Oxcarbazepine is commonly used as first-line treatment for partial and generalized tonic-clonic seizures. Owing to the high pharmacokinetic variability, several population pharmacokinetic models ha...

Background and Objectives Delayed or missed antiseizure medications (ASMs) doses are common during long-term or lifelong antiepilepsy treatment. This study aims to explore optimal individualized remedial dosing regimens for delayed or missed doses of 11 commonly used ASMs. Methods To explore remedial dosing regimens, Monte Carlo simulation was used based on previously identified and published population pharmacokinetic models. Six remedial strategies for delayed or missed doses were investigated. The deviation time outside the individual therapeutic range was used to evaluate each remedial regimen. The influences of patients9 demographics, concomitant medication, and scheduled dosing intervals on remedial regimens were assessed. RxODE and Shiny in R were used to perform Monte Carlo simulation and recommend individual remedial regimens. Results The recommended remedial regimens were highly correlated with delayed time, scheduled dosing interval, and half-life of the ASM. Moreover, the optimal remedial regimens for pediatric and adult patients were different. The renal function, along with concomitant medication that affects the clearance of the ASM, may also influence the remedial regimens. A web-based dashboard was developed to provide individualized remedial regimens for the delayed or missed dose, and a user-defined module with all parameters that could be defined flexibly by the user was also built. Discussion Monte Carlo simulation based on population pharmacokinetic models may provide a rational approach to propose remedial regimens for delayed or missed doses of ASMs in pediatric and adult patients with epilepsy.

Background and purpose: Several clinical trials have indicated that the use of canagliflozin increases the risk of lower extremity amputation. Although the US Food and Drug Administration (FDA) has withdrawn its black box warning about amputation risk for canagliflozin, the risk still exists. We sought to estimate the association between hypoglycemic medications, especially sodium-glucose co-transporter-2 inhibitors (SGLT2is), and adverse events (AEs) before the irreversible outcome of amputation as a promising early warning, based on the FDA Adverse Event Reporting System (FAERS) data.Methods: Publicly available FAERS data were analyzed using a reporting odds ratio (ROR) method and validated by a Bayesian confidence propagation neural network (BCPNN) method. The developing trend of the ROR was investigated by a series of calculations based on the accumulation of data in the FAERS database quarter by quarter.Results: Ketoacidosis, infection, peripheral ischemia, renal impairment, and inflammation including osteomyelitis might be more likely to occur among users of SGLT2is, especially canagliflozin. Osteomyelitis and cellulitis are AEs unique to canagliflozin. Among 2,888 osteomyelitis-related reports referring to hypoglycemic medications, 2,333 cases were associated with SGLT2is, with canagliflozin accounting for 2,283 of these cases and generating an ROR value of 360.89 and a lower limit of information component (IC₀₂₅) of 7.79. No BCPNN-positive signal could be generated for drugs other than insulin and canagliflozin. Reports suggesting that insulin could generate BCPNN-positive signals span from 2004 to 2021, whereas reports with BCPNN-positive signals emerged only since the second quarter (Q2) of 2017, 4 years since the approval of SGLT2is in Q2 of 2013, for canagliflozin and drug groups containing canagliflozin.Conclusion: This data-mining investigation revealed a strong association between canagliflozin treatment and developing osteomyelitis that might be a crucial forewarning to lower extremity amputation. Further studies with updated data are needed to better characterize the risk of osteomyelitis associated with SGLT2is.

Objectives:Real world studies have started to emerged on occurrence of venous thromboembolism (VTE) with cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors, but still deserve constant surveillance and evaluation. This study was to analyze this association. Methods: Adverse event cases were acquired from the US Food and Drug Administration Adverse Event Reporting System (FAERS) database betweenJanuary 1st 2015 and December 31st 2020.Signals indicating association between CDK 4/6 inhibitors and VTE were identified by reporting odds ratio (ROR). Results: CDK 4/6 inhibitors had a total of 631 reports of VTE (ROR 1.44, 95% CI 1.33-1.55) compared with non-CDK 4/6 inhibitors. Palbociclib (ROR 1.42, 95% CI 1.09-1.88) demonstratedthe highest number of VTE reports, followed by ribociclib (ROR 1.41, 95% CI 1.29-1.54) and abemaciclib (ROR 0.92, 95% CI 0.72-1.17). Conclusions:Although it is not able to confirm the casual relationship between VTE and CDK4/6 inhibitors, this study suggested signal of VTE reporting in patients receiving CDK4/6 inhibitors, which is likely to reflect a potential association. The results may enhance physicians’ awareness of the potential side effect of VTE associated with CDK 4/6 inhibitors. An early recognition of VTE signs/symptoms could decrease the morbidity and severity of such adverse events.