Lack of pharmacokinetic drug-drug interaction between ramucirumab and irinotecan in patients with advanced solid tumors.

Wang, Ding; Braiteh, Fadi; Lee, James; Denlinger, Crystal; Shepard, Dale; Chaudhary, Archana; Lin, Yong; Gao, Ling; Asakiewicz, Christopher; Nasroulah, Federico; LoRusso, Patricia; Lee, James J; Denlinger, Crystal S; Shepard, Dale R

<bold>Purpose: </bold>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).<bold>Methods: </bold>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.<bold>Results: </bold>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.<bold>Conclusions: </bold>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.

PHARMACOKINETICS; DRUG interactions; TUMOR treatment; IRINOTECAN; INTRAVENOUS injections; THERAPEUTICS; THERAPEUTIC use of monoclonal antibodies; ANTINEOPLASTIC agents; ANTINEOPLASTIC antibiotics; ASIANS; CAMPTOTHECIN; FLUOROURACIL; FOLINIC acid; MONOCLONAL antibodies; TUMORS; PHARMACODYNAMICS

Cancer Chemotherapy & Pharmacology, 2016, Vol 78, Issue 4, p727

0344-5704

Academic Journal

10.1007/s00280-016-3125-4