Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 15 de 15
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Int J Pharm ; 654: 123954, 2024 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-38428548

RESUMO

Calicheamicin is a potent, cell-cycle independent enediyne antibiotic that binds and cleaves DNA. Toxicity has led to its use in a targeted form, as an antibody-drug conjugate approved for the treatment of liquid tumors. We used a reduced calicheamicin to conjugate it to a single cysteine residue at the membrane-inserting end of a pH Low Insertion Peptide (pHLIP) that targets imaging and therapeutic agents to tumors. The cytoplasmic reduction of the disulfide releases the calicheamicin, and activation, DNA binding, and strand scission ensue. We studied the interaction of pHLIP-calicheamicin with liposomal and cellular membranes and demonstrated that the agent exhibits cytotoxic activity both in highly proliferative cancer cells and in non-proliferative immune cells, such as polarized M2 macrophages. In vivo, the agent was effective in inhibiting tumor growth in mice with no signs of toxicity. Biodistribution studies confirmed tumor targeting with no accumulation of the agent in organs and tissues. The agent was found within the tumor mass and tumor-stroma interface. Treatment of tumors led to the depletion of CD206+ M2- tumor-associated macrophages within the tumor core. pHLIP-calicheamicin could be pursued as an effective therapeutic for the treatment of solid tumors.


Assuntos
Antineoplásicos , Neoplasias , Animais , Camundongos , Calicheamicinas , Distribuição Tecidual , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Neoplasias/tratamento farmacológico , DNA , Concentração de Íons de Hidrogênio
2.
Drug Metab Dispos ; 52(2): 135-142, 2024 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-38050039

RESUMO

Antibody-drug conjugates (ADC) have gained momentum for treatment of cancers, with 14 ADCs currently approved for commercial use worldwide. Calicheamicin is one of the payloads contributing to this trend, being used for both gemtuzumab ozogamicin (GO; trade name: Mylotarg) and inotuzumab ozogamicin (IO; trade name: Besponsa). Here we discuss the catabolic pathway and metabolism of ABBV-011, a novel SEZ6-targeted, calicheamicin-based ADC being investigated for the treatment of small cell lung cancer (SCLC). Specifically, our investigation has found that disulfide bond cleavage in N-acetyl-γ-calicheamicin payload is a key liability that potentially impacts overall stability of the ADC. To our knowledge, there have been no reported observations of disulfide bond cleavage of calicheamicin ADCs. ABBV-011 utilizes a novel linker structure, leading to a distinct metabolic profile when compared with GO and IO. Despite this difference in linker structures, we propose that this liability may also be relevant for other calicheamicin ADCs. Multiple data sets supporting our investigation were acquired as part of the preclinical development of ABBV-011 and demonstrate the utility of in vitro experiments to characterize potential ADC candidates prior to clinical trials. SIGNIFICANCE STATEMENT: Several in vitro and in vivo stability studies of ABBV-011, a calicheamicin-based antibody-drug conjugate (ADC), identified circulating metabolites and catabolites and suggested that disulfide cleavage may be a key liability for the conjugated linker-payload. These observations may be relevant to other disulfide-linked ADCs such as gemtuzumab ozogamicin (Mylotarg) and inotuzumab ozogamicin (Besponsa), both of which have reported similar half-lives that possibly indicate instability.


Assuntos
Antineoplásicos , Imunoconjugados , Imunoconjugados/química , Inotuzumab Ozogamicina , Gemtuzumab , Calicheamicinas , Antineoplásicos/uso terapêutico , Dissulfetos
3.
Cancer Chemother Pharmacol ; 91(5): 441-446, 2023 05.
Artigo em Inglês | MEDLINE | ID: mdl-36892676

RESUMO

PURPOSE: Gemtuzumab ozogamicin (GO) is indicated for treatment of relapsed/refractory (R/R) acute myeloid leukemia (AML). The QT interval, pharmacokinetics (PK), and immunogenicity following the fractionated GO dosing regimen have not been previously assessed. This phase IV study was designed to obtain this information in patients with R/R AML. METHODS: Patients aged ≥ 18 years with R/R AML received the fractionated dosing regimen of GO 3 mg/m2 on Days 1, 4, and 7 of each cycle, up to 2 cycles. The primary endpoint was mean change from baseline in QT interval corrected for heart rate (QTc). RESULTS: Fifty patients received ≥ 1 dose of GO during Cycle 1. The upper limit of the 2-sided 90% confidence interval for least squares mean differences in QTc using Fridericia's formula (QTcF) was < 10 ms for all time points during Cycle 1. No patients had a post-baseline QTcF > 480 ms or a change from baseline > 60 ms. Treatment-emergent adverse events (TEAEs) occurred in 98% of patients; 54% were grade 3-4. The most common grade 3-4 TEAEs were febrile neutropenia (36%) and thrombocytopenia (18%). The PK profiles of both conjugated and unconjugated calicheamicin mirror that of total hP67.6 antibody. The incidence of antidrug antibodies (ADAs) and neutralizing antibodies was 12% and 2%, respectively. CONCLUSION: Fractionated GO dosing regimen (3 mg/m2/dose) is not predicted to pose a clinically significant safety risk for QT interval prolongation in patients with R/R AML. TEAEs are consistent with GO's known safety profile, and ADA presence appears unassociated with potential safety issues. TRIAL REGISTRY: Clinicaltrials.gov ID: NCT03727750 (November 1, 2018).


Assuntos
Leucemia Mieloide Aguda , Humanos , Gemtuzumab/efeitos adversos , Gemtuzumab/farmacocinética , Lectina 3 Semelhante a Ig de Ligação ao Ácido Siálico/uso terapêutico , Leucemia Mieloide Aguda/tratamento farmacológico , Calicheamicinas , Aminoglicosídeos/efeitos adversos
4.
Mol Cancer Ther ; 21(6): 986-998, 2022 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-35642431

RESUMO

In the past year, four antibody-drug conjugates (ADC) were approved, nearly doubling the marketed ADCs in oncology. Among other attributes, successful ADCs optimize targeting antibody, conjugation chemistry, and payload mechanism of action. Here, we describe the development of ABBV-011, a novel SEZ6-targeted, calicheamicin-based ADC for the treatment of small cell lung cancer (SCLC). We engineered a calicheamicin conjugate that lacks the acid-labile hydrazine linker that leads to systemic release of a toxic catabolite. We then screened a patient-derived xenograft library to identify SCLC as a tumor type with enhanced sensitivity to calicheamicin ADCs. Using RNA sequencing (RNA-seq) data from primary and xenograft SCLC samples, we identified seizure-related homolog 6 (SEZ6) as a surface-expressed SCLC target with broad expression in SCLC and minimal normal tissue expression by both RNA-seq and IHC. We developed an antibody targeting SEZ6 that is rapidly internalized upon receptor binding and, when conjugated to the calicheamicin linker drug, drives potent tumor regression in vitro and in vivo. These preclinical data suggest that ABBV-011 may provide a novel treatment for patients with SCLC and a rationale for ongoing phase I studies (NCT03639194).


Assuntos
Antineoplásicos , Imunoconjugados , Neoplasias Pulmonares , Carcinoma de Pequenas Células do Pulmão , Antineoplásicos/farmacologia , Calicheamicinas , Ensaios Clínicos Fase I como Assunto , Humanos , Imunoconjugados/farmacologia , Imunoconjugados/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Carcinoma de Pequenas Células do Pulmão/tratamento farmacológico , Carcinoma de Pequenas Células do Pulmão/genética
5.
Leukemia ; 36(8): 2022-2031, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35688939

RESUMO

Gemtuzumab ozogamicin (GO) is an anti-CD33 monoclonal antibody linked to calicheamicin, a DNA damaging agent, and is a well-established therapeutic for treating acute myeloid leukemia (AML). In this study, we used LASSO regression modeling to develop a 10-gene DNA damage response gene expression score (CalDDR-GEx10) predictive of clinical outcome in pediatric AML patients treated with treatment regimen containing GO from the AAML03P1 and AAML0531 trials (ADE + GO arm, N = 301). When treated with ADE + GO, patients with a high CalDDR-GEx10 score had lower complete remission rates (62.8% vs. 85.5%, P = 1.7 7 * 10-5) and worse event-free survival (28.7% vs. 56.5% P = 4.08 * 10-8) compared to those with a low CalDDR-GEx10 score. However, the CalDDR-GEx10 score was not associated with clinical outcome in patients treated with standard chemotherapy alone (ADE, N = 242), implying the specificity of the CalDDR-GEx10 score to calicheamicin-induced DNA damage response. In multivariable models adjusted for risk group, FLT3-status, white blood cell count, and age, the CalDDR-GEx10 score remained a significant predictor of outcome in patients treated with ADE + GO. Our findings present a potential tool that can specifically assess response to calicheamicin-induced DNA damage preemptively via assessing diagnostic leukemic cell gene expression and guide clinical decisions related to treatment using GO.


Assuntos
Antineoplásicos Imunológicos , Dano ao DNA , Gemtuzumab , Leucemia Mieloide Aguda , Aminoglicosídeos/efeitos adversos , Anticorpos Monoclonais Humanizados , Antineoplásicos Imunológicos/uso terapêutico , Calicheamicinas/efeitos adversos , Criança , DNA , Dano ao DNA/genética , Gemtuzumab/uso terapêutico , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Lectina 3 Semelhante a Ig de Ligação ao Ácido Siálico/metabolismo , Transcriptoma
6.
Int J Hematol ; 116(4): 612-621, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-35635686

RESUMO

Inotuzumab ozogamicin (InO) is a CD22-directed antibody conjugated with calicheamicin approved for adult relapsed or refractory CD22-positive acute lymphoblastic leukemia (ALL). This phase 1 study primarily aimed to determine the pediatric recommended doses of InO through the standard 3 + 3 design, and to evaluate the safety, tolerability, pharmacokinetic (PK) profile, immunogenicity and efficacy of InO. Dose level 1 (DL1) was 1.8 mg/m2 (days 1, 8, and 15: 0.8, 0.5, and 0.5 mg/m2, respectively). Six of the seven registered patients were eligible [median age, 7.5 (2-17) years]. Although all six patients started DL1, only five completed the dose. No dose-limiting toxicity was observed. All patients experienced adverse events (AEs), including increased alanine aminotransferase and aspartate aminotransferase in four patients. Three patients experienced serious AEs, which were hepatic veno-occlusive disease (VOD), ALL, and fever. Five patients achieved complete remission (CR) or CR with incomplete blood cell recovery (CRi), among whom 3 (60%) were negative for minimal residual disease. PK findings were similar to those in adults. No patient had anti-drug antibodies to InO. In conclusion, InO was well tolerated in children and promoted similar antileukemic efficacy as in adults. Nonetheless, the risk for VOD requires attention.


Assuntos
Calicheamicinas , Leucemia-Linfoma Linfoblástico de Células Precursoras , Adolescente , Alanina Transaminase , Aspartato Aminotransferases , Criança , Pré-Escolar , Humanos , Inotuzumab Ozogamicina , Japão , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Lectina 2 Semelhante a Ig de Ligação ao Ácido Siálico/uso terapêutico
7.
Leukemia ; 36(6): 1516-1524, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35468945

RESUMO

Inotuzumab Ozogamicin is a CD22-directed antibody conjugated to calicheamicin, approved in adults with relapsed or refractory (R/R) B cell acute lymphoblastic leukemia (BCP-ALL). Patients aged 1-18 years, with R/R CD22 + BCP-ALL were treated at the RP2D of 1.8 mg/m2. Using a single-stage design, with an overall response rate (ORR) ≤ 30% defined as not promissing and ORR > 55% as expected, 25 patients needed to be recruited to achieve 80% power at 0.05 significance level. Thirty-two patients were enrolled, 28 were treated, 27 were evaluable for response. The estimated ORR was 81.5% (95%CI: 61.9-93.7%), and 81.8% (18/22) of the responding subjects were minimal residual disease (MRD) negative. The study met its primary endpoint. Median follow up of survivors was 16 months (IQR: 14.49-20.07). One year Event Free Survival was 36.7% (95% CI: 22.2-60.4%), and Overall Survival was 55.1% (95% CI: 39.1-77.7%). Eighteen patients received consolidation (with HSCT and/or CAR T-cells therapy). Sinusoidal obstructive syndrome (SOS) occurred in seven patients. MRD negativity seemed correlated to calicheamicin sensitivity in vitro, but not to CD22 surface expression, saturation, or internalization. InO was effective in this population. The most relevant risk was the occurrence of SOS, particularly when InO treatment was followed by HSCT.


Assuntos
Calicheamicinas , Leucemia-Linfoma Linfoblástico de Células Precursoras , Doença Aguda , Adolescente , Criança , Pré-Escolar , Humanos , Lactente , Inotuzumab Ozogamicina , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Intervalo Livre de Progressão
8.
Org Biomol Chem ; 19(30): 6707-6717, 2021 08 05.
Artigo em Inglês | MEDLINE | ID: mdl-34297027

RESUMO

Among the class of enediyne antibiotics endowed with potent antitumour activities, the calicheamicin derivative known as ozogamicin is selectively targeted to several leukaemia cell types by means of tailor-made immunoconjugates. Binding of these drugs to the DNA minor groove in a sequence-specific fashion eventually causes double-stranded cleavage that results in cell death. Use of calicheamicin ε, an unreactive analogue of calicheamicin γ1I, has demonstrated that these structurally sophisticated molecules inflict bending on certain DNA oligonucleotides of defined sequence to the extent that they increase their circularization ratio upon ligation into multimers. By modelling and simulating several linear and circular DNA constructs containing high-affinity 5'-TCCT-3' and low-affinity 5'-TTGT-3' target sites in the presence and absence of calicheamicin ε, we have shed light into the structural distortions introduced by the drug upon binding to DNA. This new insight not only informs about the direction and magnitude of the DNA curvature but also provides a rationale for an improved understanding of the preferred structural and dynamic features associated with DNA target selection by calicheamicins.


Assuntos
Calicheamicinas
9.
Molecules ; 26(5)2021 Feb 27.
Artigo em Inglês | MEDLINE | ID: mdl-33673582

RESUMO

Many cancer diseases, e.g., prostate cancer and lung cancer, develop very slowly. Common chemotherapeutics like vincristine, vinblastine and taxol target cancer cells in their proliferating states. In slowly developing cancer diseases only a minor part of the malignant cells will be in a proliferative state, and consequently these drugs will exert a concomitant damage on rapidly proliferating benign tissue as well. A number of toxins possess an ability to kill cells in all states independently of whether they are benign or malignant. Such toxins can only be used as chemotherapeutics if they can be targeted selectively against the tumors. Examples of such toxins are mertansine, calicheamicins and thapsigargins, which all kill cells at low micromolar or nanomolar concentrations. Advanced prodrug concepts enabling targeting of these toxins to cancer tissue comprise antibody-directed enzyme prodrug therapy (ADEPT), gene-directed enzyme prodrug therapy (GDEPT), lectin-directed enzyme-activated prodrug therapy (LEAPT), and antibody-drug conjugated therapy (ADC), which will be discussed in the present review. The review also includes recent examples of protease-targeting chimera (PROTAC) for knockdown of receptors essential for development of tumors. In addition, targeting of toxins relying on tumor-overexpressed enzymes with unique substrate specificity will be mentioned.


Assuntos
Antineoplásicos/química , Neoplasias Pulmonares/tratamento farmacológico , Peptídeo Hidrolases/metabolismo , Neoplasias da Próstata/tratamento farmacológico , Toxinas Biológicas/química , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Calicheamicinas/farmacologia , Proliferação de Células/efeitos dos fármacos , Preparações de Ação Retardada/química , Portadores de Fármacos/química , Desenho de Fármacos , Liberação Controlada de Fármacos , Terapia Enzimática , Técnicas de Silenciamento de Genes , Humanos , Masculino , Maitansina/farmacologia , Terapia de Alvo Molecular , Peptídeo Hidrolases/genética , Pró-Fármacos/química , Pró-Fármacos/farmacologia , Tapsigargina/farmacologia , Toxinas Biológicas/farmacologia
10.
Mol Cancer Ther ; 20(6): 1112-1120, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33722856

RESUMO

Calicheamicin antibody-drug conjugates (ADCs) are effective therapeutics for leukemias with two recently approved in the United States: Mylotarg (gemtuzumab ozogamicin) targeting CD33 for acute myeloid leukemia and Besponsa (inotuzumab ozogamicin) targeting CD22 for acute lymphocytic leukemia. Both of these calicheamicin ADCs are heterogeneous, aggregation-prone, and have a shortened half-life due to the instability of the acid-sensitive hydrazone linker in circulation. We hypothesized that we could improve upon the heterogeneity, aggregation, and circulation stability of calicheamicin ADCs by directly attaching the thiol of a reduced calicheamicin to an engineered cysteine on the antibody via a disulfide bond to generate a linkerless and traceless conjugate. We report herein that the resulting homogeneous conjugates possess minimal aggregation and display high in vivo stability with 50% of the drug remaining conjugated to the antibody after 21 days. Furthermore, these calicheamicin ADCs are highly efficacious in mouse models of both solid tumor (HER2+ breast cancer) and hematologic malignancies (CD22+ non-Hodgkin lymphoma). Safety studies in rats with this novel calicheamicin ADC revealed an increased tolerability compared with that reported for Mylotarg. Overall, we demonstrate that applying novel linker chemistry with site-specific conjugation affords an improved, next-generation calicheamicin ADC.


Assuntos
Antibióticos Antineoplásicos/uso terapêutico , Calicheamicinas/uso terapêutico , Imunoconjugados/uso terapêutico , Animais , Antibióticos Antineoplásicos/farmacologia , Calicheamicinas/farmacologia , Modelos Animais de Doenças , Humanos , Imunoconjugados/farmacologia , Camundongos
11.
Blood ; 137(19): 2657-2661, 2021 05 13.
Artigo em Inglês | MEDLINE | ID: mdl-33512436

RESUMO

Adult patients with relapsed B-cell precursor acute lymphoblastic leukemia (BCP-ALL) have a dismal prognosis. To improve pharmacotherapy, we analyzed induction of apoptosis by venetoclax and inotuzumab ozogamicin in terms of cytotoxicity and mode of action. Flow cytometry-based analyses of mitochondrial outer membrane permeabilization (MOMP) and ataxia telangiectasia mutated activation demonstrate rapid induction of MOMP by venetoclax and DNA damage signaling by inotuzumab ozogamicin, respectively. In primary ALL samples and patient-derived xenograft (PDX) models, venetoclax and inotuzumab ozogamicin cooperated and synergized in combination with dexamethasone in vitro in all tested samples of ALL. In murine PDX models, inotuzumab ozogamicin, but not venetoclax, induced complete remission in a dose-dependent manner but constantly failed to achieve relapse-free survival. In contrast, combination therapy with venetoclax, dexamethasone, and inotuzumab ozogamicin induced long-term leukemia-free survival and treatment-free survival in all 3 ALL-PDX models tested. These data demonstrate synergistic and highly efficient pharmacotherapy in preclinical models that qualify for evaluation in clinical trials.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Dano ao DNA , DNA de Neoplasias/efeitos dos fármacos , Dexametasona/farmacologia , Inotuzumab Ozogamicina/farmacologia , Leucemia-Linfoma Linfoblástico de Células Precursoras B/tratamento farmacológico , Sulfonamidas/farmacologia , Adolescente , Adulto , Idoso , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Apoptose/efeitos dos fármacos , Compostos Bicíclicos Heterocíclicos com Pontes/administração & dosagem , Calicheamicinas/farmacologia , Quebras de DNA de Cadeia Dupla , Dexametasona/administração & dosagem , Sinergismo Farmacológico , Feminino , Humanos , Inotuzumab Ozogamicina/administração & dosagem , Masculino , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Pessoa de Meia-Idade , Membranas Mitocondriais/efeitos dos fármacos , Recidiva , Sulfonamidas/administração & dosagem , Ensaios Antitumorais Modelo de Xenoenxerto
12.
Minerva Med ; 111(5): 395-410, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32955828

RESUMO

After being in the therapeutic wilderness for several decades, acute myeloid leukemia has been recently thrust into the limelight with a series of drug approvals. Technical refinements in production, genetic manipulation and chemical modification of monoclonal antibodies led to growing interest in antibodies-based treatment strategies. Much of the focus of these efforts in acute myeloid leukemia has been on CD33 as a target. On September 2, 2017, the U.S. Food and Drug Administration approved gemtuzumab ozogamicin for treatment of relapsed or refractory CD33+ acute myeloid leukemia. This signals a new chapter in the long and unusual story of gemtuzumab ozogamicin, which was the first antibody-drug conjugate approved for human use by the Food and Drug Administration. In this review we have analyzed the history of this drug which, among several mishaps, is experiencing a second youth and still represents a field to be further explored.


Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Gemtuzumab/uso terapêutico , Leucemia Mieloide Aguda/tratamento farmacológico , Lectina 3 Semelhante a Ig de Ligação ao Ácido Siálico/antagonistas & inibidores , Idoso , Animais , Antineoplásicos/uso terapêutico , Antineoplásicos Imunológicos/efeitos adversos , Antineoplásicos Imunológicos/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Arsenicais/uso terapêutico , Calicheamicinas/metabolismo , Cloretos/uso terapêutico , Ensaios Clínicos como Assunto , Citarabina/administração & dosagem , Daunorrubicina/administração & dosagem , Daunorrubicina/efeitos adversos , Aprovação de Drogas , Avaliação Pré-Clínica de Medicamentos , Resistencia a Medicamentos Antineoplásicos , Gemtuzumab/efeitos adversos , Gemtuzumab/farmacocinética , Transplante de Células-Tronco Hematopoéticas , Humanos , Leucemia Mieloide Aguda/imunologia , Leucemia Promielocítica Aguda/tratamento farmacológico , Leucemia Promielocítica Aguda/genética , Camundongos , Pessoa de Meia-Idade , Estudos Multicêntricos como Assunto , Recidiva , Lectina 3 Semelhante a Ig de Ligação ao Ácido Siálico/genética , Lectina 3 Semelhante a Ig de Ligação ao Ácido Siálico/metabolismo , Tretinoína/uso terapêutico
14.
Artigo em Inglês | MEDLINE | ID: mdl-32361467

RESUMO

Antibody-Drug Conjugates (ADCs) consist of antibodies attached to cytotoxic small molecules or biological agents (i.e., payloads) through chemical linkers which may be cleavable or non-cleavable. The development of new ADCs is challenging, particularly the process of attaching the linker-payload construct to the antibody (i.e., the conjugation process). One of the major problems associated with conjugation is high hydrophobicity of the payload which can lead to low yields of the ADC through aggregation and/or lower than desired Drug-Antibody Ratios (DARs). We report here a UPLC-based assay that can be used to study the physicochemical properties of ADC payloads at an early stage of development, and to provide information on whether the hydrophilic-hydrophobic balance is suitable for conjugation or further physicochemical optimization is required. The assay is relatively simple to establish and should be of use to those working in the ADC area.


Assuntos
Bioensaio/métodos , Imunoconjugados/química , Espectrometria de Massas em Tandem/métodos , Calicheamicinas/química , Cromatografia Líquida de Alta Pressão , Doxorrubicina/química , Flurbiprofeno/química , Interações Hidrofóbicas e Hidrofílicas , Ibuprofeno/química , Irinotecano/química , Cetoprofeno/química , Maitansina/química , Conformação Molecular , Norfloxacino/química , Pentaclorofenol/química , Multimerização Proteica , Relação Estrutura-Atividade , Tolnaftato/química
15.
Clin Pharmacokinet ; 58(3): 335-347, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30062662

RESUMO

BACKGROUND AND OBJECTIVE: Gemtuzumab ozogamicin is an antibody-drug conjugate composed of the anti-CD33 monoclonal antibody hP67.6 covalently linked to N-acetyl-gamma-calicheamicin dimethylhydrazide, a potent cytotoxic antibiotic. The aim of this study was to characterize the population pharmacokinetics of gemtuzumab ozogamicin, represented by total hP67.6 antibody and unconjugated calicheamicin, in adult patients with acute myeloid leukemia to support drug dosing strategies and explore intrinsic and extrinsic factors that may influence exposure. Pharmacokinetic data from seven previous phase I and II studies in adult patients with relapsed, refractory, or de novo acute myeloid leukemia were integrated and analyzed using nonlinear mixed-effects modeling. METHODS: The pharmacokinetics of total hP67.6 antibody was described in 407 patients (5643 concentrations) who received gemtuzumab ozogamicin doses ranging from 0.25 to 9 mg/m2 using a two-compartment model with linear and time-dependent clearance components. The pharmacokinetics of unconjugated calicheamicin was characterized in 338 patients (4281 concentrations) using a two-compartment model with an input rate of formation dependent on the amount of hP67.6 eliminated. No statistically significant baseline covariates (sex, albumin, bone marrow, and peripheral blast percentage) demonstrated a clinically meaningful impact. RESULTS AND CONCLUSION: Total hP67.6 antibody disposition did not appear altered in patients with mild or moderate renal disease or hepatic impairment. Gemtuzumab ozogamicin was approved for the treatment of acute myeloid leukemia by the US Food and Drug Administration in September 2017. The model-based simulations described here provided a pharmacokinetic rationale for the approved dosing regimen of 3 mg/m2 on days 1, 4, and 7, and served as the basis for all exposure-response modeling included in the recent Biologics License Application submission. Clinical trials identifiers: 0903A1-101-US; 0903A1-103-JA; 0903B1-201-US/CA (NCT00003131); 0903B1-202-EU; 0903B1-203-US/EU (NCT00003673); 0903B1-205-US/EU/AU (NCT00037596); and 0903B1-206-US/EU/AU (NCT00037583).


Assuntos
Antineoplásicos Imunológicos/farmacocinética , Calicheamicinas/sangue , Gemtuzumab/farmacocinética , Leucemia Mieloide Aguda/tratamento farmacológico , Lectina 3 Semelhante a Ig de Ligação ao Ácido Siálico/sangue , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais , Antineoplásicos Imunológicos/administração & dosagem , Antineoplásicos Imunológicos/uso terapêutico , Calicheamicinas/farmacocinética , Desenho de Fármacos , Feminino , Gemtuzumab/administração & dosagem , Gemtuzumab/uso terapêutico , Humanos , Leucemia Mieloide Aguda/sangue , Leucemia Mieloide Aguda/etnologia , Masculino , Pessoa de Meia-Idade , Lectina 3 Semelhante a Ig de Ligação ao Ácido Siálico/antagonistas & inibidores , Lectina 3 Semelhante a Ig de Ligação ao Ácido Siálico/farmacocinética , Estados Unidos , United States Food and Drug Administration , Adulto Jovem
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...