TABLE 1.
Overview of the data and experimental outcomes in our analysis of murine and human malaria infectiona
| Parameter | P. berghei ANKA in NMRI mice | P. falciparum (3D7) in SCID mice | P. falciparum (3D7) in human |
|---|---|---|---|
| No. subjects | |||
| Control (separate) | 215 (Yes) | 132 (Yes) | 177 (No) |
| MMV390048 | 65 | 50 | 20 |
| OZ439 | 200 | 48 | 24 |
| No. subjects/dose | 3–10 | 1–2 | 6–8 |
| No. dose levels | |||
| MMV390048 | 7 SD; 5 QD | 2 DD; 6 QD | 3 SD |
| OZ439 | 14 SD; 3 TD | 10 SD; 1 DD | 3 SD |
| Minimum expt length (d) | 3–4 (up to 30) | 8 (up to 31) | 8 (up to 30) |
| Inoculum (no. iRBCs) | 2 × 107 | 3.5 × 107 | 1,800–2,800 (viable parasites) |
| Total cure (no. mice) | |||
| MMV048 | 4 × 3 mg/kg (3) | 4 × 20 mg/kg (2) | 1 × 80 mg (8) |
| OZ439 | 1 × 30 mg/kg (30) | 1 × 100 mg/kg (2) | |
| Outcomes | Activity; cure (survival, parasite clearance) | PKPD relationship; parasite clearance; cure | PKPD relationship; parasite clearance; cure |
| Parasitemia output | Percentage of infected RBCs | Percentage of infected RBCs | Concn of infected RBCs per ml |
Untreated parasite growth behavior was informed by a separate control group in murine experiments and by parasite growth data before treatment commences in human infection. Experimental outcomes evolve over the preclinical and clinical stages with increasing data richness per subject over time from crude efficacy measures, such as activity and parasite reduction, to more detailed concentration effect relationships. Measures of parasite reduction (e.g., parasite clearance rate or proportional antimalarial activity) are frequently used to evaluate compounds throughout the clinical development stages (2). SD, single dose; DD, double dose; TD, triple dose; QD, quadruple dose.