title: Nilotinib for imatinib-resistant or -intolerant chronic myeloid leukemia in chronic phase, accelerated phase, or blast crisis: a single- and multiple-dose, open-label pharmacokinetic study in Chinese patients.
abstract: BACKGROUND
  Nilotinib, an oral second-generation Bcr-Abi tyrosine kinase inhibitor, is approved in the United States and European Union for the treatment of Philadelphia chromosome-positive (Ph+), chronic-phase (CP) or accelerated-phase (AP) chronic myeloid leukemia (CML) resistant to or intolerant of prior therapy, including imatinib. Information on the pharmacokinetics of nilotinib in Chinese patients with CML is lacking, and regulatory requirements for registration of this drug are needed in China.
  
  
  OBJECTIVE
  This study assessed the pharmacokinet-ics of single and multiple oral doses of nilotinib in Chinese patients with CML and compared the pharmacokinetic profiles of nilotinib between the Chinese patients and a subgroup of white patients with CML.
  
  
  METHODS
  Chinese patients aged > or =18 years with Ph+ CML-CP, CML-AP, or CML-BC (blast crisis) resistant to or intolerant of imatinib were eligible. Patients were administered oral nilotinib 400 mg BID for 15 days. Serial blood samples were collected before and at 1, 2, 3, 5, 8, and 12 hours after the administration of a single dose (day 1) and multiple doses (day 15, steady state). Serum nilotinib concentrations were determined using a validated liquid chromatography-tandem mass spectrometry assay, and pharmacokinetic parameters of nilotinib were calculated using a noncompartmental method. Tolerability was assessed using cardiac assessments; laboratory analysis (hematology, blood chemistry, and urinalysis); and physical examination, including vital signs.
  
  
  RESULTS
  Twenty-three patients were enrolled (18 men, 5 women; mean age, 40.0 years; mean weight, 68.3 kg; CML-CP, 22 patients; CML-AP, 1). All 23 patients were included in the tolerability analysis. Two patients withdrew consent and discontinued after administration of the first dose; thus, 21 patients were included in the pharmacokinetic analysis. Median T(max) was ~2 hours after administration of single and multiple doses. At steady state, C(min) was 1025.4 ng/mL and C(max) was 2160.7 ng/mL. Mean AUCs from time 0 to the end of the dosing interval tau (AUC(0-tau)) were 5076.3 and 17,751.3 ng . h/mL at days 1 and 15, respectively, representing an accumulation factor of 3.92. Apparent oral clearance (CL/F) was 0.39 L/h/kg (range, 0.12-0.74 L/h/ kg) at steady state. The study found a 42% intersubject variability in nilotinib pharmacokinetics. Steady-state C(max), C(min), AUC(0-tau), and CL/F were not significantly different from those previously reported in a subgroup of white patients with CML who received the same 400-mg BID dose. Rash (11/23 patients [47.8%]) and elevated bilirubin, headache, and muscle pain (4 patients each [17.4%]) were the most frequently reported nonhematologic adverse events.
  
  
  CONCLUSIONS
  In this pharmacokinetic study in Chinese patients with CML resistant to or intolerant of imatinib, nilotinib 400 mg BID was rapidly absorbed after a single dose and multiple doses. The steady-state pharmacokinetic properties in this population were consistent with those reported previously in white patients with CML.
authors.affiliation: Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
authors.forename: Li
authors.initials: L
authors.lastname: Zhou
authors.forename: Fanyi
authors.initials: F
authors.lastname: Meng
authors.forename: Ophelia
authors.initials: O
authors.lastname: Yin
authors.forename: Jianxiang
authors.initials: J
authors.lastname: Wang
authors.forename: Ying
authors.initials: Y
authors.lastname: Wang
authors.forename: Yongqiang
authors.initials: Y
authors.lastname: Wei
authors.forename: Pei
authors.initials: P
authors.lastname: Hu
authors.forename: Zhixiang
authors.initials: Z
authors.lastname: Shen
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D019540:Area Under Curve; D044466:Asian People; D001549:Benzamides; D001752:Blast Crisis / Q000188:drug therapy; D002681:China; D002853:Chromatography, Liquid; D004334:Drug Administration Schedule; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D000068877:Imatinib Mesylate; D015465:Leukemia, Myeloid, Accelerated Phase / Q000188:drug therapy; D015466:Leukemia, Myeloid, Chronic-Phase / Q000188:drug therapy; D008297:Male; D008875:Middle Aged; D010879:Piperazines / Q000008:administration & dosage; D011743:Pyrimidines / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D053719:Tandem Mass Spectrometry; D044465:White People; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; C498826:nilotinib