Related Experiment Video
Updated: Apr 8, 2026
An Intestine/Liver Microphysiological System for Drug Pharmacokinetic and Toxicological Assessment
Published on: December 3, 2020
Incorporation of capillary microsampling into whole body plethysmography and modified Irwin safety pharmacology
Helen Prior1, Louise Marks1, Claire Grant1
1AstraZeneca, Innovative Medicines, Drug Safety & Metabolism, Mereside, Alderley Park, Macclesfield, Cheshire, SK10 4TG, UK.
Unlabelled:
Limited toxicokinetic data is generated during modified Irwin screen and whole body plethysmography safety pharmacology studies, due to disturbance of primary endpoints by standard blood sampling methods. We evaluated if incorporation of microsampling would impact on data quality, as providing toxicokinetic data from main test animals could reduce the need for satellite animals.
Methods:
A modified Irwin screen was performed, testing oral clonidine (0, 0.03, 0.1, or 0.3 mg/kg). One cohort of rats per dose level underwent standard blood sampling (post-4 h Irwin assessment), and another cohort underwent microsampling after the 0.5, 1, 2, 4 and 24 h Irwin assessments. The respiratory effects of oral theophylline (0 or 10 mg/kg) and oral baclofen (0 or 5 mg/kg), were tested using whole body plethysmography. Groups of animals underwent standard blood sampling (at end of recording at 4 h post-dose) or microsampling at either 0.5 h or 1 h intervals (4 or 8 microsamples, respectively).
Results:
Microsampling did not impact on the quality of the data generated. The expected effects of clonidine on behavioural parameters, and of theophylline and baclofen on changes in ventilatory parameters were observed at a similar magnitude and duration independent of sampling method.
Discussion:
The incorporation of multiple capillary microsamples into the modified Irwin or respiratory study did not adversely affect the primary endpoints. The capillary microsampling method is a refinement in blood sampling technique which can easily be adapted into safety pharmacology studies to generate pharmacokinetic profiles within the same animal as the primary data, thus enhancing scientific robustness and reducing the satellite animals required.
Insights
Incorporating microsampling into safety pharmacology studies provides toxicokinetic data without compromising primary endpoints. This method enhances scientific robustness and reduces the need for satellite animals in drug development.
Area of Science:
- Pharmacology
- Toxicology
- Drug Development
Background:
- Safety pharmacology studies, including the modified Irwin screen and whole body plethysmography, often lack comprehensive toxicokinetic data.
- Standard blood sampling methods can interfere with primary endpoint measurements, necessitating the use of satellite animals.
Purpose of the Study:
- To evaluate the impact of microsampling on data quality in safety pharmacology studies.
- To determine if microsampling can generate toxicokinetic data from main study animals, thereby reducing the requirement for satellite animals.
Main Methods:
- Modified Irwin screen and whole body plethysmography were employed.
- Animals received either standard blood sampling or capillary microsampling at various time points post-dose.
- Drug candidates included clonidine, theophylline, and baclofen.
Main Results:
- Microsampling did not adversely affect the quality of data generated in either study.
- Observed effects of clonidine on behavior and theophylline/baclofen on ventilation were comparable between sampling methods.
- Pharmacokinetic profiles could be generated from the same animals used for primary endpoint assessment.
Conclusions:
- Capillary microsampling is a suitable refinement for blood collection in safety pharmacology.
- This technique enhances scientific robustness by integrating toxicokinetic data collection with primary endpoint assessment.
- Adoption of microsampling reduces the number of animals required, aligning with the 3Rs principles (Replacement, Reduction, Refinement).
