A placebo-controlled, double-blind, dose-escalation study to assess the safety, tolerability and pharmacokinetics/pharmacodynamics of single and multiple intravenous infusions of AZD9773 in patients with severe sepsis and septic shock

Table 4 Single- and multiple-dose PK of AZD9773 total Fabs

	AZD9773 cohort 1 (50 U/kg) (n= 7)	AZD9773 cohort 2 (250 U/kg) (n= 8)	AZD9773 cohort 3 (250/50 U/kg) (n= 6)^§	AZD9773 cohort 4 (500/100 U/kg) (n= 7)^§	AZD9773 cohort 5 (750/250 U/kg) (n= 4)^§
AUC_0-12, μg.h/mL*^‡	125.2 ± 79.8	581.0 ± 94.04	449.2 ± 46.8	691.5 ± 22.7	1872 ± 28.4
AUC_0-12, μg.h/mL*	-	-	162.8 ± 82.2	251.6 ± 56.0	981.0 ± 39.3
C_inf, μg/mL*^‡	29.6 ± 112.5	156.2 ± 208.1	-	-	-
C_inf, μg/mL*	-	-	28.4 ± 52.9	42.5 ± 83.5	151.8 ± 14.7
Accumulation ratio*	-	-	1.9 ± 32.0	1.6 ± 79.1	1.6 ± 38.1
t_max, hours**	1.5 (1.4 to 3.5)	2.1 (1.0 to 4.3)	0.5 (0 to 0.7)	1.0 (0.4 to 8.5)	0.7 (0.5 to 1.6)
t_1/2, hours^†	18.0 ± 7.3	19.8 ± 5.2	-	-	-
CL, mL/min/kg^†	6.1 ± 3.4	7.6 ± 6.0	-	-	-
V_ss, mL/kg^†	92.6 ± 30.8	152.8 ± 132.8	-	-	-
Dose excreted, %*	10.6 ± 69.3	15.0 ± 100.4	15.2 ± 57.1	11.8 ± 94.0	20.9 ± 223.1

Data presented as: *Geometric mean ± coefficient of variation; **Median (range); ^†Mean ± SD; ^‡Values for single doses (cohorts 1 and 2) or loading doses (cohorts 3 to 5); ^§Values based on maintenance doses unless stated otherwise. Note: The multiple dosing profile was not followed for sufficient time to enable the calculation of t_1/2, CL and V_ss for cohorts 3 to 5. AUC_0-12, area under the serum concentration-time curve from 0 to 12 hours; C_inf, maximum (end of infusion) serum concentration; CL, total apparent drug clearance; t_1/2, terminal half-life; t_max, time to reach C_inf; V_ss, apparent volume of distribution at steady state

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