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Multiple oral dosing of ketoconazole increases dog exposure to ivermectin
Christophe Hugnet1, Anne Lespine, Michel Alvinerie
1Clinique Vétérinaire des Lavandes, 26160 La Begude de Mazenc, France. INRA-UR66, Laboratoire de Pharmacologie-Toxicologie, BP 3, 31931 Toulouse Cedex 9, France.
Purpose:
The parasiticide ivermectin and the antimicrobial drug ketoconazole are macrolides that interact with P-glycoprotein. We investigated the effects of ketoconazole at a clinical dose on the pharmacokinetics of ivermectin, a CYP3A substrate with low hepatic clearance.
Methods:
Beagle dogs received a single subcutaneous injection of ivermectin at 0.05 mg/kg alone (n=6) or in combination with a daily oral dose of ketoconazole 10 mg/kg over 5 days before and after ivermectin administration (n=6). The plasma kinetics of ivermectin and its metabolite were followed over 15 days by HPLC analysis.
Results:
Co-administered ketoconazole induced a higher plasma concentration and longer residence time of ivermectin in dogs, leading to a substantial increase in the overall exposure of the animal to the drug. Ketoconazole does not interfere with the production of the ivermectin metabolite but it may rather inhibit the elimination of the parental drug by interfering with P-gp transport.
Conclusions:
Multiple oral dosing of ketoconazole dramatically altered the pharmacokinetics of ivermectin in dogs leading to an increase in systemic exposure to the drug. Neurotoxicity of ivermectin means that inhibition of the P-gp function at the blood-brain barrier during polytherapy using P-gp inhibitors must be taken into consideration.
Insights
Ketoconazole significantly increases ivermectin exposure in dogs by inhibiting its elimination, raising concerns for potential neurotoxicity due to P-glycoprotein interactions.
Area of Science:
- Pharmacology
- Drug Interactions
- Veterinary Medicine
Background:
- Ivermectin is a parasiticide, and ketoconazole is an antimicrobial drug, both macrolides affecting P-glycoprotein.
- Ivermectin is a substrate for CYP3A with low hepatic clearance.
Purpose of the Study:
- To investigate the pharmacokinetic effects of a clinical dose of ketoconazole on ivermectin.
- To assess the interaction between ketoconazole and ivermectin in Beagle dogs.
Main Methods:
- Beagle dogs received ivermectin (0.05 mg/kg subcutaneously) alone or with ketoconazole (10 mg/kg orally daily for 5 days before and after ivermectin).
- Plasma concentrations of ivermectin and its metabolite were analyzed over 15 days using HPLC.
Main Results:
- Ketoconazole increased ivermectin plasma concentration and residence time, enhancing overall drug exposure.
- Ketoconazole did not affect ivermectin metabolite production but inhibited the elimination of parent ivermectin, likely via P-glycoprotein transport inhibition.
Conclusions:
- Ketoconazole administration significantly alters ivermectin pharmacokinetics in dogs, increasing systemic exposure.
- Inhibition of P-glycoprotein at the blood-brain barrier by ketoconazole necessitates consideration of ivermectin neurotoxicity during co-administration.
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