Claudia Kasserra

Pomalidomide: evaluation of cytochrome P450 and transporter-mediated drug-drug interaction potential in vitro and in healthy subjects.

Pomalidomide offers an alternative for patients with relapsed/refractory multiple myeloma who have exhausted treatment options with lenalidomide and bortezomib. Little is known about pomalidomides potential for drug–drug interactions (DDIs); as pomalidomide clearance includes hydrolysis and cytochrome P450 (CYP450)‐mediated hydroxylation, possible DDIs via CYP450 and drug‐transporter proteins were investigated in vitro and in a clinical study. In vitro pomalidomide was neither an inducer nor inhibitor of CYP450, nor an inhibitor of transporter proteins P glycoprotein (P‐gp), BCRP, OAT1, OAT3, OCT2, OATP1B1, and OATP1B3. Oxidative metabolism of pomalidomide was predominately mediated by CYP1A2 and CYP3A4, and pomalidomide was shown to be a P‐gp substrate. In healthy males, co‐administration of oral (4 mg) pomalidomide with ketoconazole (CYP3A/P‐gp inhibitor) or carbamazepine (CYP3A/P‐gp inducer) did not result in clinically relevant changes in pomalidomide exposure. Co‐administration of pomalidomide with fluvoxamine (CYP1A2 inhibitor) in the presence of ketoconazole approximately doubled pomalidomide exposure. Pomalidomide appears to have low potential for clinically relevant DDI and is unlikely to affect the clinical exposure of other drugs. Avoid co‐administration of strong CYP1A2 inhibitors unless medically necessary. Pomalidomide dose should be reduced by 50% if co‐administered with strong CYP1A2 inhibitors and strong CYP3A/P‐gp inhibitors.

Lenalidomide at Therapeutic and Supratherapeutic Doses Does Not Prolong QTc Intervals in the Thorough QTc Study Conducted in Healthy Men

The effect of lenalidomide on the corrected QT (QTc) interval was evaluated in healthy men and extended to patients based on the lenalidomide concentration–QTc (C–QTc) relationship. A rigorous assessment of the effect of lenalidomide on QTc intervals was conducted in healthy volunteers who each received, in randomized order, a single oral dose of 10 mg lenalidomide, 50 mg lenalidomide, 400 mg moxifloxacin (positive control) and placebo. Plasma lenalidomide exposure was compared between healthy volunteers and patients with multiple myeloma or myelodysplastic syndromes. In healthy volunteers, moxifloxacin produced the expected significant prolongation in QTcI (individual correction). For lenalidomide 10 mg and 50 mg, the time‐matched changes from placebo in the baseline‐adjusted least‐squares mean QTcI were <3 ms with the upper limit of the two‐sided 90% confidence interval for the change <10 ms at all time‐points. No subjects experienced QTcI >450 ms or change from baseline >60 ms after lenalidomide administration. Similar results were seen with QT interval data corrected by Fridericia and Bazett methods. The C–QTc analysis yielded no significant association between lenalidomide concentrations and QTcI changes up to 1522 ng/mL; this range was close to that observed in patients receiving lenalidomide doses up to 50 mg, including those with reduced drug clearance due to renal impairment. In conclusion, single doses of lenalidomide up to 50 mg were not associated with prolonged QTc intervals in healthy males. The C–QTc analysis further assured that lenalidomide doses up to 50 mg are not expected to prolong QTc intervals in patients.