Azrin N. Abd-Rahman(1), Anne Kümmel(2), Jörg J. Moehrle(3), James S. McCarthy(1, 4) Nathalie Gobeau(3)
(1)QIMR Berghofer Medical Research Institute, 300 Herston Rd, Brisbane, QLD 4006, Australia, (2)IntiQuan GmbH, Spalenring 150, 4055 Basel, Switzerland, (3)Medicines for Malaria Venture, Route de Pré-Bois 20, 1215 Meyrin, Geneva, Switzerland, (4)University of Queensland, St. Lucia, QLD 4006, Australia
Introduction: Plasmodium vivax, one of the five species of malaria parasites that infect humans, puts approximately 2.5 billion people at risk [1] and causes an estimated 7.5 million infections a year [2]. Artefenomel, an investigational antimalarial, was tested at a subtherapeutic dose in healthy volunteers infected with P.vivax blood-stage parasites.
Objectives:
- Develop a population PK/PD model describing the time course of parasitemia with the PK and parasitemia profiles observed in the infected volunteers.
- Use the model to establish the minimum effective dose of artefenomel required to clear P. vivax parasites in patients.
Methods: Eight healthy subjects were inoculated intravenously with ~680 viable P. vivax parasites and were administered a single oral dose of 200 mg artefenomel 10 days later. Parasitemia was monitored twice a day for 4 days after inoculation until drug administration, at 4, 8, 12, 16, 24, 30, 36, 48, 60, 72, 84, 96, 108 hours after drug administration and then three times per week until 28 days after inoculation. A rich PK profile was acquired in each volunteer. To enrich the PK/PD dataset from this study, the PK profiles of another study in which artefenomel was tested at three doses in healthy volunteers infected with P. falciparum (another species of plasmodium) were added, as well as parasitemia observations prior to drug administration from another P. vivax study testing another compound. To develop the PK/PD model, a two stage approach was used. First a PK model was built. One-, two- and three-compartment disposition models were tested. First- and zero-order absorption models, with or without lag time as well as linear, saturable and mixed linear and saturable elimination models were evaluated. The individual PK parameter estimates were used as regression parameters for the subsequent PD modelling stage. Different PD models were explored to link drug concentrations with parasite clearance. Finally, simulations were performed with the final PK/PD model to determine the minimal dose that is necessary to clear all parasites in patients. The minimum effective dose was defined as the lowest dose that resulted in at least a total parasite reduction ratio (PRRtotal) of 9 log10 unit.
Results: A three-compartment PK disposition model with first-order absorption, a lag time and linear elimination adequately described the PK data. Body weight was incorporated as an allometric function on clearance and volume of distribution parameters and found to improve the fit significantly. Dose was also found to be a significant covariate, resulting in a decreased clearance with increasing doses. Artefenomel-dependent parasite killing rate was well described by a sigmoid Emax model. The estimated maximum parasite killing rate (Emax) was 0.158 h-1. The artefenomel plasma concentration that resulted in 50% of the maximum effect (EC50) was determined to be 0.65 ng/mL. The PK/PD model predicted a minimum inhibitory concentration (MIC) of 0.61 ng/mL, and a minimum parasiticidal concentration at which the parasite killing rate was equal to 90% of its maximum (MPC90) of 0.81 ng/mL. A log10 parasite reduction ratio over 48 hours (PRR48) was estimated to be 2.17, with a corresponding parasite clearance half-life (PCt½) of 6.64 h. The minimum single dose that resulted in log10 PRRtotal >9 was 300 mg (13.4, 95% CI: 3 – 35.9).
Conclusions: The model adequately characterized the PK/PD of artefenomel in a P. vivax Volunteer Infection Study. It was then used to estimate the minimum effective dose to clear P. vivax parasites in patients. As artefenomel lacks activity against latent liver stage parasites (hypnozoites) it would need to be combined with a drug such as primaquine or tafenoquine to reliably cure P. vivax malaria.
References:
[1] Gething PW, Elyazar IR, Moyes CL, Smith DL, Battle KE, Guerra CA, Patil AP, Tatem AJ, Howes RE, Myers MF, George DB, Horby P, Wertheim HF, Price RN, Müeller I, Baird JK, Hay SI (2012). “A long neglected world malaria map: Plasmodium vivax endemicity in 2010”. PLoS Neglected Tropical Diseases. 6 (9): e1814. doi:10.1371/journal.pntd.0001814. PMC 3435256. PMID 22970336.
[2] World Malaria Report 2018: World Health Organization.
Reference: PAGE 28 (2019) Abstr 9017 [www.page-meeting.org/?abstract=9017]
Poster: Drug/Disease Modelling - Infection