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Experimental Therapeutics

In Vitro and In Vivo Drug-Drug Interaction Study of the Effects of Ivermectin and Oxantel Pamoate on Tribendimidine

Anna Neodo, Jessica D. Schulz, Jörg Huwyler, Jennifer Keiser
Anna Neodo
aDepartment of Medical Parasitology and Infection Biology, Swiss Tropical and Public Health Institute, Basel, Switzerland
bUniversity of Basel, Basel, Switzerland
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Jessica D. Schulz
aDepartment of Medical Parasitology and Infection Biology, Swiss Tropical and Public Health Institute, Basel, Switzerland
bUniversity of Basel, Basel, Switzerland
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Jörg Huwyler
cDepartment of Pharmaceutical Sciences, Division of Pharmaceutical Technology, University of Basel, Basel, Switzerland
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Jennifer Keiser
aDepartment of Medical Parasitology and Infection Biology, Swiss Tropical and Public Health Institute, Basel, Switzerland
bUniversity of Basel, Basel, Switzerland
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DOI: 10.1128/AAC.00762-18
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    FIG 1

    PK profiles of dADT, adADT, and ivermectin in rat plasma following a single oral dose of either tribendimidine (100 mg/kg), ivermectin (2.5 mg/kg), or both (at the same doses) administered to four, six, and six rats, respectively. Individual rats’ concentrations are shown as circles, and median concentrations are traced as lines. Blue filled circles and solid lines, monotherapy; red empty circles and dashed lines, combination therapy.

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  • TABLE 1

    CYP450 inhibition (IC50 values) by dADT, ivermectin, oxantel, dADT plus ivermectin, and dADT plus oxantel pamoate in vitro

    EnzymeMedian IC50 (μM) (range)
    dADTIvermectindADT + ivermectinOxantel
    pamoate
    dADT + oxantel
    pamoate
    Positive control
    CYP1A2>100>10>1009.0 (7.4–11.1)9.3 (7.9–10.8)0.5 (0.4–0.7) (propranolol)
    CYP2C9>1005.3 (4.5–6.2)6.9 (5.6–8.5)1.4 (1.2–1.7)0.8 (0.5–1.1)2.1 (1.9–2.4) (diclofenac)
    CYP2D6>10013.8 (10.0–27.1)1.4 (0.8–2.6)0.6 (0.5–0.6)0.3 (0.2–0.4)<0.03 (quinidine)
    CYP2C19>1006.7 (5.3–8.9)4.6 (3.2–7.0)15.6 (13.6–17.8)13.1 (11.5–14.9)1.6 (1.4–1.8) (omeprazole)
    CYP3A4>10011.3 (9.1–19.8)10.2 (8.3–14.4)13.9 (11.6–16.6)13.8 (11.9–16.0)0.006 (0.004–0.008) (ketoconazole)
  • TABLE 2

    Noncompartmental PK parameters for dADT, adADT, and ivermectin after oral administration of either tribendimidine (100 mg/kg, n = 4), ivermectin (2.5 mg/kg, n = 6), or both (n = 6) to healthy rats

    ParameterMedian value for analyte (range)a
    dADTadADTIvermectin
    MonotherapyCombinationMonotherapyCombinationMonotherapyCombination
    AUC0–t (ng h/ml)20,097 (13,216–20,331)9,796 (4,362–13,218)8,190 (6,654–9,482)3,417 (3,055–6,805)5,307 (2,195–11,236)1,633 (1,099–7,616)
    Cmax (ng/ml)4,040 (1,252–5060)2,414 (1,160–4,000)768 (652–1,641)776 (468–2,476)419 (137–932)151 (79–854)
    Tmax (h)2.0 (0.5–5.0)2.0 (0.5–4.0)2.0 (0.5–5.0)2.0 (0.5–5.0)6.5 (2.0–8.0)5.0 (4.0–8.0)
    t1/2 (h)2.6 (2.0–4.1)3.0 (1.7–5.2)3.3 (2.8–4.6)3.4 (2.0–4.5)11.2 (8.1–14.1)11.4 (8.1–31.1)
    • ↵a For dADT, the median AUC ratio (ratio of the AUC of the drug in combination to the AUC of the drug alone) was 0.925 (range, 0.890 to 0.960), and the median Cmax ratio (ratio of the Cmax of the drug in combination to the Cmax of the drug alone) was 0.962 (range, 0.911 to 1.013); for adADT, the median AUC ratio was 0.925 (range, 0.894 to 0.956), and the median Cmax ratio was 1.003 (range, 0.925 to 1.085); and for ivermectin, the median AUC ratio was 0.860 (range, 0.796 to 0.927), and the median Cmax ratio was 0.885 (range, 0.745 to 1.032) (logarithmically transformed data).

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In Vitro and In Vivo Drug-Drug Interaction Study of the Effects of Ivermectin and Oxantel Pamoate on Tribendimidine
Anna Neodo, Jessica D. Schulz, Jörg Huwyler, Jennifer Keiser
Antimicrobial Agents and Chemotherapy Dec 2018, 63 (1) e00762-18; DOI: 10.1128/AAC.00762-18

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In Vitro and In Vivo Drug-Drug Interaction Study of the Effects of Ivermectin and Oxantel Pamoate on Tribendimidine
Anna Neodo, Jessica D. Schulz, Jörg Huwyler, Jennifer Keiser
Antimicrobial Agents and Chemotherapy Dec 2018, 63 (1) e00762-18; DOI: 10.1128/AAC.00762-18
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KEYWORDS

CYP450
drug interaction
tribendimidine

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