K. Morrissey, T. Lu, K. Faber, D. Apt, J. Lauchle, J. Schutzman, G. Shankar, S. Singel, M. Dresser, J. Jin, J. Ware; Genentech, Inc., South San Francisco, CA
BACKGROUND: GDC-0941 is an orally administered potent and selective pan-inhibitor of phosphoinositide-3 kinase (PI3K) that is currently being investigated in Phase II clinical trials as an anti-cancer agent in combination with paclitaxel. GDC-0941 is an in vitro inhibitor of CYP2C8-mediated paclitaxel-6α hydroxylation (OH), with a 1+I/Ki > 1.1 and [I,fu]/Ki >0.02, and therefore further investigation of the clinical impact of GDC-0941 on paclitaxel pharmacokinetics (PK) was warranted.
METHODS: Plasma concentrations of GDC-0941, paclitaxel and 6’OH-paclitaxel were measured in two ongoing Phase Ib studies (GDC4628g, n=38; GDC4629g, n=50) with escalating oral doses of GDC-0941 (60-330 mg QD) in combination with paclitaxel at two different intravenous dose levels (90 mg/m2, QW and 200 mg/m2, Q3W). The PK parameters of GDC-0941 and paclitaxel were determined by non-compartmental analysis. The impact of GDC-0941 on the PK of paclitaxel was evaluated by comparing paclitaxel exposure to single agent population PK (popPK) predictions and by assessing alterations in the 6’OH-paclitaxel:paclitaxel AUC ratio with increasing GDC-0941 dose.
RESULTS: In both Phase Ib studies, paclitaxel PK is consistent with the published popPK model at all doses of GDC-0941 (60-330 mg QD). In addition, the 6’OH-paclitaxel:paclitaxel AUC ratio is consistent across all dose level and is independent of GDC-0941 dose.
CONCLUSION: Current data demonstrate that GDC-0941 does not have a clinical impact on paclitaxel PK and is supportive of future clinical development of these two agents in combination.