title: Pharmacological properties of NAI-603, a well-tolerated semisynthetic derivative of ramoplanin.
abstract: NAI-603 is a ramoplanin derivative designed to overcome the tolerability issues of the parent drug as a systemic agent. NAI-603 is highly active against aerobic and anaerobic Gram-positive bacteria, with MICs ranging from 0.008 to 8 μg/ml. MICs were not significantly affected by pH (range, 6 to 8), by inoculum up to 10(8) CFU/ml, or by addition of 50% human serum. Against staphylococci and enterococci, NAI-603 was rapidly bactericidal, with minimum bactericidal concentration (MBC)/MIC ratios never exceeding 4. The frequency of spontaneous resistance was low at 2× to 4× MIC (≤1×10(-6) to ≤1×10(-8)) and below the detection limit (about ≤1×10(-9)) at 8×MIC. Serial subcultures at 0.5×MIC yielded at most an 8-fold increase in MICs. In a systemic infection induced by methicillin-resistant Staphylococcus aureus (MRSA), the 50% effective dose (ED50) of intravenous (i.v.) NAI-603 was 0.4 mg/kg, lower than that of oral (p.o.) linezolid (1.4 mg/kg) and subcutaneous (s.c.) teicoplanin (1.4 mg/kg) or vancomycin (0.6 mg/kg). In neutropenic mice infected with vancomycin-resistant enterococci (VRE), the ED50s for NAI-603 were 1.1 to 1.6 mg/kg i.v., compared to 0.5 mg/kg i.v. of ramoplanin. The bactericidal activity was confirmed in vivo in the rat granuloma pouch model induced by MRSA, where NAI-603, at 40 mg/kg i.v., induced about a 2- to 3-log10-reduction in viable bacteria in the exudates, which persisted for more than 72 h. The pharmacokinetic (PK) profiles of NAI-603 and ramoplanin at 20 mg/kg show similar half-lives (3.27 and 3.80 h, respectively) with the maximum concentration (Cmax) markedly higher for NAI-603 (207 μg/ml versus 79 μg/ml). The favorable pharmacological profile of NAI-603, coupled with the absence of local tolerability issues, supports further investigation.
authors.affiliation: NAICONS, Milan, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Jabes
authors.forename: Cristina
authors.initials: C
authors.lastname: Brunati
authors.forename: GianPaolo
authors.initials: G
authors.lastname: Candiani
authors.forename: Simona
authors.initials: S
authors.lastname: Riva
authors.forename: Gabriella
authors.initials: G
authors.lastname: Romanó
authors.forename: Sonia
authors.initials: S
authors.lastname: Maffioli
authors.forename: Rosaria
authors.initials: R
authors.lastname: Rossi
authors.forename: Matteo
authors.initials: M
authors.lastname: Simone
authors.forename: Eleonora
authors.initials: E
authors.lastname: Gaspari
authors.forename: Stefano
authors.initials: S
authors.lastname: Donadio
mesh_terms: D000081:Acetamides / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use*; D047630:Depsipeptides / Q000737:chemistry*; D016983:Enterococcus / Q000187:drug effects; D005260:Female; D000069349:Linezolid; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects; D051379:Mice; D008813:Mice, Inbred ICR; D008826:Microbial Sensitivity Tests; D023303:Oxazolidinones / Q000494:pharmacology / Q000627:therapeutic use; D013203:Staphylococcal Infections / Q000188:drug therapy; D017334:Teicoplanin / Q000494:pharmacology / Q000627:therapeutic use; D014640:Vancomycin / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D000081:Acetamides; D000900:Anti-Bacterial Agents; D047630:Depsipeptides; D023303:Oxazolidinones; C041438:ramoplanin; D017334:Teicoplanin; D014640:Vancomycin; D000069349:Linezolid