Drug Interaction Report

GENERALLY AVOID: Coadministration with idelalisib may increase the plasma concentrations of drugs that are substrates of CYP450 3A4. Idelalisib has been shown to be a potent inhibitor of this isoenzyme. In healthy volunteers, administration of a single 5 mg dose of midazolam, a CYP450 3A4 probe substrate, with idelalisib 150 mg for 15 doses increased mean midazolam peak plasma concentration (Cmax) by 2.4-fold and systemic exposure (AUC) by 5.4-fold.

MANAGEMENT: Use of idelalisib should generally be avoided with drugs that are primarily metabolized by CYP450 3A4, particularly those with a narrow therapeutic range (e.g., antiarrhythmics, anticonvulsants, antineoplastics, immunosuppressants) or those that are considered sensitive substrates (e.g., ergot derivatives, statins, oral midazolam, triazolam). Dosage adjustments as well as clinical and laboratory monitoring may be appropriate for some drugs whenever idelalisib is added to or withdrawn from therapy, if coadministration is required.

Coadministration with grapefruit juice does not appear to affect the pharmacokinetics of quinine in a clinically relevant manner. Although grapefruit juice is an inhibitor of CYP450 3A4 and quinine is metabolized by this pathway to its major metabolite, 3-hydroxyquinine, a study of ten healthy volunteers found no significant differences in quinine peak plasma concentration (Cmax), time to reach Cmax (Tmax), terminal elimination half-life, systemic exposure (AUC), or apparent oral clearance (Cl/F) when a single 600 mg oral dose of quinine sulfate was administered in combination with 200 mL of orange juice (control), half-strength grapefruit juice, and full-strength grapefruit juice twice daily for 6 days each, separated by a 2-week washout period. Relative to the control period, the apparent renal clearance of quinine was markedly increased by 81% during treatment with half-strength grapefruit juice. However, since renal clearance accounts for approximately 6% of the total clearance of quinine, this change would likely have minimal clinical impact. The lack of a significant interaction is probably due to the fact that grapefruit juice primarily inhibits intestinal rather than hepatic CYP450 3A4, and quinine is not known to undergo significant presystemic metabolism as evidenced by its relatively high oral bioavailability (76% to 88%). Nevertheless, excessive consumption of grapefruit juice and tonic water (which contains quinine) was suspected as the cause of torsade de pointes arrhythmia in a patient with a history of asymptomatic long QT syndrome. Treatment with magnesium sulfate and metoprolol had no effect, but the arrhythmia resolved spontaneously 48 hours after discontinuation of the drinks. Based on current data, moderate grapefruit juice consumption is probably safe for the majority of patients taking quinine.