Plasma ivermectin with and without coadministration of 10 mg/kg chloroquine reached maximum concentration of drug in serum (Cmax) at approximately 2 to 4 hours postdose, and the elimination half-life ranged from 11 to 28 hours with an accumulation index of 0.6 to 3.7. The plasma concentration time profile for the first 24 hours and pharmacokinetic parameters of ivermectin are shown in Fig. 3 and Tables 1 and .
Ivermectin concentrations achieved in macaques. Represents the log concentration of ivermectin achieved in orally dosed macaques within 24 hours after the first dose. IVM, ivermectin; CQ, chloroquine (10 mg/kg).
Ivermectin alone was safe and well-tolerated in macaques with repeated doses at 0.3 and 1.2 mg/kg for 7 days, with no signs of neurological, gastroenterological, or hematological complications. One monkey vomited the first dose of ivermectin (1.2 mg/kg) when administered as monotherapy but had no emesis upon further dosing. Emesis was observed previously in ivermectin-treated macaques receiving a 2-mg/kg single dose, and the occurrence of emesis increased with higher doses (4, 6, 8, 12, and 24 mg/kg) (17, 18). The combination of ivermectin (0.6 and 1.2 mg/kg) and chloroquine (10 mg/kg) for 7 days was safe and well-tolerated in macaques. This finding suggests that this combination could be used in humans during P. vivax MDAs in regions where chloroquine is still an effective P. vivax blood-stage therapeutic.
Prophylactic mode in vitro results with an ivermectin parent compound indicated ivermectin activity against P. cynomolgi liver schizonts and hypnozoites (Fig. 1) but at higher concentrations than could be safely achieved in humans (10). However, there is a growing body of evidence that the activity of ivermectin is not restricted to the parent compound alone and that ivermectin metabolites may be active as well. Indeed, when comparing the effect of ivermectin metabolized by a human to that of parent compound mixed in human blood, the mosquito-lethal effect against Anopheles dirus and Anopheles minimus was 20- to 35-fold more potent (5) and the sporontocidal effect against P. vivax development in Anopheles aquasalis was 5-fold more potent (20). Even though P. berghei in vitro liver-stage IC50s were in the μg/ml range, liver schizont inhibition was achieved in vivo with ivermectin at doses plausible for use in humans (8). The points above warranted evaluation of ivermectin against P. cynomolgi in rhesus macaques even though in vitro IC50s were in the μg/ml range and ivermectin reaches only ng/ml concentrations in orally treated hosts.
There was no delay to patency of first blood-stage P. cynomolgi infection in either low- or high-dose ivermectin groups (Fig. 2). Ivermectin displayed μM levels of liver schizont efficacy in vitro; however, a lack of delay to blood-stage patency suggests a minimal impact of ivermectin on liver schizont development. Admittedly, the injection of one million P. cynomolgi sporozoites into the macaque sets a very high bar for any drug, as it only requires one sporozoite to develop into a liver schizont to continue the blood-stage malaria infection. This is in contrast to a single mosquito that is predicted to deliver <100 sporozoites during blood feeding (21). The in vitro ivermectin experiments indicated prophylactic inhibition of P. cynomolgi hypnozoite development at μM concentrations; however, the macaque ivermectin challenge clearly demonstrated development of hypnozoites, as indicated by the first and second blood-stage relapses occurring at approximately the same time as negative vehicle controls (Fig. 2). Neither in vitro nor in vivo P. cynomolgi models indicate a radical cure efficacy potential for ivermectin. A recent human challenge trial (n = 8) with intravenous injection of cryopreserved Plasmodium falciparum sporozoites (n = 3,200) and a single oral dose ivermectin (400 μg/kg) failed to show liver-stage inhibition in terms of time to blood-stage patency (22).
To the best of our knowledge, this is highest repeated dose ivermectin pharmacokinetic investigation in any mammal species (Fig. 4). There were no significant changes in the clearance per fraction of drug absorbed (CL/F) or half-life (t1/2) values (Table 1 and Fig. 5). It should be noted that this study had a small sample size, with only three macaques per ivermectin-treated group, and thus, ivermectin autoinhibition warrants further evaluation in future trials. In humans, three repeated doses of ivermectin (30 or 60 mg) every third day did not inhibit Cmax when comparing the first and third dose, suggesting a lack of autoinhibition (10). In FVB mice administered oral ivermectin (0.2 mg/kg) twice a week for 5 weeks, there was a 1.7-fold reduction in the 24-hour postdose plasma ivermectin concentrations, while the major metabolite concentration increased by 1.7-fold (23), suggesting an induction of metabolism.
Pharmacokinetic simulation of ivermectin concentration-time profile when given at 0.3, 0.6, and 1.2 mg/kg for 7 days in rhesus macaques. Illustrates the simulation of plasma ivermectin concentration-time profile. One-compartment analysis best described the observed data by using the estimates calculated by noncompartmental analysis following the first and seventh doses as initial estimates. In the simulation, Cmax had mean estimates of 150, 300, and 600 ng/ml at approximately 4 h after the first dose and reached a steady state around the fifth dose with Cmax at 243, 486, and 973 ng/ml at the ivermectin doses 0.3, 0.6, and 1.2 mg/kg, respectively. IVM, ivermectin.
Mean plasma concentration-time profiles of ivermectin 24 hours after the first and seventh dose when administered ivermectin at 0.3, 0.6, and 1.2 mg/kg with and without chloroquine (10 mg/kg). Illustrates the mean ivermectin plasma concentration (ng/ml) by time (h) profile 24 hours after the first and seventh dose with or without CQ (10 mg/kg). There was a slight reduction in peak concentrations achieved and a delay in time to achieve peak concentrations when comparing the first and seventh doses. IVM, ivermectin; CQ, chloroquin
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