Modelagem e simulação em farmacocinética baseada em fisiologia (PBPK) para predição do impacto da cirurgia bariátrica em Y de Roux na disposição cinética da gabapentina
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Data
2022-05-19
Autores
Oliveira, Isabella Santana de
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Editor
Universidade Estadual Paulista (Unesp)
Resumo
A obesidade é um problema de saúde pública que acomete 1 a cada 3 adultos e está associada ao risco de desenvolver doenças cardiovasculares, diabetes tipo 2, transtornos articulares e aumento da pressão arterial. A cirurgia de bypass gástrico em Y de Roux (RYGB) é uma das opções de tratamento para pacientes com obesidade associado ou não a comorbidades, com resultado eficaz e sustentado a longo prazo. Nos pacientes obesos com diabetes tipo 2, a hiperglicemia é uma das principais causas da ocorrência ou agravamento da dor neuropática, em razão das lesões e processo inflamatório no sistema nervoso. A gabapentina é um fármaco importante no manejo das dores neuropáticas, sendo indicada para adultos a partir de 18 anos. Ela tem absorção saturável, apresentando biodisponibilidade variável; não se liga às proteínas plasmáticas; não induz enzimas hepáticas e não é metabolizada. No estado estacionário, tem meia-vida de 6-8 horas e é eliminada inalterada por via renal. O uso de modelos PBPK para simular os efeitos da cirurgia bariátrica e da obesidade em populações virtuais, tem se mostrado bastante relevantes. A modelagem farmacocinética baseada em fisiologia (PBPK) é fundamentada em modelos matemáticos para predizer processos de absorção, distribuição, metabolismo e excreção (ADME). Neste estudo, a modelagem e simulação em PBPK foi empregada com o objetivo de predizer o efeito da cirurgia bariátrica na disposição cinética da gabapentina. O modelo PBPK de corpo inteiro foi desenvolvido e validado usando o software Pk-Sim® (versão 9.0; Open System Pharmacology). A validação do modelo da gabapentina foi realizada comparando dados preditos em uma população saudável com dados observados descritos na literatura. Para predizer a disposição cinética de GBP em pacientes bariátricos e
obesos foram avaliadas as populações virtuais: voluntários sadios com IMC entre 18,5 a 25,0 kg/m2; população obesa com IMC entre 30 a 40 kg/m2; população submetida a cirurgia tipo RYGB com IMC entre 26 a 29 kg/m2. Para a construção da população RYGB, os valores correspondentes ao pH gástrico, tempo de esvaziamento gástrico e do intestino delgado, volume do estômago e volumes do duodeno e jejuno superior foram modificados para representar as alterações anatômicas e fisiológicas decorrentes da cirurgia. O modelo foi verificado pela comparação dos parâmetros farmacocinéticos área sob a curva concentração plasmática versus tempo (AUC), concentração plasmática máxima (Cmax) e tempo
para atingir Cmax (Tmax) simulados e observados em estudos clínicos. O modelo PBPK da gabapentina se mostrou adequado segundo as boas práticas de modelagem e simulação PBPK, sugerindo discreta redução da exposição no plasma para a GBP em pacientes obesos se comparados com voluntários sadios. Para pacientes pós-RYGB observou-se aumento de 20% na AUC, 10% em Cmax e aumento em
Tmax. As alterações encontradas são discretas e sem relevância clínica. A abordagem PBPK proposta sugere que ajustes de dose de GBP não se fazem necessários para o tratamento da dor neuropática em pacientes com obesidade ou que realizaram cirurgia bariátrica.
Obesity is a public health problem that affects 1 in 3 adults and is associated with the risk of developing cardiovascular disease, type 2 diabetes, joint disorders and increased blood pressure. Roux-en-Y gastric bypass surgery (RYGB) is one of the treatment options for patients with obesity associated or not with comorbidities, with an effective and sustained long-term result. In obese patients with type 2 diabetes, hyperglycemia is one of the main causes of the occurrence or worsening of neuropathic pain, due to the lesions and inflammatory process in the nervous system. Gabapentin is an important drug in the management of neuropathic pain, being indicated for adults over 18 years of age. It has saturable absorption, showing variable bioavailability; does not bind to plasma proteins; does not induce liver enzymes and is not metabolized. At steady state, it has a half-life of 6-8 hours and is eliminated unchanged via the kidneys. The use of PBPK models to simulate the effects of bariatric surgery and obesity in virtual populations has been shown to be quite relevant. Physiology-based pharmacokinetic modeling (PBPK) is based on mathematical models to predict absorption, distribution, metabolism and excretion (ADME) processes. In this study, PBPK modeling and simulation was used to predict the effect of bariatric surgery on the kinetic disposition of gabapentin. The full-body PBPK model was developed and validated using Pk-Sim® software (version 9.0; Open System Pharmacology). Validation of the gabapentin model was performed by comparing predicted data in a healthy population with observed data described in the literature. To predict the kinetic disposition of GBP in bariatric and obese patients, virtual populations were evaluated: healthy volunteers with a BMI between 18.5 and 25.0 kg/m2; obese population with a BMI between 30 and 40 kg/m2; population undergoing RYGB surgery with a BMI between 26 and 29 kg/m2. For the construction of the RYGB population, the values corresponding to gastric pH, gastric and small intestine emptying time, stomach volume, and duodenum and upper jejunum volumes were modified to represent the anatomical and physiological changes resulting from the surgery. The model was verified by comparing the pharmacokinetic parameters area under the plasma concentration versus time curve (AUC), maximum plasma concentration (Cmax) and time to reach Cmax (Tmax) simulated and observed in clinical studies. The gabapentin PBPK model was shown to be adequate according to good PBPK modeling and simulation practices, suggesting a slight reduction in plasma exposure to GBP in obese patients compared with healthy volunteers. For post-RYGB patients there was a 20% increase in AUC, 10% increase in Cmax and increased Tmax. These alterations are discrete and without clinical relevance. The proposed PBPK approach suggests that GBP dose adjustments are not necessary for the treatment of neuropathic pain in patients with obesity or who have undergone bariatric surgery.
Obesity is a public health problem that affects 1 in 3 adults and is associated with the risk of developing cardiovascular disease, type 2 diabetes, joint disorders and increased blood pressure. Roux-en-Y gastric bypass surgery (RYGB) is one of the treatment options for patients with obesity associated or not with comorbidities, with an effective and sustained long-term result. In obese patients with type 2 diabetes, hyperglycemia is one of the main causes of the occurrence or worsening of neuropathic pain, due to the lesions and inflammatory process in the nervous system. Gabapentin is an important drug in the management of neuropathic pain, being indicated for adults over 18 years of age. It has saturable absorption, showing variable bioavailability; does not bind to plasma proteins; does not induce liver enzymes and is not metabolized. At steady state, it has a half-life of 6-8 hours and is eliminated unchanged via the kidneys. The use of PBPK models to simulate the effects of bariatric surgery and obesity in virtual populations has been shown to be quite relevant. Physiology-based pharmacokinetic modeling (PBPK) is based on mathematical models to predict absorption, distribution, metabolism and excretion (ADME) processes. In this study, PBPK modeling and simulation was used to predict the effect of bariatric surgery on the kinetic disposition of gabapentin. The full-body PBPK model was developed and validated using Pk-Sim® software (version 9.0; Open System Pharmacology). Validation of the gabapentin model was performed by comparing predicted data in a healthy population with observed data described in the literature. To predict the kinetic disposition of GBP in bariatric and obese patients, virtual populations were evaluated: healthy volunteers with a BMI between 18.5 and 25.0 kg/m2; obese population with a BMI between 30 and 40 kg/m2; population undergoing RYGB surgery with a BMI between 26 and 29 kg/m2. For the construction of the RYGB population, the values corresponding to gastric pH, gastric and small intestine emptying time, stomach volume, and duodenum and upper jejunum volumes were modified to represent the anatomical and physiological changes resulting from the surgery. The model was verified by comparing the pharmacokinetic parameters area under the plasma concentration versus time curve (AUC), maximum plasma concentration (Cmax) and time to reach Cmax (Tmax) simulated and observed in clinical studies. The gabapentin PBPK model was shown to be adequate according to good PBPK modeling and simulation practices, suggesting a slight reduction in plasma exposure to GBP in obese patients compared with healthy volunteers. For post-RYGB patients there was a 20% increase in AUC, 10% increase in Cmax and increased Tmax. These alterations are discrete and without clinical relevance. The proposed PBPK approach suggests that GBP dose adjustments are not necessary for the treatment of neuropathic pain in patients with obesity or who have undergone bariatric surgery.
Descrição
Palavras-chave
PBPK, Gabapentina, RYGB, Cirurgia bariátrica