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

doi:10.1128/AAC.00762-18

DOI: 10.1128/AAC.00762-18

Article Figures & Data

Figures

Tables
Additional Files

Open in new tab
Download powerpoint
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.

TABLE 1

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

Enzyme	Median IC₅₀ (μM) (range)
Enzyme	dADT	Ivermectin	dADT + ivermectin	Oxantel pamoate	dADT + oxantel pamoate	Positive control
CYP1A2	>100	>10	>100	9.0 (7.4–11.1)	9.3 (7.9–10.8)	0.5 (0.4–0.7) (propranolol)
CYP2C9	>100	5.3 (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	>100	13.8 (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	>100	6.7 (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	>100	11.3 (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

Parameter	Median value for analyte (range)^a
	dADT		adADT		Ivermectin
	Monotherapy	Combination	Monotherapy	Combination	Monotherapy	Combination
AUC_0–_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)
C_max (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)
T_max (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)
t_1/2 (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 C_max ratio (ratio of the C_max of the drug in combination to the C_max 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 C_max 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 C_max ratio was 0.885 (range, 0.745 to 1.032) (logarithmically transformed data).