In Vitro and In Vivo Bioequivalence Study of 3D-Printed Instant-Dissolving Levetiracetam Tablets and Subsequent Personalized Dosing for Chinese Children Based on Physiological Pharmacokinetic Modeling

Recently, the development of Binder Jet 3D printing technology has promoted the research and application of personalized formulations, which are especially useful for children’s medications. Additionally, physiological pharmacokinetic (PBPK) modeling can be used to guide drug development and drug dose selection. Multiple technologies can be used in combination to increase the safety and effectiveness of drug administration. In this study, we performed in vivo pharmacokinetic experiments in dogs with preprepared 3D-printed levetiracetam instant-dissolving tablets (LEV-IDTs). Bioequivalence analysis showed that the tablets were bioequivalent to commercially available preparations (Spritam®) for dogs. Additionally, we evaluated the bioequivalence of 3D-printed LEV-IDTs with Spritam® by a population-based simulation based on the established PBPK model of levetiracetam for Chinese adults. Finally, we established a PBPK model of oral levetiracetam in Chinese children by combining the physiological parameters of children, and we simulated the PK (pharmacokinetics) curves of Chinese children aged 4 and 6 years that were administered the drug to provide precise guidance on adjusting the dose according to the effective dose range of the drug. Briefly, utilizing both Binder jet 3D printing technology and PBPK models is a promising route for personalized drug delivery with various age groups.

Permeability of Gemcitabine and PBPK Modeling to Assess Oral Administration

Gemcitabine is a nucleoside analog effective against several solid tumors. Standard treatment consists of an intravenous infusion over 30 min. This is an invasive, uncomfortable and often painful method, involving recurring visits to the hospital and costs associated with medical staff and equipment. Gemcitabine’s activity is significantly limited by numerous factors, including metabolic inactivation, rapid systemic clearance of gemcitabine and transporter deficiency-associated resistance. As such, there have been research efforts to improve gemcitabine-based therapy efficacy, as well as strategies to enhance its oral bioavailability. In this work, gemcitabine in vitro and clinical data were analyzed and in silico tools were used to study the pharmacokinetics of gemcitabine after oral administration following different regimens. Several physiologically based pharmacokinetic (PBPK) models were developed using simulation software GastroPlus™, predicting the PK parameters and plasma concentration–time profiles. The integrative biomedical data analyses presented here are promising, with some regimens of oral administration reaching higher AUC in comparison to the traditional IV infusion, supporting this route of administration as a viable alternative to IV infusions. This study further contributes to personalized health care based on potential new formulations for oral administration of gemcitabine, as well nanotechnology-based drug delivery systems.

PBPK Modeling and Simulation and Therapeutic Drug Monitoring: Possible Ways for Antibiotic Dose Adjustment

Pharmacokinetics (PK) is a branch of pharmacology present and of vital importance for the research and development (R&D) of new drugs, post-market monitoring, and continued optimizations in clinical contexts. Ultimately, pharmacokinetics can contribute to improving patients’ clinical outcomes, helping enhance the efficacy of treatments, and reducing possible adverse side effects while also contributing to precision medicine. This article discusses the methods used to predict and study human pharmacokinetics and their evolution to the current physiologically based pharmacokinetic (PBPK) modeling and simulation methods. The importance of therapeutic drug monitoring (TDM) and PBPK as valuable tools for Model-Informed Precision Dosing (MIPD) are highlighted, with particular emphasis on antibiotic therapy since dosage adjustment of antibiotics can be vital to ensure successful clinical outcomes and to prevent the spread of resistant bacterial strains.

Investigation of the Impact of CYP3A5 and CYP2C19 Polymorphisms on Drug-Drug Interactions between Tacrolimus and Voriconazole Based on Physiologically-Based Pharmacokinetic Modeling

ABSTRACT Aims: This study aimed to develop a PBPK model for tacrolimus incorporating CYP3A5 and CYP2C19 polymorphisms to predict the DDIs between tacrolimus and voriconazole. Methods: Pharmacokinetic (PK) data in rats and healthy subjects receiving tacrolimus with and without voriconazole were used for model development and evaluation. Then, we used the final model to simultaneously investigate the effect of CYP3A5 and CYP2C19 polymorphisms on the PK data of tacrolimus when combined with voriconazole. Results: The final results showed that the predicted Cmax in CYP3A5 nonexpressers was 1.5-fold higher than expressers, and the predicted AUC0-∞ was 1.92 to 1.96-fold higher in nonexpressers. However, the Cmax and AUC0-∞ of tacrolimus both have no significant difference between different CYP2C19 metabolizers. Conclusions: A physiologically-based pharmacokinetic (PBPK) model for tacrolimus integrated with CYP3A5 and CYP2C19 polymorphisms was successfully established, providing more insights regarding the DDIs between tacrolimus and voriconazole in patients with different CYP3A5 and CYP2C19 genotypes. Furthermore, this study highlights the feasibility of PBPK modeling to predict DDIs between these two drugs and the need to include CYP3A5 polymorphisms but not CYP2C19 polymorphisms.