Based on the Phase I trial and its pharmacokinetic profile, the approved dose of idelalisib is 150 mg orally every 12 hours. A reduced dose of 100 mg twice daily is recommended when clinically indicated. Its elimination half-life is 8.2 hours. The time-to-peak plasma concentration increased from 2 to 4 hours with food; however, this was not clinically significant. It is metabolized primarily by aldehyde oxidase (AO), and to a lesser extent by cytochrome P450 3A (CYP3A), to its inactive metabolite GS-563117. Although drug–drug interactions with CYP3A inducers and/or inhibitors could theoretically affect plasma concentration of idelalisib, these may not be clinically significant as the major metabolizing enzyme is AO. Both idelalisib and its metabolite GS-563117 are highly protein-bound at 94% and 99%, respectively. Excretion is mostly hepatobiliary, with 78% of the drug found in feces and only 15% in urine. Given the minimal urinary excretion, dose adjustment in renal impairment is not necessary.22

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Chronic lymphocytic leukemia

The Phase I trial of idelalisib monotherapy in 54 patients with relapsed or refractory CLL showed an ORR of 72% and a median PFS of 15.8 months.23 This supported conducting a Phase III, randomized, double-blind, placebo-controlled trial on 220 patients with previously treated CLL in 90 centers in the USA and Europe between May 2012 and August 2013. The patients were randomized to receive rituximab (R) in combination with idelalisib (150 mg BID) or R with placebo twice daily. High-risk patients with del17p, TP53 mutation, or lack of hypermutation in the immunoglobulin heavy chain (IGHV) were included. This study was terminated early given the superior efficacy of idelalisib. The PFS in the idelalisib vs placebo groups at 24 weeks was 93% vs 46% (P<0.001), and OS at 12 months was 92% vs 80% (P=0.02), respectively.24

A recent Phase II trial investigating the role of idelalisib in combination with R in 64 treatment-naïve patients over 65 years old with CLL (n=59) or SLL (n=5) reported an ORR of 96.9%. Patients with high-risk disease, that is del17p/TP53 mutations or unmutated IGHV, had similar ORRs as well. The median duration of response and PFS were not reached by the time of the analysis, with PFS at 24 months being 92.9% and 82% at 36 months (Table 1).25

(To view a larger version of Table 1, click here.)

At the 2015 Annual Society of Hematology Meeting, results of a Phase III randomized study of BR vs BR + idelalisib for relapsed/refractory CLL, including patients with del17p, demonstrated significantly improved PFS and OS for addition of idelalisib to BR. The safety profile did not demonstrate any new or unexpected adverse events.26