Trifluridine/Tipiracil in Combination with Bevacizumab in First-Line for Metastatic Colorectal Cancer: A Way Forward. A Point of View Based on Cost-Effectiveness

Introduction: The aim of this analysis is to assess the pharmacological costs of trifluridine/tipiracil as first-line treatment in metastatic colorectal cancer (mCRC) patients who were not candidates for combination with cytotoxic chemotherapies.Discussion: TASCO1 Trial was considered (153 patients). Differences in costs between the 2 arms (trifluridine/tipiracil plus bevacizumab vs. capecitabine plus bevacizumab) was 9113 € (10 264 USD), with a cost savings of 1982 € (2232 USD) per month of overall survival (OS)-gain.Conclusion: Trifluridine/tipiracil could be consider a cost-effective treatment also in first-line for mCRC patients who were not candidates for combination with cytotoxic chemotherapies.     

Population Pharmacokinetics and Exposure–Response Analyses of Ustekinumab in Patients With Moderately to Severely Active Crohn's Disease

PurposeUstekinumab, a fully human immunoglobulin G1κ monoclonal antibody that antagonizes human interleukin-12/23p40, is an effective therapy for several immune-mediated inflammatory diseases, including Crohn's disease (CD). This work characterizes the population pharmacokinetic (PK) and exposure–response (E-R) relationships of ustekinumab in patients with CD using data from four Phase IIb/III clinical studies.MethodsSerum ustekinumab concentration–time data from 1673 patients after IV and/or SC administration of ustekinumab were fitted simultaneously using nonlinear mixed effects modeling to develop a population PK model, which was subsequently used to evaluate simulation scenarios. Logistic regression E-R models were used to assess relationships between serum ustekinumab concentrations and clinical remission after induction (n = 1910) and maintenance (n = 387) treatment.FindingsUstekinumab PK properties are well described by a two-compartment model with first-order absorption and elimination. Typical values of PK parameters for a 70-kg patient were: clearance, 0.192 L/d; volume of distribution at steady state, 4.62 L; and intercompartmental clearance, 0.287 L/d. Ustekinumab terminal elimination t_1/2 was 19 days, and bioavailability after SC administration was 78.3%. Ustekinumab clearance was not affected by coadministration of immunosuppressive agents or corticosteroids. Body weight, serum albumin, and C-reactive protein (CRP) concentrations, tumor necrosis factor (TNF) antagonist failure status, sex, race (Asian vs non-Asian), and anti-ustekinumab antibody status significantly affected ustekinumab disposition; however, the effects of these covariates on ustekinumab exposure were not clinically relevant. The population PK model predicts that a milligram/kilogram dosing approach will result in lower ustekinumab exposure in patients with lower body weight. A positive E-R relationship was established between ustekinumab concentration and efficacy outcomes. The treatment effect of ustekinumab after induction therapy was more pronounced among patients with higher baseline CRP concentrations relative to those with lower values.ImplicationsIn patients with CD, ustekinumab disposition after IV and SC administration was biexponential and consistent with those in patients with ulcerative colitis. Prior treatment with TNF antagonists or the concomitant use of immunosuppressive agents or corticosteroids had no effect on ustekinumab disposition. None of the covariates that affected ustekinumab clearance had a clinically meaningful impact on ustekinumab exposure. E-R models support recommended posology of ustekinumab in adults with CD; however, an ～6 mg/kg IV induction dose in pediatric patients with lower body weights may not provide exposure that matches that in adult patients. ClinicalTrials.gov identifiers: NCT00771667, NCT01369329, NCT01369342, and NCT01369355.