was split 70/30 with stratification by time intervals, and 5-fold cross-validation was performed. Model performance was evaluated using RMSE, MAE, and R2. ResultsThe simulation closely reproduced the prespecified time distribution, achieved the target time-concentration correlation (r {approx} -0.30), and yielded a clinically plausible dose structure. A model using time as the only predictor showed limited accuracy (RMSE = 0.316; R2 = 0.108), while adding dose provided a moderate improvement (RMSE = 0.303; R2 = 0.177). When sampling occurred exactly at 12 hours, direct prediction was biased (-0.150; RMSE = 0.357), supporting the need for an individual correction factor. In a proof-of-concept analysis of five clinical cases, SimpLi produced a lower MAE than the eLi12 formula (0.042 vs 0.056 mEq/L). ConclusionsSimpLi is a practical tool (psyandneuro.ru/bekhterev-ai/simpli/) for standardizing lithium levels to 12 hours when sampling times vary. External validation on real-world data and robustness testing across clinical scenarios are needed.