Comparison of pharmacokinetic variables for two injectable formulations of netobimin administered to calves

Carlos E Lanusse From the Institute of Parasitology of McGill University, Macdonald College, 21,111 Lakeshore Road, Ste-Anne de Bellevue, Quebec, Canada H9X ICO.

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Sivaja Ranjan From the Institute of Parasitology of McGill University, Macdonald College, 21,111 Lakeshore Road, Ste-Anne de Bellevue, Quebec, Canada H9X ICO.

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Roger K. Prichard From the Institute of Parasitology of McGill University, Macdonald College, 21,111 Lakeshore Road, Ste-Anne de Bellevue, Quebec, Canada H9X ICO.

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SUMMARY

In a 4 × 4 crossover-design study, pharmacokinetic variables of 2 injectable formulations of netobimin (trisamine salt solution and zwitterion suspension) were compared after sc administration in calves at dosage of 12.5 mg/kg of body weight. Netobimin parent drug was rapidly absorbed, being detected between 0.25 and 12 hours after treatment, with maximal plasma drug concentration (Cmax) values of 2.20 ± 1.03 μg/ml achieved at 0.75 ± 0.19 hour (trisamine) and 1.37 ± 0.59 μg/ml at 0.81 ± 0.18 hour (zwitterion). Netobimin area under the plasma concentration-time curve (AUC) was 7.59 ± 3.11 μg·h/ml (trisamine) and 6.98 ± 1.60 μg·h/ml (zwitterion). Elimination half-life (t½β) was 2.59 ± 0.63 hours (trisamine) and 3.57 ± 1.45 hours (zwitterion).

Albendazole was not detected at any time. Albendazole sulfoxide was detected from 4 hours up to 20 hours (trisamine) and from 6 hours up to 24 hours (zwitterion) after administration of the drug. The Cmax values were 0.48 ± 0.16 μg/ml and 0.46 ± 0.26 μg/ml for trisamine and zwitterion formulations, respectively, achieved at time to peak drug concentration (Tmax) values of 9.50 ± 1.41 hours (trisamine) and 11.30 ± 1.04 hours (zwitterion). Albendazole sulfoxide AUC was 3.86 ± 1.04 μg·h/ml (trisamine) and 4.40 ± 3.24 μg·h/ml (zwitterion); t½β was 3.05 ± 0.75 hours (trisamine) and 3.90 ± 1.44 hours (zwitterion). Albendazole sulfone was detected from 4 (trisamine) or 6 hours (zwitterion) to 24 hours after treatment. The AUC was 6.98 ± 1.60 μg·h/ml (trisamine) and 10.51 ± 7.41 μg·h/ml (zwitterion); Cmax was 0.76 ± 0.21 μg/ml at Tmax of 12.00 ± 1.85 hours (trisamine) and 0.70 ± 0.24 μg/ml at Tmax of 12.50 ± 2.33 hours (zwitterion). Albendazole sulfone t½β was significantly (P < 0.05) longer for the zwitterion formulation (7.77 ± 4.72 hours) than for the trisamine salt (2.87 ± 0.61 hours). Albendazole sulfone AUC was higher than albendazole sulfoxide AUC, resulting in AUC ratio of 1.8 (trisamine) and 2.4 (zwitterion).

The 2 formulations were not significantly different in terms of AUC or Tmax for netobimin and albendazole sulfone, AUC for albendazole sulfoxide, or t½β for netobimin and albendazole sulfoxide. It was concluded that the 2 netobimin injectable formulations were bioequivalent. Experimental phase had a significant effect on the AUC and Cmax for albendazole sulfoxide and on the Cmax for netobimin. One possible explanation for the differences between phases could be induction of liver microsomal enzymes by netobimin and its metabolites, resulting in increased rate of metabolism during phase 2 of the study.

SUMMARY

In a 4 × 4 crossover-design study, pharmacokinetic variables of 2 injectable formulations of netobimin (trisamine salt solution and zwitterion suspension) were compared after sc administration in calves at dosage of 12.5 mg/kg of body weight. Netobimin parent drug was rapidly absorbed, being detected between 0.25 and 12 hours after treatment, with maximal plasma drug concentration (Cmax) values of 2.20 ± 1.03 μg/ml achieved at 0.75 ± 0.19 hour (trisamine) and 1.37 ± 0.59 μg/ml at 0.81 ± 0.18 hour (zwitterion). Netobimin area under the plasma concentration-time curve (AUC) was 7.59 ± 3.11 μg·h/ml (trisamine) and 6.98 ± 1.60 μg·h/ml (zwitterion). Elimination half-life (t½β) was 2.59 ± 0.63 hours (trisamine) and 3.57 ± 1.45 hours (zwitterion).

Albendazole was not detected at any time. Albendazole sulfoxide was detected from 4 hours up to 20 hours (trisamine) and from 6 hours up to 24 hours (zwitterion) after administration of the drug. The Cmax values were 0.48 ± 0.16 μg/ml and 0.46 ± 0.26 μg/ml for trisamine and zwitterion formulations, respectively, achieved at time to peak drug concentration (Tmax) values of 9.50 ± 1.41 hours (trisamine) and 11.30 ± 1.04 hours (zwitterion). Albendazole sulfoxide AUC was 3.86 ± 1.04 μg·h/ml (trisamine) and 4.40 ± 3.24 μg·h/ml (zwitterion); t½β was 3.05 ± 0.75 hours (trisamine) and 3.90 ± 1.44 hours (zwitterion). Albendazole sulfone was detected from 4 (trisamine) or 6 hours (zwitterion) to 24 hours after treatment. The AUC was 6.98 ± 1.60 μg·h/ml (trisamine) and 10.51 ± 7.41 μg·h/ml (zwitterion); Cmax was 0.76 ± 0.21 μg/ml at Tmax of 12.00 ± 1.85 hours (trisamine) and 0.70 ± 0.24 μg/ml at Tmax of 12.50 ± 2.33 hours (zwitterion). Albendazole sulfone t½β was significantly (P < 0.05) longer for the zwitterion formulation (7.77 ± 4.72 hours) than for the trisamine salt (2.87 ± 0.61 hours). Albendazole sulfone AUC was higher than albendazole sulfoxide AUC, resulting in AUC ratio of 1.8 (trisamine) and 2.4 (zwitterion).

The 2 formulations were not significantly different in terms of AUC or Tmax for netobimin and albendazole sulfone, AUC for albendazole sulfoxide, or t½β for netobimin and albendazole sulfoxide. It was concluded that the 2 netobimin injectable formulations were bioequivalent. Experimental phase had a significant effect on the AUC and Cmax for albendazole sulfoxide and on the Cmax for netobimin. One possible explanation for the differences between phases could be induction of liver microsomal enzymes by netobimin and its metabolites, resulting in increased rate of metabolism during phase 2 of the study.

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