Modelagem farmacocinética/farmacodinâmica da associação artesunato e mefloquina

Abstract

Malaria is an infectious disease caused by protozoa of the genus Plasmodium, and despite being it is treatable and preventable, it still causes a high mortality rate worldwide. The use of safe and effective antimalarial drugs is essential for reducing mortality, especially considering that the current control strategy is based on early diagnosis and adequate treatment of cases. Artesunate-mefloquine (AR-MQ) combined therapy is a standard therapy for the treatment of uncomplicated P. falciparum malaria, with therapeutic efficacy and action against the recurrent form of Plasmodium. Despite this, it is still necessary to understand the parameters guiding the dosage and effectiveness when the drugs are evaluated in combination. Therefore, this work aimed to establish a population pharmacokinetic/pharmacodynamic (PK/PD) model relating parasitemia to total plasma concentrations of AR-MQ combined therapy. To achieve this objective, Swiss mice infected with P. berghei were randomly divided into an untreated and treated group, which received 100 mg/kg of AR + 55 mg/kg of MQ orally, in a single dose. Subsequently, plasma samples were collected for PK analysis, and the % of parasitemia was assessed. A Time-to-event (TTE) analysis was performed with the survival data obtained. PK/PD analysis was conducted using MonolixSuite™ version 2024R1 using the mixed-effects models method. The concentration versus time profile of AR and MQ were described by a 1- compartment model, absorption rate (ka) for AR and zero-order absorption (Tk0) for MQ, with linear elimination for both. A turnover inhibition model described the effect curve over time adequately, with estimated kprol and kdeath constants of 26.36 and 0.024 h-1 , respectively, IC50 42.34 µg/mL and Imax 333.34 for AR and IC50 of 0.086 µg/mL and Imax 1.42 for MQ. TTE analysis, an analysis to evaluate the influence of treatment on survival, was also performed in MonolixSuite™. The data survival curve was best described by the Weibull model. Subsequent analysis identified that AR-MQ significantly influenced in the survival time (Te_pop), estimated at 13.66 days with a Te_ARMQ beta of 0.77 days. The probability of survival 7, 15, and 30 days after treatment with AR-MQ was 94.4%, 88.9%, and 14.9%, respectively. In conclusion, this study developed a PK/PD model to describe the effect-time curve after a single administration of the AR-MQ association in mice infected by P. berghei and identified greater survival of the animals when administered the association, thus having the potential to apply the models for future preclinical investigations.