Sequoia Pharmaceuticals Presents Proof of Clinical Concept of SPI-452, a Novel Pharmacokineti...(and SQV(1000 mg) SQV (1000 mg) alone or ...),Health

Pharmacokinetic results from this study demonstrated that SPI-452 increased mean exposure levels of saquinavir which was early validation that SPI-452 was a potent pharmacokinetic enhancer. Co-administration of SPI-452 and SQV did not alter SPI-452 exposure. SPI-452 was generally safe and well tolerated in single, ascending doses of 25 mg to 600 mg and in single-dose combination with 1000 mg of SQV. No subjects withdrew from the study because of study drug, and no serious AEs were reported. Adverse events were usually mild in severity. The most common AEs reported were headache and pharyngitis.

Preclinical Evaluation

The ability of SPI-452 to inhibit CYP3A and the metabolism of HIV PIs was assessed using liver microsomes or cryopreserved hepatocytes. In these in vitro studies, SPI-452 inhibited the metabolism of all HIV PIs and one investigational HCV PI tested in human liver microsomes and primary hepatocytes similar to ritonavir. In addition, SPI-452 demonstrated no inherent antiviral activity, nor did it affect the antiviral potency of these HIV PIs in in vitro cell assay.

The ability of SPI-452 to enhance the pharmacokinetic exposure of three co-administered HIV PIs (saquinavir, lopinavir and atazanavir) was evaluated in a series of single-dose in vivo animal studies. SPI-452 consistently and significantly enhanced the systemic exposure of the co-administered HIV PIs comparable with ritonavir.

"We are very encouraged by the significant pharmacokinetic enhancing ability of SPI-452 combined with its positive safety and tolerability profile," said John Erickson, PhD, cofounder and chief scientific officer of Sequoia. "The data we have collected from multiple studies on SPI-452 strongly support the continued human testing of SPI-452 and its development as a stand- alone agent or component of a fixed-dose combination, and t
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