title: Pharmacodynamics of TD-1792, a novel glycopeptide-cephalosporin heterodimer antibiotic used against Gram-positive bacteria, in a neutropenic murine thigh model.
abstract: TD-1792 is a novel glycopeptide-cephalosporin heterodimer investigational antibiotic that displays potent bactericidal effects against clinically relevant Gram-positive organisms in vitro. The present studies evaluated the in vivo pharmacokinetics (PK) and pharmacodynamics (PD) of TD-1792 in the neutropenic murine thigh infection animal model. TD-1792, dosed subcutaneously (SC), produced dose-dependent reduction in the thigh bacterial burden of several organisms, including methicillin-susceptible and -resistant strains of Staphylococcus aureus and Staphylococcus epidermidis (MSSA, MRSA, MSSE, MRSE, respectively), penicillin-susceptible strains of Streptococcus pneumoniae (PSSP), Streptococcus pyogenes, and vancomycin-intermediate-susceptible Staphylococcus aureus (VISA). In single-dose efficacy studies, the 1-log(10) CFU kill effective dose (ED(1-log kill)) estimates for TD-1792 ranged from 0.049 to 2.55 mg/kg of body weight administered SC, and the bacterial burden was reduced by up to 3 log(10) CFU/g from pretreatment values. Against S. aureus ATCC 33591 (MRSA), the total 24-h log(10) stasis dose (ED(stasis)) and ED(1-logkill) doses for TD-1792 were 0.53 and 1.11 mg/kg/24 h, respectively, compared to 23.4 and 54.6 mg/kg/24 h for vancomycin, indicating that TD-1762 is 44- to 49-fold more potent than vancomycin. PK-PD analysis of data from single-dose and dose-fractionation studies for MRSA (ATCC 33591) demonstrated that the total-drug 24-h area under the concentration-time curve-to-MIC ratio (AUC/MIC ratio) was the best predictor of efficacy (r(2) = 0.826) compared to total-drug maximum plasma concentration of drug-to-MIC ratio (Cmax/MIC ratio; r(2) = 0.715) and percent time that the total-drug plasma drug concentration remains above the MIC (%Time>MIC; r(2) = 0.749). The magnitudes of the total-drug AUC/MIC ratios associated with net bacterial stasis, a 1-log(10) CFU reduction from baseline and near maximal effect, were 21.1, 37.2, and 51.8, respectively. PK-PD targets based on such data represent useful inputs for analyses to support dose selection decisions for clinical studies of patients.
authors.affiliation: Theravance, Inc, South San Francisco, California, USA. shegde@theravance.com
authors.forename: Sharath S
authors.initials: SS
authors.lastname: Hegde
authors.forename: Olanrewaju O
authors.initials: OO
authors.lastname: Okusanya
authors.forename: Robert
authors.initials: R
authors.lastname: Skinner
authors.forename: Jeng-Pyng
authors.initials: JP
authors.lastname: Shaw
authors.forename: Glenmar
authors.initials: G
authors.lastname: Obedencio
authors.forename: Paul G
authors.initials: PG
authors.lastname: Ambrose
authors.forename: Johanne
authors.initials: J
authors.lastname: Blais
authors.forename: Sujata M
authors.initials: SM
authors.lastname: Bhavnani
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000097:blood / Q000737:chemistry / Q000494:pharmacology*; D019540:Area Under Curve; D002511:Cephalosporins / Q000097:blood / Q000737:chemistry / Q000494:pharmacology*; D015169:Colony Count, Microbial; D019281:Dimerization; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D006020:Glycopeptides / Q000097:blood / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D007279:Injections, Subcutaneous; D051379:Mice; D008826:Microbial Sensitivity Tests; D009503:Neutropenia / Q000188:drug therapy* / Q000382:microbiology; D013203:Staphylococcal Infections / Q000188:drug therapy* / Q000382:microbiology; D013211:Staphylococcus aureus / Q000187:drug effects / Q000254:growth & development; D013212:Staphylococcus epidermidis / Q000187:drug effects / Q000254:growth & development; D013290:Streptococcal Infections / Q000188:drug therapy* / Q000382:microbiology; D013296:Streptococcus pneumoniae / Q000187:drug effects / Q000254:growth & development; D013297:Streptococcus pyogenes / Q000187:drug effects / Q000254:growth & development; D013848:Thigh / Q000382:microbiology; D014640:Vancomycin / Q000097:blood / Q000494:pharmacology*
chemical_list: D000900:Anti-Bacterial Agents; D002511:Cephalosporins; D006020:Glycopeptides; D014640:Vancomycin; C539430:cefilavancin