title: Calcium carbonate does not affect nilotinib pharmacokinetics in healthy volunteers.
abstract: BACKGROUND
  Gastric upset is a common side effect of nilotinib therapy, and calcium carbonate is frequently used concomitantly, either as antacid or as calcium supplementation. With the increasing number of oral agents in cancer therapy, oral drug-drug interactions are becoming more relevant. Nilotinib has already been shown to be absorbed to a much lesser extent when co-administered with proton pump inhibitors. Because exposure to sub-therapeutic concentrations of anticancer drugs such as nilotinib may result in selection of resistant clones and ultimately relapse, we studied the effect of a calcium carbonate supplement (Tums Ultra 1000®) on nilotinib pharmacokinetics.
  
  
  CONCLUSIONS
  Calcium carbonate may be co-administered with nilotinib without significantly affecting the pharmacokinetics of nilotinib and potentially impacting efficacy.
  
  
  OBJECTIVE
  Nilotinib is a second-generation oral tyrosine kinase inhibitor with superior efficacy compared with imatinib mesylate in the treatment for chronic phase chronic myelogenous leukemia. Calcium carbonate is commonly used as a source of calcium supplementation or as antacid to ameliorate the gastrointestinal side effects associated with nilotinib, which could have unknown effects on nilotinib absorption. The purpose of this study was to provide information on the effect of calcium carbonate on the PK of nilotinib in healthy volunteers.
  
  
  METHODS
  Healthy subjects were enrolled in a two-period, open-label, single-institution, randomized, cross-over, fixed-schedule study. In one period, each subject received 400 mg of nilotinib p.o. In the other period, 4,000 mg of calcium carbonate (4 X Tums Ultra 1000®) was administered p.o. 15 min prior to the nilotinib dose. Plasma samples were collected at specified timepoints, concentrations of nilotinib were quantitated by LC-MS, and data were analyzed non-compartmentally.
  
  
  RESULTS
  Eleven subjects were evaluable. Calcium supplementation did not significantly affect nilotinib pharmacokinetic parameters including area under the plasma concentration versus time curve (18.4 μg/mL h alone vs. 16.9 μg/mL h with calcium carbonate, p = 0.83; 80 % power); maximum plasma concentration (C(max)) (0.670 μg/mL alone vs. 6.18 μg/mL with calcium carbonate, p = 0.97); or half-life (18.9 h alone vs. 17.2 h with calcium carbonate, p = 0.18).
  
  
  CONCLUSIONS
  Our results indicate that the use of calcium carbonate does not significantly affect nilotinib pharmacokinetics.
authors.affiliation: Molecular Therapeutics/Drug Discovery Program, University of Pittsburgh Cancer Institute, Hillman Research Pavilion, Room G27D, 5117 Centre Avenue, Pittsburgh, PA, 15213-1863, USA.
authors.forename: Hussein A
authors.initials: HA
authors.lastname: Tawbi
authors.forename: An L
authors.initials: AL
authors.lastname: Tran
authors.forename: Susan M
authors.initials: SM
authors.lastname: Christner
authors.forename: Yan
authors.initials: Y
authors.lastname: Lin
authors.forename: Matthew
authors.initials: M
authors.lastname: Johnson
authors.forename: Emily
authors.initials: E
authors.lastname: Mowrey
authors.forename: Leonard R
authors.initials: LR
authors.lastname: Appleman
authors.forename: Ronald
authors.initials: R
authors.lastname: Stoller
authors.forename: Brian M
authors.initials: BM
authors.lastname: Miller
authors.forename: Merrill J
authors.initials: MJ
authors.lastname: Egorin
authors.forename: Jan H
authors.initials: JH
authors.lastname: Beumer
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000863:Antacids / Q000009:adverse effects* / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D002119:Calcium Carbonate / Q000009:adverse effects* / Q000627:therapeutic use; D002136:Calcium, Dietary / Q000009:adverse effects / Q000627:therapeutic use; D018592:Cross-Over Studies; D019587:Dietary Supplements / Q000009:adverse effects*; D005260:Female; D018565:Food-Drug Interactions; D005753:Gastric Mucosa / Q000187:drug effects / Q000378:metabolism; D005756:Gastritis / Q000139:chemically induced / Q000517:prevention & control; D006207:Half-Life; D006801:Humans; D007408:Intestinal Absorption; D008297:Male; D011505:Protein-Tyrosine Kinases / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D011743:Pyrimidines / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*
chemical_list: D000863:Antacids; D000970:Antineoplastic Agents; D002136:Calcium, Dietary; D011743:Pyrimidines; D011505:Protein-Tyrosine Kinases; C498826:nilotinib; D002119:Calcium Carbonate
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