Pharmacokinetics and unexpected safety issues of LBM415, a novel oral peptide deformylase inhibitor

Clinical Pharmacology and Therapeutics

Volumn 90, Issue 2, 2011, Pages 256-262

  Rolan, P ^a   Sun, H ^b   MacLeod, C ^c   Bracken, K ^b   Evans, T G ^b  

^a UNIVERSITY OF ADELAIDE   (Australia)

^b NOVARTIS INSTITUTES FOR BIOMEDICAL RESEARCH   (United States)

^c MERCK RESEARCH LABORATORIES   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ALANINE AMINOTRANSFERASE; BILIRUBIN; N (5 FLUORO 1 OXIDO 2 PYRIDINYL) 1 [2 (N FORMYL N HYDROXYAMINOMETHYL)HEXANOYL]PROLINAMIDE; PEPTIDE DEFORMYLASE INHIBITOR;

ADULT; ALANINE AMINOTRANSFERASE BLOOD LEVEL; AREA UNDER THE CURVE; ARTICLE; BACKACHE; BILIRUBIN BLOOD LEVEL; BITTER TASTE; CHAPPED LIPS; COMMON COLD SYMPTOM; CONSTIPATION; CYANOSIS; DECREASED APPETITE; DIARRHEA; DIZZINESS; DOUBLE BLIND PROCEDURE; DRUG CLEARANCE; DRUG ELIMINATION; DRUG HALF LIFE; DRUG SAFETY; DRUG TOLERABILITY; ECG ABNORMALITY; EPISTAXIS; EYE IRRITATION; FATIGUE; FEMALE; HEADACHE; HUMAN; HUMAN EXPERIMENT; LETHARGY; LIMB PAIN; MALE; MAXIMUM PLASMA CONCENTRATION; METHEMOGLOBINEMIA; NAUSEA; NORMAL HUMAN; NOSE CONGESTION; OXYGEN SATURATION; PHARYNGITIS; PRIORITY JOURNAL; RANDOMIZED CONTROLLED TRIAL; RASH; SIDE EFFECT; SINGLE DRUG DOSE; SLEEP DISORDER; SORE THROAT; SYNCOPE; THIRST; THORAX PAIN; TIME TO MAXIMUM PLASMA CONCENTRATION; XEROSTOMIA;

ADULT; AMIDOHYDROLASES; AREA UNDER CURVE; CYANOSIS; DOSE-RESPONSE RELATIONSHIP, DRUG; DOUBLE-BLIND METHOD; EATING; ENZYME INHIBITORS; FASTING; HALF-LIFE; HUMANS; MALE; METHEMOGLOBINEMIA; OXYGEN; PEPTIDES;

EID: 79960579543     PISSN: 00099236     EISSN: 15326535     Source Type: Journal    
DOI: 10.1038/clpt.2011.101     Document Type: Article

References (22)

1. Chen, D. & Yuan, Z. Therapeutic potential of peptide deformylase inhibitors. Expert Opin. Investig. Drugs 14, 1107-1116 (2005). (Pubitemid 41246166)
2. Jain, R., Chen, D., White, R.J., Patel, D.V. & Yuan, Z. Bacterial Peptide deformylase inhibitors: a new class of antibacterial agents. Curr. Med. Chem. 12, 1607-1621 (2005). (Pubitemid 40895004)
3. Leeds, J.A. & Dean, C.R. Peptide deformylase as an antibacterial target: a critical assessment. Curr. Opin. Pharmacol. 6, 445-452 (2006). (Pubitemid 44340668)
4. Yuan, Z. & White, R.J. The evolution of peptide deformylase as a target: contribution of biochemistry, genetics and genomics. Biochem. Pharmacol. 71, 1042-1047 (2006).
5. Bogdanovich, T. et al. Activity of LBM415 compared to those of 11 other agents against Haemophilus species. Antimicrob. Agents Chemother. 50, 2323-2329 (2006). (Pubitemid 43993169)
6. Chen, D. et al. Peptide deformylase inhibitors as antibacterial agents: identification of VRC3375, a proline-3-alkylsuccinyl hydroxamate derivative, by using an integrated combinatorial and medicinal chemistry approach. Antimicrob. Agents Chemother. 48, 250-261 (2004). (Pubitemid 38040205)
7. Ednie, L.M., Pankuch, G. & Appelbaum, P.C. Antipneumococcal activity of LBM415, a new peptide deformylase inhibitor, compared with those of other agents. Antimicrob. Agents Chemother. 48, 4027-4032 (2004). (Pubitemid 39304641)
8. Fonseca-Aten, M. et al. Evaluation of LBM415 (NVP PDF-713), a novel peptide deformylase inhibitor, for treatment of experimental Mycoplasma pneumoniae pneumonia. Antimicrob. Agents Chemother. 49, 4128-4136 (2005). (Pubitemid 41400955)
9. Fritsche, T.R., Moet, G.J. & Jones, R.N. Commercial broth microdilution panel validation and reproducibility trials for NVP PDF-713 (LBM 415), a novel inhibitor of bacterial peptide deformylase. Clin. Microbiol. Infect. 10, 857-860 (2004). (Pubitemid 39276325)
10. Fritsche, T.R., Sader, H.S., Cleeland, R. & Jones, R.N. Comparative antimicrobial characterization of LBM415 (NVP PDF-713), a new peptide deformylase inhibitor of clinical importance. Antimicrob. Agents Chemother. 49, 1468-1476 (2005). (Pubitemid 40463378)
11. Jones, R.N., Fritsche, T.R. & Sader, H.S. Antimicrobial spectrum and activity of NVP PDF-713, a novel peptide deformylase inhibitor, tested against 1,837 recent Gram-positive clinical isolates. Diagn. Microbiol. Infect. Dis. 49, 63-65 (2004). (Pubitemid 38595629)
12. Watters, A.A., Jones, R.N., Leeds, J.A., Denys, G., Sader, H.S. & Fritsche, T.R. Antimicrobial activity of a novel peptide deformylase inhibitor, LBM415, tested against respiratory tract and cutaneous infection pathogens: a global surveillance report (2003-2004). J. Antimicrob. Chemother. 57, 914-923 (2006).
13. Jones, R.N., Moet, G.J., Sader, H.S. & Fritsche, T.R. Potential utility of a peptide deformylase inhibitor (NVP PDF-713) against oxazolidinone-resistant or streptogramin-resistant Gram-positive organism isolates. J. Antimicrob. Chemother. 53, 804-807 (2004). (Pubitemid 38660282)
14. Edelstein, P.H., Hu, B. & Edelstein, M.A. In vitro and intracellular activities of LBM415 (NVP PDF-713) against Legionella pneumophila. Antimicrob. Agents Chemother. 49, 2533-2535 (2005). (Pubitemid 40734498)
15. Dean, C.R. et al. Role of the AcrAB-TolC efflux pump in determining susceptibility of Haemophilus influenzae to the novel peptide deformylase inhibitor LBM415. Antimicrob. Agents Chemother. 49, 3129-3135 (2005). (Pubitemid 41060550)
16. Dean, C.R. et al. Reduced susceptibility of Haemophilus influenzae to the peptide deformylase inhibitor LBM415 can result from target protein overexpression due to amplified chromosomal def gene copy number. Antimicrob. Agents Chemother. 51, 1004-1010 (2007). (Pubitemid 46355287)
17. Osborne, C.S. et al. In vivo characterization of the peptide deformylase inhibitor LBM415 in murine infection models. Antimicrob. Agents Chemother. 53, 3777-3781 (2009).
18. Merz, M., Seiberling, M., Höxter, G., Hölting, M. & Wortha, H.P. Elevation of liver enzymes in multiple dose trials during placebo treatment: are they predictable? J. Clin. Pharmacol. 37, 791-798 (1997). (Pubitemid 27441135)
19. Rosenzweig, P., Miget, N. & Brohier, S. Transaminase elevation on placebo during phase I trials: prevalence and significance. Br. J. Clin. Pharmacol. 48, 19-23 (1999). (Pubitemid 29296658)
20. Umbreit, J. Methemoglobin-it's not just blue: a concise review. Am. J. Hematol. 82, 134-144 (2007). (Pubitemid 46155276)
21. Shargel, L., Silverman, H.I., Cohen, P., Brisson, J. & Dennis, S. Bioavailability and cardiovascular safety of Dexatrim (phenylpropanolamine hydrochloride) from a controlled-release caplet. Biopharm. Drug Dispos. 11, 569-583 (1990). (Pubitemid 20333574)
22. Jones, R.N., Sader, H.S. & Fritsche, T.R. Antimicrobial activity of LBM415 (NVP PDF-713) tested against pathogenic Neisseria spp. (Neisseria gonorrhoeae and Neisseria meningitidis). Diagn. Microbiol. Infect. Dis. 51, 139-141 (2005). (Pubitemid 40215425)