Pharmacokinetics of oral-transmucosal ketamine in horses Carlos Rodrigo Komatsu de Alencar, Larissa Lachi-Silva, Paulo Roberto Nunes de Goes, Gustavo Finatti Sakamoto, Andréa Diniz, et al. Ciencia Rural, 2026 Ketamine is a dissociative anesthetic that has been studied as an adjuvant to control acute and chronic pain in humans. This study defined the pharmacokinetics of ketamine after oral-transmucosal (OTM) administration in horses. Six adult crossbred healthy horses (363 ± 34 kg; 8 ± 3 years) received single OTM ketamine doses of 1.5 and 3.0 mg.kg-1. Blood samples were collected over a period of eight hours. Non-compartmental analysis and population pharmacokinetic modeling were carried out. The absolute bioavailability of ketamine after OTM administration in horses was 31.12 ± 10.98% (1.5 mg.kg-1) and 26.44 ± 11.46% (3.0 mg.kg-1). Plasma concentrations were best described by a two-compartment model, assuming the proportional error model, with an absorption duration of a zero-order kinetic process (tk0), and linear elimination. Population estimates were tk0 of 0.19 h, the apparent clearance (CL/F) was 3,462.97 L.h-1, apparent volume of distribution of the central compartment (V1/F) was 1,820.49 L, apparent volume of distribution of the peripheral compartment (V2/F) was 1,317.22 L, and inter-compartmental clearance (Q/F) was 1,084.98 L.h-1. Between-subject variability in CL/F, V1/F, and Q/F best described the data. The covariates body weight and sex were not significant for incorporation in the final model. The population pharmacokinetic model described the plasma concentrations with reasonable precision and predictive power, OTM administration of ketamine in horses is apparently safe, has a high volume of distribution, bioavailability similar to other species, and the maximum concentration in approximately 15 min.
Optimal dosing of amoxicillin in obese and post-gastric bypass patients using a population pharmacokinetics-pharmacodynamics model approach Gisela Myrian de Lima Leite Dalla Rosa, Priscila Akemi Yamamoto, Maria Madalena Corrêa Melo, Gustavo F Sakamoto, Maiara C Montanha, et al. Journal of Antimicrobial Chemotherapy, 2025 Aim To characterize the impact of obesity and Roux-en-Y gastric bypass (RYGB) on systemic exposure to amoxicillin using population modeling approach. We also performed simulations to provide insights into optimising the dosing of amoxicillin against infectious bacteria in the respiratory tract. Methods Non-obese, obese, and post-RYGB patients, aged between 24 and 50 years, from two clinical studies, were evaluated. Sex, age, body size descriptors, history of bariatric surgery and renal function were assessed as potential covariates. The percentage of time of unbound amoxicillin plasma concentration above the minimum inhibitory concentration (%fT > MIC) of >40%, representing bactericidal activity, was used as a PK/PD target to calculate the probability of target attainment (PTA). The PTA threshold was defined as 90% of treated individuals achieving fT > MIC ≥ 40%. Results Amoxicillin PK was best characterized by a one-compartment model including a zero-order absorption with lag time followed by a first-order absorption and linear elimination. The relative oral bioavailability in post-RYGB patients was nearly halved compared with non-obese subjects. Age exhibited a negative correlation with clearance, consistent with amoxicillin being a hydrophilic drug primarily eliminated through the kidneys. For MIC ≤ 2 mg/L, the oral dosing regimen of 1000 mg q6h reached the therapeutic target for non-obese. For MIC ≤ 1 mg/L, 1000 mg q6h is needed in obese and post-RYGB subjects. Conclusion Amoxicillin doses of 1000 mg q6h were found to maximize the probability of attaining the PK/PD target with MIC ≤ 1 mg/L in obese and post-RYGB patients.
Physiologically-based pharmacokinetic modeling and simulation for initial dose optimization of levetiracetam in pediatrics Julia Macente, Rodolfo Hernandes Bonan, Edilainy Rizzieri Caleffi-Marchesini, Leonardo Régis Leira Pereira, Priscila De Freitas Lima, et al. Frontiers in Pharmacology, 2025 Introduction Optimizing levetiracetam (LEV) dosing in children is challenging due to high pharmacokinetic variability, which often necessitates empirical dose titration. This study aimed to develop and verify a physiologically-based pharmacokinetic (PBPK) modeling and simulation to guide and optimize initial LEV dose selection in pediatric patients. Methods A whole-body PBPK model for LEV was developed and verified in adults, then scaled and verified in a pediatric population (0.5–12 years). This model was used to simulate various dosing regimens. Subsequently, a multivariate linear regression (MLR) analysis correlated key covariates (dose, regimen, body weight, and glomerular filtration rate) with simulated steady-state peak (C max ) and trough (C tr ) concentrations to create a practical dosing tool. Results The MLR model successfully explained over 90% of the variance (R 2 > 0.9) between covariates and simulated plasma concentrations. For a twice-daily regimen, daily doses of 40–60 mg/kg were required to achieve concentrations within a target therapeutic window ( e.g., C max of 20–46 mg/L). A three-times-daily regimen allowed for a broader effective dose range of 50–80 mg/kg/day, enabling higher total daily doses while maintaining C max within a safe range. Conclusion The combined PBPK-MLR approach provides a robust, data-driven framework to support rational first-dose prescriptions of LEV in children. This tool has the potential to accelerate therapeutic effects while enhancing treatment individualization. Prospective clinical validation is required to confirm the model predictive performance for drug exposure and, consequently, its impact on therapeutic efficacy.
Analysis of the ketamine binding to total plasma protein from domestic cats Victória Paradela Pereira Motta, Fernanda Ferreira da Silva, Ícaro Putinhon Caruso, Paulo Roberto Nunes de Goes, Marilda Onghero Taffarel, et al. Brazilian Journal of Veterinary Research and Animal Science, 2024 A cetamina é um medicamento versátil amplamente utilizado nos ambientes clínico e hospitalar veterinário. A avaliação dos parâmetros de ligação da cetamina às proteínas plasmáticas totais de gatos domésticos fornece informações necessárias na determinação do parâmetro farmacocinético denominado volume de distribuição, o qual é utilizado para a prospecção de concentrações do medicamento em estudos clínicos. O objetivo deste trabalho foi avaliar a taxa de ligação da cetamina às proteínas plasmáticas totais, sua constante (Kb), e modo de ligação à albumina sérica em gatos. Após a aprovação do projeto pelo CEUA/UEM (protocolo 3292020621), uma mistura de plasma de seis animais (n=6) foi reforçada com concentrações de cetamina visando ultrafiltração com membrana de 10 kDa. Os níveis do fármaco antes e depois da ultrafiltração foram analisados pela técnica de Cromatografia Líquida acoplada a Espectrometria de Massas (LC-MS/MS) e os resultados utilizados para calcular a taxa de ligação e a constante de ligação à albumina pelo gráfico de Scatchard. Simulações de docking identificaram os mais prováveis sítios de ligação à proteína. A taxa de ligação da cetamina foi de 65% quando o fármaco atingiu concentrações plasmáticas acima de 300 ng.mL-1, e a constante de ligação foi de 2×106 mol.L–1 com coeficiente de Hill (nH) de 2,3. Estes resultados mostram uma boa correlação entre os parâmetros físico-químicos do fármaco com a avaliação estrutural por meio de docking, além de coerência com os valores relatados por outras metodologias. Este trabalho traz informações sobre o comportamento de ligação da cetamina em proteínas plasmáticas de gatos, parâmetro importante para futuras avaliações farmacocinéticas na busca de melhores protocolos para uso clínico deste medicamento na área veterinária.
Adult and pediatric physiologically-based biopharmaceutics modeling to explain lamotrigine immediate release absorption process Edilainy Rizzieri Caleffi‐Marchesini, Amanda Antunes Herling, Julia Macente, Rodolfo Hernandes Bonan, Priscila de Freitas Lima, et al. Cpt Pharmacometrics and Systems Pharmacology, 2024 Physiologically‐based biopharmaceutics modeling (PBBM) has potential to accelerate the development of new drug and formulations. An important application of PBBM is for special populations such as pediatrics that have pharmacokinetics dependent on the maturation process. Lamotrigine (LTG) is a Biopharmaceutics Classification System (BCS) II drug and is widely prescribed. Therefore, the goal of this study was to assess the biopharmaceutics risk of the low‐soluble drug LTG when the ontogeny on gastrointestinal tract (GIT) physiological parameters are considered. An oral physiologically‐based pharmacokinetic model and a PBBM were developed and verified using GastroPlus™ software for both adults and children (2–12 years old, 12–52 kg). The biopharmaceutics properties and GIT physiological parameters were evaluated by sensitivity analysis. High doses were simulated assuming a worst case scenario, that is, the dose of 200 mg for adults and 5 mg/kg (up to the maximum of 200 mg) for 2‐year‐old children. Although several authors have suggested that ontogeny may have an effect on gastrointestinal fluid volume, our study found no evidence of interference between fluid and dose volumes with in vivo dissolution of LTG. The most impactful parameter was found to be the gastric transit time. Therefore, the hypothesis is developed to examine whether LTG exhibits characteristics of a BCS II classification in vitro while showing BCS I–like behavior in vivo. This hypothesis could act as a base for conducting novel studies on model‐informed precision dosing, tailored to specific populations and clinical conditions. In addition, it could be instrumental in assessing the influence of various release profiles on in vivo performance for both adult and pediatric populations.
Exploring in vitro solubility of lamotrigine in physiologically mimetic conditions to prospect the in vivo dissolution in pediatric population Edilainy Rizzieri Caleffi‐Marchesini, Fernanda Belincanta Borghi‐Pangoni, Julia Macente, Priscila Chiamulera‐Mantovani, Josmar Mazucheli, et al. Biopharmaceutics and Drug Disposition, 2023 Pediatric drugs knowledge still leaves several gaps to be filled, all the while many biopharmaceutic properties applied to adults do not work in pediatrics. The solubility in many cases is extrapolated to pediatrics; however, sometimes it may not represent the real scenario. In this context, the aim of this study was to assess the possibility of the extrapolation of the solubility data assumed for adults to children aged 2–12 years using lamotrigine (LTG) as a model. LTG showed that its solubility is dependent on the pH of the medium, no precipitate formation was seen, and biomimetic media showed a greater capacity to solubilize it. Based on the dose number (D0) in adults, the LTG was soluble in acidic pH media and poorly soluble in neutral to basic. Similar behavior was found in conditions which mimic children aged 10–12 years at a dose of 5 and 15 mg/kg. The D0 for 5‐year‐old children at a dose of 15 mg/kg showed different behaviors between biorelevant and pharmacopeial buffers media. For children aged 2–3 years, LTG appeared to be poorly soluble under both gastric and intestinal conditions. Solubility was dependent on the volume of fluid calculated for each age group, and this may impact the development of better pharmaceutical formulations for this population, better pharmacokinetic predictions in tools as PBPK, and physiologically‐based biopharmaceutics modeling, greater accuracy in the justifications for biowaiver, and many other possibilities.
Do Crataegus pinnatifida capsules sold in Brazil undergo pharmaceutical quality control? Is there a quality control adopted in Brazil? Revista Brasileira De Plantas Medicinais, 2022
