The PRR calculated for ferroquine in this study (163; 95 % CI 141–188) corresponds to the 10–10
3 range reported earlier for quinine, mefloquine and sulfadoxine-pyrimethamine, and thus is somewhat in the lower range of 10
2–10
4 for 4-aminoquinolines and halofantrine, and 10
3–10
5 for artemisinins [
43]. The present study is expected to be typical for malaria-naïve individuals who would be more susceptible to clinical illness, and further not have clearance estimates elevated by immunity, compared to patients in malaria-endemic areas [
44]. PRR variation due to differences between patient and volunteer status was recently highlighted [
45]. As reported elsewhere [
16], it would therefore seem that the principal benefit of the added ferrocene moiety in ferroquine, compared to its predecessor chloroquine, is its activity against chloroquine-resistant parasites, with a good overall fit to Target Compound Profile 1 as described earlier [
2,
46]. In this respect it is important to note that the
P. falciparum strain tested, 3D7, is chloroquine-sensitive. Possible future use of the chloroquine-resistant challenge strain 7G8 [
47] may offer a means of addressing the activity of ferroquine against chloroquine-resistant parasites. The study described here also confirms ferroquine’s attractive in vivo half-life (11 days), which suggests that it may be a suitable partner drug when paired with short half-life and fast-acting drugs including artemisinins and related peroxides, and thereby fit to Target Compound Profile 2 [
2]. As the rate of parasite killing is believed to be constant while the drug concentration remains above the MPC, the parasite clearance half-life and PRR can be derived during the initial phase of parasite killing. The parasitaemia levels in volunteers in this experimental infection system are orders of magnitude lower than those seen in patients and it is, therefore, possible that PD effects may be affected by parasite concentration. However, PD data from two recently published studies of mefloquine [
14]) and OZ439 [
34] in the IBSM model were close to those reported in studies undertaken in patients with clinical malaria [
48,
49].
The appearance of gametocytes after anti-malarial treatment is an observation previously made, both in field studies [
50] and in IBSM studies [
33] and [
51]. The fact that the signal persisted in the presence of both ferroquine and its active metabolite suggests that at least mature female gametocytes are not cleared in vivo by ferroquine. Without mosquito transmission data it is not possible to determine if ferroquine-treated subjects would be infectious to mosquitoes. Factors that may influence this include the (unmeasured) activity of the drug against male gametocytes and possible damage to the parasites that may prevent sporogony in the mosquito.
While ferroquine was, overall, well tolerated, three subjects experienced increased transaminase readings. Although transient Grade 1 (WHO) elevations of transaminase are typically observed in IBSM studies, these typically occur at earlier timepoints than was observed in two of the three subjects reported here. In two of the three subjects transaminases peaked 3–5 days after ferroquine administration (at 693 and 536 U/L and 252 and 396 U/L for AST and ALT respectively) before returning to normal values. Intensive investigation, including a measurement of paracetamol levels did not reveal a definitive cause for these changes. Increased transaminase readings had also been seen in four adult patients in the recent ferroquine Phase II trial, which involved 187 patients, again in absence of concomitant abnormal bilirubin readings [
29]. That study, too, permitted the use of paracetamol, along with contraceptives, as the only permissible concomitant treatment. Toxic paracetamol (over-)dosing is well known to cause acute liver toxicity but even normal use may result in modestly increased AST and ALT readings in the absence of elevated bilirubin levels [
51‐
54]. Further establishment of ferroquine’s safety profile will require additional clinical trials.