Evaluation Of Drug Interaction Profile Of Idelalisib and Its Major Circulating Metabolite, GS-563117, In Healthy Subjects

Idelalisib (IDELA) is a potent PI3K inhibitor in Phase 3 development for hematologic malignancies. IDELA is metabolized primarily by aldehyde oxidase to form GS-563117 and to a lesser extent by CYP3A and UGT1A4. In vitro, IDELA inhibits Pgp (IC₅₀: 7.7 mM), OATP1B1 (IC₅₀: 10.1 mM), OATP1B3 (IC₅₀: 7.0 mM), but is not an inhibitor of common metabolizing enzymes and other uptake or secretory transporters at clinically relevant concentration. GS563117 shows time-dependent inhibition of CYP3A (IC₅₀: 5.1 mM, K_I: 0.18 mM, and k_inact: 0.033 min^-1), but is not an inhibitor of other common metabolizing enzymes, or of uptake or secretory transporters at clinically relevant concentration. The present study evaluated the potential for IDELA to affect Pgp and OATP1B1/OATP1B3, GS-563117 to affect CYP3A, and effect of a strong inducer, rifampin, on IDELA pharmacokinetics (PK).

Probe substrates of Pgp (digoxin), OATP1B1/1B3 (rosuvastatin), and CYP3A (midazolam) were each given orally as a single dose either alone or in combination with multiple doses of IDELA 150 mg BID. Additionally, a single dose of IDELA 150 mg was administered either alone or in combination with multiple doses of rifampin at 600 mg QD. Plasma exposures of digoxin, rosuvastatin, midazolam and 1'-hydroxy midazolam, rifampin, IDELA, and GS-563117 were determined using LC/MS/MS. Analysis of variance (ANOVA) using a mixed-effects model was fitted to the natural logarithmic transformation of PK parameters. The 90% confidence intervals were constructed for the ratio of geometric means of PK parameters when each of the probe drugs (or IDELA) is dosed in combination with IDELA (or rifampin) versus when dosed alone, with 70-143% defined as the lack of interaction boundaries. Safety assessments were performed throughout the study.

A total of 24 subjects were enrolled in the study and randomized to two cohorts. The majority of subjects were male, white, and median age was 38.

The most frequently reported adverse events (AE) were headache (∼25% subjects) and pyrexia (∼17%). Treatment-emergent Grade 3 increase in transaminases occurred in 5/24 subjects, and were reversible. Two subjects experienced serious AE following completion of study treatment. There were no clinically significant changes in vital signs or safety ECGs.

Digoxin and rosuvastatin PK were unaffected when given in combination with IDELA 150 mg BID vs dosing alone (Table 1).

Coadministration with IDELA resulted in increased plasma exposures of midazolam increased and decreased 1'-OH-midazolam consistent with the in vitro finding of CYP3A inhibition by IDELA's major metabolite, GS-563117.

Coadministration of IDELA with rifampin caused a substantial decrease in IDELA and GS-563117 exposures, indicating greater contribution of CYP3A to IDELA metabolism under a strongly induced state.

GS-563117, which is the major metabolite of IDELA, is a moderate inhibitor of CYP3A; accordingly, caution is necessary when coadministering narrow therapeutic index agents that are CYP3A substrates with IDELA. Coadministration of strong inducers of CYP3A with IDELA should also be avoided to prevent decreased exposure to IDELA. Overall, IDELA and its metabolite do not affect common intestinal, hepatic or renal drug transporters.

Jin:Gilead Sciences: Employment, Equity Ownership. Robeson:Gilead Sciences: Employment, Equity Ownership. Zhou:Gilead Sciences: Employment, Equity Ownership. Moyer:Gilead Sciences: Employment, Equity Ownership. Wilbert:Gilead Sciences: Employment, Equity Ownership. Murray:Gilead Sciences: Employment, Equity Ownership. Ramanathan:Gilead Sciences: Employment, Equity Ownership.