Busulfan is a bifunctional alkylating agent that is widely used before hematopoietic stem cell transplantation (HSCT), in combination with other chemotherapeutic drugs. As of 2020, there is no population pharmacokinetic (popPK) model for busulfan in Chinese pediatric patients. A systemic external evaluation of 11 published popPK models was conducted in Chinese pediatric patients undergoing HSCT. Forty pediatric patients were enrolled in this study, with a total of 183 blood concentrations. The relative prediction error (PE%), median PE%, median absolute PE%, and percentage of PE% within ±20% and ±30% were calculated in prediction-based diagnostics. Simulation-based diagnostics were conducted through a predictionand variability-corrected visual predictive check and the normalized prediction distribution error. The relative individual prediction error was calculated using Bayesian forecasting with 1 to 3 concentration points. The 1-compartment open linear popPK model, which was built by Su-jin Rhee et al (model H), incorporating the patient's body surface area, age, dosing day, and aspartate aminotransferase as significant covariates had preferable predictability than other popPK models. In prediction-based diagnostics, the median PE%, percentage of PE% within ±20%, and percentage of PE% within ±30% of model H were 8.48%, 45.35%, and 59.56%, respectively. The normalized prediction distribution error of model H showed that it followed the normal distribution. Based on Bayesian forecasting, model H showed good predictive performance. Thus, model H was the most appropriate model that can be used clinically for individualized dosage adjustments in Chinese pediatric HSCT patients.
Purpose
Medication adherence is essential for effective seizure control. However, delayed or missed doses are inevitable in epilepsy pharmacotherapy. The current remedial measures recommended by the Food and Drug Administration (FDA) for missed or delayed pregabalin doses are generic and lack supporting clinical evidence. The present study used a Monte Carlo simulation to explore remedial strategies for delayed or missed pregabalin doses in patients with epilepsy.
Methods
A Monte Carlo simulation was performed using a published population pharmacokinetic (pop PK) model. The applicability of the FDA recommendations compared to five proposed remedial regimens (Strategies A–E) was assessed based on the total deviation time outside the on-therapy range.
Results
All proposed remedial strategies were associated with renal function and the duration of dosing delay. The total deviation times for Strategies C–E were shorter than those for Strategy A (skip the dose and take the next regular dose as scheduled) when pregabalin was taken near the next scheduled time. An alternative recommendation is to take 1.2-, 1.3-, or 1.5-fold the regular dose at the next scheduled time if a single dose is missed. In the case of two missed doses, it is advisable to administer 1.2-, 1.3-, or 1.7-fold the regular dose.
Conclusion
Model-based simulations provided quantitative evidence for the effectiveness and feasibility of remedial strategies for missed or delayed pregabalin doses. The proposed remedial strategies can help in supplementing or correcting FDA instructions and mitigating the risk of out-of-range treatment.
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