Basic Science and Experimental StudyA Pharmacokinetic Analysis of Molecular Cardiac Surgery With Recirculation Mediated Delivery of βARKct Gene Therapy: Developing a Quantitative Definition of the Therapeutic Window
Section snippets
Methods
The complete study design consisted of 3 separate parts:
- 1.
MCARD of gene with blood sample collection and variable monitoring.
- 2.
Applying a PK model to the data derived from blood samples and components.
- 3.
Quantitative analysis of GC biodistribution in tissues after animal sacrifices at 10 weeks.
Results
Significantly higher cardiac versus systemic [cardiac; systemic] concentrations were observed (Log GC/mL) over the time of recirculation at 5 minutes [9.16 ± 0.15; 3.21 ± 0.38], 10 minutes [8.81 ± 0.19; 3.62 ± 0.37], 15 minutes [8.75 ± 0.12; 3.69 ± 0.31], and 20 minutes [8.66 ± 0.22; 3.95 ± 0.26] (Fig. 3; P < .00001). The average initial concentration (1014 GC dose/circuit volume) was 11.55 ± 0.08 and a function of cardiac circuit start volume, which varies from subject to subject in the range
Discussion
In most cases, MCARD transfers >99% of the initial dose from the cardiac circuit to the cardiac interstitium or at the cardiac endothelial barriers, based on these 2 facts: Negligible vector remains in either compartment at the end of the 20-minute recirculation period; and the cardiac and systemic timepoints at 5, 10, 15, and 20 minutes all contain much less than 1% of initial dose (Fig. 3). Our most significant finding was that, surprisingly, most transfer occurs in the first 5 minutes of
Disclosures
None.
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Funding: National Heart Lung and Blood Institute (1-R01-HL083078-01A2).
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