ABSTRACT
BACKGROUND: Reducing nivolumab dose intensity could increase patients' life quality and decrease the financial burden while maintaining efficacy. The aims of this study were to develop a population PK model of nivolumab based on data from unselected metastatic cancer patients and to simulate extended-interval regimens allowing to maintain minimal effective plasma concentrations (MEPC). METHODS: Concentration-time data (992 plasma nivolumab concentrations, 364 patients) were modeled using a two-compartment model with linear elimination clearance in Monolix software. Extended-interval regimens allowing to maintain steady-state trough concentrations (Cmin,ss) above the MEPC of 2.5 mg/L or 1.5 mg/L in >90% of patients were simulated. RESULTS: Increasing 3-times the dosing interval from 240 mg every two weeks (Q2W) to Q6W and 2-times from 480 mg Q4W to Q8W resulted in Cmin,ss above 2.5 mg/L in 95.8% and 95.4% of patients, respectively. 240 mg Q8W and 480 mg Q10W resulted in Cmin,ss above 1.5 mg/L in 91.0% and 91.8% of patients, respectively. Selection of a 240 mg Q6W regimen would decrease by 3-fold the annual treatment costs compared to standard regimen of 240 mg Q2W (from 78,744 to 26,248 in France). CONCLUSIONS: Clinical trials are warranted to confirm the non-inferiority of extended-interval compared to standard regimen.
Subject(s)
Drug Administration Schedule , Neoplasms , Nivolumab , Humans , Nivolumab/administration & dosage , Nivolumab/pharmacokinetics , Neoplasms/drug therapy , Neoplasms/pathology , Female , Male , Aged , Middle Aged , Computer Simulation , Antineoplastic Agents, Immunological/administration & dosage , Antineoplastic Agents, Immunological/pharmacokinetics , Adult , Aged, 80 and over , Immune Checkpoint Inhibitors/administration & dosage , Immune Checkpoint Inhibitors/pharmacokinetics , Models, BiologicalABSTRACT
BACKGROUND: Tramadol poisoning rarely causes serotonin toxicity, which mechanisms remain poorly understood. We investigated alterations in tramadol pharmacokinetics in a tramadol-poisoned patient who presented with marked and prolonged serotonin toxicity. CASE REPORT: A 21-year-old male self-ingested 750 mg-tramadol, 200 mg-sotalol, 400 mg-propranolol and 6 mg-lorazepam. He was a kidney transplant patient treated with mycophenolate, tacrolimus, prednisone, and paroxetine. He developed transitory cardiovascular failure and prolonged serotonin toxicity requiring sedation, muscle paralysis, and cyproheptadine, with a favorable outcome. METHODS: We measured plasma concentrations of tramadol, M1, M2, and M5 using liquid-chromatography-tandem mass spectrometry, calculated elimination half-lives and metabolic ratios of the compounds, and genotyped cytochromes involved in tramadol metabolism. RESULTS: Elimination half-lives of tramadol (6.1 h) and M1 (7.1 h) were normal while those of M2 (26.5 h) and M5 (16.7 h) prolonged. M1 metabolic ratio (0.12) was 2-fold reduced, M2 metabolic ratio (197) 1000-fold increased and M5 metabolic ratio (0.12) normal. This metabolic profile in a patient with normal CYP2D6-metabolizer status based on genotyping supports CYP2D6 inhibition by paroxetine and propranolol, two strong mechanism-based inhibitors. Only M2 present in sufficient concentrations up to 48 h could explain the prolonged serotonin toxicity. CONCLUSION: Marked and prolonged serotonin toxicity was attributed to increased M2 production due to paroxetine- and propranolol-related CYP2D6 inhibition of tramadol metabolism.
