Pharmacokinetic profile of defibrotide in patients with renal impairment

Figures & data

Figure 1 Study design.

Notes: Part 1: Intermittent hemodialysis subjects. Part 2: Severe or end–stage renal disease (not dialysis-dependent) and matching healthy subjects. ^aDoses administered via 2-h intravenous infusion every 6 h over a 24-h period starting on the afternoon of day 1 (dose 1) and ending on the afternoon of day 2 (dose 4).
Abbreviation: h, hour.

Table 1 Demographic and baseline characteristics

Characteristics	Part 1	Part 2
	Hemodialysis	Renal-impaired and healthy matching subjects
	ESRD, DD (N=6)	Severe renal disease/ESRD, not DD (cohort 1) (n=6)	Healthy matching subjectsa (cohort 2) (n=6)	Part 2 total (N=12)
Age, years
Mean (SD)	49.8 (8.1)	65.7 (7.2)	65.0 (6.6)	65.3 (6.6)
Median (min, max)	50.0 (38, 63)	66.5 (54, 76)	67.0 (52, 71)	67.0 (52, 76)
Sex, n (%)
Male	3 (50.0)	5 (83.3)	5 (83.3)	10 (83.3)
Female	3 (50.0)	1 (16.7)	1 (16.7)	2 (16.7)
Race, n (%)
Black or	5 (83.3)	1 (16.7)	1 (16.7)	2 (16.7)
African–American
White	1 (16.7)	5 (83.3)	5 (83.3)	10 (83.3)
Ethnicity, n (%)
Hispanic or Latino	1 (16.7)	3 (50.0)	3 (50.0)	6 (50.0)
Not Hispanic or Latino	5 (83.3)	3 (50.0)	3 (50.0)	6 (50.0)
Body mass index, kg/m^2
Mean (SD)	31.0 (6.8)	32.7 (5.4)	30.5 (4.9)	31.6 (5.1)
CV%	21.8	16.5	15.9	15.9
Median (min, max)	29.6 (22.9, 39.1)	32.2 (26.7, 40.0)	30.3 (24.6, 38.7)	31.3 (24.6, 40.0)

Notes:

a Healthy subjects were matched to renal-impaired subjects for age (±10 years), body mass index (±20%), sex, and race.

Abbreviations: CV%, percent coefficient of variation; DD, dialysis-dependent; ESRD, end-stage renal disease; max, maximum; min, minimum; SD, standard deviation.

Table 2 Part 1: plasma defibrotide PK parameters in dialysis-dependent subjects with ESRD

PK parameter, mean (CV%)	Nondialysis day (day 1) (N=6)	Dialysis daya (day 4) (N=6)
AUC0–t, µg·h/mL	102 (40.0)	111 (39.9)
AUC0–∞, µg·h/mL	103 (40.3)	114 (40.6)
Cmax, µg/mL	45.1 (35.1)	50.1 (38.1)
tmax,b h	1.90 (1.50, 1.95)	1.78 (1.75, 1.95)
t1/2, h	0.712 (21.9)	0.967 (17.6)
CL, L/h	5.87 (24.9)	5.38 (26.1)
Vss, L	6.34 (33.2)	6.90 (28.4)

Notes:

a The 4-h hemodialysis session was begun 1 h after initiation of the 2-h defibrotide intravenous infusion.

b Median (minimum, maximum).

Abbreviations: AUC_0–t, area under the plasma concentration–time curve from start of infusion (time 0 h) to the time of the last quantifiable plasma concentration following dose administration; AUC_0–∞, AUC from time 0 h extrapolated to infinity; CL, systemic plasma clearance; C_max, maximum observed plasma concentration; CV%, percent coefficient of variation; ESRD, end-stage renal disease; h, hour; PK, pharmacokinetic; t_1/2, apparent terminal phase half-life; t_max, time of C_max; V_ss, volume of distribution at steady state.

Figure 2 Plasma concentrations (±SD) following a single dose of defibrotide: nondialysis day versus dialysis day. The 4-h hemodialysis session was begun 1 h after initiation of the defibrotide 2-h intravenous infusion.

Abbreviations: h, hour; SD, standard deviation.

Table 3 Plasma defibrotide PK parameters in DD subjects (N=6, Part 1) and following single and multiple doses in renal-impaired (n=6) and healthy matching subjects (n=6, Part 2)

PK parametera	Geometric LS meanb		%ratios of LS meansc,d (90% CI)	Intrasubject CV%
Part 1	Nondialysis day	Dialysis daye
Cmax	43.0	47.2	109.71 (97.23, 123.78)	10.4
AUC0–t	95.8	103.8	108.39 (97.85, 120.07)	8.8
AUC0–∞	96.8	106.4	109.98 (99.39, 121.70)	8.7
Part 2	Renal-impaired, not DD	Healthy matching subjects
Dose 1
Cmax	53.6	39.6	135.37 (105.06, 174.42)	24.6
AUC0–t	113.4	74.5	152.18 (117.60, 196.94)	25.0
AUC0–∞	114.6	74.9	153.01 (117.70, 198.91)	25.5
Dose 4
Cmax	52.6	38.0	138.34 (106.05, 180.46)	25.8
AUC0–t	108.9	68.3	159.55 (118.15, 215.47)	29.3
AUCτ	109.0	68.4	159.36 (118.11, 215.05)	29.2

Notes:

a Defibrotide given as 6.25 mg/kg 2-h intravenous infusion.

b Geometric LS mean from the analysis of variance presented following back transformation to the original scale. The 90% CIs are presented following back transformation to the original scale.

c Part 1: ratio of dialysis day to nondialysis day.

d Part 2: ratio of severe and end-stage renal disease subjects to healthy matching subjects.

e The 4-h hemodialysis session was begun 1 h after initiation of the defibrotide 2-h intravenous infusion.

Abbreviations: AUC_0–t, area under the plasma concentration–time curve from start of infusion (time 0 h) to the time of the last quantifiable plasma concentration; AUC_0–∞, AUC from time 0 h extrapolated to infinity; AUC_τ, AUC during the dosing interval (6 h); CI, confidence interval; C_max, maximum observed plasma concentration; CV%, percent coefficient of variation; DD, dialysis-dependent; h, hour; LS, least-squares; PK, pharmacokinetic.

Figure 3 Plasma defibrotide concentrations (±SD) following the first and fourth (last) doses of defibrotide: semilog and linear scales.

Abbreviations: ESRD, end-stage renal disease; h, hour; SD, standard deviation.

Table 4 Part 2 of the study: plasma defibrotide PK parameters following single and multiple doses in renal-impaired and healthy matching subjects

PK parameter, mean (CV%)	Dose 1		Dose 4
	Severe renal disease/ESRD, not DD (n=6)	Healthy matching subjects (n=6)	Severe renal disease/ESRD, not DD (n=6)	Healthy matching subjects (n=6)
AUC0–t, µg·h/mL	117 (25.4)	76.2 (25.0)	113 (28.2)	70.8 (32.7)
AUCτ, µg·h/mL	NA	NA	113 (28.2)	70.9 (32.6)
AUC0–∞, µg·h/mL	118 (26.1)	76.6 (25.1)	NA	NA
Cmax, µg/mL	54.9 (23.6)	40.7 (27.7)	53.8 (22.4)	39.3 (28.6)
tmax,a h	2.08 (1.50, 2.25)	2.03 (1.50, 2.08)	2.03 (1.98, 2.08)	1.94 (1.50, 2.03)
t1/2, h	0.725 (25.5)	0.562 (39.8)	0.498 (40.4)	0.217 (16.3)b
CL, L/h	5.40 (28.3)	7.44 (11.9)	5.73 (30.0)	8.20 (16.8)
Vss, L	5.20 (24.1)	4.49 (7.7)	5.29 (30.1)	4.30 (11.5)b

Notes:

a Median (minimum, maximum).

b n=5.

Abbreviations: AUC_0–t, area under the plasma concentration–time curve from start of infusion (time 0 h) to the time of the last quantifiable plasma concentration following dose administration; AUC_0–∞, AUC from time 0 h extrapolated to infinity; AUC_τ, AUC during the dosing interval (6 h); CL, systemic plasma clearance; C_max, maximum observed plasma concentration; CV%, percent coefficient of variation; DD, dialysis-dependent; ESRD, end-stage renal disease; h, hour; NA, not applicable; PK, pharmacokinetic; t_1/2, apparent terminal phase half-life; t_max, time of C_max; V_ss, volume of distribution at steady state.

Table 5 Urinary defibrotide PK parameters following single and multiple doses in renal-impaired and healthy matching subjects

PK parameter, mean (CV%)	Dose 1		Dose 4
	Severe renal disease/ESRD, not DD (n=6)	Healthy matching subjects (n=6)	Severe renal disease/ESRD, not DD (n=6)	Healthy matching subjects (n=6)
Ae(0–6), mg	30.9 (49.6)	79.9 (31.9)	28.4 (52.3)	69.4 (76.2)
fe(0–6), %	5.22 (50.8)	14.02 (20.0)	4.78 (53.5)	11.81 (64.1)
CLR, L/h	0.290 (74.2)	1.04 (21.6)	0.268 (69.4)	0.891 (48.0)

Abbreviations: Ae(0–6), amount of defibrotide excreted unchanged in urine over a 6-h collection interval; CL_R, renal clearance; CV%, percent coefficient of variation; DD, dialysis-dependent; ESRD, end-stage renal disease; fe(0–6), fraction of defibrotide excreted unchanged in urine over a 6-h collection interval; h, hour; PK, pharmacokinetic.