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Abstract: SA-OR104

Pharmacokinetic and Pharmacodynamic Evaluation of a New Vascular Calcification Inhibitor (INS-3001) in Rats

Session Information

Category: Pharmacology (PharmacoKinetics, -Dynamics, -Genomics)

  • 1700 Pharmacology (PharmacoKinetics, -Dynamics, -Genomics)

Authors

  • Maillard, Marc P., Lausanne University Hospital, Lausanne, Switzerland
  • Mordasini, David, Lausanne University Hospital, Lausanne, Switzerland
  • Spaggiari, Dany, Lausanne University Hospital, Lausanne, Switzerland
  • Phan, Olivier, Lausanne University Hospital, Lausanne, Switzerland
  • Ivarsson, Mattias E., Inositec Inc., Zurich, Switzerland
  • Maj, Roberto, Inositec Inc., Zurich, Switzerland
  • Décosterd, Laurent Arthur, Lausanne University Hospital, Lausanne, Switzerland
  • Burnier, Michel, Lausanne University Hospital, Lausanne, Switzerland
Background

Morbidity and mortality of patients with CKD increase with the progression of vascular calcifications. In the context of the development of drugs capable of reducing pathological crystallization, myo-inositol hexaphosphate (IP6) has been shown to be a promising candidate but needs to be administered via intravenous infusion. This study demonstrates the in vivo inhibitory effect of an IP6 analog (INS-3001), and characterizes its pharmacokinetic profile in uremic and non-uremic rats.

Methods

Efficacy of INS-3001 versus IP6 to prevent severe vascular calcification was studied in non-uremic rats (vitamin D3 model, n = 5 – 11/group), while the PK of INS-3001 was determined after after single i.v. or s.c dosing of 10mg/kg in uremic rats (adenine diet model) and non-uremic controls (n = 6/group). Vascular calcifications were visualized by von Kossa staining and calcium tissue content measured by ICP-MS. INS-3001 concentrations in EDTA plasma were measured using a HILIC-MS/MS bioanalytical method.

Results

INS-3001 significantly blunted carotid calcification reducing the amount of calcium in tissues by a factor of two compared to controls (p=0.017) while a numerical decrease was observed at the level of abdominal aorta (p>0.05). Treatment with IP6 could not be completed due to the appearance of necrotic lesions at the injection site.
INS-3001 displayed high s.c. bioavailability. In the s.c. group, uremic rats displayed higher AUC, mean residence time and Tmax than non-uremic controls (1327.1 vs 802.3 µg/mL*min; 124 vs 66 min; 23 vs 50 min, respectively) whereas Cmax remained unchanged (8348 vs 8325 ng/mL). Similar trends were observed following i.v. administration.

Conclusion

IINS-3001 is a potent inhibitor of vascular calcification after Vitamin D overdose in rats, in addition INS-3001 has a beneficial effect on the renal function of animals in this model.
The uremic state appeared to significantly influence the rat plasma PKs of INS-3001 after s.c. and i.v. administration. The data suggests that uremia extends plasma exposure of INS-3001 without increasing peak plasma levels and that therapeutic levels can be attained following s.c. administration in the context of uremia.

Funding

  • Government Support - Non-U.S.