E.K. Phongi(1), M de Kock(1), L Wiesner(1), T. Wells(2), E. Decloedt(1, 3), K.I. Barnes(1), P. Denti(1).
(1) Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa; (2) Medicines for Malaria Venture, (MMV), Geneva Switzerland; (3) Department of Clinical Pharmacology, Stellenbosch University, Cape Town, South Africa
Objectives: OZ439 is a novel synthetic anti-malarial compound related to the artemisinin, but with a longer elimination half-life, which is being developed to be administered as part of a combination therapy for the cure of uncomplicated malaria [1]. The aim was to characterise the pharmacokinetics (PK) of escalating doses of OZ439 alone and in combination with mefloquine (one of the potential partner drugs studied) in healthy volunteers.
Methods: Two cohorts of South African healthy adult volunteers received respectively 100 mg and 400 mg single doses of OZ439 [2]. All volunteers were studied over two periods, the first period evaluated OZ439 alone, and the second period in co-administration with mefloquine. Cohort 1 had 12 volunteers and Cohort 2 has 18 volunteers. During period 1 venous blood samples were collected pre-dose and at 1, 2, 3, 4, 6, 8, 10, 16, 24, 36, 48, 72, and 96 hours post-dose. During period 2, additional samples were collected also on day 8, 11, 15, 28 and 35 post-dose. NONMEM 7.3 with FOCE-I was used to analyse the PK data. Allometric scaling [3] was used to account for the effect of body size, using different predictors such as fat-free mass (FFM), fat mass and total weight. Data below the limit of quantification was imputed with half the value of low limit of quantification, and only the first values in a series was retained in the analysis.
Results: A three compartment disposition model with 1st-order elimination and transit compartment absorption fitted the data well. Scaling for FFM improved the estimation of clearance (CL), while body fat was the best predictor for the size of the larger peripheral compartment. The model estimated the typical value of CL to be 85 L/h. The data displayed a dose-exposure nonlinearity with higher exposures observed with increasing dose. No significant drug-drug interaction with mefloquine was detected
Conclusions: We described the PK of OZ439 and found that distribution is affected by body fat. The more-than-proportional increase in exposure with higher doses points towards probable saturation of metabolism or transporters. Integration of metabolite concentrations in the model may help elucidating this.
References:
[1] J. J. Moehrle, S. Duparc, C. Siethoff, P. L. M. van Giersbergen, J. C. Craft, S. Arbe-Barnes, S. A. Charman, M. Gutierrez, S. Wittlin, and J. L. Vennerstrom, “First-in-man safety and pharmacokinetics of synthetic ozonide OZ439 demonstrates an improved exposure profile relative to other peroxide antimalarials,” Br. J. Clin. Pharmacol., vol. 75, no. 2, pp. 535–548, 2013.
[2] K. I. Barnes, “A phase I healthy volunteer study investigating the safety , tolerability & pharmacokinetics of co-administered single doses of OZ439 and mefloquine.,” 2012.
[3] B. J. Anderson and N. H. G. Holford, “Mechanism-based concepts of size and maturity in pharmacokinetics.,” Annu. Rev. Pharmacol. Toxicol., vol. 48, pp. 303–332, 2008.
Reference: PAGE 25 (2016) Abstr 6004 [www.page-meeting.org/?abstract=6004]
Poster: Drug/Disease modeling - Infection