Table 2.
Reference Study Type |
Population | OLR Dose Route |
PK/PD | Safety Tolerability |
---|---|---|---|---|
[11] Preclinical |
neutropenic CD-1 male mice infected by an Aspergillus terreus strain (OLR MIC = 0.008 mg/L) |
10 mg/kg/q12h orally or IV |
Cmin orally = 0.8 mg/L Cmin IV = 0.3 mg/L AUC0–24h ≈ 22.5 mg·h/L |
No adverse events |
[24] Preclinical |
neutropenic CD-1 male mice infected by wild-type and TR34/L98H Aspergillus fumigatus strains (OLR MIC = 0.03 mg/L) |
24 mg/kg/q24h or 8 mg/kg/q8h or 15 mg/kg/q8h IV |
Linear PK between 4 and 15 mg/kg/q8h; Protein binding ≈ 99%; Time-dependent antifungal effect:
|
No adverse events * |
[25] Preclinical |
neutropenic CD-1 male mice infected by Aspergillus flavus strains (OLR MIC = 0.03 mg/L) |
24 mg/kg/q24h or 8 mg/kg/q8h or 15 mg/kg/q8h IV |
Serum GM total suppression for Cmin = 0.3 mg/L and Cmin/MIC ≈ 10 in the invasive sinusitis cellular model and near-total suppression for 15 mg/kg/q8h in the sinopulmonary aspergillosis murine model; 27% reduction in serum GM comparable to that of a posaconazole AUC = 47 mg·h/L achieved for a mean Cmin/MIC = 13.38 [9,10,11,12,13,14,15,16,17,18,19] |
NM |
[26] Preclinical |
neutropenic CD-1 female mice infected by a wild-type A. fumigatus strain (OLR MIC = 0.008 mg/L) |
2.5–5–10–15–20 mg/kg single dose IP |
Linear PK between 2.5 and 20 mg/kg; Area under the concentration–time curve linearly correlated to the dose (R = 0.96); Tmax reached within 0.5 h between 2.5 and 15 mg/kg; Cmin above the efficacy level required as seen on other murine models for doses 10, 15 and 20 mg/kg |
No adverse events |
[29] Phase I double-blind, randomized, placebo-controlled clinical trial |
40 healthy male volunteers aged between 18 and 45 years divided into 5 cohorts of 8 |
0.25–0.75–1.5–3–4 mg/kg single dose IV |
NM | Serious AE: 0% Minor AE: 16.67% (i.e., epistaxis, paresthesia, headache, eczema) |
* Preliminary studies were conducted to determine the maximal tolerated dose. AE: adverse events. AUC: area under the concentration–time curve. AUC-GM: area under the serum galactomannan–time curve. Cmax: maximal plasmatic concentration. Cmin: minimal plasmatic concentration. GM: galactomannan. IP: intraperitoneal. IV: intravenous. NM: not mentioned. OLR: olorofim. PD: pharmacodynamics. PK: pharmacokinetics. PSC: posaconazole. Tmax: time needed to reach the Cmax after administration.