Mefloquine

Written informed consent from the head of household or an adult household representative was obtained by the field worker prior to conducting surveillance in a household. Field workers provided written informed consent for the human-landing catches, were paid for their work and provided with malaria chemoprophylaxis, consisting of mefloquine (250 mg tab orally once weekly) or doxycycline (100 mg tab orally each day). They were also offered medical treatment for any illness that developed during the period of their employment.
Ethical approval for this study was provided by the Uganda National Council for Science and Technology, the Makerere University School of Medicine Research and Ethics Committee, the University of California, San Francisco Committee on Human Research, London School of Hygiene and Tropical Medicine ethical committee and the School of Biological and Biomedical Sciences Ethics Committee, Durham University.

The WWARN QA/QC proficiency testing program for pharmacology laboratories assesses the ability of pharmacology laboratories to assay blood or plasma samples for concentrations of antimalarial compounds and their metabolites. Participation in the proficiency testing program is open to all laboratories doing either therapeutic efficacy studies or other research on antimalarial drug exposure. The program currently offers plasma-based samples for eight antimalarial drug compounds and metabolites: chloroquine/desethylchloroquine, mefloquine/carboxymefloquine, primaquine/carboxyprimaquine, amodiaquine/desethylamodiaquine, piperaquine, lumefantrine/desbutyl-lumefantrine, dihydroartemisinin, and artesunate. Commercially obtained and controlled plasma is spiked with accurately weighed certified reference materials. All active ingredients and the plasma are controlled by the manufacturer and reflected in certificates of analysis. Each analyte is sent in a range of concentrations, including the highest and lowest concentrations expected to be found in clinical samples (Table 1), which allows each laboratory to test the limits of its assay.

The PK/PD models for mefloquine and artesunate/dihydroartemisinin (active metabolite of artesunate) were constructed using nonlinear mixed-effects modeling (MonolixSuite software, version 2021R1, Antony, France; Lixoft SAS, 2021). Pharmacokinetic parameters were estimated using the build-in stochastic approximation expectation-maximization algorithm. Various compartment model with different order absorption and elimination were performed to fit with drug concentration-time data. Pharmacokinetic parameters were normally distributed when transformed to log-scale. The pharmacodynamic model was evaluated using E_max model (turn-over rate) with production inhibition. The model was corrected with the fraction of unbound drug (f_u) in plasma and tissue and was tested for sigmoidicity characteristics. Pharmacodynamic parameters were tested following non-transformed and log-normal transformation. The pharmacodynamic equation is shown below;
$$\frac{d\left(parasite\right)}{d\left(t\right)}=K_{in}*\left(\frac{1-C*fu}{C*fu+{IC}_{50}*fu}\right)-K_{out}*parasite$$
Where parasite is number of parasite; C is drug plasma-concentration profiles; IC₅₀ is the half maximal inhibitory concentration that inhibit parasite growth by 50%; K_in is indirect turnover model with full inhibition of production; K_out is the degradation rate of parasite. The residual variability and the types of error models were evaluated using proportional, constant, and combined error models with power law. Predefined criteria for a model selection were: (i) the decrease in minimum objective function value (OFV), Akaike Information Criteria (AIC), Bayesian Information Criteria (BIC), and Corrected Bayesian Information Criteria (BICc), and (ii) the percentage of root mean square errors (RSE%), Graphical Goodness of Fit (GOF) including the observed versus predicted concentrations, scatter plot of residual, and the virtual predictive check (VPC). A significant level for the inclusion of the covariates (age, sex, bodyweight, and mefloquine level before treatment) in the model was set at α = 0.05.
The plotting of model-based individual prediction (IPRED) and population prediction (PRED) versus observed concentrations (GOF) was used for model evaluation. VPC included the observational data versus simulated data (1,000 patients) with the 10th, 50th, and 90th percentiles.

The final PK/PD (1,000 virtual patients with 10 simulations) models were used to simulate optimal dosages of mefloquine in the combination regimens that provided high clinical efficacy using Monte Carlo simulations (Simulix version 2021R1, Antony, France; Lixoft SAS, 2021). The simulated dose regimens (oral administration) for mefloquine-resistant P. falciparum included: (i) 750 mg on day 1 (day 0), followed by 500 mg on day 2, (ii) 500 mg once daily for 42 days, (iii) 500 mg every 72 hours for 42 days, (iv) 500 mg every 96 hours for 42 days, and (v) 250 mg every 12 hours for 42 days. The simulated regimens for mefloquine-sensitive strains were: (i) 750 mg on day 1 and 500 mg on day 2, (ii) 500 mg on day 1 and 250 mg on day 2, (iii) 750 mg on day 1, (iv) 500 mg on day 1, and (v) 250 mg on day 1, 2, and 3. The simulated regimens are based on trials and erros until it provides the curative rate close to 100%.