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PI‐15
Author(s) -
Zhu Y.,
Statkevich P.,
Curtis D.,
Sugrue M.,
Kieran M.
Publication year - 2006
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1016/j.clpt.2005.12.036
Subject(s) - pharmacology , transferase , medicine , chemistry , biochemistry , enzyme
BACKGROUND/AIMS Lonafarnib (L, SCH 66336) is an oral farnesyl protein transferase inhibitor (FPTI). Ras mutations or over‐expression have been identified in both adult and pediatric brain tumors. Pre‐clinical studies have demonstrated that both ras mutant and non‐mutated tumors that signal through this pathway can be effectively inhibited by FPTI. In addition to assessment of the dosing‐limiting toxicities and maximally tolerated dose (MTD), an objective of this Phase 1 study was to assess the pharmacokinetics (PK) of L in children with brain tumors. METHODS Patients (n=3–9/dose) received 70 to 150 mg/m 2 L orally twice daily. Plasma samples were collected and analyzed for plasma L concentrations to assess the multiple‐dose PK of L. RESULTS Mean (%CV) PK parameters of L are: (Table)Dose (mg/m 2 ) n Cmax (μg/mL) Tmax (hr) AUC( T ) (μg·hr/mL)70 5 0.81 (27) 4 (2–6) 6.20 (26) 90 9 1.84 (43) 4 (1–8) 15.7 (43) 115 3 4.37 (112) 4 (1–6) 27.8 (114) 150 8 3.57 (65) 4 (0–8) 30.4 (76) Referen 200 mg in adults 21 2.79 (59) 4 (0–12) 25.5 (64)L was safe and well tolerated at doses of 70 to 150 mg/m 2 in children with brain tumors. lonafarnib is slowly absorbed; median tmax values are 4 hr. increases in L exposure are dose‐related. CONCLUSIONS The PK of L at doses of 115 and 150 mg/m 2 in children are similar to those at 200 mg (MTD) in adults. Further clinical studies to assess the efficacy of L in pediatric patients with brain tumors are warranted. Clinical Pharmacology & Therapeutics (2005) 79 , P10–P10; doi: 10.1016/j.clpt.2005.12.036