Population Pharmacokinetics of Levofloxacin and Moxifloxacin, and the Probability of Target Attainment in Ethiopian Patients with Multidrug-Resistant Tuberculosis

Figures & data

Table 1 Demographic and Clinical Characteristics of Ethiopian MDR-TB Patients Recieving the Standardized LFX- (n=21) and MXF- (n=18) Based Regimen

Characteristics	Total N=39	LFX-Regimen (n= 21)	MXF-Regimen (n=18)
Age	26 (20–32)	26 (20–30)	26 (20–37)
Male	20 (51.3)	12 (57.1)	8 (44.4)
Weight (Kg)	49 (43.0–52.4)	45 (42.5–52.3)	51 (46.6–65.0)
Height (cm)	165.5 (160–172)	168 (160–174)	165 (161.5–171.5)
BMI (kg/m^2)	17.1 (15.6–18.9)	16.7 (15.6–18)	17.3 (16.2–19.2)
Co-existing illness	13 (33.3)	8 (38.1)	5 (27.8)
Prior TB treatment	30 (77)	15 (71.4)	15 (83.3)
Smoking	5 (12.8)	3 (14)	2 (11.1)
Malnourished*	19 (48.7)	9 (42.9)	10 (55.6)
Cavitary disease	18 (46.2)	9 (42.9)	9 (50)
Cr. (mg/dL)	0.9 (0.8–1.3)	1 (0.8–1.3)	1 (0.8–1.4)
AST (IU/L)	29 (20–38)	25 (18.0–34.6)	31 (21.0–40)
ALT (IU/L)	23 (15–45)	19.2 (14.0–35)	28 (17.8–50.2)
Hgb (g/dl)	13.8 (12.3–15.1)	12.8 (12.1–14.3)	13.4 (12.2–14.3)

Notes: Data presented as n (%) or median (IQR); *Patients with BMI less than 16 kg/m² were considered as malnourished.

Abbreviations: AST, alanine aminotransferase; ALT, alanine transaminase; ALB, albumin; BMI, body mass index; cm, centimeter; g/dl, grams per deciliter; Hgb, hemoglobin; IU/L, international units (IU) per liter.

Table 2 Overall and Final One-Compartment Model for LFX (n=21) and MXF (n=18), and Covariates Included in the Model in Ethiopian MDR-TB Patients

Drug	PK Parameter	Final Model
		GM (%RSE)	%CV (Shrinkage, %)
LFX	Ka (1/h)	0.2 (4.0)	14 (60)
	V (Liter)	122 (21.5)	26 (30)
	Cl (L/h)	10.4 (7.7)	66 (60)
	Tlag (h)	0.2 (6.1)	3.4 (60)
	Cr (mg/dL)	1.1 (10)	14.7 (NA)
	−2LL	449.2
	AIC	473.2
	BIC	507.2	(9)
MXF	Ka (1/h)	0.5 (18.8)	59 (50)
	V (Liter)	102.2 (10.0)	10 (40)
	Cl (Liters/h)	20 (3.5)	2.7 (70)
	BMI (Kg.m2)	17.8 (1.1)	4.5 (NA)
	−2LL	184.2
	AIC	202.2
	BIC	225.7	(3)

Note: Lag time (Tlag) is the time taken for the drugs to appear in circulation following the drug dosing.

Abbreviations: AIC, Akaike’s information criterion; BIC, Bayesian information criterion; Cl, clearance; Percent coefficient of variation (% CV= 100 x IIV/parameter estimate); Ka, absorption constant; GM, geometric mean; IIV, interindividual variability; −2LL, minus two log likelihood; LFX, levofloxacin; MXF, moxifloxacin; NA, not applicable; PK, pharmacokinetics; %RSE, percentage of relative standard error (%RSE = 100 x standard error/parameter estimate); Cr, serum creatinine; Tlag, lag time for absorption; V, apparent volume of distribution.

Figure 1 Goodness-of-fit plots for the final population pharmacokinetics of LFX (A) and MXF (B): conditional weighted residuals versus time (CWRES versus IVAR) (a); conditional weighted residuals versus population predicted concentrations (CWRES versus PRED) (b); observed versus individual predicted concentrations (DV versus IPRED) (c); observed versus population predicted concentrations (DV versus PRED) (d). The red lines in the panels represent smoothed regression lines.

Figure 2 Visual predictive checks (a) and WRES versus Standard Normal Quantiles (b) for the final model of LFX (A) and MXF (B): red lines represent the 5th, 50th, and 95th percentiles of the observed concentrations; the shaded areas represent the 90% confidence intervals of the 5th, 50th, and 95th percentiles of the simulated concentrations, respectively; the dots represent the observed data; DV represents observed concentration; DV0, observed concentration at zero time; IVAR, time; WRES, weighted residuals.

Table 3 Descriptive Summary of the Non-Compartmental Analysis of the Estimated Individual PK Parameters for the Original and Simulated Doses of LFX (n=21) and MXF (n=18) in Ethiopian MDR-TB Patients

Drug	Dose (mg)	Cmax±SE (mg/L)	Cmax (IQR) (mg/L)	AUC0-24±SE (h. mg/L)	AUC0-24 (IQR) (h. mg/L)
LFX*	750	7.8 ±0.6	7.5 (5.5–9.7)	63.8 ±6.4	60.9 (40.0–81.8)
	1000	10.3 ±0.8	10.0 (7.3–12.8)	85.3 ±8.6	81.5 (51.9–109.2)
	1500	15.4 ±1.2	15.1 (10.8–19.2)	128 ±13.0	122.7 (77.8–164.1)
LFX^†	750	5.8 ±0.5	5.3 (4.6–6.7)	66.5 ±9.5	58.1 (45.0–80.5)
	1000	8.2 ±0.7	7.4 (6.1–9.4)	97.9 ±9.3	103.4 (71.5–108.6)
MXF*	600	2.7 ± 0.4	2.6 (1.5–3.9)	31.5 ± 4.1	25.1 (19.0–47.0)
	800	3.5 ± 0.4	3.5 (2.0–5.0)	40.6 ± 4.8	33.4 (25.2–62.7)
	1000	4.40 ± 0.6	4.4 (2.5–6.3)	50.8 ± 6.0	41.8 (31.6–78.4)
MXF^†	600	2.9 ± 0.4	3.2 (1.4–3.9)	33.4 ± 4.2	28.2 (19.3–50.8)

Notes: *Simulated doses and ^†Observed doses.

Abbreviations: AUC0-24, area under the concentration-time curve over twenty-four hours; C_max, maximum serum concentration; IQR, interquartile range; mg/L, milligram per liter; SE, standard error.

Figure 3 Box plot for simulated C_max (a) and AUC0-24 (b) of LFX (A) and MXF (B): the dashed line indicates the minimum threshold for C_max and AUC0-24.

Figure 4 Percent probability of target attainment, PTA (%) for the maximal mycobacterial kill (AUC0-24/MIC ≥146) (A) and resistance suppression (AUC0-24/MIC ≥360) (B) of the simulated doses of LFX (750 mg, 1000 mg, and 1500 mg) against the assumed MIC values in Ethiopian MDR-TB patients (n=21).

Note: The formula used for the calculation of the percent probability of target attainment (PTA) was: .

Figure 5 Percent probability of target attainment, PTA (%) for the maximal mycobacterial kill (AUC0-24/MIC≥53) (A) and resistance suppression (AUC0-24/MIC ≥100) (B) of the simulated doses of MXF (600 mg, 800 mg, 1000 mg) against the assumed MIC values in Ethiopian MDR-TB patients (n=18).

Note: The formula used for the calculation of the percent probability of target attainment (%PTA) was: .