Table 4.

Summary of phase I clinical trials of eritoran^*

Study (Author/date)	Purpose	Dose of eritoran administered	Mean plasma eritoran levels	LPS challenge used	Outcome/Results	Adverse reactions noted**
Wong et al, 200327	Determine the safety/tolerability of ascending single doses of eritoran in healthy male volunteers (monitored for 120 h after drug infusion), and to determine the in vivo PK and ex vivo PD activity of the drug.	350, 1000, 2000 or 3500 mcg given over 30 minutes (total n = 29, including placebo)	115, 365, 722 and 1214 ng/mL, respectively	0, 1 or 10 ng/mL added to 0.4 mL of whole blood ex vivo	Eritoran shown to be safe at doses administered, with dose-dependent increase in Cmax and AUC, with maximum concentration just after infusion completion. Eritoran had a small Vdss (41–54 mL/kg) and slow clearance from plasma (t1/2 42–51 h). Ex vivo antagonist activity against LPS maintained up to 8h post infusion with higher doses.	Headache, injection site reaction or hemorrhage, pharyngitis
Lynn et al, 200336	Assess the ability of eritoran to block the effects of LPS in vivo in healthy male volunteers	50, 100 or 250 mcg given over 30 minutes (total n = 24, including placebo)		4 ng/kg, administered intravenously 15 minutes after starting eritoran infusion	Eritoran limited LPS stimulated changes in vital signs and increases in cytokine with no significant increase in adverse effects.	Headache
Rossignol et al, 200429	Determine the safety, PK, PD and lipid distribution profile of eritoran during 72 h infusions of various doses of the drug in healthy male volunteers	500, 2000 or 3500 mcg/h for 72 h (total n = 23, including placebo)	4, 18 or 41 mcg/mL, respectively	0, 0.1, 1 or 10 ng/mL added to 0.4 mL of whole blood ex vivo	Eritoran safely tolerated and noted to have small Vdss (46–50 mL/kg) and long t1/2 (50–62 h). Ex vivo response to LPS inhibited by >85% up to 72 h after end of infusion, dependant on dose of eritoran and LPS. Majority of drug bound to HDL; eritoran inactivated by HDL, but not by LDL, VLDL or albumin.	Phlebitis, rhinitis, headache
Lynn et al, 200437	Assess the in vivo PD activity of eritoran after 4 and 72 h infusions in healthy male volunteers with various lipid profiles challenged with LPS	3.5mg/h × 72h (252 mg); 3mg/h × 4h (12 mg); or 0.5mg/h × 4h (2mg) (total n = 38, including placebo)	Cmax 46, 34, 41, 4 and 1 mcg/mL, respectively	4ng/kg at end of infusion, or 48 h or 72 h after completing the 72 h infusion, or 8 h after completing the 4 h infusion.	Higher doses (252 mg and 12 mg) of eritoran completetely blocked LPS effects (up to 72h and 8h, respectively) after dosing. Lowest dose (2mg) ameliorated but did not completely inhibit LPS effects 8 h post-dose. Lipid profile did not affect eritoran efficacy.	Phlebitis† with 72 h infusion, but not with the 4 h infusion
Rossignol et al, 200828	Assess safety and the PD and PK profiles of eritoran in healthy male and female volunteers with intermittent (twice daily) infusions of eritoran	11, 33, 77 or 105 mg in divided loading and maintenance doses every 12 h (n = 33, including placebo)	1345 – 14,816 ng/mL	0, 0.05, 1 or 10ng/mL added to whole blood ex vivo	Eritoran was safely tolerated. Efficacy in blocking LPS induced cytokine production ex vivo was dependent on the dose of both eritoran and LPS.	Injection site pain † and inflammation, elevated liver enzymes, flushing, conjunctivitis
Liang et al, 200334	Assess the PK profile of eritoran in subjects with hepatic disease compared to healthy volunteers	3mg/h × 4h, 3mg/h × 2h, then 1.5mg/h × 2h every 12h (total n = 48)	3698 – 4183 ng/mL	NA	PK parameters in subjects with liver disease were comparable to those in healthy volunteers; measured eritoran levels in these volunteers were independent of hepatic function.	None

PK, pharmacokinetics; PD, pharmacodynamics; C_max, maximum concentration; LPS, lipopolysaccharide; HDL, high density lipoprotein; LDL, low density lipoprotein; VLDL, very low density lipoprotein; TRL; triglyceride rich lipoprotein; AUC, area under the curve; V_dss, volume of distribution at steady state; t_1/2, elimination half life; NA, not applicable. Pharmacokinetic parameter values provided in the text are ranges or approximations from the phase I clinical studies above.

^*Of note, one other phase I study testing eritoran treatment over 14 days in leukemia patients prior to and during bone marrow engraftment after a myeloablative bone marrow transplant regimen was posted on clinicaltrials.gov in September 2008. However, it was reported terminated two months later due to what was described as a “business decision (resources)” (NCT00756912).

^**Adverse reactions noted in this column were not significantly different from placebo except for those marked with ^† in References 28 and 37.