Impact of Ferroquine on the Solubilization of Artefenomel (OZ439) during in Vitro Lipolysis in Milk and Implications for Oral Combination Therapy for Malaria

Abstract

Milk is an attractive lipid-based formulation for the delivery of poorly water-soluble drugs to pediatric populations. We recently observed that solubilization of artefenomel (OZ439) during in vitro intestinal lipolysis was driven by digestion of triglycerides in full-cream bovine milk, reflecting the ability of milk to act as an enabling formulation in the clinic. However, when OZ439 was co-administered with a second antimalarial drug, ferroquine (FQ) the exposure of OZ439 was reduced. The current study therefore aimed to understand the impact of the presence of FQ on the solubilization of OZ439 in milk during in vitro intestinal digestion. Synchrotron small-angle X-ray scattering was used for in situ monitoring of drug solubilization (inferred via decreases in the intensity of drug diffraction peaks) and polymorphic transformations that occurred during the course of digestion. Quantification of the amount of each drug solubilized over time and analysis of their distributions across the separated phases of digested milk were determined using high-performance liquid chromatography. The results show that FQ reduced the solubilization of OZ439 during milk digestion, which may be due to competitive binding of FQ to the digested milk products. Interactions between the protonated FQ-H + and ionized liberated free fatty acids resulted in the formation of amorphous salts, which removes the low-energy crystalline state as a barrier to dissolution of FQ, while inhibiting the solubilization of OZ439. We conclude that although milk could enhance the solubilization of poorly water-soluble OZ439 during in vitro digestion principally due to the formation of fatty acids, the solubilization efficiency was reduced by the presence of FQ by competition for the available fatty acids. Assessment of the solubilization of both drugs during digestion of fixed-dose combination lipid formulations (such as milk) is important and may rationalize changes in bioavailability when compared to that of the individual drugs in the same formulation.

A randomized, double-blind, phase 2b study to investigate the efficacy, safety, tolerability and pharmacokinetics of a single-dose regimen of ferroquine with artefenomel in adults and children with uncomplicated Plasmodium falciparum malaria

“…A new fixed-dose combination of ferroquine (IND 115 244) and artefenomel (IND 104 549), which have different mechanisms of action, was developed by Sanofi in partnership with Medicines for Malaria Venture (MMV) for the single-dose treatment of uncomplicated malaria in adults and children. Artefenomel, previously known as OZ439, is a synthetic trioxolane endoperoxidic anti-malarial agent [ 26 , 27 ] which, like artemisinins, has multiple mechanisms of action including reacting with iron within the parasite food vacuole to produce free radicals, leading to alkylation of key parasitic proteins [ 26 , 28 , 29 ]. Artefenomel was selected for development based on improved blood stability and an extended plasma half-life relative to artemisinins in rat [ 28 ].…”

“…Ferroquine is a ferrocenyl derivative of chloroquine that is active against chloroquine-resistant P. falciparum strains with a promising anti-malarial therapeutic potential in humans [ 31 , 32 ]. It has been proposed to act by preventing haemozoin formation generating reactive oxygen species and inducing lipid peroxidation [ 29 , 31 ]. Ferroquine is metabolized to one major metabolite (N-demethyl derivative, SSR97213), equally active in vitro.…”

The influence of lipid digestion on the fate of orally administered drug delivery vehicles

“…For weakly basic drugs the formation of fatty acids during digestion can be crucial in driving the solubilisation of drug through formation of lipophilic ion pairs [ 57 ]. The solubilisation of solid crystalline drug during digestion has been shown for pharmaceutical lipids [ 71 ], milk [ 57 , 67 , 72 ] and infant formula [ 73 ]. Halofantrine as a model drug was shown to be fully solubilised into full cream milk during digestion but not lower fat milk or casein solutions ( Figure 5 ) [ 57 ].…”

“…In the case of artefenomel introduced in the previous section, the digestion of milk lipids led to the rapid solubilisation of artefenomel FB 1, which subsequently reprecipitated as the FB 2 polymorph ( Figure 6 , left panel). Full digestion of the milk lipids did not enable complete solubilisation of artefenomel FB 2 and co-formulation with ferroquine reduced the solubilisation of FB form 2 [ 72 ]. Importantly, subsequent studies showed that the selection of an infant formula with an optimal lipid composition and lipid:drug ratio enabled full solubilisation of artefenomel during digestion ( Figure 6 , right panel) [ 73 ].…”

“…The dependence of solubilisation on fat content in the different infant formulas is also illustrated on the right, note that lower bar height indicates greater drug solubilisation. Adapted from [ 72 , 73 ] with permission, future requests for reproduction should be made to ACS publications ( https://pubs.acs.org/doi/10.1021/acs.molpharmaceut.8b01333 & https://pubs.acs.org/doi/abs/10.1021/acs.molpharmaceut.0c00475 ).…”