Table 4 TCP-1 profiles, molecules that clear asexual parasitemia
From: New developments in anti-malarial target candidate and product profiles
TCP-1 criteria at human proof of concept | Minimum essential | Ideal |
|---|---|---|
Dosing regimen; adult/pediatric dose | Oral, single dose (predicted) <1000Â mg/<250Â mg; oral, three doses <400Â mg/<100Â mg for areas of multidrug resistance | Oral, single dose (predicted); <100Â mg/25Â mg |
Rate of onset of action and clinical parasite reduction ratio from single dose | Rapid clearance of parasites at least as fast as mefloquine (≤72 h from the highest burdens) and projected >106-fold reduction in parasites | Immediate and rapid clearance of parasites at least as fast as artesunate; >Projected 1012-fold reduction in parasites |
Susceptibility to loss of efficacy due to acquired resistance | No fit and transmissible drug-resistant parasites identified; identification of combination partner with no cross resistance | Very low (similar to chloroquine); no cross-resistance with asexual blood-stage combination partner. Resistance markers investigated |
Relative clinical efficacy from patients in areas known to be resistant to current first line medications | Clinical efficacy against all known resistance (3-day dosing) | Clinical efficacy against all known resistance (single dose) |
Drug- drug interactions | No unsurmountable risks with potential anti-malarial partners | No interactions with other anti-malarial, anti-retroviral or TB medicines |
Safety | Therapeutic ratio >tenfold between therapeutic exposure and NOAEL (no adverse effects level) in preclinical studies, and easily ‘monitorable’ adverse event or biomarker for human studies | Therapeutic ratio >50-fold between therapeutic exposure and NOAEL in preclinical studies and easily ‘monitorable’ adverse event or biomarker for human studies |
G6PD (glucose-6-phosphate dehydrogenase) deficiency status | Measured—no enhanced hemolysis risk from testing in SCID mice engrafted with human blood from volunteers with reduced G6PD activity; clinical confirmation | Measured —no enhanced hemolysis risk in subjects with reduced G6PD activity, with clinical confirmation |
Formulation | Simple and inexpensive to produce, not requiring proprietary methodology or kits; can readily be produced in endemic countries | Simple and inexpensive to produce, not requiring proprietary methodology or kits; can readily be produced in endemic countries |
Cost of active ingredient in final medicine | Similar to current medication: ≤$0.5 for adults, $0.1 for infants under 2 years | Similar to older medications: <$0.25 for adults, $0.05 for infants under 2 years |
Estimated stability of final product under Zone IVb conditions (30 °C 75% humidity), in final packaging | ≥24 months | ≥3–5 years |