Table 1.
Summary of key concentration-related pharmacodynamic endpoints for tafenoquine
| Actual or estimated concentration parameter of interest (ng/ml) | Regimen | |||||
|---|---|---|---|---|---|---|
| 0.6, 2 and 6 mg/kg/day × 3 against Pc in Rhesus monkeys [15] (HED = 36, 120 and 360 mg/day)a |
1 and 3 mg/kg/day × 3 against Pv in Aotus monkeys [17] (HED = 60 and 180 mg/day)a |
600 mg × 1 in nonimmune patients [14] | 200 mg/day × 3 + 200 mg once per week in nonimmune and semi-immune subjects (see also Fig. 1, [16, 18]) | 100 mg/day × 3 + 100 mg once per week (hypothetical) (see also Fig. 1, [16]) | 400 mg/day × 3 + 400 mg once per month in Thai soldiers [18, 19] | |
| Cmax | 50, 150 and 500 | ~90 and 250 | 400 | 280 | 140 | 730 |
| Steady state trough (median) | NA | NA | NA | 220 | 110 | Month 1–238b
Month 6–104b |
| Steady state trough (5%) | NA | NA | NA | 90 | 45 | NA |
| Steady state Cmax | NA | NA | NA | 320 | 160 | ~350–500 |
| Major pharmacologic effects and/or concentration at failure or relapse | 2 and 6 mg/kg cleared established infection, no recrudescense at 6 mg/kg | 1 and 3 mg/kg cleared established infection, no recrudescence at 3 mg/kg | Pf = 49 at day 31, Cmax in failed subject was 244 ng/ml | No Pf or Pv failures during deployment in non-immunes with 4 post-deployment Pv relapses—concentration unknown Similar efficacy to mefloquine against Pf in semi-immune subjects |
NA | Pv = 20, 21 and Pf = 39 at 6–12 weeks after dosing Pv = 38 in subject non-compliant with medication |
| In vitro parameters | IC50 97 in 44 MDR Pf strains from Thai/Cambodian border [22] IC99 3108 in 44 MDR Pf strains from Thai/Cambodian border [22] IC50 64-110 in 2 MDR Southeast Asia Pf strains [23] IC50 2041 in 166 African Pf strains [24] IC50 202 in seven MDR laboratory strains [25] |
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C max maximum concentration, MDR multidrug resistant, NA not available, NR not reported, Pv Plasmodium vivax, Pf Plasmodium falciparum, Pc Plasmodium cynomolgi, HED human equivalent dose assuming a 65 kg subject
aHED calculated assumed conversion factor 0.916 from a mg/kg dose in monkeys to a mg dose in a 65 kg human. The conversion factor was derived based on an observed median Cmax of 50 ng/ml in Rhesus monkeys at a dose 0f 0.6 mg/kg/day for 3 days versus a simulated Cmax of 280 ng/ml following a 200 mg × 3 loading dose in a 65 kg human and assuming Cmax scales linearly with dose. The same conversion factor between Rhesus monkeys and humans was assumed for Aotus monkeys
bNot at steady state; trough concentrations declined