Lack of pharmacokinetic (PK) interactions between lonafarnib (L) and imatinib (I)

Background L (SCH 66336), an oral farnesyl protein transferase inhibitor, is being developed for the treatment of hematologic malignancies. In vitro data suggest that L can inhibit proliferation of I‐resistant cells and increases I‐induced apoptosis. An objective of this Phase 1 study was to evaluate the potential for a PK interaction between L and I. Methods Patients (n=1–4/dose) received 100 or 125 mg L orally twice daily in combination with 400 or 600 mg I orally once daily. Plasma samples were collected and analyzed for plasma L and I concentrations to assess the multiple‐dose PK of L and I. Results Mean (%CV) AUC(τ) values of L and I are: (see Table) The AUC values of I in this study when administered with L were similar to those reported when I was administered alone. Additionally, the multiple‐dose PK of L in this study when 100 mg L was administered with 400 mg I was similar to those in previous studies when 100 mg L was administered alone. The AUC of L was lower when co‐administered with 600 mg I as compared to 400 mg I, which is possibly due to an increase in volume from the fluid retention of higher dose of I. Conclusions Multiple doses of L do not apparently affect the PK of I, and vice versa. Further clinical studies to assess the efficacy of this combination are warranted. Clinical Pharmacology & Therapeutics (2005) 77 , P17–P17; doi: 10.1016/j.clpt.2004.11.069Dose (mg) I AUC (μg hr/mL) L AUC (μg hr/mL)100 L + 400 I 38.7 (9%) 9.07 (46%) 125 L + 400 I 42.2 (NA) 24.3 (NA) 100 L + 600 I 63.8 (33%) 2.30 (57%) 125 L + 600 I 87.5 (36%) 11.2 (29%) 100 L alone — 8.77 (67%) 400 I alone 40.1 (39%) —600 I alone 51.7 (52%) —