Implementation of automated blood sampling in a canine cardiovascular safety pharmacology study to support PK/PD
Elham Ataei Alizadeh1, Georg Rast2, Jessica Schiwon2
1Department of Drug Discovery Sciences, General Pharmacology Group, Boehringer Ingelheim Pharma GmbH & Co KG, Germany; Laboratory of Physiopharmacology, University of Antwerp, Antwerp, Belgium.
Introduction:
Pharmacokinetic (PK) and pharmacodynamic (PD) modeling can elucidate the temporal interplay between drug concentration and physiological effects. Its use in safety pharmacology studies has been hindered, since collecting an adequate number of blood samples from conscious animals poses challenges. This study introduces an automatic blood sampling system into a cardiovascular safety pharmacology study to enable the collection of frequent blood samples from conscious animals to allow for a PK/PD assessment.
Method:
For this investigation, we employed a telemetry-based approach to obtain cardiovascular data from 4 Beagle dogs. To assess the PK profile of the test compound, an automated blood sampling device was used to facilitate the collection of up to 20 blood samples at predefined time points over the 7-h study period. The cross-over study was conducted using conscious, freely-moving animals, with Moxifloxacin administered as the test compound.
Results:
Moxifloxacin administered orally in doses of 10 mg/kg, 30 mg/kg and 100 mg/kg reached Cmax of 6340 ± 1087, 15,840 ± 5471 and 29,033 ± 6540 nM, respectively, resulting in a QTc prolongation of 7 ms for 10 mg/kg, 17 ms for 30 mg/kg and 35 ms for 100 mg/kg. Based on the PK/PD analysis, a 5 ms QTc prolongation occurs with a Moxifloxacin concentration of 6.2 μM and a 10 ms QTc prolongation occurs with 12 μM. The feasibility of integrating automated blood samples in a cardiovascular safety pharmacology study using conscious animals has been demonstrated, by collecting enough PK data to support a PK/PD evaluation.
Conclusion:
The implementation of the automatic blood sampling system provides a significant advancement in safety pharmacology studies, offering a potent instrument for supporting PK/PD modeling.
