In macaques, coadministration of ivermectin (0.6 or 1.2 mg/kg) and chloroquine (10 mg/kg) for 7 days was safe and well-tolerated. Coadministration of chloroquine and ivermectin did not have an effect on the Cmax or area under the concentration-time curve (AUC) of ivermectin (Table 1 and 2 and Fig. 6) or chloroquine (Fig. 7). The 1.2- and 0.6-mg/kg doses in macaques have approximate human equivalent doses (HEDs) of 0.55 mg/kg (total, 3.85 mg/kg) and 0.27 mg/kg (total, 1.89 mg/kg), respectively. This suggests that repeated daily dosing of ivermectin at 0.6 or 0.3 mg/kg could be used in combination with chloroquine in humans. While billions of ivermectin and chloroquine treatments have been administered to humans, there is very limited safety evidence for their coadministration. Only one study, on P. vivax, has coadministered ivermectin (0.2 mg/kg single dose) and chloroquine (0.6 mg/kg on the first day, 0.45 mg/kg on the second and third day), and they did so in 10 persons with no adverse events passively reported
Relative ivermectin parameter values for Cmax (left) and AUC24 (right). Illustrates the linear pharmacokinetics of ivermectin as Cmax and AUC increased in a dose-dependent manner. Higher dose of ivermectin resulted in increased drug exposure with repeated dosing. Chloroquine did not interfere with ivermectin pharmacokinetics.
Relative chloroquine parameter values for Cmax (left) and AUC24 (right). Illustrates that ivermectin did not have any effect on chloroquine Cmax or AUC24 (paired sample t test, P > 0.05). IVM, ivermectin; CQ, chloroquine; PQ, primaquine.
rmectin (24), chloroquine (25), and hydroxychloroquine (26, 27) have been shown in vitro to inhibit replication of the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). All three drugs distribute into lung tissues at higher concentrations than plasma for chloroquine and hydroxychloroquine in rats (28), for hydroxychloroquine in mice (29), and for ivermectin in goats (30) and cattle (31). The preclinical safety evidence in macaques presented here and in vitro efficacy warrant further investigation of ivermectin and chloroquine or hydroxychloroquine in SARS-CoV-2-infected persons.
This work verifies that the rhesus macaque model provides a robust system for evaluating ivermectin pharmacokinetics. Newer formulations of ivermectin in development for humans, such as implants and expandable pill formulations (32, 33), could be evaluated in rhesus macaques. Novel methods of Plasmodium knowlesi control, such as treatment of wild primates with ivermectin baits to target wild Anopheles populations, could potentially be evaluated in this ivermectin macaque model system.
Although ivermectin was able to inhibit the liver-stage development of P. cynomolgi in vitro, no demonstrable effect was observed with in vivo macaque challenge. Repeated doses of ivermectin (0.3, 0.6, and 1.2 mg/kg) for 7 days in macaques was safe, with a corresponding rise in drug exposures (AUC), but no signs of autoinhibition. Coadministration of ivermectin (0.6 or 1.2 mg/kg) and chloroquine was safe and well-tolerated, with no drug-drug interactions altering ivermectin or chloroquine pharmacokinetics. Further ivermectin and chloroquine trials in humans are warranted for P. vivax control and SARS-CoV-2 chemoprophylaxis and treatment.
ACKNOWLEDGMENT
thank the AFRIMS Department of Veterinary Medicine for conducting the macaque trial, especially Laksanee Inamnuay, Kesara Chumpolkulwong, Natthasorn Komchareon, Chardchai Burom, Noppon Popruk, Sujitra Tayamun, Mana Saithasao, Alongkorn Hanrujirakomjorn, Nuttawat Wongpim, Khrongsak Saengpha, Phakorn Wilaisri, Chakkapat Detpattanan, Rachata Jecksaeng, Siwakorn Sirisrisopa, Yongyuth Kongkaew, Sakda Wosawanonkul, Sonchai Jansuwan, Amnart Andaeng, Chaisit Pornkhunviwat, Manas Kaewsurind, Wuthichai Puenchompu, Sawaeng Sripakdee, Dejmongkol Onchompoo, Thanaphon Rattanathan, Paitoon Hintong, and Siwadol Samano. We also thank the Department of Entomology Malariology and Insectary Sections, especially Ratawan Ubalee and Siriporn Phasomkusolsil, for supporting the sporozoite production. Monoclonal antibody 7.2 (anti-GAPDH) was obtained from The European Malaria Reagent Repository (http://www.malariaresearch.eu).
Credited to ASM Journal