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Pharmacokinetic Drug Interaction Between AEE788 and RAD001 Causing Thrombocytopenia in Patients With Glioblastoma

Pharmacokinetic Drug Interaction Between AEE788 and RAD001 Causing Thrombocytopenia in Patients With Glioblastoma

David A Reardon, Timothy Cloughesy, Jeremy Rich, W K Alfred Yung, Lotus Yung, Clifford DiLea, Jerry Huang, Margaret Dugan, William Mietlowski, Andrea Maes, Charles Conrad

Cancer Chemother Pharmacol. 2012 Jan;69(1):281-7.

PMID: 21984222

Abstract:

Purpose:
Treating glioblastoma through the simultaneous inhibition of multiple transduction pathways may prove more effective than single-pathway inhibition. We evaluated the safety, biologic activity, and pharmacokinetic profile of oral AEE788, a selective inhibitor of epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF), plus oral RAD001, a mammalian target of rapamycin inhibitor, in glioblastoma patients.
Methods:
This phase IB/II, open-label, multicenter, 2-arm, dose-escalation study enrolled adult glioblastoma patients at first or second recurrence/relapse. Primary objective was to determine the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of AEE788 combined with RAD001. Secondary objectives included determining the safety/tolerability, pharmacokinetics, pharmacodynamics, and antitumor activity of the combination.
Results:
Sixteen patients were enrolled (AEE788 200 mg/day + RAD001 5 mg/day, 2 patients; AEE788 150 mg/day + RAD001 5 mg every other day [qod], 14); all patients discontinued the study most commonly because of disease progression. Four patients experienced DLT (AEE788 200 mg/day + RAD001 5 mg/day, 1 patient; AEE788 150 mg/day + RAD001 5 mg qod, 3). Both patients receiving AEE788 (200 mg/day) plus RAD001 (5 mg/day) experienced clinically significant thrombocytopenia requiring a dose reduction/interruption. AEE788 appeared to inhibit the metabolism of RAD001. The study was terminated prematurely before an MTD was determined because of safety findings in other studies evaluating AEE788 monotherapy.
Conclusions:
The coadministration of AEE788 and RAD001 in glioblastoma patients caused a clinically significant thrombocytopenia and a higher-than-expected RAD001 area under the curve concentration when dosed at 200 and 5 mg/day, respectively. After a dose reduction to AEE788 (150 mg/day) and RAD001 (5 mg qod), the combination appeared to be better tolerated.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP497839620	AEE788		497839-62-0	Price

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