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1.
Biometrics ; 78(1): 300-312, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-33527351

RESUMO

Phase I dose-finding trials in oncology seek to find the maximum tolerated dose of a drug under a specific schedule. Evaluating drug schedules aims at improving treatment safety while maintaining efficacy. However, while we can reasonably assume that toxicity increases with the dose for cytotoxic drugs, the relationship between toxicity and multiple schedules remains elusive. We proposed a Bayesian dose regimen assessment method (DRtox) using pharmacokinetics/pharmacodynamics (PK/PD) to estimate the maximum tolerated dose regimen (MTD-regimen) at the end of the dose-escalation stage of a trial. We modeled the binary toxicity via a PD endpoint and estimated the dose regimen toxicity relationship through the integration of a dose regimen PD model and a PD toxicity model. For the first model, we considered nonlinear mixed-effects models, and for the second one, we proposed the following two Bayesian approaches: a logistic model and a hierarchical model. In an extensive simulation study, the DRtox outperformed traditional designs in terms of proportion of correctly selecting the MTD-regimen. Moreover, the inclusion of PK/PD information helped provide more precise estimates for the entire dose regimen toxicity curve; therefore the DRtox may recommend alternative untested regimens for expansion cohorts. The DRtox was developed to be applied at the end of the dose-escalation stage of an ongoing trial for patients with relapsed or refractory acute myeloid leukemia (NCT03594955) once all toxicity and PK/PD data are collected.


Assuntos
Antineoplásicos , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Teorema de Bayes , Ensaios Clínicos Fase I como Assunto , Relação Dose-Resposta a Droga , Humanos , Estudos Longitudinais , Dose Máxima Tolerável
2.
Br J Clin Pharmacol ; 88(5): 2052-2064, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-34705283

RESUMO

AIMS: Addition of isatuximab (Isa) to pomalidomide/dexamethasone (Pd) significantly improved progression-free survival (PFS) in patients with relapsed/refractory multiple myeloma (RRMM). We aimed to characterize the relationship between serum M-protein kinetics and PFS in the phase 3 ICARIA-MM trial (NCT02990338), and to evaluate an alternative dosing regimen of Isa by simulation. METHODS: Data from the ICARIA-MM trial comparing Isa 10 mg/kg weekly for 4 weeks then every 2 weeks (QW-Q2W) in combination with Pd versus Pd in 256 evaluable RRMM patients were used. A joint model of serum M-protein dynamics and PFS was developed. Trial simulations were then performed to evaluate whether efficacy is maintained after switching to a monthly dosing regimen. RESULTS: The model identified instantaneous changes (slope) in serum M-protein as the best on-treatment predictor for PFS and baseline patient characteristics impacting serum M-protein kinetics (albumin and ß2-microglobulin on baseline levels, non-IgG type on growth rate) and PFS (presence of plasmacytomas). Trial simulations demonstrated that switching to a monthly Isa regimen at 6 months would shorten median PFS by 2.3 weeks and induce 42.3% patients to progress earlier. CONCLUSIONS: Trial simulations supported selection of the approved Isa 10 mg/kg QW-Q2W regimen and showed that switching to a monthly regimen after 6 months may reduce clinical benefit in the overall population. However, patients with good prognostic characteristics and with a stable, very good partial response may switch to a monthly regimen after 6 months without compromising the risk of disease progression. This hypothesis will be tested in a prospective clinical trial.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Mieloma Múltiplo , Anticorpos Monoclonais Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Ensaios Clínicos Fase III como Assunto , Dexametasona/uso terapêutico , Humanos , Mieloma Múltiplo/tratamento farmacológico , Intervalo Livre de Progressão , Estudos Prospectivos , Talidomida/análogos & derivados
3.
Br J Clin Pharmacol ; 80(3): 534-47, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26095234

RESUMO

AIM: Applying physiologically-based pharmacokinetic (PBPK) modelling in paediatric cancer drug development is still challenging. We aimed to demonstrate how PBPK modelling can be applied to optimize dose and sampling times for a paediatric pharmacokinetic (PK) bridging study in oncology and to compare with the allometric scaling population PK (AS-popPK) approach, using docetaxel as an example. METHODS: A PBPK model for docetaxel was first developed for adult cancer patients using Simcyp® and subsequently used to predict its PK profiles in children by accounting for age-dependent physiological differences. Dose (mg m(-2) ) requirements for children aged 0-18 years were calculated to achieve targeted exposure in adults. Simulated data were then analyzed using population PK modelling with MONOLIX® in order to perform design optimization with the population Fisher information matrix (PFIM). In parallel, the AS-popPK approach was performed for the comparison. RESULTS: The PBPK model developed for docetaxel adequately predicted its PK profiles in both adult and paediatric cancer patients (predicted clearance and volume of distribution within 1.5 fold of observed data). The revised dose of docetaxel for a child over 1.5 years old was higher than the adult dose. Considering clinical constraints, the optimal design contained two groups of 15 patients, having three or four sampling times and had good predicted relative standard errors (RSE<30%) for almost all parameters. The AS-popPK approach performed reasonably well but could not predict for very young children. CONCLUSION: This research shows the clinical utility of PBPK modelling in combination with population PK modelling and optimal design to support paediatric oncology development.


Assuntos
Antineoplásicos/farmacocinética , Modelos Biológicos , Neoplasias/metabolismo , Taxoides/farmacocinética , Adolescente , Adulto , Fatores Etários , Antineoplásicos/administração & dosagem , Antineoplásicos/uso terapêutico , Criança , Pré-Escolar , Ensaios Clínicos como Assunto , Simulação por Computador , Docetaxel , Descoberta de Drogas , Humanos , Lactente , Neoplasias/tratamento farmacológico , Valor Preditivo dos Testes , Taxoides/administração & dosagem , Taxoides/uso terapêutico , Distribuição Tecidual
4.
J Pharmacokinet Pharmacodyn ; 41(1): 15-33, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24317870

RESUMO

Bootstrap methods are used in many disciplines to estimate the uncertainty of parameters, including multi-level or linear mixed-effects models. Residual-based bootstrap methods which resample both random effects and residuals are an alternative approach to case bootstrap, which resamples the individuals. Most PKPD applications use the case bootstrap, for which software is available. In this study, we evaluated the performance of three bootstrap methods (case bootstrap, nonparametric residual bootstrap and parametric bootstrap) by a simulation study and compared them to that of an asymptotic method (Asym) in estimating uncertainty of parameters in nonlinear mixed-effects models (NLMEM) with heteroscedastic error. This simulation was conducted using as an example of the PK model for aflibercept, an anti-angiogenic drug. As expected, we found that the bootstrap methods provided better estimates of uncertainty for parameters in NLMEM with high nonlinearity and having balanced designs compared to the Asym, as implemented in MONOLIX. Overall, the parametric bootstrap performed better than the case bootstrap as the true model and variance distribution were used. However, the case bootstrap is faster and simpler as it makes no assumptions on the model and preserves both between subject and residual variability in one resampling step. The performance of the nonparametric residual bootstrap was found to be limited when applying to NLMEM due to its failure to reflate the variance before resampling in unbalanced designs where the Asym and the parametric bootstrap performed well and better than case bootstrap even with stratification.


Assuntos
Simulação por Computador , Modelos Biológicos , Modelos Estatísticos , Dinâmica não Linear , Incerteza , Inibidores da Angiogênese/farmacocinética , Humanos , População , Receptores de Fatores de Crescimento do Endotélio Vascular/farmacocinética , Proteínas Recombinantes de Fusão/farmacocinética , Software
5.
CPT Pharmacometrics Syst Pharmacol ; 13(6): 941-953, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38558299

RESUMO

A joint modeling framework was developed using data from 75 patients of early amcenestrant phase I-II AMEERA-1-2 dose escalation and expansion cohorts. A semi-mechanistic tumor growth inhibition (TGI) model was developed. It accounts for the dynamics of sensitive and resistant tumor cells, an exposure-driven effect on tumor proliferation of sensitive cells, and a delay in the initiation of treatment effect to describe the time course of target lesion tumor size (TS) data. Individual treatment exposure overtime was introduced in the model using concentrations predicted by a population pharmacokinetic model of amcenestrant. This joint modeling framework integrated complex RECISTv1.1 criteria information, linked TS metrics to progression-free survival (PFS), and was externally evaluated using the randomized phase II trial AMEERA-3. We demonstrated that the instantaneous rate of change in TS (TS slope) was an important predictor of PFS and the developed joint model was able to predict well the PFS of amcenestrant phase II monotherapy trial using only early phase I-II data. This provides a good modeling and simulation tool to inform early development decisions.


Assuntos
Neoplasias da Mama , Intervalo Livre de Progressão , Humanos , Feminino , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Modelos Biológicos , Ensaios Clínicos Fase II como Assunto , Pessoa de Meia-Idade , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapêutico , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacologia , Ensaios Clínicos Fase I como Assunto
6.
Pharm Stat ; 12(3): 129-40, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23457061

RESUMO

A version of the nonparametric bootstrap, which resamples the entire subjects from original data, called the case bootstrap, has been increasingly used for estimating uncertainty of parameters in mixed-effects models. It is usually applied to obtain more robust estimates of the parameters and more realistic confidence intervals (CIs). Alternative bootstrap methods, such as residual bootstrap and parametric bootstrap that resample both random effects and residuals, have been proposed to better take into account the hierarchical structure of multi-level and longitudinal data. However, few studies have been performed to compare these different approaches. In this study, we used simulation to evaluate bootstrap methods proposed for linear mixed-effect models. We also compared the results obtained by maximum likelihood (ML) and restricted maximum likelihood (REML). Our simulation studies evidenced the good performance of the case bootstrap as well as the bootstraps of both random effects and residuals. On the other hand, the bootstrap methods that resample only the residuals and the bootstraps combining case and residuals performed poorly. REML and ML provided similar bootstrap estimates of uncertainty, but there was slightly more bias and poorer coverage rate for variance parameters with ML in the sparse design. We applied the proposed methods to a real dataset from a study investigating the natural evolution of Parkinson's disease and were able to confirm that the methods provide plausible estimates of uncertainty. Given that most real-life datasets tend to exhibit heterogeneity in sampling schedules, the residual bootstraps would be expected to perform better than the case bootstrap.


Assuntos
Ensaios Clínicos como Assunto/métodos , Modelos Estatísticos , Projetos de Pesquisa , Viés , Simulação por Computador , Intervalos de Confiança , Interpretação Estatística de Dados , Humanos , Funções Verossimilhança , Modelos Lineares , Doença de Parkinson/tratamento farmacológico , Estatísticas não Paramétricas
7.
CPT Pharmacometrics Syst Pharmacol ; 12(12): 1846-1858, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-37002644

RESUMO

This study aimed to support dosing regimen selection for isatuximab as a single agent or in combination with dexamethasone for Japanese patients with relapsed/refractory multiple myeloma (RRMM). A joint model characterizing the dynamics of serum M-protein kinetics and its association with progression-free survival (PFS) was developed using data from 201 evaluable Japanese and non-Japanese patients with RRMM enrolled in two monotherapy phase I/II trials, where Japanese patients (n = 31) received isatuximab at 10 or 20 mg/kg once weekly (qw) for 4 weeks then every 2 weeks (q2w) in subsequent cycles (10 or 20 mg/kg qw-q2w). Among non-Japanese patients, 38 received isatuximab 20 mg/kg qw-q2w in combination with dexamethasone. Trial simulations were then performed to evaluate the effect of the isatuximab dosing regimens on both serum M-protein and PFS with and without dexamethasone. The model identified instantaneous changes in serum M-protein as the best on-treatment predictor for PFS. Trial simulations demonstrated that 20 mg/kg qw-q2w induced a greater decrease (30% vs. 22%) of serum M-protein at week 8 and prolonged median PFS by 2.4 weeks compared with 10 mg/kg qw-q2w. Although Japanese patients did not receive isatuximab plus dexamethasone in the phase I/II trial, simulations predicted that isatuximab 20 mg/kg qw-q2w plus dexamethasone would induce a greater decrease (67% vs. 43%) of serum M-protein and a prolonged median PFS by 7.2 weeks compared with isatuximab alone. Trial simulations support the approved isatuximab 20 mg/kg qw-q2w regimen when administered as a single agent and in combination with dexamethasone in Japanese patients.


Assuntos
Mieloma Múltiplo , Humanos , Mieloma Múltiplo/tratamento farmacológico , Japão , Anticorpos Monoclonais Humanizados/uso terapêutico , Dexametasona , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico
8.
CPT Pharmacometrics Syst Pharmacol ; 11(6): 766-777, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35355430

RESUMO

Isatuximab is an approved anti-CD38 monoclonal antibody with multiple antitumor modes of action. An exposure-response (E-R) analysis using data from patients with relapsed/refractory multiple myeloma (RRMM) enrolled in a phase Ib clinical study who received isatuximab at doses from 5 to 20 mg/kg weekly for 1 cycle (4 weeks) followed by every 2 weeks thereafter (qw/q2w) in combination with pomalidomide/dexamethasone (n = 44) was first used to determine the optimal dose/schedule for the phase III ICARIA-MM study. It was complemented by an E-R analysis from a second phase Ib study of patients who received isatuximab at doses from 3 to 10 mg/kg q2w or 10 or 20 mg/kg qw/q2w in combination with lenalidomide/dexamethasone (n = 52). Plasma trough concentration at week 4 (CT4W) was the best predictor for response, and the benefit of the initial 4-weekly administration was confirmed. Although the predicted overall response rate (ORR) was higher at 20 mg/kg vs. 10 mg/kg, the 95% confidence intervals were overlapping. Considering the high probability of success to reach the targeted ORR of greater than or equal to 60%, 10 mg/kg qw/q2w was selected. Results of the E-R analysis from the lenalidomide/dexamethasone study and published disease modeling using data from both phase Ib clinical studies reinforced 10 mg/kg qw/q2w as the optimal dose/schedule for the phase III ICARIA-MM study. E-R analysis showed that higher CT4W was associated with higher ORR. Developed models supported the phase III isatuximab dosing regimen selection/confirmation of 10 mg/kg qw/q2w for use in combination with pomalidomide/dexamethasone in patients with RRMM.


Assuntos
Mieloma Múltiplo , Anticorpos Monoclonais Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Dexametasona/uso terapêutico , Humanos , Lenalidomida/uso terapêutico , Mieloma Múltiplo/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Talidomida/análogos & derivados
9.
Br J Clin Pharmacol ; 72(3): 402-14, 2011 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-21575034

RESUMO

AIM: Aflibercept (VEGF-Trap), a novel anti-angiogenic agent that binds to VEGF, has been investigated for the treatment of cancer. The aim of this study was to develop a mechanism-based pharmacokinetic (PK) model for aflibercept to characterize its binding to VEGF and its PK properties in healthy subjects. METHODS: Data from two phase I clinical studies with aflibercept administered as a single intravenous infusion were included in the analysis. Free and bound aflibercept concentration-time data were analysed using a nonlinear mixed-effects modelling approach with MONOLIX 3.1. RESULTS: The best structural model involved two compartments for free aflibercept and one for bound aflibercept, with a Michaelis-Menten type binding of free aflibercept to VEGF from the peripheral compartment. The typical estimated clearances for free and bound aflibercept were 0.88 l day(-1) and 0.14 l day(-1), respectively. The central volume of distribution of free aflibercept was 4.94 l. The maximum binding capacity was 0.99 mg day(-1) and the concentration of aflibercept corresponding to half of maximum binding capacity was 2.91 µg ml(-1). Interindividual variability of model parameters was moderate, ranging from 13.6% (V(max) ) to 49.8% (Q). CONCLUSION: The present PK model for aflibercept adequately characterizes the underlying mechanism of disposition of aflibercept and its nonlinear binding to VEGF.


Assuntos
Proteínas Recombinantes de Fusão/farmacocinética , Ensaios Clínicos como Assunto , Humanos , Masculino , Modelos Biológicos , Ligação Proteica , Receptores de Fatores de Crescimento do Endotélio Vascular , Fator A de Crescimento do Endotélio Vascular/metabolismo
10.
CPT Pharmacometrics Syst Pharmacol ; 10(8): 928-940, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34185964

RESUMO

This analysis describes the pharmacokinetic/pharmacodynamic (PK/PD) modeling framework that supported selection of the isatuximab (anti-CD38 monoclonal antibody) dosing regimen alongside its early clinical development in patients with relapsed/refractory multiple myeloma (RRMM). The PK/PD mathematical model characterized the variations of patient serum M-protein concentrations, the primary marker of tumor burden in multiple myeloma (MM). Three separate PK/PD models were built sequentially as data became available from phase I clinical trials. The primary PK/PD analysis was initiated using monotherapy phase I study data (n = 122), followed by analysis of data collected from phase Ib combination studies with lenalidomide and dexamethasone (Rd, n = 40) and then with pomalidomide and dexamethasone (Pd, n = 31). Using the PK/PD model, abnormal "myeloma" protein (M-protein) profiles under different isatuximab dosing regimens were simulated. Overall, simulations revealed that regimens which included a loading period of four weekly administrations followed by administration every 2 weeks thereafter (QW4-Q2W), reduced M-protein levels more than a Q2W regimen without a loading period. For isatuximab monotherapy, a 20 mg/kg dose induced greater reduction in serum M-protein levels compared with doses equal or lower than 10 mg/kg. For isatuximab in combination with either Rd or Pd, simulations yielded no substantial benefit in terms of M-protein reduction between isatuximab 10 mg/kg and 20 mg/kg. These PK/PD analyses supported the use of isatuximab 10 mg/kg QW4-Q2W in combination with Pd in the phase III trial.


Assuntos
Anticorpos Monoclonais Humanizados/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Modelos Biológicos , Mieloma Múltiplo/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados/farmacocinética , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Ensaios Clínicos Fase I como Assunto , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas do Mieloma/metabolismo
11.
Cancer Chemother Pharmacol ; 72(1): 167-80, 2013 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-23673444

RESUMO

OBJECTIVE: Aflibercept (Zaltrap®) is a novel antiangiogenic agent that binds to vascular endothelial growth factor (VEGF) and inhibits VEGF-dependent tumor growth. We aimed to characterize the population pharmacokinetics (PK) of free and bound aflibercept in patients with solid tumors to examine the influence of covariates on their PK and to evaluate the proposed dosing regimens by simulation. METHODS: Data from 9 clinical trials with 1,506 cancer patients receiving aflibercept (2-9 mg/kg every 2 or 3 weeks; 1 h IV infusion) as a monotherapy or in combination with various chemotherapies were included. Free and bound aflibercept concentrations were analyzed using a non-linear mixed-effects modeling approach with MONOLIX 4.1.2. RESULTS: An approximation of a target-mediated drug disposition model with irreversible binding of free aflibercept to VEGF adequately described the PK of free and bound aflibercept. The typical estimated clearances for free (CL(f)) and bound aflibercept (CL(b)) were 0.88 and 0.19 L/day, respectively. The volumes of distribution for free (V(p)) and bound (V(b)) aflibercept were similar (~4 L). CL f and V(p) increased with body weight and were lower in women. Patients with low albumin (ALB) or high alkaline phosphatase (ALK) had faster CL(f) compared to a typical patient. Pancreatic cancer may be associated with changes in binding of aflibercept to VEGF. Simulations of different dosing regimens showed that adequate saturation of circulating VEGF was achieved with a dose of 4 mg/kg every 2 weeks. CONCLUSIONS: Aflibercept kinetics was most affected by gender, body weight, ALB, ALK and pancreatic cancer. Simulations supported the rationale for the recommended dose of 4 mg/kg every 2 weeks for aflibercept.


Assuntos
Inibidores da Angiogênese/farmacocinética , Modelos Biológicos , Neoplasias/tratamento farmacológico , Receptores de Fatores de Crescimento do Endotélio Vascular/farmacocinética , Proteínas Recombinantes de Fusão/farmacocinética , Fator A de Crescimento do Endotélio Vascular/sangue , Adulto , Idoso , Inibidores da Angiogênese/administração & dosagem , Inibidores da Angiogênese/metabolismo , Inibidores da Angiogênese/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Peso Corporal , Carcinoma Pulmonar de Células não Pequenas/sangue , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Estudos de Coortes , Neoplasias Colorretais/sangue , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/metabolismo , Simulação por Computador , Relação Dose-Resposta a Droga , Feminino , Humanos , Neoplasias Pulmonares/sangue , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/metabolismo , Masculino , Taxa de Depuração Metabólica , Pessoa de Meia-Idade , Neoplasias/sangue , Neoplasias/metabolismo , Neoplasias Pancreáticas/sangue , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/metabolismo , Receptores de Fatores de Crescimento do Endotélio Vascular/administração & dosagem , Receptores de Fatores de Crescimento do Endotélio Vascular/metabolismo , Receptores de Fatores de Crescimento do Endotélio Vascular/uso terapêutico , Proteínas Recombinantes de Fusão/administração & dosagem , Proteínas Recombinantes de Fusão/metabolismo , Proteínas Recombinantes de Fusão/uso terapêutico , Caracteres Sexuais , Fator A de Crescimento do Endotélio Vascular/metabolismo
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