Seeking an optimal dosing regimen for OZ439/DSM265 combination therapy for treating uncomplicated falciparum malaria

Abstract

Background: The efficacy of artemisinin-based combination therapies (ACTs), the first-line treatments for uncomplicated falciparum malaria, has been declining in malaria-endemic countries due to the emergence of malaria parasites resistant to these compounds. Novel alternative therapies are needed urgently to prevent the likely surge in morbidity and mortality due to failing ACTs.

Objectives: This study investigates the efficacy of the combination of two novel drugs, OZ439 and DSM265, using a biologically informed within-host mathematical model.

Methods: A within-host model was developed, which accounts for the differential killing of these compounds against different stages of the parasite's life cycle and accommodates the pharmacodynamic interaction between the drugs. Data of healthy volunteers infected with falciparum malaria collected from four trials (three that administered OZ439 and DSM265 alone, and the fourth a combination of OZ439 and DSM265) were analysed. Model parameters were estimated in a hierarchical Bayesian framework.

Results: The posterior predictive simulations of our model predicted that 800 mg of OZ439 combined with 450 mg of DSM265, which are within the safe and tolerable dose range, can provide above 90% cure rates 42 days after drug administration.

Conclusions: Our results show that the combination of OZ439 and DSM265 can be a promising alternative to replace ACTs. Our model can be used to inform future Phase 2 and 3 clinical trials of OZ439/DSM265, fast-tracking the deployment of this combination therapy in the regions where ACTs are failing. The dosing regimens that are shown to be efficacious and within safe and tolerable limits are suggested for future investigations.

Trial registration: ClinicalTrials.gov NCT02389348 NCT02573857.

© The Author(s) 2021. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Figures

Figure 1.

Combined effect of OZ439 and DSM265, EOD in Equation 7, for three different types of interaction and the following arbitrarily selected set of PD parameter values: Emax,D = Emax,O = 0.4; γD = 3; γO = 3; EC50,D = EC50,O = 100 ng/mL, where O and D in the sub-indices denote correspondence to OZ439 and DSM265, respectively. The (1), (2) and (3) surfaces correspond to α  = 0.3 (synergism), α  = 1 (zero interaction) and α = 7 (antagonism). This figure appears in colour in the online version of JAC and in black and white in the print version of JAC.

Figure 2.

PK profiles of OZ439 and DSM265 for the OZ439/DSM265 combination therapy. The points show the measured drug concentrations and the lines are the generated simulations using the mode of the conditional distribution of the individual PK parameters—the population parameters are listed in Table 3. A two-compartment model with first- and zero-order absorption rates were used for OZ439 and DSM265, respectively. Volunteers 1–8 received 200 mg of OZ439 and 100 mg of DSM265, and volunteers 9–13 received 200 mg of OZ439 and 50 mg of DSM265. This figure appears in colour in the online version of JAC and in black and white in the print version of JAC.

Figure 3.

Posterior predictive check of the within-host PK/PD model fitted to the parasitaemia of volunteers in the combination therapy trial. The black circles are the observed parasitaemia; the red line and the shaded area denote the median and 95% CrI (between 2.5th and 97.5th percentiles) of 8000 simulations of the model using the posterior samples of the individual PD parameters (see Materials and methods section). Volunteers 1–8 belong to cohort A (OZ439: 200 mg; DSM265: 100 mg) and volunteers 9–13 to cohort B (OZ439: 200 mg; DSM265: 50 mg); see Table 1 for details of the cohorts. The grey vertical line at time = 0 shows the administration time of OZ439; DSM265 was administered 2 h after the OZ439 administration; see Table 1. The LLOQ, shown with the horizontal line, was 10 parasites/mL. This figure appears in colour in the online version of JAC and in black and white in the print version of JAC.

Figure 4.

Expected cure rate within 42 days for different doses of OZ439 and DSM265 combination therapy. For each dose combination, simulations for 20 datasets, each including 100 (new/hypothetical) patients, were generated. The simulations were performed using the individual posterior predictive distributions of the PD parameters (see Table 4 and Model fitting and simulation section) and the obtained 42 day cure rates averaged over the 20 datasets are shown in the grid squares (the lower and upper limits of the 42 day cure rates are shown in Figure S6). The values of parasitaemia at the time of drug administration in the simulations were drawn from a log-normal distribution constructed using the reported values in malaria-endemic countries: median = 52 250 (range: 2560–605 329) parasites/mL. Single doses of OZ439 and DSM265 were administered at times 0 and 2 h, respectively. The dose combinations that yielded a 42 day cure rate ≥90% are outlined with black borders. Cure rate: proportion of patients in each dataset who had parasitaemia below the LLOQ (10 parasites/mL) over 42 days of follow-up. This figure appears in colour in the online version of JAC and in black and white in the print version of JAC.