Table 1.
Cryptosporidiosis therapeutic candidates
| In-vitro activity | In-vivo efficacy | Pharmacokinetic profile | |||||||||||||||
| Lead compound | Development phase | Target | C. parvum (Iowa) EC50 (μmol/l) | C. hominis (TU502) EC50 (μmol/l) | Enzymatic IC50 (μmol/l) | IFNγ KO mouse | NSG mouse | Dairy calf | GB piglet | Human | Dose | C max | AUC0–last | F% | T1/2 | Vdss | Comments |
| Nitazoxanide | Launched | CpPFOR; possible modulation of host interferons | 2.84 ± 1.90 | 2.82 ± 0.45 | NA | No | No | No | Efficacious at 100 mg b.i.d. for 10 days | Yes in immunocompetent individuals | 100 mg single dose (oral suspension, children 1–3 years) | 3.11 μg/ml | 11.7 μg·h/l | NR | 1.03–1.6 h | NR | All reported parameters are based on the metabolite, tizoxanide; tizoxanide is highly protein bound (>99%) |
| Clofazimine | Clinical (phase IIa) | Unknown | 0.0149 ± 0.0085 | 0.341 ± 0.302 | NA | Efficacious at 10 mg/kg q.d. | No | Weakly active at 30 mg/kg (unpublished) | ND | No | 100 mg Lamprene (day 5; parts A and B in clinical trial) | 280.7 ng/ml (part A); 514.1 ng/ml (part B) | 6863 ng·h/ml (part A); 11 298 ng·h/ml (part B) | NR | 336.5 h (part A); 535.5 h (part B) | NR | Low oral bioavailability; high lipophilicity and permeability in GI tract; clinical trial data showed about two-fold less plasma exposure in participants without diarrhea (part B); less than 2% of the cumulative CFZ doses was recovered in stool in both groups over the 5 days of stool collection |
| KDU731; CpPI4K-SD Lead | Preclinical | CpPI(4)K | 0.063 ± 0.028 | 0.130 ± 0.074 | 0.025 ± 0.004 | Efficacious at 10 mg/kg q.d. | ND | Efficacious at 5 mg/kg b.i.d. | ND | ND | KDU731: 2.3 mg/kg (oral, mouse); 5 mg/kg (i.v., mouse); 5 mg/kg (oral, calf) | 406 nmol/l (oral, mouse); 228 nmol/l (calf) | 2306 nmol/l·h (oral, mouse); 1909 nmol/l·h (calf) | 37% (oral, mouse) | 2.47 h (oral, mouse) | 1.12 l/kg (i.v., mouse) | No correlation between efficacy and plasma exposure |
| BKI-1708 | Preclinical | CpCDPK1 | 0.41 | NR | 0.0007 | Efficacious at 8 mg/kg b.i.d. (BKI-1708); many others | Efficacious at 10 mg/kg b.i.d. (BKI-1553); others | Efficacious at 5 mg/kg b.i.d. (BKI-1369); others | Efficacious at 10 mg/kg b.i.d. (BKI-1369) | ND | BKI-1708: 10 mg/kg (oral, mouse) | 2.9 μM | 247.1 μmol·min/l | NR | 42.6 min | NR | Varied PK/PD across three series scaffolds; GI exposure necessary for efficacy; no correlation with plasma exposure |
| AN7973 | Discovery (late lead) | CpCPSF3 (putative) | 0.13–0.43 | 0.63 | NA | Efficacious at 10 mg/kg q.d. | Efficacious at 10 mg/kg q.d. | Efficacious at 10 mg/kg q.d. | ND | ND | 10 mg/kg (oral, mouse); 5 mg/kg (oral, calf) | 8.63 μg/ml (mouse); 3.57 μg/mL (calf) | 92.7 μg·h/ml (mouse); 190 μg·h/ml (calf) | 37% (mouse) | 6.6 h (mouse); 31 h (calf) | NR | Half life ∼5× greater in calves than mice; high concentrations found in feces |
| Compound 2093 | Discovery (late lead) | CpMetRS | 0.006–0.029 | 0.015 | 0.0009 ± 0.0004 | Efficacious at 25 mg/kg b.i.d. | Efficacious at 50 mg/kg b.i.d. | Initial efficacy, then resistance observed in calf model at 15 mg/kg b.i.d. | ND | ND | 50 mg/kg (oral, mouse) | 5.8 μM | 1863 μmol·min/l | NR | NR | NR | Calf PK and efficacy studies: plasma and fecal levels >3× EC90 for over 24 h |
| MMV665917 | Discovery (late lead) | Unknown | 1.9–2.3 | 4.1 | NA | Efficacious at 30 mg/kg b.i.d. | Efficacious at 30 mg/kg b.i.d. | Efficacious at 22 mg/kg q.d. | Efficacious at 20 mg/kg b.i.d. | ND | 55 mg/kg (oral, mouse); 22 mg/kg (oral, calf); 10 and 20 mg/kg (oral, piglet) | NR | NR | NR | NR | NR | PK in healthy mice: high fecal and plasma concentrations with sustained exposure; PK from infected calf model: sustained fecal and serum concentrations >3× EC90; PK from infected piglet model: plasma exposure remained >3× EC90; gut contents showed concentrations > EC90 60 h after treatment ended |
| Compound 5 | Discovery (late lead) | CpKRS | 1.3 | 6.0 | 0.13 | Efficacious at 20 mg/kg q.d. | Efficacious at 20 mg/kg q.d. | ND | ND | ND | 10 mg/kg (oral, mouse); 3 mg/kg (i.v., mouse) | 5.4 μg/mL (oral) | 1300–3000 μg·min/ml (oral) | 100% | 2.5 h (i.v.) | 1 l/kg (i.v.) | Very high oral bioavailability |
| BRD7929 | Discovery (lead Op) | CpPheRS | 0.008–0.073 | 0.010 | 0.060 (ChPheRS) | ND | Efficacious at 10 mg/kg q.d. | ND | ND | ND | 1 mg/kg (oral, mouse); 0.6 mg/kg (i.v., mouse) | NR | NR | 80% | 32 h (i.v.) | 29 l/kg | BRD7929 has high oral bioavailability, volume of distribution, and solubility; compounds in series with higher bioavailability had better efficacy, possibly because of permeability |
AUC0–last, area under the curve; time-averaged concentration of drug in plasma; Cmax, maximum or peak serum (plasma) concentration of a drug after a single dose; F%, oral bioavailability; GB piglet, gnotobiotic piglet model (C. hominis); T1/2, half-life in plasma; Vdss, volume of distribution at steady state.