title: Lack of pharmacokinetic drug-drug interaction between ramucirumab and irinotecan in patients with advanced solid tumors.
abstract: The objective of this phase II study was to evaluate the potential of pharmacokinetic (PK) drug-drug interactions between ramucirumab and irinotecan or its metabolite, SN-38, when administered with folinic acid and 5-fluorouracil (FOLFIRI).
  
  
  
  Patients received intravenous infusions of FOLFIRI and ramucirumab 8 mg/kg on Day 1 of a 2-week cycle. FOLFIRI was administered alone in Cycle 1; ramucirumab followed by FOLFIRI was administered in all subsequent cycles. Blood was collected at regular intervals after infusions in Cycles 1 and 2 to determine irinotecan, SN-38, and ramucirumab concentrations. PK parameters were derived by noncompartmental analysis.
  
  
  
  Twenty-nine patients received treatment. The dose-normalized area under the concentration versus time curve from zero to infinity [AUC(0-∞)] and the maximum observed concentration (C max) of irinotecan and SN-38 were comparable between Cycle 1 (FOLFIRI alone) and Cycle 2 (ramucirumab + FOLFIRI). The ratios of geometric least squares (LS) means for irinotecan were 0.93 (90 % CI 0.83-1.05) for AUC(0-∞) and 1.04 (90 % CI 0.97-1.12) for C max. The ratios of geometric LS means for SN-38 were 0.95 (90 % CI 0.88-1.04) for AUC(0-∞) and 0.97 (90 % CI 0.85-1.12) for C max. The most common treatment-emergent adverse events, regardless of grade, were fatigue (19 patients, 65.5 %), diarrhea, (16 patients, 55.2 %), and neutropenia (15 patients, 51.7 %). Grade ≥3 neutropenia was reported in 7 (24.1 %) patients.
  
  
  
  There was no PK drug-drug interaction between ramucirumab and irinotecan or its metabolite, SN-38. Ramucirumab with FOLFIRI was well tolerated in this study, with no new safety concerns.
authors: Henry Ford Hospital, 2799 West Grand Boulevard, Detroit, MI, 48202, USA. dwang1@hfhs.org.
authors: Ding
authors: D
authors: Wang
authors: Comprehensive Cancer Centers of Nevada, Las Vegas, NV, USA.
authors: Fadi
authors: F
authors: Braiteh
authors: University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
authors: James J
authors: JJ
authors: Lee
authors: Fox Chase Cancer Center, Philadelphia, PA, USA.
authors: Crystal S
authors: CS
authors: Denlinger
authors: Cleveland Clinic, Cleveland, OH, USA.
authors: Dale R
authors: DR
authors: Shepard
authors: Eli Lilly and Company, Indianapolis, IN, USA.
authors: Archana
authors: A
authors: Chaudhary
authors: Eli Lilly and Company, Indianapolis, IN, USA.
authors: Yong
authors: Y
authors: Lin
authors: Eli Lilly and Company, Bridgewater, NJ, USA.
authors: Ling
authors: L
authors: Gao
authors: Eli Lilly and Company, Bridgewater, NJ, USA.
authors: Christopher
authors: C
authors: Asakiewicz
authors: Eli Lilly and Company, Bridgewater, NJ, USA.
authors: Federico
authors: F
authors: Nasroulah
authors: Yale Cancer Center, New Haven, CT, USA.
authors: Patricia
authors: P
authors: LoRusso
mesh_terms: D000328:Adult; D000368:Aged; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D019540:Area Under Curve; D044466:Asian People; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use; D004347:Drug Interactions; D005260:Female; D005472:Fluorouracil / Q000494:pharmacology; D006801:Humans; D000077146:Irinotecan; D002955:Leucovorin / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D000096662:Ramucirumab
chemical_list: D000903:Antibiotics, Antineoplastic; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D000972:Antineoplastic Agents, Phytogenic; D002166:Camptothecin; D005472:Fluorouracil; D000077146:Irinotecan; D002955:Leucovorin; D000096662:Ramucirumab
keywords: Drug–drug interactions; FOLFIRI; Irinotecan; Pharmacokinetics; Ramucirumab; SN-38