Table 2.

Parameter estimates based on the final model

Parameter	Description	Typical estimate	RSE%a	95% CIb
Drug PK parametersc
CL/F (L · h−1)	Oral clearance at the preinduced state in a patient weighing 70 kg	10.0 FIX	‐	‐
V/F (L)	Apparent volume of distribution in a patient weighing 70 kg	86.7 FIX	‐	‐
MTT (h)	Mean transit time	0.713 FIX	‐	‐
NN	Number of transit compartments	1.00 FIX	‐	‐
Emax	Maximal increase in the enzyme production rate	1.04 FIX	‐	‐
EC50 (mg · L−1)	Rifampicin concentration at which half the Emax is reached	0.0705 FIX	‐	‐
kENZ (h−1)	Rate constant for first‐order degradation of the enzyme pool	0.00369 FIX	‐	‐
F	Bioavailability	1.00 FIX	‐	‐
(Ffat)CL/F	Contribution of fat‐free mass and body weight to CL/F	0.311 FIX	‐	‐
(Ffat)V/F	Contribution of fat‐free mass and body weight to V/F	0.188 FIX	‐	‐
Multistate Tuberculosis Pharmacometric modeld
kG (days−1)e	Fast‐multiplying bacterial growth rate	0.206 FIX	‐	‐
kFN (days−1)	Transfer rate from fast‐ to nonmultiplying state	8.97·10−7 FIX	‐	‐
kSN (days−1)	Transfer rate from slow‐ to nonmultiplying state	0.186 FIX	‐	‐
kSF (days−1)	Transfer rate from slow‐ to fast‐multiplying state	0.0145 FIX	‐	‐
kNS (days−1)	Transfer rate from non‐ to slow‐multiplying state	0.00123 FIX	‐	‐
kFSlin (days−2)f	Time‐dependent transfer rate from fast‐ to slow‐multiplying state	0.00166 FIX	‐	‐
F0 (mL−1)	Initial bacterial number of fast‐multiplying state	4.10 FIX	‐	‐
S0 (mL−1)	Initial bacterial number of slow‐multiplying state	9770 FIX	‐	‐
Bmax (mL−1)d	System carrying capacity per mL sputum	2.61·109	30.5	1.51·109−4.52·109
IIV Bmax (%)g	Interindividual variability in Bmax	152	15.9	97.8–191
Exposure‐response parameters
FGon/off	Fractional inhibition of growth of fast‐multiplying state	1.00 FIX	‐	‐
SDk (L·mg−1·days−1)	Second‐order slow‐multiplying state death rate	0.200	41.6	0.0854–0.390
NDk (L·mg−1·days−1)	Second‐order nonmultiplying state death rate	0.106	19.0	0.0643–0.188
Residual error parameters
ε (CV%)	Additive residual error on log scale (approximates a proportional error on normal scale) for all replicates	110	12.0	83.7–133
εrepl (CV%)	Additive residual error on log scale (approximates a proportional error on normal scale) between replicates	23.1	10.2	18.4–27.2

CI, confidence interval; FIX, parameter was fixed during estimation; PK, pharmacokinetic; RSE, relative standard error.

^aRelative standard error from the covariance step in NONMEM18 reported on the approximate SD scale.

^b95% CI is the 95% percentile confidence interval from a nonparametric bootstrap (1,000 samples).

^cAll drug PK model parameters were fixed to estimates reported by Smythe et al.19

^dAll Multistate Tuberculosis Pharmacometric Model parameters except B_max were fixed to estimates reported by Clewe et al.15

$\frac{dF}{dt}=k_G·\left(\frac{B_{\mathrm{m}\mathrm{a}\mathrm{x}}}{F+S+N}\right)·F$

^e

$k_{FS}={k_{FS}}_{lin}·t$

^fIIV is the inter‐individual variability expressed as coefficient of variation (CV).