RESUMO
ABSTRACT: We investigated efficacy and safety of mavorixafor, an oral CXCR4 antagonist, in participants with warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome, a rare immunodeficiency caused by CXCR4 gain-of-function variants. This randomized (1:1), double-blind, placebo-controlled, phase 3 trial enrolled participants aged ≥12 years with WHIM syndrome and absolute neutrophil count (ANC) ≤0.4 × 103/µL. Participants received once-daily mavorixafor or placebo for 52 weeks. The primary end point was time (hours) above ANC threshold ≥0.5 × 103/µL (TATANC; over 24 hours). Secondary end points included TAT absolute lymphocyte count ≥1.0 × 103/µL (TATALC; over 24 hours); absolute changes in white blood cell (WBC), ANC, and absolute lymphocyte count (ALC) from baseline; annualized infection rate; infection duration; and total infection score (combined infection number/severity). In 31 participants (mavorixafor, n = 14; placebo, n = 17), mavorixafor least squares (LS) mean TATANC was 15.0 hours and 2.8 hours for placebo (P < .001). Mavorixafor LS mean TATALC was 15.8 hours and 4.6 hours for placebo (P < .001). Annualized infection rates were 60% lower with mavorixafor vs placebo (LS mean 1.7 vs 4.2; nominal P = .007), and total infection scores were 40% lower (7.4 [95% confidence interval [CI], 1.6-13.2] vs 12.3 [95% CI, 7.2-17.3]). Treatment with mavorixafor reduced infection frequency, severity, duration, and antibiotic use. No discontinuations occurred due to treatment-emergent adverse events (TEAEs); no related serious TEAEs were observed. Overall, mavorixafor treatment demonstrated significant increases in LS mean TATANC and TATALC, reduced infection frequency, severity/duration, and was well tolerated. The trial was registered at www.clinicaltrials.gov as #NCT03995108.
Assuntos
Síndromes de Imunodeficiência , Doenças da Imunodeficiência Primária , Receptores CXCR4 , Verrugas , Humanos , Feminino , Receptores CXCR4/antagonistas & inibidores , Masculino , Doenças da Imunodeficiência Primária/tratamento farmacológico , Verrugas/tratamento farmacológico , Método Duplo-Cego , Adulto , Pessoa de Meia-Idade , Síndromes de Imunodeficiência/tratamento farmacológico , Quinolinas/efeitos adversos , Quinolinas/administração & dosagem , Quinolinas/uso terapêutico , Adolescente , Adulto Jovem , Criança , Contagem de Linfócitos , Aminoquinolinas , Benzimidazóis , ButilaminasRESUMO
The redesign of the previously reported thiophene-3-yl-methyl urea series, as a result of potential cardiotoxicity, was successfully accomplished, resulting in the identification of a novel potent series of CCR5 antagonists containing the imidazolidinylpiperidinyl scaffold. The main redesign criteria were to reduce the number of rotatable bonds and to maintain an acceptable lipophilicity to mitigate hERG inhibition. The structure-activity relationship (SAR) that was developed was used to identify compounds with the best pharmacological profile to inhibit HIV-1. As a result, five advanced compounds, 6d, 6e, 6i, 6h, and 6k, were further evaluated for receptor selectivity, antiviral activity against CCR5 using (R5) HIV-1 clinical isolates, and in vitro and in vivo safety. On the basis of these results, 6d and 6h were selected for further development.
Assuntos
Fármacos Anti-HIV/farmacologia , Benzoatos/farmacologia , Antagonistas dos Receptores CCR5 , Replicação Viral/efeitos dos fármacos , Animais , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/química , Benzoatos/síntese química , Benzoatos/química , Células CHO , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Cricetinae , Cricetulus , Desenho de Fármacos , Células HEK293 , HIV-1/efeitos dos fármacos , HIV-1/fisiologia , Interações Hospedeiro-Patógeno/efeitos dos fármacos , Humanos , Imidazóis/síntese química , Imidazóis/química , Imidazóis/farmacologia , Imidazolidinas/química , Leucócitos Mononucleares/citologia , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/virologia , Modelos Químicos , Estrutura Molecular , Piperidinas/química , Receptores CCR5/genética , Receptores CCR5/metabolismo , Relação Estrutura-AtividadeRESUMO
Preapheresis peripheral blood (PB) CD34(+) cell count is a strong predictor of hematopoietic stem cell (HSC) mobilization and is routinely used to optimize the timing, cost, and success of HSC collection in patients with multiple myeloma. However, a uniform PB CD34(+) cell count that predicts mobilization failure has not been defined, resulting in the development of institute-specific algorithms for mobilization, particularly regarding the decision of when to use the novel stem cell mobilization agent plerixafor. In this post hoc analysis, we evaluated the mobilization efficacy of plerixafor plus granulocyte colony-stimulating factor (G-CSF) versus placebo plus G-CSF in patients with multiple myeloma, stratified by preapheresis PB CD34(+) cell count: <10, <15, <20, and ≥20 cells/µL. Regardless of the PB CD34(+) cell count, the total yield of CD34(+) cells from apheresis was significantly higher in the plerixafor group than in the placebo group, and significantly more patients in the plerixafor group collected the minimum (≥2 × 10(6) cells/kg) and optimum (≥6 × 10(6) cells/kg) stem cell yields on each day of apheresis. As a corollary, the greater stem cell collection in plerixafor-treated patients resulted in the need for significantly fewer days of apheresis to reach minimum and optimum cell doses across all cell count groups. For all CD34(+) cell count groups, the proportion of patients proceeding to transplantation and the median time to platelet and neutrophil engraftment were similar in the plerixafor and placebo groups. Our findings demonstrate that in patients with multiple myeloma who might be predicted to fail mobilization based on low PB CD34(+) cell count, the addition of plerixafor to G-CSF allows for collection of the minimal and optimal cell doses in a greater proportion of patients compared with G-CSF alone. In addition, plerixafor plus G-CSF significantly improves the likelihood of optimal HSC collection in patients with higher preapheresis PB CD34(+) cell counts (≥20 cells/µL) compared with placebo plus G-CSF. Collectively, this analysis of predicted poor mobilizers validates the superiority of plerixafor plus G-CSF compared with G-CSF alone, which had been demonstrated previously in the overall patient population.
Assuntos
Antígenos CD34/imunologia , Fator Estimulador de Colônias de Granulócitos/farmacologia , Mobilização de Células-Tronco Hematopoéticas/métodos , Transplante de Células-Tronco Hematopoéticas , Compostos Heterocíclicos/farmacologia , Fatores Imunológicos/farmacologia , Adolescente , Adulto , Idoso , Antígenos CD34/metabolismo , Benzilaminas , Biomarcadores/metabolismo , Remoção de Componentes Sanguíneos , Ciclamos , Método Duplo-Cego , Combinação de Medicamentos , Feminino , Humanos , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/imunologia , Mieloma Múltiplo/patologia , Mieloma Múltiplo/terapia , Placebos , Receptores CXCR4/antagonistas & inibidores , Receptores CXCR4/imunologia , Transplante AutólogoRESUMO
A series of CCR5 antagonists representing the thiophene-3-yl-methyl ureas were designed that met the pharmacological criteria for HIV-1 inhibition and mitigated a human ether-a-go-go related gene (hERG) inhibition liability. Reducing lipophilicity was the main design criteria used to identify compounds that did not inhibit the hERG channel, but subtle structural modifications were also important. Interestingly, within this series, compounds with low hERG inhibition prolonged the action potential duration (APD) in dog Purkinje fibers, suggesting a mixed effect on cardiac ion channels.
RESUMO
In order to enter and infect human cells HIV must bind to CD4 in addition to either the CXCR4 or the CCR5 chemokine receptor. AMD11070 was the first orally available small molecule antagonist of CXCR4 to enter the clinic. Herein we report the molecular pharmacology of AMD11070 which is a potent inhibitor of X4 HIV-1 replication and the gp120/CXCR4 interaction. Using the CCRF-CEM T cell line that endogenously expresses CXCR4 we have demonstrated that AMD11070 is an antagonist of SDF-1α ligand binding (IC50 = 12.5 ± 1.3 nM), inhibits SDF-1 mediated calcium flux (IC50 = 9.0 ± 2.0 nM) and SDF-1α mediated activation of the CXCR4 receptor as measured by a Eu-GTP binding assay (IC50 =39.8 ± 2.5 nM) or a [(35)S]-GTPγS binding assay (IC50 =19.0 ± 4.1 nM), and inhibits SDF-1α stimulated chemotaxis (IC50 =19.0 ± 4.0 nM). AMD11070 does not inhibit calcium flux of cells expressing CXCR3, CCR1, CCR2b, CCR4, CCR5 or CCR7, or ligand binding to CXCR7 and BLT1, demonstrating selectivity for CXCR4. In addition AMD11070 is able to inhibit the SDF-1ß isoform interactions with CXCR4; and N-terminal truncated variants of CXCR4 with equal potency to wild type receptor. Further mechanistic studies indicate that AMD11070 is an allosteric inhibitor of CXCR4.
Assuntos
Aminoquinolinas/farmacologia , Aminoquinolinas/farmacocinética , Benzimidazóis/farmacologia , Benzimidazóis/farmacocinética , HIV-1/efeitos dos fármacos , Receptores CXCR4/metabolismo , Internalização do Vírus/efeitos dos fármacos , Administração Oral , Aminoquinolinas/administração & dosagem , Animais , Fármacos Anti-HIV/administração & dosagem , Fármacos Anti-HIV/farmacocinética , Fármacos Anti-HIV/farmacologia , Benzimidazóis/administração & dosagem , Disponibilidade Biológica , Butilaminas , Linhagem Celular , Quimiocina CXCL12/antagonistas & inibidores , Quimiocina CXCL12/genética , Quimiocina CXCL12/metabolismo , Cães , Regulação da Expressão Gênica/efeitos dos fármacos , HIV-1/fisiologia , Compostos Heterocíclicos com 1 Anel , Humanos , Estrutura Molecular , Ligação Proteica , Receptores CXCR4/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos , Replicação Viral/efeitos dos fármacosRESUMO
A series of CCR5 antagonists were optimized for potent inhibition of R5 HIV-1 replication in peripheral blood mononuclear cells. Compounds that met acceptable ADME criteria, selectivity, human plasma protein binding, potency shift in the presence of α-glycoprotein were evaluated in rat and dog pharmacokinetics.
Assuntos
Amidas/síntese química , Fármacos Anti-HIV/síntese química , Antagonistas dos Receptores CCR5 , Desenho de Fármacos , HIV-1 , Leucócitos Mononucleares , Amidas/química , Amidas/farmacologia , Animais , Fármacos Anti-HIV/química , Fármacos Anti-HIV/farmacologia , Cães , Humanos , Concentração Inibidora 50 , Leucócitos Mononucleares/efeitos dos fármacos , Estrutura Molecular , Piperidinas/síntese química , Piperidinas/química , Piperidinas/farmacologia , Piridinas/síntese química , Piridinas/química , Piridinas/farmacologia , Ratos , Replicação Viral/efeitos dos fármacosRESUMO
The viral resistance of marketed antiviral drugs including the emergence of new viral resistance of the only marketed CCR5 entry inhibitor, maraviroc, makes it necessary to develop new CCR5 allosteric inhibitors. A mutagenesis/modeling approach was used (a) to remove the potential hERG liability in an otherwise very promising series of compounds and (b) to design a new class of compounds with an unique mutant fingerprint profile depending on residues in the N-terminus and the extracellular loop 2. On the basis of residues, which were identified by mutagenesis as key interaction sites, binding modes of compounds were derived and utilized for compound design in a prospective manner. The compounds were then synthesized, and in vitro evaluation not only showed that they had good antiviral potency but also fulfilled the requirement of low hERG inhibition, a criterion necessary because a potential approved drug would be administered chronically. This work utilized an interdisciplinary approach including medicinal chemistry, molecular biology, and computational chemistry merging the structural requirements for potency with the requirements of an acceptable in vitro profile for allosteric CCR5 inhibitors. The obtained mutant fingerprint profiles of CCR5 inhibitors were used to translate the CCR5 allosteric binding site into a general pharmacophore, which can be used for discovering new inhibitors.
Assuntos
Fármacos Anti-HIV/farmacologia , Desenho de Fármacos , Canais de Potássio Éter-A-Go-Go/antagonistas & inibidores , HIV-1/efeitos dos fármacos , Leucócitos Mononucleares/efeitos dos fármacos , Ureia/farmacologia , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/química , Antagonistas dos Receptores CCR5 , Relação Dose-Resposta a Droga , Humanos , Testes de Sensibilidade Microbiana , Modelos Moleculares , Estrutura Molecular , Peso Molecular , Mutagênese , Estereoisomerismo , Relação Estrutura-Atividade , Ureia/análogos & derivados , Ureia/químicaRESUMO
Based on the attrition rate of CCR5 small molecule antagonists in the clinic the discovery and development of next generation antagonists with an improved pharmacology and safety profile is necessary. Herein, we describe a combined molecular modeling, CCR5-mediated cell fusion, and receptor site-directed mutagenesis approach to study the molecular interactions of six structurally diverse compounds (aplaviroc, maraviroc, vicriviroc, TAK-779, SCH-C and a benzyloxycarbonyl-aminopiperidin-1-yl-butane derivative) with CCR5, a coreceptor for CCR5-tropic HIV-1 strains. This is the first study using an antifusogenic assay, a model of the interaction of the gp120 envelope protein with CCR5. This assay avoids the use of radioactivity and HIV infection assays, and can be used in a high throughput mode. The assay was validated by comparison with other established CCR5 assays. Given the hydrophobic nature of the binding pocket several binding models are suggested which could prove useful in the rational drug design of new lead compounds.
Assuntos
Antagonistas dos Receptores CCR5 , Inibidores da Fusão de HIV/farmacologia , HIV-1/fisiologia , HIV-1/efeitos dos fármacos , Ensaios de Triagem em Larga Escala , Modelos Moleculares , Mutagênese Sítio-Dirigida , Mutação , Conformação Proteica , Receptores CCR5/genética , Reprodutibilidade dos Testes , Estereoisomerismo , Internalização do VírusRESUMO
A novel series of CCR5 antagonists were identified based on the redesign of Schering C. An SAR was established based on inhibition of CCR5 (RANTES) binding and these compounds exhibited potent inhibition of R5 HIV-1 replication in peripheral blood mononuclear cells.
Assuntos
Amidas/química , Antagonistas dos Receptores CCR5 , Óxidos N-Cíclicos/química , HIV-1/efeitos dos fármacos , Piperidinas/química , Piridinas/química , Amidas/síntese química , Amidas/farmacocinética , Animais , Cães , Desenho de Fármacos , Humanos , Oximas , Ratos , Receptores CCR5/metabolismo , Relação Estrutura-Atividade , Replicação Viral/efeitos dos fármacosRESUMO
A novel series of CXCR4 antagonists were identified based on the substantial redesign of AMD070. These compounds possessed potent anti-HIV-1 activity and showed excellent pharmacokinetics in rat and dog.
Assuntos
Fármacos Anti-HIV/síntese química , Desenho de Fármacos , HIV-1/efeitos dos fármacos , Receptores CXCR4/antagonistas & inibidores , Replicação Viral/efeitos dos fármacos , Aminoquinolinas , Animais , Fármacos Anti-HIV/química , Fármacos Anti-HIV/farmacocinética , Benzimidazóis , Butilaminas , Replicação do DNA/efeitos dos fármacos , Cães , HIV-1/fisiologia , Compostos Heterocíclicos com 1 Anel/química , Estrutura Molecular , RatosRESUMO
An early lead from the AMD070 program was optimized and a structure-activity relationship was developed for a novel series of heterocyclic containing compounds. Potent CXCR4 antagonists were identified based on anti-HIV-1 activity and Ca(2+) flux inhibition that displayed good pharmacokinetics in rat and dog.
Assuntos
Fármacos Anti-HIV/síntese química , HIV-1/efeitos dos fármacos , Receptores CXCR4/antagonistas & inibidores , Replicação Viral/efeitos dos fármacos , Administração Oral , Aminoquinolinas , Animais , Fármacos Anti-HIV/química , Fármacos Anti-HIV/farmacocinética , Benzimidazóis , Butilaminas , Sinalização do Cálcio , Cães , HIV-1/fisiologia , Compostos Heterocíclicos com 1 Anel/química , Humanos , Ratos , Receptores CXCR4/metabolismo , Relação Estrutura-AtividadeRESUMO
Autologous hematopoietic stem cell transplantation (ASCT) is an established treatment for patients with hematologic malignancies, yet the impact of transplanted CD34(+) cell dose on clinical outcomes is unresolved. We conducted post hoc analyses of transplanted CD34(+) cell dose and hematopoietic recovery following ASCT in 438 patients with non-Hodgkin lymphoma (NHL) or multiple myeloma (MM), using data from 2 multicenter phase 3 clinical studies that compared plerixafor plus granulocyte-colony stimulating factor (G-CSF) versus placebo plus G-CSF as stem cell mobilization regimens. Days to engraftment and the proportion of patients who reached predetermined blood count thresholds were compared across 3 CD34(+) cell dose levels: 2-4 × 10(6) cells/kg, 4-6 × 10(6) cells/kg, and >6 × 10(6) cells/kg, regardless of mobilization treatment. Short-term neutrophil and platelet engraftment times were similar regardless of cell dose. A significant linear trend was observed between transplanted CD34(+) cell dose and the proportion of patients with platelet count >150 × 10(9)/L at 100 days (P < .001), 6 months (P = .026), and 12 months (P = .020) in patients with NHL, and at 100 days in patients with MM (P = .004). A linear trend was also observed between transplanted cell dose and the proportion of patients with platelet count >100 × 10(9)/L at 100 days (P < .001) and 6 months (P = .023) in patients with NHL. A higher cell dose was associated with a lower percentage of NHL patients requiring red blood cell transfusions (P = .006). Our analyses confirm previous findings that transplanted CD34(+) cell dose may be associated with better long-term platelet recovery after ASCT.
Assuntos
Antígenos CD34/imunologia , Plaquetas/imunologia , Fator Estimulador de Colônias de Granulócitos/uso terapêutico , Compostos Heterocíclicos/uso terapêutico , Linfoma não Hodgkin/terapia , Mieloma Múltiplo/terapia , Transplante de Células-Tronco de Sangue Periférico/métodos , Benzilaminas , Ciclamos , Feminino , Mobilização de Células-Tronco Hematopoéticas/métodos , Células-Tronco Hematopoéticas/efeitos dos fármacos , Células-Tronco Hematopoéticas/imunologia , Humanos , Linfoma não Hodgkin/sangue , Linfoma não Hodgkin/imunologia , Masculino , Mieloma Múltiplo/sangue , Mieloma Múltiplo/imunologia , Contagem de Plaquetas , Análise de Sobrevida , Transplante AutólogoRESUMO
Pharmacological manipulation of CXCR4 has proven clinically useful for mobilization of stem and progenitor cells and in several preclinical models of disease. It is a key component in the localization of leukocytes and stem cells. For patients with multiple myeloma and non-Hodgkin's Lymphoma, treatment with plerixafor, an inhibitor of CXCL12 binding to CXCR4, plus G-CSF mobilizes stem cells for autologous transplantation to a greater degree than the treatment with G-CSF alone, and in some cases when patients could not be mobilized with cytokines, chemotherapy, or the combination. Stem cells from healthy donors mobilized with single agent plerixafor have been used for allogeneic transplantation in acute myelogenous leukemia (AML) patients, although this is still in the early phase of clinical development. Plerixafor is also undergoing evaluation to mobilize tumor cells in patients with AML and chronic lymphocytic leukemia (CLL) to enhance the effectiveness of chemotherapy regimens. Plerixafor's effect on neutrophils may also restore circulating neutrophil counts to normal levels in patients with chronic neutropenias such as in WHIMs syndrome. Other areas where inhibition of CXCR4 may be useful based upon preclinical or clinical data include peripheral vascular disease, autoimmune diseases such as rheumatoid arthritis, pulmonary inflammation, and HIV.
Assuntos
Doenças Hematológicas/tratamento farmacológico , Receptores CXCR4/antagonistas & inibidores , Animais , Benzilaminas , Ensaios Clínicos como Assunto , Ciclamos , Avaliação Pré-Clínica de Medicamentos , Quimioterapia Combinada , Fator Estimulador de Colônias de Granulócitos/uso terapêutico , Doenças Hematológicas/imunologia , Mobilização de Células-Tronco Hematopoéticas , Compostos Heterocíclicos/farmacologia , Compostos Heterocíclicos/uso terapêutico , Humanos , Transplante de Células-TroncoRESUMO
The redesign of azamacrocyclic CXCR4 chemokine receptor antagonists resulted in the discovery of novel, small molecule, orally bioavailable compounds that retained T-tropic (CXCR4 using, X4) anti-HIV-1 activity. A structure-activity relationship (SAR) was determined on the basis of the inhibition of replication of X4 HIV-1 NL4.3 in MT-4 cells. As a result of lead optimization, we identified (S)-N'-((1H-benzo[d]imidazol-2-yl)methyl)-N'-(5,6,7,8-tetrahydroquinolin-8-yl)butane-1,4-diamine (AMD070) 2 as a potent and selective antagonist of CXCR4 with an IC(50) value of 13 nM in a CXCR4 125I-SDF inhibition binding assay. Compound 2 inhibited the replication of T-tropic HIV-1 (NL4.3 strain) in MT-4 cells and PBMCs with an IC(50) of 2 and 26 nM, respectively, while remaining noncytotoxic to cells at concentrations exceeding 23 microM. The pharmacokinetics of 2 was evaluated in rat and dog, and good oral bioavailability was observed in both species. This compound represents the first small molecule orally bioavailable CXCR4 antagonist that was developed for the treatment of HIV-1 infection.
Assuntos
Fármacos Anti-HIV/síntese química , HIV-1/efeitos dos fármacos , Compostos Heterocíclicos com 1 Anel/síntese química , Receptores CXCR4/antagonistas & inibidores , Administração Oral , Aminoquinolinas , Animais , Fármacos Anti-HIV/química , Fármacos Anti-HIV/farmacologia , Benzimidazóis , Disponibilidade Biológica , Butilaminas , Cálcio/metabolismo , Linhagem Celular , Permeabilidade da Membrana Celular , Cães , HIV-1/fisiologia , Compostos Heterocíclicos com 1 Anel/química , Compostos Heterocíclicos com 1 Anel/farmacologia , Humanos , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/metabolismo , Leucócitos Mononucleares/virologia , Ensaio Radioligante , Ratos , Estereoisomerismo , Relação Estrutura-Atividade , Replicação Viral/efeitos dos fármacosRESUMO
Bis-tetraazamacrocycles such as the bicyclam AMD3100 (1) are a class of potent and selective anti-HIV-1 agents that inhibit virus replication by binding to the chemokine receptor CXCR4, the coreceptor for entry of X4 viruses. By sequential replacement and/or deletion of the amino groups within the azamacrocyclic ring systems, we have determined the minimum structural features required for potent antiviral activity in this class of compounds. All eight amino groups are not required for activity, the critical amino groups on a per ring basis are nonidentical, and the overall charge at physiological pH can be reduced without compromising potency. This approach led to the identification of several single ring azamacrocyclic analogues such as AMD3465 (3d), 36, and 40, which exhibit EC(50)'s against the cytopathic effects of HIV-1 of 9.0, 1.0, and 4.0 nM, respectively, antiviral potencies that are comparable to 1 (EC(50) against HIV-1 of 4.0 nM). More importantly, however, the key structural elements of 1 required for antiviral activity may facilitate the design of nonmacrocyclic CXCR4 antagonists suitable for HIV treatment via oral administration.
Assuntos
Fármacos Anti-HIV/química , Fármacos Anti-HIV/síntese química , HIV-1/efeitos dos fármacos , Compostos Heterocíclicos/química , Compostos Heterocíclicos/síntese química , Receptores CXCR4/antagonistas & inibidores , Linfócitos T , Replicação Viral/efeitos dos fármacos , Fármacos Anti-HIV/farmacologia , Infecções por HIV/tratamento farmacológico , Compostos Heterocíclicos/farmacologia , Humanos , Modelos Químicos , Estrutura Molecular , Piridinas/química , Piridinas/farmacologia , Relação Estrutura-AtividadeAssuntos
Mobilização de Células-Tronco Hematopoéticas/métodos , Transplante de Células-Tronco Hematopoéticas/métodos , Células-Tronco Hematopoéticas/efeitos dos fármacos , Compostos Heterocíclicos/farmacologia , Antígenos de Histocompatibilidade Classe I/genética , Animais , Fármacos Anti-HIV/farmacologia , Benzilaminas , Ciclamos , Cães , Haplótipos , Antígenos de Histocompatibilidade Classe I/imunologiaRESUMO
In a phase 3 multicenter, randomized, double-blinded, placebo-controlled study of 298 patients with non-Hodgkin lymphoma (NHL), granulocyte colony-stimulating factor (G-CSF) plus plerixafor increased the proportion of patients who mobilized >or=5 x 10(6) CD34(+) hematopoietic stem cells (HSCs)/kg compared with placebo plus G-CSF (P < .001). Patients in either study arm who failed mobilization (< 0.8 x 10(6) CD34(+) cells/kg in 2 collections or <2 x 10(6) CD34(+) cells/kg in 4 collections) were eligible to enter the opened-label rescue protocol. Following a 7-day minimum rest period, these patients received G-CSF (10 microg/kg/day) for 4 days, followed by daily plerixafor (0.24 mg/kg) plus G-CSF and apheresis for up to 4 days. Of the 68 patients failing initial mobilization (plerixafor, n = 11; placebo, n = 57), 62 patients (91%) entered the rescue procedure (plerixafor, n = 10; placebo, n = 52). Four of 10 patients (40%) from the plerixafor group and 33 of 52 (63%) from the placebo group mobilized sufficient CD34(+) cells (>or= 2 x 10(6) cells/kg) for transplantation from the rescue mobilization alone (P = .11). Engraftment of neutrophils (11 days) and platelets (20 days) was similar to that in patients who did not fail initial mobilization, and all patients had durable grafts at the 12-month follow-up. Common plerixafor-related adverse events (AEs) included mild gastrointestinal (GI) effects and injection site reactions. There were no drug-related serious AEs. These data support that plerixafor plus G-CSF can safely and effectively remobilize patients with NHL who have failed previous mobilization.
Assuntos
Fator Estimulador de Colônias de Granulócitos/administração & dosagem , Mobilização de Células-Tronco Hematopoéticas/métodos , Compostos Heterocíclicos/administração & dosagem , Linfoma não Hodgkin/terapia , Benzilaminas , Remoção de Componentes Sanguíneos/métodos , Terapia Combinada , Ciclamos , Método Duplo-Cego , Feminino , Fator Estimulador de Colônias de Granulócitos/efeitos adversos , Mobilização de Células-Tronco Hematopoéticas/efeitos adversos , Transplante de Células-Tronco Hematopoéticas , Compostos Heterocíclicos/efeitos adversos , Humanos , Linfoma não Hodgkin/sangue , Linfoma não Hodgkin/tratamento farmacológico , Linfoma não Hodgkin/cirurgia , Masculino , Pessoa de Meia-IdadeRESUMO
PURPOSE: This study evaluates the safety and efficacy of plerixafor (AMD3100), a CXCR4 antagonist, in mobilizing hematopoietic stem cells for autologous stem-cell transplantation in non-Hodgkin's lymphoma (NHL) patients. PATIENTS AND METHODS: This is a phase III, multicenter, randomized (1:1), double-blind, placebo-controlled study. Patients with non-Hodgkin's lymphoma requiring an autologous hematopoietic stem-cell transplantation in first or second complete or partial remission were eligible. Patients received granulocyte colony-stimulating factor (G-CSF; 10 microg/kg) subcutaneously daily for up to 8 days. Beginning on evening of day 4 and continuing daily for up to 4 days, patients received either plerixafor (240 microg/kg) or placebo subcutaneously. Starting on day 5, patients began daily apheresis for up to 4 days or until > or = 5 x 10(6) CD34+ cells/kg were collected. The primary end point was the percentage of patients who collected > or = 5 x 10(6) CD34+ cells/kg in 4 or fewer apheresis days. RESULTS: This report presents all data for all patients (n = 298) through 12 months follow-up. Eighty-nine (59%) of 150 patients in the plerixafor group and 29 (20%) of 148 patients in the placebo group met the primary end point (P < .001). One hundred thirty-five patients (90%) in plerixafor group and 82 patients (55%) in placebo group underwent transplantation after initial mobilization. Median time to engraftment was similar in both groups. The most common plerixafor-associated adverse events were GI disorders and injection site reactions. CONCLUSION: Plerixafor and G-CSF were well tolerated and resulted in a significantly higher proportion of patients with non-Hodgkin's lymphoma achieving the optimal CD34+ cell target for transplantation in fewer apheresis days, compared with G-CSF alone.
Assuntos
Fator Estimulador de Colônias de Granulócitos/administração & dosagem , Mobilização de Células-Tronco Hematopoéticas , Transplante de Células-Tronco Hematopoéticas/métodos , Compostos Heterocíclicos/administração & dosagem , Linfoma não Hodgkin/terapia , Adulto , Idoso , Benzilaminas , Ciclamos , Diarreia/etiologia , Método Duplo-Cego , Feminino , Cefaleia/etiologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Infusões Subcutâneas , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Náusea/etiologia , Estudos Prospectivos , Transplante Autólogo , Resultado do Tratamento , Adulto JovemRESUMO
CXCR4 is widely expressed in multiple cell types, and is involved in neonatal development, hematopoiesis, and lymphocyte trafficking and homing. Disruption of the CXCL12/CXCR4 interaction has been implicated in stem cell mobilization. Additionally CXCR4 is a co-receptor for HIV. Selective small molecule antagonists of CXCR4 therefore have therapeutic potential. AMD3465 is an N-pyridinylmethylene monocyclam CXCR4 antagonist which can block infection of T-tropic, CXCR4-using HIV. Using the CCRF-CEM T-cell line which expresses CXCR4 we have demonstrated that AMD3465 is an antagonist of SDF-1 ligand binding (K(i) of 41.7+/-1.2nM), and inhibits SDF-1 mediated signaling as shown by inhibition of GTP binding, calcium flux, and inhibition of chemotaxis. AMD3465 is selective for CXCR4 and does not inhibit chemokine-stimulated calcium flux in cells expressing CXCR3, CCR1, CCR2b, CCR4, CCR5 or CCR7, nor does it inhibit binding of LTB(4) to its receptor, BLT1. The pharmacokinetics of AMD3465 was investigated in mice and dogs. Absorption was rapid following subcutaneous administration. AMD3465 was cleared from dog plasma in a biphasic manner with a terminal half-life of 1.56-4.63h. Comparison of exposure to the intravenous and subcutaneous doses indicated 100% bioavailability following subcutaneous administration. AMD3465 caused leukocytosis when administered subcutaneously in mice and dogs, with peak mobilization occurring between 0.5 and 1.5h following subcutaneous dosing in mice and with maximum peak plasma concentration of compound preceding peak mobilization in dogs, indicating that AMD3465 has the potential to mobilize hematopoietic stem cells. These data demonstrate the therapeutic potential for the CXCR4 antagonist AMD3465.
Assuntos
Compostos Heterocíclicos/farmacologia , Piridinas/farmacologia , Piridinas/farmacocinética , Receptores CXCR4/antagonistas & inibidores , Absorção , Animais , Área Sob a Curva , Células CHO , Cálcio/análise , Cálcio/metabolismo , Linhagem Celular , Quimiocina CXCL12/antagonistas & inibidores , Quimiotaxia/efeitos dos fármacos , Cricetinae , Cricetulus , Cães , Relação Dose-Resposta a Droga , Fluoresceínas/metabolismo , Corantes Fluorescentes/metabolismo , Meia-Vida , Humanos , Concentração Inibidora 50 , Rim/citologia , Leucocitose/etiologia , Masculino , Dose Máxima Tolerável , Taxa de Depuração Metabólica , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos DBA , Estrutura Molecular , Ligação Proteica , Piridinas/efeitos adversos , Piridinas/sangue , Piridinas/química , TransfecçãoRESUMO
This phase 3, multicenter, randomized (1:1), double-blind, placebo-controlled study evaluated the safety and efficacy of plerixafor with granulocyte colony-stimulating factor (G-CSF) in mobilizing hematopoietic stem cells in patients with multiple myeloma. Patients received G-CSF (10 microg/kg) subcutaneously daily for up to 8 days. Beginning on day 4 and continuing daily for up to 4 days, patients received either plerixafor (240 microg/kg) or placebo subcutaneously. Starting on day 5, patients began daily apheresis for up to 4 days or until more than or equal to 6 x 10(6) CD34(+) cells/kg were collected. The primary endpoint was the percentage of patients who collected more than or equal to 6 x 10(6) CD34(+) cells/kg in less than or equal to 2 aphereses. A total of 106 of 148 (71.6%) patients in the plerixafor group and 53 of 154 (34.4%) patients in the placebo group met the primary endpoint (P < .001). A total of 54% of plerixafor-treated patients reached target after one apheresis, whereas 56% of the placebo-treated patients required 4 aphereses to reach target. The most common adverse events related to plerixafor were gastrointestinal disorders and injection site reactions. Plerixafor and G-CSF were well tolerated, and significantly more patients collected the optimal CD34(+) cell/kg target for transplantation earlier compared with G-CSF alone. This study is registered at www.clinicaltrials.gov as #NCT00103662.