Open-Label, Single-Dose, Parallel-Group Study in Healthy Volunteers To Determine the Drug-Drug Interaction Potential between KAE609 (Cipargamin) and Piperaquine

Daniel S. Stein; Jay Prakash Jain; Michael Kangas; Gilbert Lefèvre; Surendra Machineni; Paul Griffin; Jason Lickliter

doi:10.1128/AAC.00340-15

DOI: 10.1128/AAC.00340-15

Article Figures & Data

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FIG 1
Semilogarithmic plots of arithmetic mean KAE609 plasma concentrations according to time and treatment group. Inset, first 24 h after dosing.
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FIG 2
Semilogarithmic plots of median KAE609 concentrations according to time and treatment group (full profile). ○, 75 mg KAE609 plus 320 mg PPQ; #, 25 mg KAE609 plus 1,280 mg PPQ; ×, 25 mg KAE609.
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FIG 3
Semilogarithmic plots of arithmetic mean piperaquine plasma concentrations according to time and treatment group. ○, 75 mg KAE609 plus 320 mg PPQ; #, 25 mg KAE609 plus 1,280 mg PPQ; △, 320 mg PPQ; □, 1,280 mg PPQ. Inset, first 24 h after dosing.
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FIG 4
Arithmetic means (and standard deviations) of changes in QTcF from baseline according to time and treatment group. At predosing and 2, 4, 8, 12, and 24 h postdosing, triplicate ECG assessments were made. The average of the triplicate assessments was calculated, and the change from baseline is shown. Baseline was taken at 0 h on day 1. ○, 75 mg KAE609 plus 320 mg PPQ; #, 25 mg KAE609 plus 1,280 mg PPQ; △, 320 mg PPQ; □, 1,280 mg PPQ; ×, 25 mg KAE609.
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FIG 5
KAE609 concentration effects on changes in QTcF from baseline for KAE609 alone and in the presence of piperaquine. ◊, KAE609 plus PPQ; ×, 25 mg KAE609. Solid line, regression for KAE609 plus PPQ; dotted line, regression for 25 mg KAE609. R² = 0.0273 for KAE609 plus PPQ; R² = 0.0003 for 25 mg KAE609.
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FIG 6
Piperaquine concentration effects on changes in QTcF from baseline for piperaquine alone and in the presence of KAE609. ◊, KAE609 plus PPQ; shields, PPQ. Solid line, regression for KAE609 plus PPQ; dotted line, regression for PPQ. R² = 0.0709 for KAE609 plus PPQ; R² = 0.0693 for PPQ.

Tables

Figures

TABLE 1

Plasma PK parameters for KAE609 in the presence and absence of piperaquine

Parameter	Value for treatment group receiving:
Parameter	75 mg KAE609 + 320 mg PPQ (n = 25)^a	25 mg KAE609 + 1,280 mg PPQ (n = 24)	25 mg KAE609 (n = 25)^b
C_max (mean ± SD [%CV]) (ng/ml)	760 ± 176 (23.2)	226 ± 60.0 (26.6)	269 ± 57.5 (21.3)
T_max (median [range]) (h)	3.00 (1.00–46.5)	3.00 (2.00–6.00)	3.00 (1.00–12.0)
AUC_0–24 (mean ± SD [%CV]) (μg · h/ml)	9.35 ± 1.90 (20.4)	2.77 ± 0.80 (28.7)	2.93 ± 0.70 (23.9)
AUC_last (mean ± SD [%CV]) (μg · h/ml)	18.6 ± 5.53 (29.8)	5.87 ± 3.97 (67.6)	5.35 ± 1.44 (26.8)
AUC_inf (mean ± SD [%CV]) (μg · h/ml)	18.6 ± 5.55 (29.8)	6.10 ± 4.54 (74.5)	5.42 ± 1.45 (26.7)
t_1/2 (mean ± SD [%CV]) (h)	24.4 ± 6.82 (28.0)	26.4 ± 13.0 (49.1)	25.2 ± 9.12 (36.2)
V_z/F (mean ± SD [%CV]) (liters)	149 ± 46.4 (31.2)	172 ± 56.9 (33.1)	170 ± 49.3 (28.9)
CL/F (mean ± SD [%CV]) (liters/h)	4.34 ± 1.16 (26.6)	5.01 ± 1.76 (35.1)	4.98 ± 1.53 (30.7)

↵a n = 23 for AUC_last, AUC_inf, t_1/2, and V_z/F.
↵b n = 24 for AUC_last, AUC_inf, t_1/2, and V_z/F.

TABLE 2

PK parameters for piperaquine in the presence and absence of KAE609

Parameter	Value for treatment group receiving:
Parameter	75 mg KAE609 + 320 mg PPQ (n = 25)^a	1,280 mg PPQ + 25 mg KAE609 (n = 24)^b	320 mg PPQ (n = 24)^c	1,280 mg PPQ (n = 12)^d
C_max (mean ± SD [%CV]) (ng/ml)	24.2 ± 16.8 (69.4)	299 ± 191 (63.7)	20.4 ± 8.40 (41.2)	219 ± 124 (56.6)
T_max (median [range]) (h)	3.00 (1.00–46.5)	3.00 (2.00–6.00)	3.00 (1.00–12.0)	3.00 (1.00–4.00)
AUC_0–24 (mean ± SD [%CV]) (μg · h/ml)	0.27 ± 0.14 (53.0)	2.30 ± 1.00 (43.2)	0.243 ± 0.09 (38.9)	1.84 ± 0.84 (45.8)
AUC_0–168 (mean ± SD [%CV]) (μg · h/ml)	0.84 ± 0.40 (47.4)	5.15 ± 1.89 (36.8)	0.850 ± 0.33 (38.2)	4.15 ± 1.47 (35.4)
AUC_0–672 (mean ± SD [%CV]) (μg · h/ml)	1.72 ± 0.92 (53.4)	8.49 ± 2.84 (33.5)	1.74 ± 0.68 (39.4)	6.70 ± 2.13 (31.8)
AUC_last (mean ± SD [%CV]) (μg · h/ml)	2.07 ± 1.28 (61.6)	10.8 ± 3.53 (32.7)	2.16 ± 0.98 (45.4)	8.36 ± 2.64 (31.5)
AUC_inf (mean ± SD [%CV]) (μg · h/ml)	2.60 ± 1.49 (57.2)	12.0 ± 3.70 (30.9)	2.82 ± 1.13 (40.1)	8.99 ± 2.86 (31.8)
t_1/2 (mean ± SD [%CV]) (h)	510 ± 339 (66.6)	485 ± 113 (23.3)	551 ± 284 (51.5)	536 ± 172 (32.1)
V_z/F (mean ± SD [%CV]) (liters)	99,300 ± 49,500 (49.9)	83,400 ± 35,000 (41.9)	96,700 ± 44,500 (46.0)	125,000 ± 71,700 (57.5)
CL/F (mean ± SD [%CV]) (liters/h)	155 ± 80.9 (52.4)	120 ± 50.0 (41.7)	131 ± 59.9 (45.6)	155 ± 46.1 (29.8)

↵a n = 22 for AUC_last, n = 21 for t_1/2 and V_z/F, and n = 19 for AUC_inf.
↵b n = 21 for AUC_last, AUC_inf, t_1/2, and V_z/F.
↵c n = 22 for AUC_inf, t_1/2, and V_z/F.
↵d n = 9 for AUC_last and n = 7 for AUC_inf, t_1/2, and V_z/F.

TABLE 3

Incidences of AEs according to preferred terms

Preferred term^a	No. (%) of subjects
Preferred term^a	75 mg KAE609 + 320 mg PPQ (n = 25)	25 mg KAE609 + 1,280 mg PPQ (n = 24)	25 mg KAE609 (n = 25)	320 mg PPQ (n = 24)	1,280 mg PPQ (n = 12)	Total (n = 110)
At least one AE	12 (48.0)	15 (62.5)	10 (40.0)	14 (58.3)	10 (83.3)	61 (55.5)
Upper respiratory tract infection	4 (16.0)	6 (25.0)	4 (16.0)	8 (33.3)	8 (66.7)	30 (27.3)
Headache	0 (0.0)	2 (8.3)	4 (16.0)	4 (16.7)	2 (16.7)	12 (10.9)
Diarrhea	0 (0.0)	2 (8.3)	2 (8.0)	1 (4.2)	0 (0.0)	5 (4.5)
Oropharyngeal pain	3 (12.0)	1 (4.2)	0 (0.0)	0 (0.0)	0 (0.0)	4 (3.6)
Photosensitivity reaction/sunburn^b	1 (4.0)	1 (4.2)	1 (4.0)	0 (0.0)	0 (0.0)	3 (2.7)
Gastritis	0 (0.0)	2 (8.3)	0 (0.0)	1 (4.2)	0 (0.0)	3 (2.7)
Contusion	0 (0.0)	1 (4.2)	1 (4.0)	1 (4.2)	0 (0.0)	3 (2.7)
Abdominal pain	0 (0.0)	0 (0.0)	0 (0.0)	2 (8.3)	0 (0.0)	2 (1.8)
Myalgia	1 (4.0)	0 (0.0)	1 (4.0)	0 (0.0)	0 (0.0)	2 (1.8)
Lethargy	0 (0.0)	0 (0.0)	1 (4.0)	0 (0.0)	1 (8.3)	2 (1.8)
Dry skin	0 (0.0)	2 (8.3)	0 (0.0)	0 (0.0)	0 (0.0)	2 (1.8)

↵a AEs are presented in descending order of total frequency.
↵b These two preferred terms were combined due to their clinical similarity on the basis of reported terms.

TABLE 4

Statistical analysis of comparisons for mean maximal changes in QTcF from baseline

Treatment comparison	LS mean maximal change from baseline (ms)^a						LS estimate of difference (90% CI) (ms)	P
Treatment comparison	75 mg KAE609 + 320 mg PPQ	25 mg KAE609 + 1,280 mg PPQ	320 mg PPQ	1,280 mg PPQ	1,280 mg PPQ + 25 mg KAE609	25 mg KAE609	LS estimate of difference (90% CI) (ms)	P
75 mg KAE609 + 320 mg PPQ vs 320 mg PPQ	5.04		5.90				−0.86 (−4.41 to 2.68)	0.6864
25 mg KAE609 + 1,280 mg PPQ vs 1,280 mg PPQ		9.50		7.12			2.37 (−2.08 to 6.82)	0.3775
25 mg KAE609 + 1,280 mg PPQ vs 25 mg KAE609					11.20	3.70	7.47 (3.55–11.4)	0.0025

↵a At predosing and 2, 4, 8, 12, and 24 h postdosing, triplicate ECG assessments were available. Averages of triplicate assessments were calculated, and the values for baseline and changes from baseline were derived accordingly. The repeated measurements were not taken into account for the calculation of statistics. The maximal changes from baseline for ECG intervals of less than 24 h were analyzed using a linear fixed-effects model with treatment as a fixed effect and KAE609 and PPQ concentrations at maximal changes as covariates. LS, least-squares.