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. 2024 May 10;10(5):345. doi: 10.3390/jof10050345

Table 2.

Preclinical and clinical studies of olorofim’s pharmacokinetics and pharmacodynamics.

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:
  • -

    Dose fractionation studies revealed a reduction in serum GM when administered every 12 h and a total suppression of serum GM when administered every 8 h (p = 0.028 and p = 0.024 respectively)

  • -

    PK indexes studies revealed a correlation between Cmin/MIC and the effect of OLR (assessed by serum GM at the end of the experiment and the area under GM-time curve), as well as the fraction of the dosing interval during which the total plasma concentration was above the MIC T > MIC 1 mg/L

Target reduction of 27% of the AUC-GM was achieved for Cmin/MIC = 9.1; therefore Cmin = 0.27 mg/L
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.