# Pharmacokinetic and pharmacodynamic modeling of anti-plasmodial drugs mefloquine plus artesunate: insights on translational application

## TL;DR

This study models how the drug combination of artesunate and mefloquine works in mice to treat malaria, showing that combining them is more effective than using either drug alone.

## Contribution

The study introduces a population pharmacokinetic/pharmacodynamic model for ASMQ in mice, revealing drug potency and dosing efficacy through simulations.

## Key findings

- A two-compartment model best described the concentration-time profiles of artesunate and mefloquine in mice.
- Combination therapy suppressed parasitemia by ~85% and sustained efficacy, unlike artesunate monotherapy which led to parasite recrudescence.
- IC₅₀ values of 10.93 nM for artesunate and 29.1 nM for mefloquine indicate strong drug potency.

## Abstract

A combination between artesunate (AS) and mefloquine (MQ) (ASMQ) is widely employed for the treatment of uncomplicated P. falciparum. Despite this, pharmacokinetic (PK) and underlying relationship between PK and pharmacodynamic (PD) are relatively less known than other standard combination therapy. This study aimed to develop population PK models for ASMQ combination therapy in P. berghei-infected mice and to further characterize the PK/PD relationships by assessing the impact of different dosing strategies through a model-based simulation. Plasma PK was assessed in infected mice receiving a single oral dose of 100 mg/kg AS and 55 mg/kg MQ after allometric scaling to mice dose. A two-compartment model with first-order absorption and linear elimination best described both drugs' concentration-time profiles. PK/PD modeling, performed using a turnover model in MonolixSuite 2024R1, revealed IC₅₀ values of 10.93 nM for artesunate and 29.1 nM for mefloquine, indicating strong potency. Simulations demonstrated that both ASMQ dosing regimens (100/55 and 25/55 mg/kg) resulted in comparable parasitemia suppression (~85%) and sustained efficacy. In contrast, AS monotherapy exhibited a rapid initial parasite clearance, but this was followed by a parasite recrudescence. These findings underscore the value of combination therapy and highlight the utility of integrated PK/PD modeling to inform antimalarial treatment optimization in preclinical studies and support translational application.