Albendazole and ivermectin co-administration: pharmacokinetic assessment and clinical efficacy against multiple resistant nematodes in lambs.

ALVAREZ, L.; LIFSCHITZ, A.; ENTROCASSO, C.; MANAZZA, J; LANUSSE, C.; ALVAREZ, L.; LIFSCHITZ, A.; ENTROCASSO, C.; MANAZZA, J; LANUSSE, C.

Torino, Italia

Congreso; 10th International Congress of the European Association for Veterinary Pharmacology and Toxicology; 2006

European Association for Veterinary Pharmacology and Toxicology

  Introduction: Helminth infections are the most important cause of productivity losses in livestock, being chemically-based treatments the main tool to control parasitism. However, the development of resistance to the available anthelmintic drugs is a seriously increasing problem. Mixtures of drugs from different chemical families have been proposed as a valid strategy to delay the development of resistance. It has been suggested that drug combinations may be efficacious against resistant nematode strains where the failure of individual drugs is documented. However, the limited available information is unclear on the potential additive and/or synergistic anthelmintic effect occurring after co-administration of two drugs with different mode of action. Furthermore, potential pharmacokinetic interactions between co-administered anthelmintics should be understood before any practical use can be advised.  The main goals of the current trial were: a) to characterise the plasma pharmacokinetic (PK) behaviour of albendazole (ABZ) and ivermectin (IVM) administered either alone or co-administered to lambs, and b) to compare the clinical efficacy of ABZ and IVM given separately or co-administered to lambs naturally infected with gastrointestinal nematodes resistant to both molecules. Materials and Methods: Seventy Corriedale lambs (27.3 ± 4.3 kg), naturally infected with multiple resistant gastrointestinal nematodes were involved in the following trials: a) “PK study”: The experimental animals were allocated into 6 groups (n=10 each) and treated either with ABZ intravenous (i.v.) (3.8 mg/kg) (Group I), IVM i.v. (0.2 mg/kg) (Group II), ABZ i.v. + IVM i.v. (Group III), ABZ intraruminal (ir) (3.8 mg/kg) (Group IV), IVM subcutaneous (sc) (0.2 mg/kg) (Group V) and ABZ i.r. + IVM s.c. (Group VI). Blood samples were collected over 72 h (ABZ treated lambs) or 15 days (IVM treated lambs) post-treatment. Plasma samples were analysed by HPLC after clean up and solid phase extraction. The estimated PK parameters were statistically compared using parametric and non parametric statistical tests.  b) “Clinical efficacy trial”: The indirect estimation of the efficacy of the different treatments was performed by the faecal egg count reduction test (FECRT) (1). An untreated control Group (n=10) was included in this trial to assess the comparative anthelmintic efficacy of the treatments given to Groups I to VI of the "PK study". Additionally, four animals randomly chosen from the untreated control and treated Groups I, II and III were sacrificed 15 days post-treatment to evaluate the comparative treatment efficacy against different resistant nematode parasites. Animal procedures were done following internationally accepted animal welfare guidelines (2). Faecal egg and nematode burden counts were done following available parasitological guidelines (1, 3). The results were statistically compared by ANOVA plus the Tuckey test. Results: ABZ, ABZ-sulphoxide (ABZSO, active metabolite) and ABZ-sulphone (ABZSO2, inactive metabolite) were recovered in plasma after the i.v. administration of ABZ. No significant differences in AUC, clearance and MRT values  for ABZ and ABZSO were observed between Groups I and III. However, the ABZSO AUC value in Group IV (19.8 ± 2.6 µg.h/ml) was significantly lower (P<0.01) to that obtained for the Group VI (28.2 ± 3.7 µg.h/ml). The IVM plasma AUC obtained after its i.v. co-administration with ABZ was 88 % higher (P< 0.05) compared to the treatment with IVM alone. Any marked difference on IVM PK parameters was observed between the treatments ABZ+IVM and IVM alone injected subcutaneously (Groups V and VI). The following egg output reduction values were obtained: 67.2% (Group I), 78.3% (Group II), 91.9% (Group III), 44.3% (Group IV), 77.9% (Group V) and 68.6% (Group VI). The efficacy against resistant Haemonchus contortus was 84.4, 95.3 and 92.2% for treatment Groups I, II and III, respectively, while the efficacy against Trichostrongylus colubriformis for the same treatment Groups was 75.4, 100 and 96.1%. Discussion and Conclusions: As earlier shown in our lab (4), ABZ activity against resistant nematodes parasites was close related to the systemic availability of the active molecules. The higher plasma availability observed following the i.v. treatment compared to the i.r. administration of ABZ to sheep, correlated with the improved efficacy patterns obtained following the intravascular treatment. The enhancement on ABZSO and IVM availabilities obtained after the co-administration was not sufficient to increase the efficacy against the resistant nematodes involved in this trial. However, the data obtained here indicate that the co-administration of ABZ and IVM does not induce an adverse kinetic interaction, and additive anthelmintic effects against multiple resistant nematodes may be achieved. Further research is needed to improve the understanding and potential advantages of this drug combination strategy for parasite control. References 1. Coles et al. Vet Parasitol 1992; 44: 35-44. 2. American Veterinary Medical Association. J Am Vet Med Assoc 2001; 218: 669-696. 3. Wood et al. Vet Parasitol 1995; 58: 181-213. 4. Moreno et al. Exp Parasitol 2004; 106: 150-157. Acknowledgments This work was supported by Fundación Antorchas, Argentina (Project 14248-127).