RESUMO
PURPOSE: The aim of the study was to characterize the population pharmacokinetics (PK) of the intravenous formulation of trastuzumab, assess the impact of patient and pathological covariates on trastuzumab PK, and perform simulations to support dosing recommendations in special situations. METHODS: Serum trastuzumab concentrations were obtained from 1582 patients with metastatic breast cancer (MBC), early breast cancer (EBC), advanced gastric cancer (AGC), or other tumor types/healthy volunteers in 18 phase I, II, and III trials and analyzed by nonlinear mixed-effects modeling. RESULTS: A two-compartment model with parallel linear and nonlinear elimination best described the data. During treatment, linear clearance (CL) dominated, resulting in a total CL of 0.173-0.337 L/day, which is similar to other IgG1 monoclonal antibodies. Covariates influencing CL were baseline body weight, aspartate aminotransferase, albumin, gastric cancer, and the presence of liver metastases. MBC and EBC had similar PK parameters, while CL was higher in AGC. Simulations indicated that at least 95% of patients with BC reach concentrations < 1 µg/mL (~ 97% washout) by 7 months. A dose delay in BC or AGC patients of > 1 week would take approximately 6 weeks to get back within steady-state exposure range. CONCLUSIONS: Trastuzumab PK for the intravenous formulation was well-described across cancer types, disease status, and regimens. No dose adjustment is required for any of the identified patient covariates. A 7-month serum washout period for trastuzumab is recommended. A reloading dose is required if a maintenance dose is missed by > 1 week.
Assuntos
Antineoplásicos Imunológicos/administração & dosagem , Antineoplásicos Imunológicos/farmacocinética , Modelos Estatísticos , Neoplasias/tratamento farmacológico , Receptor ErbB-2/antagonistas & inibidores , Trastuzumab/administração & dosagem , Trastuzumab/farmacocinética , Administração Intravenosa , Estudos de Casos e Controles , Ensaios Clínicos Fase I como Assunto , Ensaios Clínicos Fase II como Assunto , Ensaios Clínicos Fase III como Assunto , Feminino , Seguimentos , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Neoplasias/epidemiologia , Neoplasias/patologia , Prognóstico , Receptor ErbB-2/imunologia , São Francisco/epidemiologia , Distribuição TecidualRESUMO
PURPOSE: The NeoSphere trial evaluated pertuzumab in the neoadjuvant setting [early breast cancer (EBC)] with pathological complete response (pCR) as the primary efficacy end point. This analysis of pertuzumab aimed to (1) compare its pharmacokinetics (PK) in patients with EBC versus advanced cancers, (2) to further evaluate PK drug-drug interactions (DDIs) when given in combination with trastuzumab, and (3) to assess the relationship between exposure and efficacy to assess the clinical dosing regimen in the EBC patients. METHODS: Pertuzumab serum concentration data from 180 patients in NeoSphere were compared to historical observations and potential DDI was assessed, by applying simulation techniques using a population PK model. The impact of pertuzumab exposure on pCR rate was evaluated using a logit response model (n = 88). RESULTS: The observed PK matched the population PK model simulations, confirming that the PK in neoadjuvant EBC appear to be in agreement with the historical observations. No evidence of a DDI effect of trastuzumab or docetaxel on pertuzumab was observed supporting the doses when given in combination. In NeoSphere >90% of EBC patients achieved the non-clinical target serum concentration. There was no association between the pertuzumab serum concentration and pCR within the range observed in this study (20-100 µg/mL) supporting no dose adjustments needed for patients with lower exposure. CONCLUSIONS: This analysis further supports the lack of DDI between the two therapeutic proteins and the appropriateness of the approved fixed non-body-weight-adjusted pertuzumab dose in the treatment of neoadjuvant EBC with pertuzumab in combination with trastuzumab and docetaxel.
Assuntos
Anticorpos Monoclonais Humanizados/farmacocinética , Antineoplásicos/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Terapia Neoadjuvante , Receptor ErbB-2/análise , Adulto , Idoso , Anticorpos Monoclonais Humanizados/administração & dosagem , Neoplasias da Mama/química , Docetaxel , Feminino , Humanos , Modelos Logísticos , Pessoa de Meia-Idade , Taxoides/administração & dosagem , Trastuzumab/administração & dosagemRESUMO
PURPOSE: To characterize the population pharmacokinetics (PK) of pertuzumab across clinical trials in a variety of solid tumors, evaluate the potential impact of patient characteristics on PK, and confirm the appropriateness of the fixed (non-weight-based) dose. METHODS: Pertuzumab concentration data collected following intravenous administration during eleven phase I/II studies and the pivotal phase III trial CLEOPATRA were analyzed using nonlinear mixed-effects modeling. The potential impact of patient and laboratory characteristics and HER2 target-related variables on pertuzumab PK were investigated in a covariate analysis. The final model was used to confirm selection of fixed, non-weight-based dosing of pertuzumab, and to compare pertuzumab PK in CLEOPATRA with the other studies. RESULTS: The analysis included 4,525 serum concentration measurements from 481 patients with solid tumors. Pertuzumab PK in the 2-25 mg/kg dose range was described by a two-compartment linear model with first-order elimination. The elimination clearance and central compartment volume were 0.235 L/day, and 3.11 L, respectively, and the terminal elimination half-life was 18.0 days. Baseline serum albumin and lean body weight had statistically significant effects on pertuzumab clearance; however, simulations showed that the magnitude of their effects on pertuzumab exposure was minimal compared with overall variability and was not clinically relevant. Thus, variations in these factors do not require dose adjustments. CONCLUSIONS: The fixed, non-weight-based dosing of pertuzumab, 840 mg loading dose followed by a 420 mg maintenance dose every 3 weeks, in patients with the solid tumors in this analysis is well supported by the population pharmacokinetic modeling and simulation results.
Assuntos
Anticorpos Monoclonais Humanizados , Genes erbB-2/fisiologia , Neoplasias , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/farmacocinética , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacocinética , Peso Corporal , Ensaios Clínicos como Assunto , Técnicas de Apoio para a Decisão , Relação Dose-Resposta a Droga , Feminino , Meia-Vida , Humanos , Infusões Intravenosas , Masculino , Taxa de Depuração Metabólica , Pessoa de Meia-Idade , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Neoplasias/patologia , Dinâmica não Linear , Albumina SéricaRESUMO
BACKGROUND AND OBJECTIVE: Enrichment strategies which select subjects who appear to respond to the drug have been used in drug studies to demonstrate clinical efficacy. We have used clinical trial simulation techniques to examine factors that are relevant in clinical trial design based on enrichment where poor responders are excluded from the double-blind phase of the study. METHODS: Simulations were performed for an analgesic trial design involving an open-dose titration phase (enrichment phase) followed by a double-blind, randomized, placebo-controlled maintenance phase. Enrichment was examined by excluding subjects above a predefined pain score (cutoff) from analysis of efficacy for the maintenance phase. Cutoff pain scores ranging from 4 to 7 on a 0 to 10 categorical scale were examined. A database consisting of chronic pain patients who participated in studies with a new formulation of buprenorphine was used to build the simulation model. Since no data were available for the key model variable "correlation between treatment and placebo response", values of 0.25, 0.5, and 0.75 were used for the simulations. RESULTS: A correlation between treatment and placebo effect ranging from 0.75 to 0.25 will cause the likelihood of trial success to vary from 50% to 95%. This model also shows that recruitment efficiency will decrease with the use of lower cutoff pain scores. CONCLUSION: Prior to using enrichment techniques, investigators must consider the correlation between treatment effect and placebo response to optimize clinical trial design.