Pharmacokinetics and Unexpected Safety Issues of LBM415, a Novel Oral Peptide Deformylase Inhibitor

• Published in: Clinical pharmacology and therapeutics 2011-08, Vol.90 (2), p.256-262
• Main Authors: Rolan, P, Sun, H, MacLeod, C, Bracken, K, Evans, TG
• Format: Article
• Language: English
• Subjects: Adult; Amidohydrolases - antagonists & inhibitors; Area Under Curve; Biological and medical sciences; Cyanosis - chemically induced; Dose-Response Relationship, Drug; Double-Blind Method; Eating; Enzyme Inhibitors - administration & dosage; Enzyme Inhibitors - adverse effects; Enzyme Inhibitors - pharmacokinetics; Fasting; Half-Life; Humans; Male; Medical sciences; Methemoglobinemia - chemically induced; Oxygen - metabolism; Peptides - administration & dosage; Peptides - adverse effects; Peptides - pharmacokinetics; Pharmacology. Drug treatments
• ISSN: 0009-9236; 1532-6535
• DOI: 10.1038/clpt.2011.101

Peptide deformylase (PDF) inhibitors represent a potential new class of antibiotics targeting a large number of bacterial species. We studied the pharmacokinetics and safety of LBM415, a novel PDF inhibitor, administered as a single oral dose at 100–3,000 mg in the fasted state and at 1,000 mg in the fed state in healthy volunteers. LBM415 was then administered at dosages ranging from 100 mg q.d. to 1,000 mg t.i.d. for 11 days. Dose‐proportional pharmacokinetics was observed, with a peak plasma concentration (Cmax) of 17.85 ± 5.96 µg/ml at 1,000 mg b.i.d. (the projected therapeutic dose) and an area under the concentration‐time curve (AUC)0–24h of 36.83 ± 10.36 µg/ml·h. The half‐life, as determined after a 1,000‐mg single dose, was 2.18 ± 0.61 h. The compound was well tolerated at low doses, but at the highest dose, 1,000 mg t.i.d., reversible cyanosis and low oxygen saturation, attributable to methemoglobinemia, were detected on day 11. Oxygen saturation was as low as 88% in one subject on day 11. Clinical Pharmacology & Therapeutics (2011) 90 2, 256–262. doi:10.1038/clpt.2011.101