TABLE 1.

PopPK^a parameter estimates for the final model

Parameterb	Values forc:
	Final modeld		Bootstrape
	Fixed effect (%RSEf)	IIV, %CV (%RSEf)	Fixed effect (95% CI)	IIV %CV (95% CI)
Infusion time, fixed (h)	0.810 FIXED	8.26 FIXED	0.810 FIXED	8.26 FIXED
F1	0.857 (0.965)		0.85 (0.834, 0.86)
Zero-order duration (h)	0.175 (28.3)	258 (7.39)	0.475 (0.441, 0.586)	210 (179, 221)
Ka (h–1)	1.47 (9.25)	77.0 (8.36)	0.964 (0.923, 1.03)	74.1 (70.1, 78.4)
Lag time (h)	0.226 (0.0376)	100 (5.47)	0.178 (0.135, 0.227)	119 (101, 129)
CL (liter/h)	5.39 (6.98)	32.2 (2.87)	5.48 (5.34, 5.6)	32.2 (30.4, 34.2)
wt (power model)g	0.408 (10.2)		0.451 (0.411, 0.492)
Infection (%) (linear model)	22.0 (39.3)		21.4 (18.7, 24.1)
Vc (liter)	58.5 (3.36)	25.2 (4.67)	59.1 (57.9, 60.4)	25.3 (22.6, 28.5)
wt (power model)g	0.903 (3.53)		0.937 (0.886, 0.975)
Infection (%) (linear model)	9.87 (37.4)		10.7 (8.81, 13.9)
Diabetes (%) (linear model)	−14.3 (22.2)		−14.0 (–18.6, −9.49)
Q (L/h)	1.43 (4.09)		1.44 (1.36, 1.52)
wt (power model)g	Same as for CL		Same as for CL
Vp (L)	15.6 (2.41)	15.8 (8.54)	15.8 (15.3, 16.4)	16.2 (13.7, 18.5)
wt (power model)g	0.678 (6.87)		0.677 (0.609, 0.731)
Correlation CL-Vc (%)		62.1 (5.28)		61.9 (52.1, 68.5)
RV
RV for non-phase 3 trials (%)	12.3 (1.36)		12.4 (11.8, 12.9)
RV for study 104 and phase 3 trials (fold)h	4.92 (4.63)		4.57 (4.13, 5.34)
RV for oral data (fold)h	2.01 (5.22)		2.23 (1.87, 2.66)

^apopPK, population pharmacokinetics.

^b

Equations for the main model parameters:

$$C{L}_i=T{V}_{\mathit{CL}}\cdot {\left(\frac{\mathit{WT}}{77.3}\right)}^{{\theta }_{\mathit{WT}-\mathit{CL}}}\cdot \left(1\hspace{0.17em}+\hspace{0.17em}{\theta }_{\mathit{Infec}-\mathit{CL}}\cdot \mathit{INFEC}\right)\cdot e^{{\eta }_{C{L}_i}}$$

$$V{c}_i=T{V}_{\mathit{Vc}}\cdot {\left(\frac{\mathit{WT}}{77.3}\right)}^{{\theta }_{\mathit{WT}-\mathit{Vc}}}\cdot \left(1\hspace{0.17em}+\hspace{0.17em}{\theta }_{\mathit{Infec}-\mathit{Vc}}\cdot \mathit{INFEC}\right)\cdot \left(1\hspace{0.17em}+\hspace{0.17em}{\theta }_{\mathit{Diab}-\mathit{Vc}}\cdot \mathit{DIAB}\right)\cdot e^{{\eta }_{V{c}_i}}$$

$$V{p}_i=T{V}_{\mathit{Vp}}\cdot {\left(\frac{\mathit{WT}}{77.3}\right)}^{{\theta }_{\mathit{WT}-\mathit{Vp}}}\cdot e^{{\eta }_{V{p}_i}}$$

where CL_i, V_ci, V_pi, TV_CL, TV_Vc, TV_Vp, and TV_Q represent the individual and typical parameter values, respectively, for CL, V_c, and V_p. θ_WT–xx represents the effect of body weight (WT) on the different parameters. θ_Infec–xx represents the relative effect of bacterial infection. θ_Diab–xx represents the relative effect of diabetes. Infection (INFEC) and diabetes (DIAB) are flag variables taking the value of 1 in case of infection or diabetes and 0 if otherwise. η_xxi represents the IIV. CL, clearance; F1, relative bioavailability; K_a, absorption rate constant; RV, residual variability; SAEM, stochastic approximation of expectation-maximization; SE, standard error; TV, typical volume; V_c, volume of distribution in the central compartment; V_p, volume of distribution in the peripheral compartment.

^cCV, coefficient of variation; IIV, interindividual variability; RSE, relative standard error.

^dModel parameters were estimated using SAEM from 9,756 PK observations in 1,312 individuals.

^eMean and 95% confidence intervals were generated using only the successful runs (n = 432) from a nonparametric bootstrap (n = 1,000).

^fRSE obtained from the NONMEM R matrix computed on an importance sampling step. The relative SEs for omega and sigma are reported on the approximate standard deviation scale (SE/variance estimate)/2.

^gVolumes and CL are reported for a typical individual of 77.3 kg.

^hFold increase on the square root scale.