Desenvolvimento de um Modelo Farmacocinético Baseado na Fisiológica (PBPK) para prever o ajuste de dose da bupropiona co - administrada com rifampicina em pacientes fumantes com tuberculose

Abstract

Smoking cessation in patients diagnosed with tuberculosis (TB) or Latent M. tuberculosis infection (ILTB) improves the prognosis of the disease, preventing the emergence of resistant strains and reduces treatment failure. Bupropion (BUP) is an antidepressant also used by those patients who quit smoking, being extensively metabolized to hydroxIbproppropion (OHBUP) by CYP2B6. Rifampicin (RIF) is one of the anti-tuberculosis drugs (antiTB) used to treat TB and ILTB, known for its ability to induce CYP2B6. The pharmacokinetic drug interaction between these drugs did not impact complications in the pharmacokinetic parameters (PK) of BUP and its main metabolite. Physiollogicaly-Based Pharmacokinetic Modeling (PBPK) is a valuable tool to asses if the chronic administration of both drugs can interfere with the expected clinical results. The aim of the present study was to evaluate a potential drug-drug interaction between bupropion and rifampicin in patients with tuberculosis through PBPK modeling during three months of concomitant use. The data for model development and validation for each of the drugs (BUP, OHBUP and RIF) were leverage from the literature . The PK-Sim® software was used to model the concentration-time profiles. Model development was performed using data in silico / in vitro / in vivo comparing the observed PK parameters with model simulations. The results demonstrate the model's capability to characterize PK parameters at different doses for bupropiom, hydroxybupropion and rifampicin, as well as a pharmacokinetic drug interaction already purchased., there was no significant impact on the pharmacokinetics of BUP and OHBUP after three months of treatment, guaranteeing the dose / exposure related to the treatment effectiveness for smoking cessation as well as the help for patients with depression. The integration of clinical guides can improve pharmacological therapy for clinical patients with TB or ILTB.