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1.
J Pharmacokinet Pharmacodyn ; 51(1): 65-75, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-37943398

RESUMO

Biological therapies may act as immunogenic triggers leading to the formation of anti-drug antibodies (ADAs). Population pharmacokinetic (PK) models can be used to characterize the relationship between ADA and drug disposition but often rely on the ADA bioassay results, which may not be sufficiently sensitive to inform on this characterization.In this work, a methodology that could help to further elucidate the underlying ADA production and impact on the drug disposition was explored. A mixed hidden-Markov model (MHMM) was developed to characterize the underlying (hidden) formation of ADA against the biologic, using certolizumab pegol (CZP), as a test drug. CZP is a PEGylated Fc free TNF-inhibitor used in the treatment of rheumatoid arthritis and other chronic inflammatory diseases.The bivariate MHMM used information from plasma drug concentrations and ADA measurements, from six clinical studies (n = 845), that were correlated through a bivariate Gaussian function to infer about two hidden states; production and no-production of ADA influencing PK. Estimation of inter-individual variability was not supported in this case. Parameters associated with the observed part of the model were reasonably well estimated while parameters associated with the hidden part were less precise. Individual state sequences obtained using a Viterbi algorithm suggested that the model was able to determine the start of ADA production for each individual, being a more assay-independent methodology than traditional population PK. The model serves as a basis for identification of covariates influencing the ADA formation, and thus has the potential to identify aspects that minimize its impact on PK and/or efficacy.


Assuntos
Antirreumáticos , Artrite Reumatoide , Humanos , Certolizumab Pegol/farmacocinética , Certolizumab Pegol/uso terapêutico , Anticorpos , Artrite Reumatoide/tratamento farmacológico , Algoritmos , Antirreumáticos/uso terapêutico
2.
Sci Rep ; 10(1): 18464, 2020 10 28.
Artigo em Inglês | MEDLINE | ID: mdl-33116155

RESUMO

Certolizumab pegol is a Fab' antibody fragment for treatment of rheumatoid arthritis and Crohn's disease which is conjugated to a 40 kDa PEG molecule in order to increase the protein half-life. PEGylation may have disadvantages including immunogenicity, hypersensitivity, vacuolation, decreased binding affinity and biological activity of the protein. To overcome these problems, PASylation has been developed as a new approach. The nucleotide sequence encoding 400 amino acid PAS residues was genetically fused to the corresponding nucleotide sequences of both chains of certolizumab. Then, the bioactivity as well as physicochemical and pharmacokinetic properties of the recombinant PASylated expressed protein was assayed. Circular dichroism spectroscopy demonstrated that the random coil structure of PAS sequences did not change the secondary structure of the PASylated Fab' molecule. It was observed that PASylation influenced the properties of the Fab' molecule by which the hydrodynamic radius and neutralization activity were increased. Also, the antigen binding and binding kinetic parameters improved in comparison to the PEGylated Fab' antibody. Pharmacokinetic studies also showed prolonged terminal half-life and improved pharmacokinetic parameters in PASylated recombinant protein in comparison to the PEGylated and Fab' control molecules. The results reconfirmed the efficiency of PASylation approach as a potential alternative method in increasing the half-life of pharmaceutical proteins.


Assuntos
Certolizumab Pegol , Polietilenoglicóis , Animais , Artrite Reumatoide/tratamento farmacológico , Linhagem Celular , Certolizumab Pegol/química , Certolizumab Pegol/farmacocinética , Certolizumab Pegol/farmacologia , Doença de Crohn/tratamento farmacológico , Feminino , Meia-Vida , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Polietilenoglicóis/química , Polietilenoglicóis/farmacocinética , Polietilenoglicóis/farmacologia
3.
Clin Transl Sci ; 13(4): 743-751, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32100960

RESUMO

Anti-tumor necrosis factor (anti-TNF) drugs are often prescribed for the treatment of rheumatoid arthritis (RA) and other immune-mediated inflammatory diseases. Although this treatment has been shown to be effective in many patients, up to 40% of patients do not achieve disease control. Drug concentration in plasma may be a factor affecting the observed variability in therapeutic response. In this study, we aimed to identify the plasma concentrations of the anti-TNF certolizumab pegol (CZP), associated with improvement in disease activity in patients with RA. Data were pooled from three randomized, controlled clinical trials with a combined total of 1,935 patients analyzed. Clinical outcomes of low disease activity (LDA) and remission were defined as Disease Activity Score in 28 joints with C-reactive protein (DAS28(CRP)) ≤ 2.7 and < 2.3, respectively. Quartile analysis results indicated that there may be an exposure-response relationship between CZP concentration and LDA/remission outcomes at weeks 12 and 24; the association was strongest for LDA (P < 0.05). Receiver operating characteristic (ROC) analysis showed that CZP concentrations ≥ 28.0 µg/ml at week 12, and ≥ 17.6 µg/ml at week 24, were associated with a greater likelihood of achieving LDA/remission outcomes. Although confirmatory studies are warranted to define the optimal CZP therapeutic range at weeks 12 and 24, these data indicate that CZP concentrations may be associated with improvement of disease activity.


Assuntos
Antirreumáticos/farmacocinética , Artrite Reumatoide/tratamento farmacológico , Certolizumab Pegol/farmacocinética , Monitoramento de Medicamentos/métodos , Adulto , Idoso , Antirreumáticos/administração & dosagem , Artrite Reumatoide/sangue , Artrite Reumatoide/diagnóstico , Certolizumab Pegol/administração & dosagem , Relação Dose-Resposta a Droga , Estudos de Viabilidade , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Curva ROC , Ensaios Clínicos Controlados Aleatórios como Assunto , Índice de Gravidade de Doença , Resultado do Tratamento , Fator de Necrose Tumoral alfa/antagonistas & inibidores
4.
Mol Imaging Biol ; 22(1): 105-114, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31065895

RESUMO

PURPOSE: Tumor necrosis factor alpha (TNFα) drives inflammation and bone degradation in patients with rheumatoid arthritis (RA). Some RA patients experience a rapid clinical response to TNFα inhibitors such as certolizumab pegol (CZP) while other patients show limited to no response. Current methods for imaging RA have limited sensitivity and do not assist in the selection of patients most likely to respond to immune-mediated therapy. Herein, we developed a novel positron emission tomography (PET) radiotracer for immuno-PET imaging of TNFα in transgenic human TNFα-expressing mice. PROCEDURES: CZP was modified with p-isothiocyanatobenzyl-deferoxamine (DFO) and radiolabeled with Zr-89. The biological activity of [89Zr]DFO-CZP was evaluated by HPLC and binding assay using human recombinant TNFα (hTNFα). The feasibility of specific immuno-PET imaging of human TNFα was assessed in a transgenic mouse model of RA that expresses human TNFα. This model resembles the progression of RA in humans by maintaining lower levels of circulating hTNFα and exhibits chronic arthritis in the forepaw and hind paw joints. The dosimetry of [89Zr]DFO-CZP in humans was estimated using microPET/CT imaging in Sprague Dawley rats. RESULTS: [89Zr]DFO-CZP was isolated with radiolabeling yields of 85 ± 6 % (n = 5) and specific activities ranging from 74 to 185 MBq/mg (n = 5). Following size exclusion purification, the radiochemical purity of [89Zr]DFO-CZP was greater than 97 %. [89Zr]DFO-CZP retained high immunoreactivity with more than 95 % of the radioactivity shifted into higher molecular weight complexes. Images showed increasing uptake of the tracer in forepaw and hind paw joints with disease progression. No uptake was observed in the model previously administered with an excess amount of unmodified CZP and in normal control mice, demonstrating in vivo specific uptake of [89Zr]DFO-CZP. CONCLUSION: The feasibility of immuno-PET imaging of human TNFα with [89Zr]DFO-CZP has been demonstrated in a preclinical model of RA.


Assuntos
Artrite Experimental/patologia , Artrite Reumatoide/patologia , Certolizumab Pegol/farmacocinética , Imunoconjugados/farmacocinética , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/métodos , Radioisótopos/farmacocinética , Fator de Necrose Tumoral alfa/metabolismo , Zircônio/farmacocinética , Animais , Antirreumáticos/farmacocinética , Artrite Experimental/diagnóstico por imagem , Artrite Experimental/tratamento farmacológico , Artrite Experimental/metabolismo , Artrite Reumatoide/diagnóstico por imagem , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/metabolismo , Modelos Animais de Doenças , Feminino , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Ratos , Ratos Sprague-Dawley , Distribuição Tecidual
5.
Dermatol Ther ; 32(6): e13137, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31639245

RESUMO

Psoriasis is a chronic, multifactorial inflammatory disease; its clinical severity can vary widely. Treatment of severe cases during pregnancy is of special interest. To date there is scarce information available and most data comes from other medical specialties that use similar treatments. Immunosuppressors are strongly discouraged during pregnancy and breastfeeding. Amongst biologic agents, anti-TNFα having been the longest on the market has allowed for the most experience. It is known that transplacental transport of these drugs does not occur until gestational week 22, once organogenesis is completed. Within this group certolizumab pegol, seems to be the safest choice, as its molecular structure does not cross the placental barrier. Beyond pregnancy, it is important to take into account these drugs' half-life and passage to breast milk, as well as its impact on neonatal immunization.


Assuntos
Produtos Biológicos/administração & dosagem , Complicações na Gravidez/tratamento farmacológico , Psoríase/tratamento farmacológico , Produtos Biológicos/efeitos adversos , Produtos Biológicos/farmacocinética , Aleitamento Materno , Certolizumab Pegol/administração & dosagem , Certolizumab Pegol/efeitos adversos , Certolizumab Pegol/farmacocinética , Fármacos Dermatológicos/administração & dosagem , Fármacos Dermatológicos/efeitos adversos , Fármacos Dermatológicos/farmacocinética , Feminino , Humanos , Imunossupressores/administração & dosagem , Imunossupressores/efeitos adversos , Imunossupressores/farmacocinética , Recém-Nascido , Gravidez , Complicações na Gravidez/patologia , Inibidores do Fator de Necrose Tumoral/administração & dosagem , Inibidores do Fator de Necrose Tumoral/efeitos adversos , Inibidores do Fator de Necrose Tumoral/farmacocinética
6.
Acta Med Port ; 32(4): 305-312, 2019 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-31067425

RESUMO

INTRODUCTION: Inflammatory bowel disease activity is associated with adverse pregnancy outcomes. Anti-tumor necrosis factor α therapy is often required to treat flares and to maintain disease remission. However, there are concerns regarding treatment with these agents during pregnancy, as they actively cross the placental barrier. MATERIAL AND METHODS: Studies regarding anti-tumor necrosis factor α therapy during pregnancy were identified from PubMed from 1958 to January 2018. The reference lists of the selected studies were reviewed to identify complementary publications. RESULTS AND DISCUSSION: Anti-tumor necrosis factor α agents are efficient treatments for moderate-to-severe inflammatory bowel disease and may ensure remission during pregnancy. Although these drugs cross the placenta, they are considered safe for both the mother and the fetus. Furthermore, up-to-date guidelines support therapy continuation during pregnancy aiming for disease control. The same guidelines also consider stopping treatment during the third trimester to limit maternal-fetal drug transfer. However, data shows that this strategy does not completely prevent fetus exposure. In addition, stopping treatment incurs in risk of disease flare and threatens subsequent therapy response. Fetus drug exposure has not showed an association with adverse childhood development. However, as infant drug levels could be detected up to seven months after birth, postponement of live virus vaccination is recommended. CONCLUSION: There should be no disagreement among the medical community as to the need to maintain therapy aiming for disease remission during gestation in inflammatory bowel disease. Anti-tumor necrosis factor α agents are safe for both the mother and the fetus.


Introdução: O melhor preditor de complicações durante a gravidez, na doença inflamatória intestinal, é a atividade da doença. A terapêutica com agentes anti-tumor necrosis factor α atravessa a barreira placentária o que levanta questões relativamente à sua segurança durante a gravidez. Material e Métodos: Revisão bibliográfica suportada a partir de artigos indexados na PubMed (1958 a 01/2018) sobre a terapêutica anti-tumor necrosis factor α durante a gravidez na doença inflamatória intestinal. Resultados e Discussão: Os agentes anti-tumor necrosis factor α são eficazes na doença inflamatória intestinal e podem garantir a remissão clínica durante a gravidez. Estes fármacos atravessam a barreira placentária, mas são seguros para a mãe e feto. Neste sentido, as orientações atuais defendem a manutenção terapêutica durante a gravidez para assegurar a remissão clínica. Paralelamente, as mesmas orientações consideram a suspensão terapêutica durante o terceiro trimestre para limitar a exposição fetal ao fármaco. No entanto, esta estratégia não só não previne totalmente a exposição fetal, como aumenta o risco de agudização da doença e da perda de resposta à terapêutica após o seu reinício. Esta exposição fetal não está associada a alterações do desenvolvimento in utero ou neonatal. Ainda assim, uma vez que é possível dosear fármaco no recém-nascido até aos sete meses de vida, recomenda-se adiar a administração de vacinas vivas em recém-nascidos expostos. Conclusão: Não deve haver discordância na comunidade médica quanto à necessidade de garantir a remissão da doença inflamatória intestinal durante a gestação. Os agentes anti-tumor necrosis factor α devem ser vistos como opções terapêuticas seguras para mãe e feto durante a gravidez.


Assuntos
Anti-Inflamatórios/farmacocinética , Doenças Inflamatórias Intestinais/tratamento farmacológico , Troca Materno-Fetal , Complicações na Gravidez/tratamento farmacológico , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Adalimumab/farmacocinética , Adalimumab/uso terapêutico , Corticosteroides/efeitos adversos , Corticosteroides/farmacocinética , Corticosteroides/uso terapêutico , Anti-Inflamatórios/uso terapêutico , Anticorpos Monoclonais/farmacocinética , Anticorpos Monoclonais/uso terapêutico , Certolizumab Pegol/farmacocinética , Certolizumab Pegol/uso terapêutico , Feminino , Humanos , Infliximab/farmacocinética , Infliximab/uso terapêutico , Placenta/metabolismo , Guias de Prática Clínica como Assunto , Gravidez , Trimestres da Gravidez/metabolismo
8.
Aliment Pharmacol Ther ; 47(2): 229-237, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29159893

RESUMO

BACKGROUND: Therapeutic drug monitoring may optimize therapy for Crohn's disease (CD). AIM: To use a population pharmacokinetic model that accounts for the time-varying nature of covariates to simulate certolizumab pegol (CZP) concentrations to evaluate the exposure-response relationship for CZP in Crohn's disease. METHODS: Adults (N = 2157) with Crohn's disease were treated with CZP in nine clinical trials. Simulated CZP concentrations were compared to outcomes at weeks 6 and 26, including Crohn's disease activity index (CDAI) response (decrease from baseline ≥ 100 points), remission (CDAI ≤ 150), C-reactive protein (CRP) ≤ 5 mg/L, faecal calprotectin (FC) ≤ 250 µg/g, and a composite endpoint of CDAI ≤ 150 and FC ≤ 250 µg/g. Multivariable analyses identified covariates associated with outcomes and receiver operating characteristic analyses determined optimal CZP concentrations. RESULTS: CZP concentrations at weeks 2, 4 and 6 were higher in patients with clinical response, remission, CRP ≤ 5 mg/L or FC ≤ 250 µg/g at week 6 than without. In multivariable analyses, higher CZP concentrations at week 6 were associated with the composite outcome at weeks 6 and 26 (P < .001). Although the exposure-response relationship varied among patients, approximate CZP concentrations of at least 36.1 µg/mL (positive predictive value [PPV] 22.8% and negative predictive value [NPV] 92.7%) and at least 14.8 µg/mL (PPV 28.0% and NPV 90.4%) at weeks 6 and 12 were associated with weeks 6 and 26 outcomes. CONCLUSIONS: An exposure-response relationship was apparent for CZP in Crohn's disease and achieving higher CZP concentrations may increase the likelihood of attaining efficacy outcomes, but this remains to be evaluated prospectively.


Assuntos
Certolizumab Pegol/uso terapêutico , Doença de Crohn/tratamento farmacológico , Monitoramento de Medicamentos/métodos , Quimioterapia de Indução , Quimioterapia de Manutenção , Adulto , Certolizumab Pegol/farmacocinética , Ensaios Clínicos como Assunto/estatística & dados numéricos , Doença de Crohn/diagnóstico , Doença de Crohn/epidemiologia , Doença de Crohn/metabolismo , Feminino , Humanos , Quimioterapia de Indução/efeitos adversos , Quimioterapia de Manutenção/efeitos adversos , Masculino , Prognóstico , Resultado do Tratamento
9.
Ann Rheum Dis ; 77(2): 228-233, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29030361

RESUMO

OBJECTIVES: There is a need for effective and safe treatment during pregnancy in women with chronic inflammatory diseases. This study evaluated placental transfer of certolizumab pegol (CZP), an Fc-free anti-tumour necrosis factor drug, from CZP-treated pregnant women to their infants. METHODS: CRIB was a pharmacokinetic (PK) study of women ≥30 weeks pregnant receiving commercial CZP for a locally approved indication (last dose ≤35 days prior to delivery). Blood samples were collected from mothers, umbilical cords and infants at delivery, and infants again at weeks 4 and 8 post-delivery. CZP plasma concentrations were measured with a highly sensitive and CZP-specific electrochemiluminescence immunoassay (lower limit of quantification 0.032 µg/mL). RESULTS: Sixteen women entered and completed the study. Maternal CZP plasma levels at delivery were within the expected therapeutic range (median [range] 24.4 [5.0-49.4] µg/mL). Of the 16 infants, 2 were excluded from the per-protocol set: 1 due to missing data at birth and 1 due to implausible PK data. Of the remaining 14 infants, 13 had no quantifiable CZP levels at birth (<0.032 µg/mL), and 1 had a minimal CZP level of 0.042 µg/mL (infant/mother plasma ratio 0.0009); no infants had quantifiable CZP levels at weeks 4 and 8. Of 16 umbilical cord samples, 1 was excluded due to missing data; 3/15 had quantifiable CZP levels (maximum 0.048 µg/mL). CONCLUSIONS: There was no to minimal placental transfer of CZP from mothers to infants, suggesting lack of in utero foetal exposure during the third trimester. These results support continuation of CZP treatment during pregnancy, when considered necessary. TRIAL REGISTRATION NUMBER: NCT02019602; Results.


Assuntos
Antirreumáticos/sangue , Certolizumab Pegol/sangue , Sangue Fetal/química , Adolescente , Adulto , Antirreumáticos/efeitos adversos , Antirreumáticos/farmacocinética , Doenças Autoimunes/tratamento farmacológico , Certolizumab Pegol/efeitos adversos , Certolizumab Pegol/farmacocinética , Feminino , Humanos , Lactente , Recém-Nascido , Medições Luminescentes/métodos , Placenta , Gravidez , Vigilância de Produtos Comercializados , Estudos Prospectivos , Adulto Jovem
10.
Ann Rheum Dis ; 76(11): 1890-1896, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28814432

RESUMO

BACKGROUND: Women with chronic inflammatory diseases face uncertainty regarding the safety of biologics during breast feeding. CRADLE was the first industry-sponsored study to evaluate certolizumab pegol (CZP) concentrations in human breast milk and estimate average daily infant dose (ADID) of maternal CZP. METHODS: CRADLE (NCT02154425) was a pharmacokinetic study of lactating mothers receiving CZP. After ≥3 CZP doses, breast milk samples were collected across one dosing period (14 days for 200 mg every 2 weeks [Q2W]; 28 days for 400 mg every 4 weeks [Q4W]). Optimal analytical methods were developed to determine CZP and polyethylene glycol (PEG) levels in breast milk. ADID and relative infant dose (RID) were estimated. Safety events in mothers and infants were assessed. RESULTS: 19 CZP-treated mothers were screened; 17 entered the sampling period: 16 on 200 mg Q2W, 1 on 400 mg Q4W. 77/137 (56%) breast milk samples had no measurable CZP. For 4/17 mothers, all samples were below the lower limit of quantification (LLOQ). Estimated ADID was 0-0.0104 mg/kg/day; median RID: 0.15%. PEG was undetectable in 134/137 samples (results could not be determined in three samples). Infants of CZP-exposed mothers had a safety profile consistent with that of unexposed similar-age infants. CONCLUSION: When quantifiable, CZP concentrations were <3× LLOQ (<1% plasma concentration observed with therapeutic dose), indicating no/minimal CZP transfer from plasma to breast milk. RID was 0.15% of maternal dose; <10% is considered unlikely to be of clinical concern. No PEG transfer was observed. CZP absorption by infants via breast milk is unlikely due to its low oral bioavailability and Fc--free molecular structure. These findings are reassuring and support continuation of CZP treatment during breast feeding. TRIAL REGISTRATION NUMBER: NCT02154425; Results.


Assuntos
Antirreumáticos/farmacocinética , Certolizumab Pegol/farmacocinética , Leite Humano/efeitos dos fármacos , Doenças Reumáticas/tratamento farmacológico , Adulto , Antirreumáticos/análise , Certolizumab Pegol/análise , Feminino , Humanos , Lactente , Recém-Nascido , Leite Humano/química , Polietilenoglicóis/análise , Vigilância de Produtos Comercializados , Estudos Prospectivos
11.
Clin Pharmacokinet ; 56(12): 1513-1523, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-28353055

RESUMO

BACKGROUND: Certolizumab pegol is an effective biologic for patients with Crohn's disease (CD). Individual differences in certolizumab pegol apparent clearance (CL/F) affect exposure and possibly efficacy. A previously developed population pharmacokinetic (PK) model did not account for dynamic changes in clinical parameters during therapy. OBJECTIVE: The aim of this study was to refine the existing PK model to capture the time-varying influence of covariates. METHODS: Data collected from 2157 Crohn's disease patients in nine studies were analyzed using nonlinear mixed-effects modeling software (NONMEM). Certolizumab pegol concentration-time data were described by a one-compartment PK model with first-order absorption, and one-compartment disposition with linear, time-dependent elimination using antidrug antibody (ADAb) concentration as a continuous variable. RESULTS: The final dataset consisted of 12,926 analyzable records. Parameter estimates were absorption rate constant 1.83/day, CL/F 0.527 L/day, and apparent volume of distribution (V/F) 8.33 L. ADAb concentration (2.5-214 units/mL) increased the median CL/F by 142-174%. For a typical patient, body weight (46.8-100.5 kg) increased the median CL/F and V/F from 82 to 120%. Albumin (32-48 g/L) decreased and C-reactive protein (0.5-54.0 mg/L) increased the median CL/F from 123 to 85% and from 83 to 113%, respectively. Between-patient variability of CL/F was 19.6%. CONCLUSIONS: By incorporating time-varying covariates, this population PK model reduces between-patient variability on CL/F estimates, and the relative influence of ADAb can now be assessed. As Crohn's disease patient covariates are often time-dependent, this model is more reflective of patient drug exposure with sustained treatment.


Assuntos
Certolizumab Pegol/farmacocinética , Doença de Crohn/tratamento farmacológico , Modelos Biológicos , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos/imunologia , Proteína C-Reativa/metabolismo , Certolizumab Pegol/administração & dosagem , Ensaios Clínicos como Assunto , Feminino , Humanos , Imunossupressores/administração & dosagem , Imunossupressores/farmacocinética , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Dinâmica não Linear , Albumina Sérica Humana/metabolismo , Fatores de Tempo , Distribuição Tecidual , Adulto Jovem
12.
Inflamm Bowel Dis ; 22(8): 1999-2015, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-27135483

RESUMO

BACKGROUND: Biological tumor necrosis factor (TNF) inhibitors have revolutionized the treatment of inflammatory bowel disease and redefined treatment goals to include mucosal healing. Clinicians are faced with challenges such as inadequate responses, treatment failures, side effects, and high drug costs. The objective is to review optimization of anti-TNF therapy by use of personalized treatment strategies based on circulating drug levels and antidrug antibodies (Abs), i.e. therapeutic drug monitoring (TDM). Furthermore, to outline TDM-related pitfalls and their prevention. METHODS: Literature review. RESULTS: Circulating anti-TNF drug trough level is a marker for the pharmacokinetics (PK) of TNF inhibitors. Because of a number of factors, including antidrug antibodies, PK varies between and within patients across time leading to variable clinical outcomes. Differences in intestinal inflammatory phenotype influencing the pharmacodynamic (PD) responses to TNF inhibitors also affect treatment outcomes. As an alternative to handling anti-TNF-treated patients by empiric strategies, TDM identifies underlying PK and PD-related reasons for treatment failure and aids decision making to secure optimal clinical and economic outcomes. Although promising, evidence does not the support use of TDM to counteract treatment failure in quiescent disease. Use of TDM is challenged by methodological biases, difficulties related to differentiation between PK and PD problems, and temporal biases due to lack of chronology between changes in PK versus symptomatic and objective disease activity manifestations. Biases can be accommodated by knowledgeable interpretation of results obtained by validated assays with clinically established thresholds, and by repeated assessments over time using complimentary techniques. CONCLUSIONS: TDM-guided anti-TNF therapy at treatment failure has been brought from bench to bedside.


Assuntos
Anticorpos/sangue , Monitoramento de Medicamentos , Imunossupressores/sangue , Imunossupressores/uso terapêutico , Doenças Inflamatórias Intestinais/tratamento farmacológico , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Adalimumab/sangue , Adalimumab/imunologia , Adalimumab/farmacocinética , Adalimumab/uso terapêutico , Anticorpos Monoclonais/sangue , Anticorpos Monoclonais/imunologia , Anticorpos Monoclonais/farmacocinética , Anticorpos Monoclonais/uso terapêutico , Certolizumab Pegol/sangue , Certolizumab Pegol/imunologia , Certolizumab Pegol/farmacocinética , Certolizumab Pegol/uso terapêutico , Humanos , Imunossupressores/imunologia , Imunossupressores/farmacocinética , Infliximab/sangue , Infliximab/imunologia , Infliximab/farmacocinética , Infliximab/uso terapêutico , Falha de Tratamento
13.
J Clin Pharmacol ; 55(8): 866-74, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-25735646

RESUMO

Certolizumab pegol (CZP), an anti-tumor necrosis factor α agent, is an effective therapy for Crohn's disease (CD). A population pharmacokinetic (PK) analysis of subcutaneously administered CZP was performed using data from 2157 CD patients from 9 separate studies. The aim was to determine which covariates influence the disposition of CZP. The final CZP population PK model consisted of a baseline, first-order absorption, and 1-compartment disposition. CZP antibodies were treated as a structural model covariate and caused apparent clearance (CL/F) to increase from 0.685 to 2.74 L/day. Body surface area (BSA) influenced both CL/F and apparent volume of distribution (V/F) in a linear fashion; both parameters increased by more than 53% and 49%, respectively, across the range of BSA measurements in the data. Albumin influenced CZP CL/F in a nonlinear fashion; CL/F decreased from 1.05 to 0.613 L/day with increasing albumin concentrations in antibody-negative patients. C-reactive protein (CRP) had a borderline influence and CL/F increased by more than 20% across the range of CRP measurements in the data set. Race had a minor influence on V/F. The determined covariates' impact on CZP disposition may be of clinical utility in CZP therapy of CD patients when the PK/pharmacodynamic relationship becomes available.


Assuntos
Certolizumab Pegol/farmacocinética , Doença de Crohn/metabolismo , Imunossupressores/farmacocinética , Modelos Biológicos , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Índice de Massa Corporal , Superfície Corporal , Peso Corporal , Proteína C-Reativa/análise , Certolizumab Pegol/imunologia , Doença de Crohn/sangue , Doença de Crohn/imunologia , Feminino , Humanos , Imunossupressores/imunologia , Masculino , Pessoa de Meia-Idade , Adulto Jovem
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