Safety, tolerability and pharmacokinetic profile of single and multiple oral doses of arterolane (RBx11160) maleate in healthy subjects

Abstract

Arterolane (RBx11160, OZ277) maleate is a rapidly acting synthetic trioxolane anti-malarial. This randomized, placebo controlled study was a phase I study to evaluate the clinical safety and tolerability as well as pharmacokinetics (PKs) of arterolane maleate including food effect. Eight single rising oral doses of arterolane (25, 50, 100, 150, 200, 300, 400, 600 mg), food effect under fed and fasting conditions at 100 mg dose and four multiple oral dose regimens (25, 50, 100, 200 mg) were administered once daily for 7 days in 64 healthy young males (Caucasian). A randomized, placebo-controlled study was also conducted in healthy elderly males and females (Caucasian) to investigate PKs, safety and tolerability of single oral dose (100 mg) of arterolane. All doses were well tolerated after oral administration. The initial peak of arterolane was apparent at 2-3 hours post-dose followed by a secondary peak at approximately 5 hours post-dose. Thereafter, plasma arterolane concentration declined with a geometric mean t1/2 of approximately 2-4 hours. The PKs of arterolane appeared to be time-invariant after repeated once-daily dosing. The incidence of adverse events was similar for placebo and active treatments. Arterolane had similar PKs and tolerability in elderly and younger subjects and between elderly males and females.

Plasmodium falciparum K13 Mutations Differentially Impact Ozonide Susceptibility and Parasite Fitness In Vitro

“…With OZ277, complete inhibition of parasite survival was never observed, with the maximum pulse concentration of 700 nM affording a 3.6% survival. In comparison, peak plasma concentrations of 112 nM to 155 nM were observed in individuals receiving either a recommended 3-day regimen of 150 mg/day OZ277 in combination with piperaquine (750 mg/day) or a 7-day course of 150 mg daily of OZ277 monotherapy (29, 31, 42). …”

“…Importantly, both ozonides exhibit longer half-lives in plasma compared to the endoperoxide DHA. The half-life of OZ277 in plasma is only 2- to 3-fold longer than for DHA, with a lower plasma exposure in P. falciparum -infected patients compared to healthy volunteers (29, 30). OZ277 is nevertheless available in India in combination with piperaquine (Synriam) (31).…”

Artemisinin Action and Resistance in Plasmodium falciparum

“…The combination of OZ277 (arterolane) and piperaquine, known as Synriam™, is available in India. The usefulness of OZ277 may be limited however, as its half-life is only 2– to 3–fold longer than that of DHA [15], and it is reported to have lower plasma exposure in malaria patients than in uninfected volunteers [16]. OZ439 (artefenomel) is currently being assessed either alone or as a combination therapy in Phase II human clinical trials ([12, 17, 18]; ClinicalTrials.gov NCT02083380).…”

Parasite-Mediated Degradation of Synthetic Ozonide Antimalarials Impacts In Vitro Antimalarial Activity

“…OZ439 (artefenomel) is one of the most advanced antimalarial drug candidates currently in clinical development (5)(6)(7)(8), and its first-generation predecessor, OZ277 (arterolane), is approved for use in India as a fixed-dose combination with piperaquine (9)(10)(11)(12). Both of these ozonides are fully synthetic, and like the artemisinins (13), contain a peroxide bond that is required for activity (14)(15)(16).…”