Abstract
Abstract 1774
Phosphatidylinositol 3-kinases (PI3Ks) regulate several cellular functions including motility, proliferation, and survival. PI3K pathway signaling is mediated by the Class I PI3K isoforms, α, β, δ and γ. The PI3K p110δ isoform is preferentially expressed in cells of hematological origin and in a variety of malignant cells. CAL-101 is a potent p110δ inhibitor with an EC50 of 62 nM in a whole-blood p110δ assay and >200-fold selectivity for p110δ relative to other PI3K isoforms. Consistent with this target selectivity, nonclinical toxicology and safety pharmacology data supported initial clinical assessment of oral CAL-101 in single-dose, multiple-dose, and food-effect studies in healthy volunteers. Because CAL-101 is a CYP450 3A4 substrate, the effect of ketoconazole (a potent CYP450 3A4 inhibitor) on CAL-101 pharmacokinetics was also evaluated in healthy volunteers. Preliminary evaluation of disposition, metabolism and elimination in healthy volunteers was achieved by coadministering a trace amount of [14C]CAL-101 and unlabeled CAL-101 either orally or intravenously (IV) with samples evaluated by accelerator mass spectrometry. CAL-101 pharmacokinetics (PK) were subsequently evaluated in patients with lymphoid malignancies. In healthy volunteers, CAL-101 was well tolerated at 400 mg (the highest single dose tested) and at 200 mg BID through 7 days (the highest multiple dose tested). The drug has also been symptomatically well tolerated in patients with lymphoid malignancies receiving CAL-101 at dose levels through 350 mg/kg (the highest dose tested) over many months. Monitorable, reversible transaminase elevations have been observed in some patients, most commonly in patients with lymphoma. No maximum tolerated dose (MTD) has been apparent. Increases in Cmax and AUC are less than dose proportional, revealing minimal gains in plasma exposure at dose levels >150 mg BID. The mean volume of distribution was moderate at 57.7 L. The t1/2 was ∼8 hours across all dose levels and there was no plasma accumulation over 7 or 28 days. The collective data support BID dosing at ≥150 mg; dose levels in this range maintain steady-state trough plasma concentrations that are >10-fold above the EC50 for the in vitro whole-blood assay. [14C]CAL-101 was metabolized to only 1 metabolite in plasma and CAL-101-derived materials were primarily excreted in feces (>65% of total dose) with minimal elimination via urine (<15% of total dose). A high-fat, high-calorie meal had no effect on Cmax but slowed absorption, leading to a shift in observed median Tmax from 1.5 h to 4.5 h, and a moderate 1.4-fold increase in AUC; these data suggest that CAL-101 can be given with or without food. When administered following 4 days of ketoconazole, increases in mean CAL-101 Cmax and AUC values were 1.3- and 1.8-fold, respectively; thus, CAL-101 is not a sensitive substrate for CYP450 3A4 and coadministration of CAL-101 with CYP450 3A4 inhibitors does not appear to be contraindicated. Taken together with clinical data documenting PI3K pathway inhibition, modulation of chemokine signaling, and substantial dose-dependent antitumor activity, these findings provide a characterization of CAL-101 clinical pharmacology that supports CAL-101 development as an investigational therapy for cancer and other indications.
Disclosures:
Webb: Calistoga Pharmaceuticals: Employment. Chen:Calistoga Pharmaceuticals: Employment. Yu:Calistoga Pharmaceuticals: Employment. Peterman:Calistoga Pharmaceuticals: Employment. Holes:Calistoga Pharmaceuticals: Employment. Lannutti:Calistoga Pharmaceutical Inc.: Employment. Miller:Calistoga Pharmaceuticals: Employment. Ulrich:Calistoga Pharmaceuticals: Employment, Equity Ownership.
Effect of various oral dose levels of a trimethoprim/sulphadiazine mixture on Bordetella bronchiseptica infection and on the proliferation of trimethoprim-resistant faecal coliforms in pigs
