Delamanid Central Nervous System Pharmacokinetics in Tuberculous Meningitis in Rabbits and Humans

DOI: 10.1128/AAC.00913-19

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FIG 1
Plasma concentrations of DLM (A) and DM-6705 (B) in infected and uninfected rabbits after a single 5-mg/kg oral dose of DLM. Uninfected and infected rabbits represent 3 rabbits each. Mean ± standard deviation is shown.
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FIG 2
Cerebrospinal fluid (CSF) concentrations of DLM (A) and DM-6705 (B) in infected and uninfected rabbits after a single oral dose of 5 mg/kg of DLM. (C) Total DLM CSF/plasma ratio in uninfected and infected rabbits. Data are for 2 uninfected rabbits euthanized at 24 h, 2 infected rabbits euthanized at 9 h, 1 uninfected rabbit euthanized at 9 h, and 1 infected rabbit euthanized at 24 h. The median ± interquartile range (IQR) is shown.
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FIG 3
(A and B) Brain tissue concentrations for DLM (A) and DM-6705 (B) in infected and uninfected rabbits after a single oral dose of 5 mg/kg of DLM. (C and D) Brain/plasma ratios for DLM (C) and DM-6705 (D) at the time of brain tissue collection in infected and uninfected rabbits after a single oral dose of 5 mg/kg of DLM. Data are for 2 uninfected rabbits euthanized at 24 h, 2 infected rabbits euthanized at 9 h, 1 uninfected rabbit euthanized at 9 h, and 1 infected rabbit euthanized at 24 h. The median ± interquartile range (IQR) is shown.

TABLE 1

Summary of rabbit plasma PK data

Parameter^a	Value for the following compound in the indicated rabbits:
	DLM			DM-6705
	Uninfected	Infected	P	Uninfected	Infected	P
C_max (ng/ml)	195.6	255.8		3.5	5.5
Mean concn (ng/ml)
9 h	96.4	213.3		1.8	9.6
24 h	50.3	40.1		2.4	2.1
T_max (h)	12	12		12	12
t_1/2 (h)	14.1	13.9		14.3	14.1
AUC_0–24 (ng·h/ml)	2,785.6	3,811.2	0.01	49.7	84.8	0.29
AUC_0–48 (ng·h/ml)	3,461.3	4,229	0.01	69.5	97.8	0.31
AUC_0–∞ (ng·h/ml)	3,554.5	4,255.3		84.6	97.8
MRT_0–48 (h)	15.4	12.2	0.22	56.9	36.8	0.24
MRT_0–∞ (h)	16.5	12.5		66.5	36.8
k_el′ (h⁻¹)	0.07	0.08		0.05	0.07

↵a AUC_0–24, AUC_0–48, and AUC_0–∞, area under the concentration-time curve from 0 to 24 h, 0 to 48 h, and 0 h to infinity, respectively; MRT_0–48 and MRT_0–∞, mean retention time from 0 to 48 h and 0 h to infinity, respectively.

TABLE 3

Human plasma and CSF MS results for patients 1, 2, and 3 after oral dosing at 100 mg twice daily^a

↵a Concentrations were initially measured at lab 1. Samples from patient 1 were also sent to lab 2 so that DM-6705 could be measured. BLQ, below the limit of detection; NT, not tested.