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1.
J Pharmacol Exp Ther ; 355(2): 288-96, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26359312

RESUMO

Lampalizumab is an antigen-binding fragment of a humanized monoclonal antibody against complement factor D (CFD), a rate-limiting enzyme in the activation and amplification of the alternative complement pathway (ACP), which is in phase III clinical trials for the treatment of geographic atrophy. Understanding of the pharmacokinetics, pharmacodynamics, and biodistribution of lampalizumab following intravitreal administration in the ocular compartments and systemic circulation is limited but crucial for selecting doses that provide optimal efficacy and safety. Here, we sought to construct a semimechanistic and integrated ocular-systemic pharmacokinetic-pharmacodynamic model of lampalizumab in the cynomolgus monkey to provide a quantitative understanding of the ocular and systemic disposition of lampalizumab and CFD inhibition. The model takes into account target-mediated drug disposition, target turnover, and drug distribution across ocular tissues and systemic circulation. Following intravitreal administration, lampalizumab achieves rapid equilibration across ocular tissues. Lampalizumab ocular elimination is relatively slow, with a τ1/2 of approximately 3 days, whereas systemic elimination is rapid, with a τ1/2 of 0.8 hours. Target-independent linear clearance is predominant in the eye, whereas target-mediated clearance is predominant in the systemic circulation. Systemic CFD synthesis was estimated to be high (7.8 mg/day); however, the amount of CFD entering the eye due to influx from the systemic circulation was small (<10%) compared with the lampalizumab dose and is thus expected to have an insignificant impact on the clinical dose-regimen decision. Our findings support the clinical use of intravitreal lampalizumab to achieve significant ocular ACP inhibition while maintaining low systemic exposure and minimal systemic ACP inhibition.


Assuntos
Anticorpos Monoclonais Humanizados/farmacologia , Fator D do Complemento/antagonistas & inibidores , Atrofia Geográfica/metabolismo , Fragmentos Fab das Imunoglobulinas/farmacologia , Administração Intravenosa , Animais , Anticorpos Monoclonais Humanizados/farmacocinética , Anticorpos Monoclonais Humanizados/uso terapêutico , Humor Aquoso/metabolismo , Feminino , Atrofia Geográfica/tratamento farmacológico , Fragmentos Fab das Imunoglobulinas/uso terapêutico , Injeções Intravítreas , Macaca fascicularis , Masculino , Modelos Biológicos , Retina/metabolismo , Corpo Vítreo/metabolismo
2.
J Pharmacol Exp Ther ; 351(3): 527-37, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25232192

RESUMO

Anti-factor D (AFD; FCFD4514S, lampalizumab) is a humanized IgG Fab fragment directed against factor D (fD), a rate-limiting serine protease in the alternative complement pathway (AP). Evaluation of AFD as a potential intravitreal (IVT) therapeutic for dry age-related macular degeneration patients with geographic atrophy (GA) is ongoing. However, it is unclear whether IVT administration of AFD can affect systemic AP activation and potentially compromise host-immune responses. We characterized the pharmacologic properties of AFD and assessed the effects of AFD administered IVT (2 or 20 mg) or intravenous (0.2, 2, or 20 mg) on systemic complement activity in cynomolgus monkeys. For the IVT groups, serum AP activity was reduced for the 20 mg dose group between 2 and 6 hours postinjection. For the intravenous groups, AFD inhibited systemic AP activity for periods of time ranging from 5 minutes (0.2 mg group) to 3 hours (20 mg group). Interestingly, the concentrations of total serum fD increased up to 10-fold relative to predose levels following administration of AFD. Furthermore, AFD was found to inhibit systemic AP activity only when the molar concentration of AFD exceeded that of fD. This occurred in cynomolgus monkeys at serum AFD levels ≥2 µg/ml, a concentration 8-fold greater than the maximum serum concentration observed following a single 10 mg IVT dose in a clinical investigation in patients with GA. Based on these findings, the low levels of serum AFD resulting from IVT administration of a clinically relevant dose are not expected to appreciably affect systemic AP activity.


Assuntos
Complemento C3a/antagonistas & inibidores , Fator D do Complemento/antagonistas & inibidores , Fragmentos Fab das Imunoglobulinas/administração & dosagem , Degeneração Macular/tratamento farmacológico , Animais , Bovinos , Complemento C3a/imunologia , Fator D do Complemento/imunologia , Relação Dose-Resposta a Droga , Feminino , Humanos , Fragmentos Fab das Imunoglobulinas/imunologia , Injeções Intravítreas , Macaca fascicularis , Degeneração Macular/sangue , Degeneração Macular/imunologia , Masculino , Camundongos , Resultado do Tratamento
3.
Circulation ; 119(22): 2928-35, 2009 Jun 09.
Artigo em Inglês | MEDLINE | ID: mdl-19470891

RESUMO

BACKGROUND: The challenge of angiogenesis science is that stable sustained vascular regeneration in humans has not been realized despite promising preclinical findings. We hypothesized that angiogenic therapies powerfully self-regulate by dynamically altering tissue characteristics. Induced neocapillaries increase drug clearance and limit tissue retention and subsequent angiogenesis even in the face of sustained delivery. METHODS AND RESULTS: We quantified how capillary flow clears fibroblast growth factor after local epicardial delivery. Fibroblast growth factor spatial loading was significantly reduced with intact coronary perfusion. Penetration and retention decreased with transendothelial permeability, a trend diametrically opposite to intravascular delivery, in which factor delivery depends on vascular leak, but consistent with a continuum model of drug transport in perfused tissues. Model predictions of fibroblast growth factor sensitivity to manipulations of its diffusivity and transendothelial permeability were validated by conjugation to sucrose octasulfate. Induction of neocapillaries adds pharmacokinetic complexity. Sustained local fibroblast growth factor delivery in vivo produced a burst of neovascularization in ischemic myocardium but was followed by drug washout and a 5-fold decrease in fibroblast growth factor penetration depth. CONCLUSIONS: The very efficacy of proangiogenic compounds enhances their clearance and abrogates their pharmacological benefit. This self-limiting property of angiogenesis may explain the failures of promising proangiogenic therapies.


Assuntos
Fatores de Crescimento de Fibroblastos/sangue , Microcirculação/fisiologia , Microvasos/fisiologia , Neovascularização Fisiológica , Farmacocinética , Animais , Permeabilidade Capilar , Difusão , Endotélio Vascular , Fatores de Crescimento de Fibroblastos/metabolismo , Isquemia , Modelos Teóricos , Ratos , Ratos Sprague-Dawley
4.
Sci Transl Med ; 9(395)2017 06 21.
Artigo em Inglês | MEDLINE | ID: mdl-28637922

RESUMO

Geographic atrophy is an advanced form of age-related macular degeneration (AMD) and a leading cause of vision loss for which there are no approved treatments. Genetic studies in AMD patients have implicated dysregulation of the alternative complement pathway in the pathogenesis of geographic atrophy. Lampalizumab is a potential therapeutic that targets complement factor D, a pivotal activator of the alternative complement pathway. The MAHALO phase 2 clinical trial was a multicenter, randomized, controlled study that evaluated lampalizumab administered by intravitreal injection monthly (n = 42) and every other month (n = 41) versus sham control (n = 40) in patients with geographic atrophy secondary to AMD. The primary endpoint was the mean change in lesion area from baseline to month 18 as measured by fundus autofluorescence. Specific AMD-associated genetic polymorphisms were also analyzed. The MAHALO study met its primary efficacy endpoint with an acceptable safety profile; monthly lampalizumab treatment demonstrated a 20% reduction in lesion area progression versus sham control [80% confidence interval (CI), 4 to 37%]. A more substantial monthly treatment benefit of 44% reduction in geographic atrophy area progression versus sham control (95% CI, 15 to 73%) was observed in a subgroup of complement factor I (CFI) risk-allele carriers (57% of the patients analyzed were CFI risk-allele carriers). The MAHALO study shows a potential treatment effect in patients with geographic atrophy and supports therapeutic targeting of the alternative complement pathway for treating AMD pathogenesis.


Assuntos
Atrofia Geográfica/tratamento farmacológico , Atrofia Geográfica/metabolismo , Fragmentos Fab das Imunoglobulinas/uso terapêutico , Degeneração Macular/tratamento farmacológico , Degeneração Macular/metabolismo , Idoso , Fator D do Complemento/antagonistas & inibidores , Fator D do Complemento/metabolismo , Via Alternativa do Complemento , Progressão da Doença , Feminino , Atrofia Geográfica/patologia , Humanos , Degeneração Macular/patologia , Masculino , Pessoa de Meia-Idade
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