Pharmacokinetics (PK) of lonafarnib (L), a farnesyl protein transferase inhibitor

L (SCH 66336), a tricyclic farnesyl protein transferase inhibitor, is being developed for the treatment of various cancers. Three Phase 1 studies with different oral dosing schedules were conducted to explore the safety and to characterize the PK of L. 79 patients received 25‐400 mg L, twice daily with food (continuously, 7 days on/21‐day cycle, and 14 days on/28–day cycle). Plasma and urine samples were collected and L concentrations were determined by LC‐MS/MS. The single and multiple dose PK were determined using model‐independent methods. The PK characteristics are: L is absorbed and eliminated slowly after oral administration with food. Mean Cmax occurs between 2.5 and 8 hr; mean t1/2 ranges from 3 to 10 hr. L accumulates in plasma after twice daily dosing. The accumulation factor ranged from 3 to 5, which is greater than predicted by the elimination t1/2. Plasma concentrations increase in a greater than dose‐proportional manner. Elimination t1/2 appears to increase and clearance appears to decrease as dose increases and following multiple‐ vs. single‐dose administration. Steady state is attained by Day 7. Urinary recovery of L is less than 0.1% of the dose.These results indicate dose‐dependent PK and support the twice daily dosing of L in ongoing clinical trials. Clinical Pharmacology & Therapeutics (2004) 75 , P59–P59; doi: 10.1016/j.clpt.2003.11.226