Mouse Models for Antibacterial PK/PD PDF
Preview Mouse Models for Antibacterial PK/PD
Mouse Models for Antibacterial PK/PD David Andes University of Wisconsin Disclosures • Research grants and/or consulting: Astellas, Merck, GSK, Scynexis, Cubist, Forrest, Rempex, Dipexium, Nexcida, Durata, Actelion, Zavante, Paratek, Meiji, Geom, Cidara, Melinta, Theravance, Iterum, Sentinella, Kalidex, Novozymes, Trius, Taxis • Member ABIM Outline • What PK/PD questions can the models address? • What study variables impact PK/PD answers? • Can the model PK/PD results predict clinical efficacy? Why do we conduct PK-PD infection models? Improving the Probability of Positive Outcome Bug Host Drug What do we do? Tie Drug Potency to Antimicrobial Exposure = Pharmacodynamics n o i t a r t n e AUC:MIC Ratio c Peak:MIC n o C g u r D m MIC MIC Time Above MIC u r e S Time MIC = minimum inhibitory concentration; AUC = area under the curve; T = time In vivo PK/PD Work Horse(s) • Murine thigh and lung models – Mimics soft tissue/sepsis and pneumonia, respectively – Neutropenic – Organism burden primary endpoint – Supports growth of most bacteria – Multiple drug administration routes – Large group of comparator antibacterial agents – Outcomes correlated with treatment success in patients – Useful for trial dosing regimen selection and susceptibility breakpoint development Study Design Antibiotic -2 hr Tnereaphy Therapy 24 hr Infect 4 h g hi 3 T U/ s 2 F r u C o 1 0 H 1 g 4 0 o 2 n L er -1 ge i ov -2 qq 61h2 h n q 24 h a -3 h C -4 0.1 1 10 100 1000 10000 Dose (mg/kg/24 h) Bacterial Burden Assessment Pharmacodynamic Analysis How do we determine how much and how often to administer an antibiotic?
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