The high failure rate of central nervous system (CNS) drugs is partly associated with an insufficient understanding of target site exposure. Blood–brain barrier (BBB) permeability evaluation tools are needed to explore drugs’ ability to access the CNS. An outstanding aspect of physiologically based pharmacokinetic (PBPK) models is the integration of knowledge on drug-specific and system-specific characteristics, allowing the identification of the relevant factors involved in target site distribution. We aimed to qualify a PBPK platform model to be used as a tool to predict CNS concentrations when significant transporter activity is absent and human data are sparse or unavailable. Data from the literature on the plasma and CNS of rats and humans regarding acetaminophen, oxycodone, lacosamide, ibuprofen, and levetiracetam were collected. Human BBB permeability values were extrapolated from rats using inter-species differences in BBB surface area. The percentage of predicted AUC and Cmax within the 1.25-fold criterion was 85% and 100% for rats and humans, respectively, with an overall GMFE of <1.25 in all cases. This work demonstrated the successful application of the PBPK platform for predicting human CNS concentrations of drugs passively crossing the BBB. Future applications include the selection of promising CNS drug candidates and the evaluation of new posologies for existing drugs.

This study employed physiologically‐based pharmacokinetic–pharmacodynamics (PBPK/PD) modeling to predict the effect of obesity and gastric bypass surgery on the pharmacokinetics and intragastric pH following omeprazole treatment. The simulated plasma concentrations closely matched the observed data from non‐obese, morbidly obese, and post‐gastric bypass populations. Obesity significantly reduces CYP3A4 and CYP2C19 activities, as reflected by the metabolic ratio [omeprazole sulphone]/[omeprazole] and [5‐hydroxy‐omeprazole]/[omeprazole]. The morbidly obese model accounted for the down‐regulation of CYP2C19 and CYP3A4 to recapitulate the observed data. Sensitivity analysis showed that intestinal CYP3A4, gastric pH, small intestine bypass, and the delay in bile release do not have a major influence on omeprazole exposure. Hepatic CYP3A4 had a significant impact on the AUC of (S)‐omeprazole, while hepatic CYP2C19 affected both (R)‐ and (S)‐omeprazole AUC. After gastric bypass surgery, the activity of CYP3A4 and CYP2C19 is restored. The PBPK model was linked to a mechanism‐based PD model to assess the effect of omeprazole on intragastric pH. Following 40 mg omeprazole, the mean intragastric pH was 4.3, 4.6, and 6.6 in non‐obese, obese, and post‐gastric bypass populations, and the daily time with pH >4 was 14.7, 16.4, and 24 h. Our PBPK/PD approach provides a comprehensive understating of the impact of obesity and weight loss on CYP3A4 and CYP2C19 activity and omeprazole pharmacokinetics. Given that simulated intragastric pH is relatively high in post‐RYGB patients, irrespective of the dose of omeprazole, additional clinical outcomes are imperative to assess the effect of proton pump inhibitor in preventing marginal ulcers in this population.

Background/Objectives: Omeprazole is widely used for managing gastrointestinal disorders like GERD, ulcers, and H. pylori infections. However, its use in pediatrics presents challenges due to drug interactions (DDIs), metabolic variability, and safety concerns. Omeprazole’s pharmacokinetics (PK), primarily influenced by CYP2C19 metabolism, is affected by ontogenetic changes in enzyme expression, complicating dosing in children. Methods: This study aimed to develop and validate a physiologically based pharmacokinetic (PBPK) model for omeprazole and its metabolites to predict age-related variations in metabolism and response. Results: The PBPK model successfully predicted exposure to parent and metabolites in adults and pediatrics, incorporating competitive and mechanism-based inhibition of CYP2C19 and CYP3A4 by omeprazole and its metabolites. By accounting for age-dependent metabolic pathways, the model enabled priori predictions of omeprazole exposure in different age groups. Linking PK to the pharmacodynamics (PD) model, we described the impact of age-related physiological changes on intragastric pH, the primary outcome for proton pump inhibitors efficacy. Conclusions: The PBPK-PD model allowed for the virtual testing of dosing scenarios, providing an alternative to clinical studies in pediatrics where traditional DDI studies are challenging. This approach offers valuable insights for accurate dosing recommendations in pediatrics, accounting for age-dependent variability in metabolism, and underscores the potential of PBPK modeling in guiding pediatric drug development.

Background: The purpose of this study was to compare the efficacy and safety of high-dose atorvastatin (40 mg) versus high-dose rosuvastatin (20 mg) in Egyptian patients with type 2 diabetes and previous acute coronary syndrome history. Materials and methods: This open-labeled prospective, randomized clinical trial compared once daily atorvastatin 40 mg (Ator®) versus once daily rosuvastatin 20 mg (Crestor®). The primary outcome was the 50% reduction in low-density lipoprotein cholesterol levels at 12 weeks. The secondary outcome was the achievement of low-density lipoprotein cholesterol level < 55 mg/dL. Results: A total number of 108 patients had a significant percentage of improvement in atorvastatin arm (n = 59) and rosuvastatin arm (n = 49) in low-density lipoprotein cholesterol, total cholesterol, triglycerides, and high-density lipoprotein-cholesterol achieved (p ≤ 0.05). In atorvastatin arm, 32.2% of patients achieved fifty percent reduction in low-density lipoprotein cholesterol while 34.7% of patients in rosuvastatin arm (p > 0.05). Twenty percent of patients achieved low-density lipoprotein cholesterol < 55 mg/dL in atorvastatin group compared to eighteen percent only in rosuvastatin group (p > 0.05). Regarding safety, the mean difference in liver transaminases was non-significant between the two groups (p > 0.05). Muscular symptoms were experienced by 1.7% patients receiving atorvastatin 40 mg and 10.2% of those receiving rosuvastatin 20 mg (p > 0.05). Conclusions: In Egyptian context, both high doses statin therapy were comparable regarding efficacy and safety in patients with type 2 diabetes and previous history of acute coronary syndrome. The Clinicaltrial.gov registration ID is: NCT05306990. Background: The purpose of this study was to compare the efficacy and safety of high-dose atorvastatin (40 mg) versus high-dose rosuvastatin (20 mg) in Egyptian patients with type 2 diabetes and previous acute coronary syndrome history. Materials and methods: This open-labeled prospective, randomized clinical trial compared once daily atorvastatin 40 mg (Ator®) versus once daily rosuvastatin 20 mg (Crestor®). The primary outcome was the 50% reduction in low-density lipoprotein cholesterol levels at 12 weeks. The secondary outcome was the achievement of low-density lipoprotein cholesterol level < 55 mg/dL. Results: A total number of 108 patients had a significant percentage of improvement in atorvastatin arm (n = 59) and rosuvastatin arm (n = 49) in low-density lipoprotein cholesterol, total cholesterol, triglycerides, and high-density lipoprotein-cholesterol achieved (p ≤ 0.05). In atorvastatin arm, 32.2% of patients achieved fifty percent reduction in low-density lipoprotein cholesterol while 34.7% of patients in rosuvastatin arm (p > 0.05). Twenty percent of patients achieved low-density lipoprotein cholesterol < 55 mg/dL in atorvastatin group compared to eighteen percent only in rosuvastatin group (p > 0.05). Regarding safety, the mean difference in liver transaminases was non-significant between the two groups (p > 0.05). Muscular symptoms were experienced by 1.7% patients receiving atorvastatin 40 mg and 10.2% of those receiving rosuvastatin 20 mg (p > 0.05). Conclusions: In Egyptian context, both high doses statin therapy were comparable regarding efficacy and safety in patients with type 2 diabetes and previous history of acute coronary syndrome. The Clinicaltrial.gov registration ID is: NCT05306990.

Background/Objectives: Spironolactone (SP) has been used off-label in pediatrics since its approval, but its use is challenged by limited pharmacokinetic (PK) data in adults and especially in children. Methods: Physiologically based pharmacokinetic (PBPK) models for SP and its active metabolites, canrenone (CAN) and 7α thio-methyl spironolactone (TMS), in adults were developed. These models aim to enhance understanding of SP’s PK and provide a basis for predicting PK and optimizing SP dosing in infants and neonates. Given SP’s complex metabolism, we assumed complete conversion to CAN and TMS by CES1 enzymes, fitting CES1-mediated metabolism to the parent-metabolite model using PK data. We incorporated ontogeny for CES1 and CYP3A4 and other age-related physiological changes into the model to anticipate PK in the pediatric population. Results: The PBPK models for SP, CAN, and TMS accurately captured the observed PK data in healthy adults across various dosing regimens, including the impact of food on drug exposure. The pediatric PBPK model was evaluated using PK data from infants and neonates. Simulations indicate that 2.5 mg/kg in 6-month to 2-year infants and 2 mg/kg in 1–6-months infants matched the total unbound systemic exposure equivalent to the standard recommended daily maintenance dose of 100 mg in adults for treating edema. Conclusions: The developed PBPK model provides valuable insights for dosing decisions and optimizing therapeutic outcomes, especially in populations where clinical studies are challenging.