Performance Evaluation of Montelukast Pediatric Formulations: Part II — a PBPK Modelling Approach

This study aimed to build a physiologically based pharmacokinetic (PBPK) model coupled with age-appropriate in vitro dissolution data to describe drug performance in adults and pediatric patients. Montelukast sodium was chosen as a model drug. Two case studies were investigated: case study 1 focused on the description of formulation performance from adults to children; case study 2 focused on the description of the impact of medicine co-administration with vehicles on drug exposure in infants. The PBPK model for adults and pediatric patients was developed in Simcyp® v18.2 informed by age-appropriate in vitro dissolution results obtained in a previous study. Oral administration of montelukast was simulated with the ADAM™ model. For case study 1, the developed PBPK model accurately described montelukast exposure in adults and children populations after the administration of montelukast chewable tablets. Two-stage dissolution testing in simulated fasted gastric to intestinal conditions resulted in the best description of in vivo drug performance in adults and children. For case study 2, a good description of in vivo drug performance in infants after medicine co-administration with vehicles was achieved by incorporating in vitro drug dissolution (under simulated fasted gastric to fed intestinal conditions) into a fed state PBPK model with consideration of the in vivo dosing conditions (mixing of formulation with applesauce or formula). The case studies presented demonstrate how a PBPK absorption modelling strategy can facilitate the description of drug performance in the pediatric population to support decision-making and biopharmaceutics understanding during pediatric drug development. Graphical abstract

Dynamic Contrast-Enhanced Magnetic Resonance Imaging for the Prediction of Monoclonal Antibody Tumor Disposition

The prediction of monoclonal antibody (mAb) disposition within solid tumors for individual patients is difficult due to inter-patient variability in tumor physiology. Improved a priori prediction of mAb pharmacokinetics in tumors may facilitate the development of patient-specific dosing protocols and facilitate improved selection of patients for treatment with anti-cancer mAb. Here, we report the use of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), with tumor penetration of the contrast agent gadobutrol used as a surrogate, to improve physiologically based pharmacokinetic model (PBPK) predictions of cetuximab pharmacokinetics in epidermal growth factor receptor (EGFR) positive xenografts. In the initial investigations, mice bearing Panc-1, NCI-N87, and LS174T xenografts underwent DCE-MRI imaging with the contrast agent gadobutrol, followed by intravenous dosing of an 125Iodine-labeled, non-binding mAb (8C2). Tumor concentrations of 8C2 were determined following the euthanasia of mice (3 h–6 days after 8C2 dosing). Potential predictor relationships between DCE-MRI kinetic parameters and 8C2 PBPK parameters were evaluated through covariate modeling. The addition of the DCE-MRI parameter Ktrans alone or Ktrans in combination with the DCE-MRI parameter Vp on the PBPK parameters for tumor blood flow (QTU) and tumor vasculature permeability (σTUV) led to the most significant improvement in the characterization of 8C2 pharmacokinetics in individual tumors. To test the utility of the DCE-MRI covariates on a priori prediction of the disposition of mAb with high-affinity tumor binding, a second group of tumor-bearing mice underwent DCE-MRI imaging with gadobutrol, followed by the administration of 125Iodine-labeled cetuximab (a high-affinity anti-EGFR mAb). The MRI-PBPK covariate relationships, which were established with the untargeted antibody 8C2, were implemented into the PBPK model with considerations for EGFR expression and cetuximab-EGFR interaction to predict the disposition of cetuximab in individual tumors (a priori). The incorporation of the Ktrans MRI parameter as a covariate on the PBPK parameters QTU and σTUV decreased the PBPK model prediction error for cetuximab tumor pharmacokinetics from 223.71 to 65.02%. DCE-MRI may be a useful clinical tool in improving the prediction of antibody pharmacokinetics in solid tumors. Further studies are warranted to evaluate the utility of the DCE-MRI approach to additional mAbs and additional drug modalities.

Blood-brain Barrier Crossing using Magnetic Stimulated Nanoparticles

Due to the low permeability and high selectivity of the blood-brain barrier (BBB), existing brain therapeutic technologies are limited by the inefficient BBB crossing of conventional drugs. Magnetic nanoparticles (MNPs) have shown great potential as nano-carriers for efficient BBB crossing under the external static magnetic field (SMF). To quantify the impact of SMF on MNPs' in vivo dynamics towards BBB crossing, we developed a physiologically based pharmacokinetic (PBPK) model for intraperitoneal (IP) injected superparamagnetic iron oxide nanoparticles coated by gold and conjugated with poly(ethylene glycol) (PEG) (SPIO-Au-PEG NPs) in mice. Unlike most reported PBPK models that ignore brain permeability, we first obtained the brain permeabilities with and without SMF by determining the concentration of SPIO-Au-PEG NPs in the cerebral blood and brain tissue. This concentration in the brain was simulated by the advection-diffusion equations and was numerically solved in COMSOL Multiphysics. The results from the PBPK model after incorporating the brain permeability showed a good agreement (regression coefficient R2 = 0.825) with the in vivo results, verifying the capability of using the proposed PBPK model to predict the in vivo biodistribution of SPIO-Au-PEG NPs under the exposure to SMF. Furthermore, the in vivo results revealed that the brain bioavailability under the exposure to SMF (4.01%) is slightly better than the control group (3.68%). In addition, the modification of SPIO-Au-PEG NPs with insulin (SPIO-Au-PEG-insulin) showed an improvement of the brain bioavailability by 24.47 % in comparison to the non-insulin group. With the SMF stimulation, the brain bioavailability of SPIO-Au-PEG-insulin was further improved by 3.91 % compared to the group without SMF.

Physiologically Based Pharmacokinetic Modeling of Cefadroxil in Mouse, Rat, and Human to Predict Concentration–Time Profile at Infected Tissue

The aim of this study was to develop physiologically based pharmacokinetic (PBPK) models capable of simulating cefadroxil concentrations in plasma and tissues in mouse, rat, and human. PBPK models in this study consisted of 14 tissues and 2 blood compartments. They were established using measured tissue to plasma partition coefficient (Kp) in mouse and rat, absolute expression levels of hPEPT1 along the entire length of the human intestine, and the transporter kinetic parameters. The PBPK models also assumed that all the tissues were well-stirred compartments with perfusion rate limitations, and the ratio of the concentration in tissue to the unbound concentration in plasma is identical across species. These PBPK models were validated strictly by a series of observed plasma concentration–time profile data. The average fold error (AFE) and absolute average fold error (AAFE) values were all less than 2. The models’ rationality and accuracy were further demonstrated by the almost consistent Vss calculated by the PBPK model and noncompartmental method, as well as the good allometric scaling relationship of Vss and CL. The model suggests that hPEPT1 is the major transporter responsible for the oral absorption of cefadroxil in human, and the plasma concentration–time profiles of cefadroxil were not sensitive to dissolution rate faster than T85% = 2 h. The cefadroxil PBPK model in human is reliable and can be used to predict concentration–time profile at infected tissue. It may be useful for dose selection and informative decision-making during clinical trials and dosage form design of cefadroxil and provide a reference for the PBPK model establishment of hPEPT1 substrate.

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.

Plasma concentration profiles for hepatotoxic pyrrolizidine alkaloid senkirkine in humans extrapolated from rat data sets using a simplified physiologically based pharmacokinetic model

Aim: The main aim of the current study was to obtain forward dosimetry assessments of pyrrolizidine alkaloid senkirkine plasma and liver concentrations by setting up a human physiologically based pharmacokinetic (PBPK) model based on the limited information available. Background: The risks associated with plant-derived pyrrolizidine alkaloids as natural toxins have been assessed. Objective: The pyrrolizidine alkaloid senkirkine was investigated because it was analyzed in a European transcriptomics study of natural hepatotoxins and in a study of the alkaloidal constituents of traditional Japanese food plants Petasites japonicus. The in silico human plasma and liver concentrations of senkirkine were modeled using doses reported for acute-term toxicity in humans. Methods: Using a simplified PBPK model established using rat pharmacokinetic data, forward dosimetry was conducted. Since in vitro rat and human intrinsic hepatic clearances were similar; an allometric scaling approach was applied to rat parameters to create a human PBPK model. Results: After oral administration of 1.0 mg/kg in rats in vivo, water-soluble senkirkine was absorbed and cleared from plasma to two orders of magnitude below the maximum concentration in 8 h. Human in silico senkirkine plasma concentration curves were generated after virtual daily oral administrations of 3.0 mg/kg senkirkine (the dose involved in an acute fatal hepatotoxicity case). A high concentration of senkirkine in the culture medium caused in vitro hepatotoxicity as evidenced by lactate dehydrogenase leakage from human hepatocyte-like HepaRG cells. Conclusion: Higher virtual concentrations of senkirkine in human liver and plasma than those in rat plasma were estimated using the current rat and human PBPK models. Current simulations suggest that if P. japonicus (a water-soluble pyrrolizidine alkaloid-producing plant) is ingested daily as food, hepatotoxic senkirkine could be continuously present in human plasma and liver.

PBPK Simulation-Based Evaluation of Ganciclovir Crystalluria Risk Factors: Effect of Renal Impairment, Old Age, and Low Fluid Intake

Dosing guidance is often lacking for chronic kidney disease (CKD) due to exclusion of such patients from pivotal clinical trials. Physiologically based pharmacokinetic (PBPK) modelling supports model-informed dosing when clinical data are lacking, but application of these approaches to patients with impaired renal function is not yet at full maturity. In the current study, a ganciclovir PBPK model was developed for patients with normal renal function and extended to CKD population. CKD-related changes in tubular secretion were explored in the mechanistic kidney model and implemented either as proportional or non-proportional decline relative to GFR. Crystalluria risk was evaluated in different clinical settings (old age, severe CKD and low fluid intake) by simulating ganciclovir medullary collecting duct (MCD) concentrations. The ganciclovir PBPK model captured observed changes in systemic pharmacokinetic endpoints in mild-to-severe CKD; these trends were evident irrespective of assumed pathophysiological mechanism of altered active tubular secretion in the model. Minimal difference in simulated ganciclovir MCD concentrations was noted between young adult and geriatric populations with normal renal function and urine flow (1 mL/min), with lower concentrations predicted for severe CKD patients. High crystalluria risk was identified at reduced urine flow (0.1 mL/min) as simulated ganciclovir MCD concentrations exceeded its solubility (2.6–6 mg/mL), irrespective of underlying renal function. The analysis highlighted the importance of appropriate distribution of virtual subjects’ systems data in CKD populations. The ganciclovir PBPK model illustrates the ability of this translational tool to explore individual and combined effects of age, urine flow, and renal impairment on local drug renal exposure. Graphical Abstract

A Physiologically Based Pharmacokinetic Model for In Vivo Alpha Particle Generators Targeting Neuroendocrine Tumors in Mice

In vivo alpha particle generators have great potential for the treatment of neuroendocrine tumors in alpha-emitter-based peptide receptor radionuclide therapy (α-PRRT). Quantitative pharmacokinetic analyses of the in vivo alpha particle generator and its radioactive decay products are required to address concerns about the efficacy and safety of α-PRRT. A murine whole-body physiologically based pharmacokinetic (PBPK) model was developed for 212Pb-labeled somatostatin analogs (212Pb-SSTA). The model describes pharmacokinetics of 212Pb-SSTA and its decay products, including specific and non-specific glomerular and tubular uptake. Absorbed dose coefficients (ADC) were calculated for bound and unbound radiolabeled SSTA and its decay products. Kidneys received the highest ADC (134 Gy/MBq) among non-target tissues. The alpha-emitting 212Po contributes more than 50% to absorbed doses in most tissues. Using this model, it is demonstrated that α-PRRT based on 212Pb-SSTA results in lower absorbed doses in non-target tissue than α-PRRT based on 212Bi-SSTA for a given kidneys absorbed dose. In both approaches, the energies released in the glomeruli and proximal tubules account for 54% and 46%, respectively, of the total energy absorbed in kidneys. The 212Pb-SSTA-PBPK model accelerates the translation from bench to bedside by enabling better experimental design and by improving the understanding of the underlying mechanisms.

Prediction of Survival After Partial Hepatectomy Using a Physiologically Based Pharmacokinetic Model of Indocyanine Green Liver Function Tests

The evaluation of hepatic function and functional capacity of the liver are essential tasks in hepatology as well as in hepatobiliary surgery. Indocyanine green (ICG) is a widely applied test compound that is used in clinical routine to evaluate hepatic function. Important questions for the functional evaluation with ICG in the context of hepatectomy are how liver disease such as cirrhosis alters ICG elimination, and if postoperative survival can be predicted from preoperative ICG measurements. Within this work a physiologically based pharmacokinetic (PBPK) model of ICG was developed and applied to the prediction of the effects of a liver resection under various degrees of cirrhosis. For the parametrization of the computational model and validation of model predictions a database of ICG pharmacokinetic data was established. The model was applied (i) to study the effect of liver cirrhosis and liver resection on ICG pharmacokinetics; and (ii) to evaluate the model-based prediction of postoperative ICG-R15 (retention ratio 15 min after administration) as a measure for postoperative outcome. Key results are the accurate prediction of changes in ICG pharmacokinetics caused by liver cirrhosis and postoperative changes of ICG-elimination after liver resection, as validated with a wide range of data sets. Based on the PBPK model, individual survival after liver resection could be classified, demonstrating its potential value as a clinical tool.