Aspiro Therapeutics

DAPTOMYCIN

daptomycin

Post-LOE

INTRAVENOUS · POWDER

12.1 Mechanism of Action Daptomycin is an antibacterial drug [see ] . 12.2 Pharmacodynamics Based on animal models of infection, the antimicrobial activity of daptomycin appears to correlate with the AUC/MIC (area under the concentration-time curve/minimum inhibitory concentration) ratio for certain pathogens, including S. aureus . The principal pharmacokinetic/pharmacodynamic parameter best associated with clinical and microbiological cure has not been elucidated in clinical trials with Daptomycin for injection. 12.3 Pharmacokinetics Daptomycin for Injection Administered over a 30-Minute Period in Adults The mean and standard deviation (SD) pharmacokinetic parameters of daptomycin at steady-state following intravenous (IV) administration of Daptomycin for injection over a 30-minute period at 4 to 12 mg/kg every 24h to healthy young adults are summarized in Table 11. Table 11: Mean (SD) Daptomycin Pharmacokinetic Parameters in Healthy Adult Volunteers at Steady-State Dose Daptomycin for injection was administered by IV infusion over a 30-minute period. Doses of Daptomycin for injection in excess of 6 mg/kg have not been approved. (mg/kg) Pharmacokinetic Parameters AUC 0-24 , area under the concentration-time curve from 0 to 24 hours; t 1/2 , elimination half-life; V ss , volume of distribution at steady-state; CL T , total plasma clearance; C max , maximum plasma concentration. AUC 0-24 (mcg∙h/mL) t 1/2 (h) V ss (L/kg) CL T (mL/h/kg) C max (mcg/mL) 4 (N=6) 494 (75) 8.1 (1.0) 0.096 (0.009) 8.3 (1.3) 57.8 (3.0) 6 (N=6) 632 (78) 7.9 (1.0) 0.101 (0.007) 9.1 (1.5) 93.9 (6.0) 8 (N=6) 858 (213) 8.3 (2.2) 0.101 (0.013) 9.0 (3.0) 123.3 (16.0) 10 (N=9) 1039 (178) 7.9 (0.6) 0.098 (0.017) 8.8 (2.2) 141.1 (24.0) 12 (N=9) 1277 (253) 7.7 (1.1) 0.097 (0.018) 9.0 (2.8) 183.7 (25.0) Daptomycin pharmacokinetics were generally linear and time-independent at Daptomycin for injection doses of 4 to 12 mg/kg every 24h administered by IV infusion over a 30-minute period for up to 14 days. Steady-state trough concentrations were achieved by the third daily dose. The mean (SD) steady-state trough concentrations attained following the administration of 4, 6, 8, 10, and 12 mg/kg every 24h were 5.9 (1.6), 6.7 (1.6), 10.3 (5.5), 12.9 (2.9), and 13.7 (5.2) mcg/mL, respectively. Daptomycin for injection Administered over a 2-Minute Period in Adults Following IV administration of Daptomycin for injection over a 2-minute period to healthy adult volunteers at doses of 4 mg/kg (N=8) and 6 mg/kg (N=12), the mean (SD) steady-state systemic exposure (AUC) values were 475 (71) and 701 (82) mcg∙h/mL, respectively. Values for maximum plasma concentration (C max ) at the end of the 2-minute period could not be determined adequately in this study. However, using pharmacokinetic parameters from 14 healthy adult volunteers who received a single dose of Daptomycin for injection 6 mg/kg IV administered over a 30-minute period in a separate study, steady-state C max values were simulated for Dap

2016

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