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Clinical Therapeutics

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
Daniel S. Stein
Novartis Institute for BioMedical Research, East Hanover, New Jersey, USA
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Jay Prakash Jain
Novartis Institute for BioMedical Research, Hyberabad, India
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Michael Kangas
Novartis Institute for BioMedical Research, Basel, Switzerland
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Gilbert Lefèvre
Novartis Institute for BioMedical Research, Basel, Switzerland
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Surendra Machineni
Integrated Quantitative Sciences, Hyderabad, India
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Paul Griffin
Q-Pharm Pty. Ltd., QIMR Berghofer Medical Research Institute, Mater Health Services and Mater Research, and the University of Queensland, Brisbane, Queensland, Australia
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Jason Lickliter
Nucleus Network Ltd., Melbourne, Victoria, Australia
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DOI: 10.1128/AAC.00340-15
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  • FIG 1
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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.

  • FIG 2
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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.

  • FIG 3
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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.

  • FIG 4
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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.

  • FIG 5
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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.

  • FIG 6
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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

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  • TABLE 1

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

    ParameterValue for treatment group receiving:
    75 mg KAE609 + 320 mg PPQ (n = 25)a25 mg KAE609 + 1,280 mg PPQ (n = 24)25 mg KAE609 (n = 25)b
    Cmax (mean ± SD [%CV]) (ng/ml)760 ± 176 (23.2)226 ± 60.0 (26.6)269 ± 57.5 (21.3)
    Tmax (median [range]) (h)3.00 (1.00–46.5)3.00 (2.00–6.00)3.00 (1.00–12.0)
    AUC0–24 (mean ± SD [%CV]) (μg · h/ml)9.35 ± 1.90 (20.4)2.77 ± 0.80 (28.7)2.93 ± 0.70 (23.9)
    AUClast (mean ± SD [%CV]) (μg · h/ml)18.6 ± 5.53 (29.8)5.87 ± 3.97 (67.6)5.35 ± 1.44 (26.8)
    AUCinf (mean ± SD [%CV]) (μg · h/ml)18.6 ± 5.55 (29.8)6.10 ± 4.54 (74.5)5.42 ± 1.45 (26.7)
    t1/2 (mean ± SD [%CV]) (h)24.4 ± 6.82 (28.0)26.4 ± 13.0 (49.1)25.2 ± 9.12 (36.2)
    Vz/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 AUClast, AUCinf, t1/2, and Vz/F.

    • ↵b n = 24 for AUClast, AUCinf, t1/2, and Vz/F.

  • TABLE 2

    PK parameters for piperaquine in the presence and absence of KAE609

    ParameterValue for treatment group receiving:
    75 mg KAE609 + 320 mg PPQ (n = 25)a1,280 mg PPQ + 25 mg KAE609 (n = 24)b320 mg PPQ (n = 24)c1,280 mg PPQ (n = 12)d
    Cmax (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)
    Tmax (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)
    AUC0–24 (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)
    AUC0–168 (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)
    AUC0–672 (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)
    AUClast (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)
    AUCinf (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)
    t1/2 (mean ± SD [%CV]) (h)510 ± 339 (66.6)485 ± 113 (23.3)551 ± 284 (51.5)536 ± 172 (32.1)
    Vz/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 AUClast, n = 21 for t1/2 and Vz/F, and n = 19 for AUCinf.

    • ↵b n = 21 for AUClast, AUCinf, t1/2, and Vz/F.

    • ↵c n = 22 for AUCinf, t1/2, and Vz/F.

    • ↵d n = 9 for AUClast and n = 7 for AUCinf, t1/2, and Vz/F.

  • TABLE 3

    Incidences of AEs according to preferred terms

    Preferred termaNo. (%) of subjects
    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 AE12 (48.0)15 (62.5)10 (40.0)14 (58.3)10 (83.3)61 (55.5)
    Upper respiratory tract infection4 (16.0)6 (25.0)4 (16.0)8 (33.3)8 (66.7)30 (27.3)
    Headache0 (0.0)2 (8.3)4 (16.0)4 (16.7)2 (16.7)12 (10.9)
    Diarrhea0 (0.0)2 (8.3)2 (8.0)1 (4.2)0 (0.0)5 (4.5)
    Oropharyngeal pain3 (12.0)1 (4.2)0 (0.0)0 (0.0)0 (0.0)4 (3.6)
    Photosensitivity reaction/sunburnb1 (4.0)1 (4.2)1 (4.0)0 (0.0)0 (0.0)3 (2.7)
    Gastritis0 (0.0)2 (8.3)0 (0.0)1 (4.2)0 (0.0)3 (2.7)
    Contusion0 (0.0)1 (4.2)1 (4.0)1 (4.2)0 (0.0)3 (2.7)
    Abdominal pain0 (0.0)0 (0.0)0 (0.0)2 (8.3)0 (0.0)2 (1.8)
    Myalgia1 (4.0)0 (0.0)1 (4.0)0 (0.0)0 (0.0)2 (1.8)
    Lethargy0 (0.0)0 (0.0)1 (4.0)0 (0.0)1 (8.3)2 (1.8)
    Dry skin0 (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 comparisonLS mean maximal change from baseline (ms)aLS estimate of difference (90% CI) (ms)P
    75 mg KAE609 + 320 mg PPQ25 mg KAE609 + 1,280 mg PPQ320 mg PPQ1,280 mg PPQ1,280 mg PPQ + 25 mg KAE60925 mg KAE609
    75 mg KAE609 + 320 mg PPQ vs 320 mg PPQ5.045.90−0.86 (−4.41 to 2.68)0.6864
    25 mg KAE609 + 1,280 mg PPQ vs 1,280 mg PPQ9.507.122.37 (−2.08 to 6.82)0.3775
    25 mg KAE609 + 1,280 mg PPQ vs 25 mg KAE60911.203.707.47 (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.

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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
Antimicrobial Agents and Chemotherapy May 2015, 59 (6) 3493-3500; DOI: 10.1128/AAC.00340-15

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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
Antimicrobial Agents and Chemotherapy May 2015, 59 (6) 3493-3500; DOI: 10.1128/AAC.00340-15
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