Understanding Physiologically Based Pharmacokinetics

Quantum mechanics and physiologically based pharmacokinetics at the rescue: a new model for LNPs's PK If someone asks me what I'd consider the most complex aspect of LNP delivery, I would probably go with the dynamics of LNP distribution, metabolism, and elimination within any biological system. Why? Well, for once, traditional studies on LNPs' PK are sparse and often lack detailed mechanistic insights, hindering optimization to great levels. But, here comes a new paper to make life a bit better in the form of a new system integrating physiologically based pharmacokinetic (PBPK) and quantum mechanics models, enhanced with multi-source data across different biological species, including Hela cells, rats, mice, and humans. What did they find? 1) By employing models to compare LNPs with varying ionizable lipids, particle sizes, and dosages, the authors identified several key parameters that dominated their PK and concluded that the metabolism of ionizable lipids is primarily constrained by the rate of LNP disassembly rather than by the hydrolysis of the lipids themselves. 2) More importantly, they quantitatively derived the efficacy of RNA release from endosomes for three different ionizable lipids, providing predictive insights into the likelihood of successful RNA release—a critical step for the therapeutic action of RNA-LNPs. 3) Interestingly, the biodegradability of these lipids was assessed using quantum mechanics methods, with results aligning closely with those from the PBPK modeling, thereby affirming the model's accuracy and reliability. This study marks the first successful construction of a transportation model for RNA-LNPs across various species, integrating diverse in vitro and in vivo data through sophisticated QM/PBPK multi-level modeling. I'm pretty eager to see what comes after. Learn more here: https://lnkd.in/ea8FuPcZ #Nanotechnology #Pharmacokinetics #RNAtherapy #DrugDelivery #Biotechnology #InnovativeResearch #HealthcareInnovation

This excellent paper by Liu et. al. describes studies on whole-body disposition and physiologically based pharmacokinetic modeling of adeno-associated viruses and the transgene product. Quoting from the abstract: "To facilitate model-informed drug development (MIDD) of adeno-associated virus (AAV) therapy, here we have developed a physiologically based pharmacokinetic (PBPK) model for AAVs following preclinical investigation in mice. After 2E11 Vg/mouse dose of AAV8 and AAV9 encoding a monoclonal antibody (mAb) gene, whole-body disposition of both the vector and the transgene mAb was evaluated over 3 weeks. At steady-state, the following tissue-to-blood (T/B) concentration ratios were found for AAV8/9: ∼50 for liver; ∼10 for heart and muscle; ∼2 for brain, lung, kidney, adipose, and spleen; ≤1 for bone, skin, and pancreas. T/B values for mAb were compared with the antibody biodistributioncoefficients, and five different clusters of organs were identified based on their transgene expression profile. All the biodistribution data were used to develop a novel AAV PBPK model that incorporates: (i) whole-body distribution of the vector; (ii) binding, internalization, and intracellular processing of the vector; (iii) transgene expression and secretion; and (iv) whole-body disposition of the secreted transgene product. The model was able to capture systemic and tissue PK of the vector and the transgene-produced mAb reasonably well. Pathway analysis of the PBPK model suggested that liver, muscle, and heart are the main contributors for the secreted transgene mAb. Unprecedented PK data and the novel PBPK model developed here provide the foundation for quantitative systems pharmacology (QSP) investigations of AAV-mediated gene therapies. The PBPK model can also serve as a quantitative tool for preclinical study design and preclinical-to-clinical translation of AAV-based gene therapies."

Learn about dose optimization using physiologically based pharmacokinetic modeling for pediatric patients in AAPS PharmSciTech. The pharmacokinetics of renally eliminated antibiotics can be influenced by changes associated with renal function and development in a growing subject. Little is known about the effects of renal insufficiency on the pharmacokinetics of meropenem in pediatric subjects. The aim of this study was to develop a physiologically based pharmacokinetic (PBPK) model of meropenem for pediatric patients that can be used to optimize meropenem dosing in pediatric patients with renal impairment (RI). The PBPK model was developed using GastroPlus™ 9.9 based on clinical data obtained from the literature and then scaled to pediatric patients with RI for dose optimization of meropenem. The goodness of fit of the model was assessed by comparing the predicted values of AUC0-t, AUC0-α, and Cmax with the observed data and the average fold errors (AFE). The AFE values for AUC0-t, AUC0-α, and Cmax in the pediatric population were measured to be 1.60, 1.08, and 1.48, respectively. In addition, dose optimization was performed in virtual pediatric populations with varying degrees of RI and a dose reduction to 10 mg/kg and 7.5 mg/kg was recommended for moderate and severe RI, respectively. In all virtual pediatric populations with RI, the plasma concentration reached the recommended time above the minimum inhibitory concentration (MIC) at all optimized doses. The developed PBPK model for meropenem provides a quantitative tool to assess the impact of RI on the pharmacokinetics of meropenem in pediatric patients, which may be useful for optimizing the dosing regimen. Najia Rahman Muhammad Sarfraz Abubakar B. @syed bar shyum naqvi Daniel Davis, Ph.D., PharmD Johana Suh Claudio Salomon Sanyog Jain Michael Repka QI (Tony) ZHOU Link: https://rdcu.be/d6Whv