title: In Vivo Pharmacodynamic Target Investigation of Two Bacterial Topoisomerase Inhibitors, ACT-387042 and ACT-292706, in the Neutropenic Murine Thigh Model against Streptococcus pneumoniae and Staphylococcus aureus.
abstract: ACT-387042 and ACT-292706 are two novel bacterial topoisomerase inhibitors with broad-spectrum activity against Gram-positive and -negative bacteria, including methicillin-resistant Staphylococcus aureus and penicillin- and fluoroquinolone-resistant Streptococcus pneumoniae We used the neutropenic murine thigh infection model to characterize the pharmacokinetics (PK)/pharmacodynamics (PD) of these investigational compounds against a group of 10 S. aureus and S. pneumoniae isolates with phenotypic resistance to beta-lactams and fluoroquinolones. The in vitro activities of the two compounds were very similar (MIC range, 0.03 to 0.125 mg/liter). Plasma pharmacokinetics were determined for each compound by using four escalating doses administered by the subcutaneous route. In treatment studies, mice had 10(7.4) to 10(8) CFU/thigh at the start of therapy with ACT-387042 and 10(6.7) to 10(8.3) CFU/thigh at the start of therapy with ACT-292706. A dose-response relationship was observed with all isolates over the dose range. Maximal kill approached 3 to 4 log10 CFU/thigh compared to the burden at the start of therapy for the highest doses examined. There was a strong relationship between the PK/PD index AUC/MIC ratio (area under the concentration-time curve over 24 h in the steady state divided by the MIC) and therapeutic efficacy in the model (R(2), 0.63 to 0.82). The 24-h free-drug AUC/MIC ratios associated with net stasis for ACT-387042 against S. aureus and S. pneumoniae were 43 and 10, respectively. The 24-h free-drug AUC/MIC ratios associated with net stasis for ACT-292706 against S. aureus and S. pneumoniae were 69 and 25, respectively. The stasis PD targets were significantly lower for S. pneumoniae (P < 0.05) for both compounds. The 1-log-kill AUC/MIC ratio targets were ∼2- to 4-fold higher than stasis targets. Methicillin, penicillin, or ciprofloxacin resistance did not alter the magnitude of the AUC/MIC ratio required for efficacy. These results should be helpful in the design of clinical trials for topoisomerase inhibitors.
authors.affiliation: University of Wisconsin, Madison, Wisconsin, USA.
authors.forename: A J
authors.initials: AJ
authors.lastname: Lepak
authors.affiliation: Actelion Pharmaceuticals Ltd., Allschwil, Switzerland.
authors.forename: P
authors.initials: P
authors.lastname: Seiler
authors.affiliation: Actelion Pharmaceuticals Ltd., Allschwil, Switzerland.
authors.forename: J P
authors.initials: JP
authors.lastname: Surivet
authors.affiliation: Actelion Pharmaceuticals Ltd., Allschwil, Switzerland.
authors.forename: D
authors.initials: D
authors.lastname: Ritz
authors.affiliation: Actelion Pharmaceuticals Ltd., Allschwil, Switzerland.
authors.forename: C
authors.initials: C
authors.lastname: Kohl
authors.affiliation: University of Wisconsin, Madison, Wisconsin, USA dra@medicine.wisc.edu.
authors.forename: D R
authors.initials: DR
authors.lastname: Andes
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D019540:Area Under Curve; D004334:Drug Administration Schedule; D054796:Drug Dosage Calculations; D024901:Drug Resistance, Multiple, Bacterial / Q000187:drug effects; D005260:Female; D007279:Injections, Subcutaneous; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects / Q000254:growth & development; D051379:Mice; D008813:Mice, Inbred ICR; D008826:Microbial Sensitivity Tests; D009287:Naphthyridines / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D009503:Neutropenia / Q000097:blood / Q000188:drug therapy* / Q000382:microbiology / Q000473:pathology; D011008:Pneumococcal Infections / Q000097:blood / Q000188:drug therapy* / Q000382:microbiology / Q000473:pathology; D011714:Pyrans / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D011724:Pyridazines / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D018461:Soft Tissue Infections / Q000097:blood / Q000188:drug therapy* / Q000382:microbiology / Q000473:pathology; D013203:Staphylococcal Infections / Q000097:blood / Q000188:drug therapy* / Q000382:microbiology / Q000473:pathology; D013296:Streptococcus pneumoniae / Q000187:drug effects / Q000254:growth & development; D013848:Thigh / Q000382:microbiology / Q000473:pathology; D059003:Topoisomerase Inhibitors / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology
chemical_list: C000622948:ACT-292706; C000622947:ACT-387042; D000900:Anti-Bacterial Agents; D009287:Naphthyridines; D011714:Pyrans; D011724:Pyridazines; D059003:Topoisomerase Inhibitors