PMID- 24094464 OWN - NLM STAT- MEDLINE DCOM- 20140711 LR - 20220602 IS - 1879-114X (Electronic) IS - 0149-2918 (Linking) VI - 35 IP - 11 DP - 2013 Nov TI - Exposure-response (safety) analysis to identify linifanib dose for a Phase III study in patients with hepatocellular carcinoma. PG - 1770-7 LID - S0149-2918(13)00946-6 [pii] LID - 10.1016/j.clinthera.2013.09.002 [doi] AB - BACKGROUND: Hepatocellular carcinoma (HCC) is the third most common cause of cancer-related deaths and the fifth most common cancer globally. Hepatocellular carcinoma produces highly vascular tumors that overexpress vascular endothelial growth factor (VEGF), thus making VEGF a promising therapeutic target. The competitive inhibitor linifanib (ABT-869) has selectivity for VEGF and platelet-derived growth factor (PDGF) receptors and minimal activity against unrelated tyrosine and serine and threonine kinases. However, the optimal dosing regimen for linifanib in HCC patients is not yet known. OBJECTIVE: This study attempts to identify a linifanib dose or dosing regimen with an acceptable safety profile for a Phase III study in HCC patients. METHODS: The pharmacokinetic (PK) properties of linifanib were characterized from 2 Phase I and 3 Phase II clinical trials. Of the 266 patients evaluated, the median weight was 68 kg (range, 35-177 kg), 64% were male, and 87.6% of patients received an oral solution of linifanib, whereas 12.4% received a tablet formulation. Approximately 95% of patients received drug based on weight, with the remaining on a fixed-dosing regimen. A population PK analysis was conducted to characterize the linifanib exposure for each patient. Linifanib Cmax and AUC derived from the population PK properties were correlated with the rates of adverse events (AEs). RESULTS: Linifanib PK properties are dose proportional for the 0.10-mg/kg to 0.25-mg/kg once daily dose range and are time independent after repeated oral dosing. The Tmax of linifanib is approximately 3 hours, and the t(1/2) is approximately 1 day. The most common AEs related to linifanib PK were hypertension (P = 0.02 for Cmax and P = 0.01 for AUC), diarrhea (P = 0.001 for Cmax and P = 0.0012 for AUC), proteinuria (P = 0.001 for Cmax and P = 0.002 for AUC), and asthenia (P = 0.03 for AUC). Weight and sex were identified as covariates for Cmax, and sex was identified as a covariate for AUC. The predicted AE range for females was slightly higher compared with males; however, the AE range is tighter for the weight range for fixed dosing compared with weight-based dosing, regardless of sex. CONCLUSIONS: The PK properties of linifanib support a one-compartment model with first-order absorption and elimination. Comparison of weight-based and fixed dosing revealed predicted AE rates to be similar, with a tighter AE range for fixed dosing. The safety profile of linifanib, therefore, supports a 17.5 mg fixed starting dose for Phase III clinical studies. CI - Copyright (c) 2013 Elsevier HS Journals, Inc. All rights reserved. FAU - Chiu, Yi-Lin AU - Chiu YL AD - AbbVie, North Chicago, Illinois. Electronic address: Yi-Lin.Chiu@abbvie.com. FAU - Carlson, Dawn M AU - Carlson DM FAU - Pradhan, Rajendra S AU - Pradhan RS FAU - Ricker, Justin L AU - Ricker JL LA - eng PT - Clinical Trial, Phase I PT - Clinical Trial, Phase II PT - Journal Article PT - Multicenter Study DEP - 20131002 PL - United States TA - Clin Ther JT - Clinical therapeutics JID - 7706726 RN - 0 (Antineoplastic Agents) RN - 0 (Indazoles) RN - 0 (Pharmaceutical Solutions) RN - 0 (Phenylurea Compounds) RN - 0 (Tablets) RN - CO93X137CW (linifanib) SB - IM MH - Administration, Oral MH - Adult MH - Aged MH - Aged, 80 and over MH - Antineoplastic Agents/administration & dosage/*adverse effects/*pharmacokinetics MH - Dose-Response Relationship, Drug MH - Female MH - Humans MH - Indazoles/administration & dosage/*adverse effects/*pharmacokinetics MH - Male MH - Middle Aged MH - Neoplasm Metastasis MH - Neoplasms/*drug therapy/metabolism MH - Pharmaceutical Solutions MH - Phenylurea Compounds/administration & dosage/*adverse effects/*pharmacokinetics MH - Tablets MH - Young Adult OTO - NOTNLM OT - HCC OT - PDGF OT - VEGF OT - linifanib EDAT- 2013/10/08 06:00 MHDA- 2014/07/12 06:00 CRDT- 2013/10/08 06:00 PHST- 2013/05/13 00:00 [received] PHST- 2013/08/16 00:00 [revised] PHST- 2013/09/03 00:00 [accepted] PHST- 2013/10/08 06:00 [entrez] PHST- 2013/10/08 06:00 [pubmed] PHST- 2014/07/12 06:00 [medline] AID - S0149-2918(13)00946-6 [pii] AID - 10.1016/j.clinthera.2013.09.002 [doi] PST - ppublish SO - Clin Ther. 2013 Nov;35(11):1770-7. doi: 10.1016/j.clinthera.2013.09.002. Epub 2013 Oct 2.