Radical curative efficacy of tafenoquine combination regimens in Plasmodium cynomolgi-infected Rhesus monkeys (Macaca mulatta)

Abstract

Background: Tafenoquine is an 8-aminoquinoline being developed for radical cure (blood and liver stage elimination) of Plasmodium vivax. During monotherapy treatment, the compound exhibits slow parasite and fever clearance times, and toxicity in glucose-6-phosphate dehydrogenase (G6PD) deficiency is a concern. Combination with other antimalarials may mitigate these concerns.

Methods: In 2005, the radical curative efficacy of tafenoquine combinations was investigated in Plasmodium cynomolgi-infected naïve Indian-origin Rhesus monkeys. In the first cohort, groups of two monkeys were treated with a three-day regimen of tafenoquine at different doses alone and in combination with a three-day chloroquine regimen to determine the minimum curative dose (MCD). In the second cohort, the radical curative efficacy of a single-day regimen of tafenoquine-mefloquine was compared to that of two three-day regimens comprising tafenoquine at its MCD with chloroquine or artemether-lumefantrine in groups of six monkeys. In a final cohort, the efficacy of the MCD of tafenoquine against hypnozoites alone and in combination with chloroquine was investigated in groups of six monkeys after quinine pre-treatment to eliminate asexual parasites. Plasma tafenoquine, chloroquine and desethylchloroquine concentrations were determined by LC-MS in order to compare doses of the drugs to those used clinically in humans.

Results: The total MCD of tafenoquine required in combination regimens for radical cure was ten-fold lower (1.8 mg/kg versus 18 mg/kg) than for monotherapy. This regimen (1.8 mg/kg) was equally efficacious as monotherapy or in combination with chloroquine after quinine pre-treatment to eliminate asexual stages. The same dose of (1.8 mg/kg) was radically curative in combination with artemether-lumefantrine. Tafenoquine was also radically curative when combined with mefloquine. The MCD of tafenoquine monotherapy for radical cure (18 mg/kg) appears to be biologically equivalent to a 600-1200 mg dose in humans. At its MCD in combination with blood schizonticidal drugs (1.8 mg/kg), the maximum observed plasma concentrations were substantially lower than (20-84 versus 550-1,100 ng/ml) after administration of 1, 200 mg in clinical studies.

Conclusions: Ten-fold lower clinical doses of tafenoquine than used in prior studies may be effective against P. vivax hypnozoites if the drug is deployed in combination with effective blood-schizonticidal drugs.

Figure 1

Course of parasitaemia in Cohort 2 monkeys given tafenoquine (TQ) at 6 mg/kg base/day or 2 mg/kg base/day alone or in combination with 16 mg/kg chloroquine base/day for three days. The abbreviation DL refers to the detection limit of parasitaemia by microscopy. For the purposes of illustration parasitaemia levels falling below the limit of detection (approximate location indicated by hashed line) were arbitrarily assigned a value of 1 parasite/μl. Arrows indicate drug administration.

Figure 2

The course of infection in the two Cohort 2 control monkeys given chloroquine alone at 16 mg/kg/base/day for three days. For the purposes of illustration parasitaemia levels falling below the limit of detection were arbitrarily assigned a value of 1 parasite/μl. The transient increase in parasitaemia in one of the monkeys after initial clearance is interpreted to be a delay in the primary attack. The concentrations of chloroquine and desethylchloroquine observed at the time of peak parasitaemia in one monkey are indicated.

Figure 3

Methaemoglobin levels in Rhesus monkeys given a total dose of 18 mg/kg (6 mg/kg/day × 3) tafenoquine and human subjects given chloroquine (CQ), a single 600 mg or three 600 mg doses of tafenoquine (TQ). Clinical data are from Walsh et al (2004).

Figure 4

Tafenoquine plasma concentration time curves for 22 individual monkeys given tafenoquine at a dose of 0.6 mg/kg/day for three days under various conditions. No other data for tafenoquine plasma levels for tafenoquine were available at any other dose. The arrows indicate the times of dosing. Maximum observed tafenoquine plasma concentrations were between 20-85 ng/ml between 48 and 96 h after dosing. Data were unavailable for the two monkeys that relapsed at this dose. Data (red circles and solid line) were available for only one of two monkeys in Cohort 2 where this dose given alone for radical cure failed in both animals, and chloroquine rescue was required.