Systemic pharmacokinetics following intravitreal injections of ranibizumab, bevacizumab or aflibercept in patients with neovascular AMD.

BACKGROUND: Data comparing systemic exposure and systemic vascular endothelial growth factor (VEGF) suppression of ranibizumab, bevacizumab and aflibercept following intravitreal injection are lacking. METHODS: Fifty-six patients with wet age-related macular degeneration received intravitreal ranibizumab (0.5 mg), bevacizumab (1.25 mg), or aflibercept (2.0 mg). Serum pharmacokinetics and plasma free VEGF were evaluated after the first and third injections. RESULTS: Following the first dose, systemic exposure to aflibercept was 5-, 37-, and 9-fold higher than ranibizumab, whereas, bevacizumab was 9-, 310-, and 35-fold higher than ranibizumab, based on geometric mean ratio of peak and trough concentrations and area under the curve, respectively. The third dose showed accumulation of bevacizumab and aflibercept but not ranibizumab. Aflibercept substantially suppressed plasma free VEGF, with mean levels below lower limit of quantitation (10 pg/mL) as early as 3 h postdose until ≥7 days postdose. Mean free (unbound) VEGF levels with ranibizumab were largely unchanged, with mean trough level of 14.4 pg/mL compared with baseline of 17 pg/mL. CONCLUSIONS: There are notable differences in systemic pharmacokinetics and pharmacodynamics among anti-VEGF treatments after intravitreal administration. All three agents rapidly moved into the bloodstream, but ranibizumab very quickly cleared, whereas bevacizumab and aflibercept demonstrated greater systemic exposure and produced a marked reduction in plasma free VEGF. TRIAL REGISTRATION NUMBER: NCT02118831.

Safety and pharmacokinetics of recombinant factor XIII-A2 administration in patients with congenital factor XIII deficiency.

Congenital factor XIII (FXIII) deficiency is associated with a tendency for severe bleeding, a risk for spontaneous abortion, and a high rate of spontaneous intracranial hemorrhage. This phase 1 escalating-dose study was developed to evaluate the safety and pharmacokinetics of a single administration of human recombinant FXIII-A2 (rFXIII-A2) homodimer in adults with congenital FXIII deficiency. Pharmacokinetics and activity of rXIII and changes in endogenous B subunit levels were assessed. Recombinant FXIII-A2 homodimer were complexed with endogenous FXIII-B subunits to form an FXIII-A2B2 heterotetramer with a half-life of 8.5 days, similar to that of endogenous FXIII. The median dose response was a 2.4% increase in FXIII activity based on unit per kilogram rFXIII administered. After the administration of rFXIII-A2, clot solubility normalized as measured by clot lysis in urea. Clot strength and resistance to fibrinolysis, as assessed by thromboelastography, also improved. Safety reviews were conducted before each dose escalation; no serious adverse events, including bleeding or thrombosis, were noted during the study. In addition, there was no evidence of the generation of specific antibodies to rFXIII or yeast proteins. Recombinant FXIII appears to be a safe and potentially effective alternative for FXIII replacement in patients with FXIII deficiency.

Population pharmacokinetics of recombinant factor XIII in cynomolgus monkeys.

Hemostasis in humans and other animals is a complex process that controls blood loss after a vascular injury. Factor XIII (FXIII) stabilizes clots primarily by cross-linking fibrin, thus protecting a newly formed clot from fibrinolysis by plasmin. Congenital deficiencies in humans involving FXIII are associated with delayed bleeding and wound healing and severe spontaneous hemorrhaging. These symptoms can be alleviated by intravenous administration of enriched FXIII plasma fractions. Circulating plasma FXIII is found as a heterotetramer that dissociates in the presence of calcium and thrombin into an active dimer and 2 inactive monomers. The recombinant FXIII under investigation is the active dimer alone. A 3-compartment, nonlinear population pharmacokinetic model was implemented in NONMEM V and then used to analyze data from preclinical studies in cynomolgus monkeys. The model simultaneously describes endogenous production of dimer (0.622 microg kg(-1) hr(-1)) and monomer (12.1 microg kg(-1) hr(-1)), and the administration of recombinant dimer. The model incorporates the rate and extent of complexation of recombinant dimer with available endogenous monomer (6.59 mg(-1) kg hr(-1)) to form the heterotetramer. Half-lives for dimer, heterotetramer, and monomer (3.33 hours, 2.83 days, and 3.94 hours for A(2), A(2)B(2), and B, respectively) were estimated, along with their variability in the population studied.

Safety and pharmacokinetics of recombinant factor XIII in healthy volunteers: a randomized, placebo-controlled, double-blind, multi-dose study.

Factor XIII (FXIII) is a plasma transglutaminase that covalently cross-links fibrin proteins to one another and to other proteins, increasing the mechanical strength of blood clots. Endogenous FXIII is the final enzyme in the clotting cascade and circulates as a heterotetramer comprising 2 FXIII-A subunits and 2 FXIII-B subunits. Recombinant human FXIII A2 (rFXIII) homodimer is produced in Saccharomyces cerevisiae. Upon injection, rFXIII combines with the free FXIIIB subunit that circulates in excess to form the rA2B2 tetramer. In this placebo-controlled, double-blind, multi-dose study, the safety, pharmacokinetics, and pharmacodynamics of rFXIII were studied in 24 healthy volunteers, who were randomized in 2 cohorts of 12 subjects each. In each cohort, 8 subjects received 5 daily intravenous doses of rFXIII (10 or 25 U/kg), and 4 subjects received placebo. Recombinant FXIII was well tolerated. No deaths or serious adverse events occurred. The type and frequency of adverse events showed no pattern or dose response. No clinically significant changes in haematology, serum chemistry, or urinalysis laboratory values were observed. No clinical coagulopathy or thrombosis was observed. Recombinant FXIII did not produce any anti-yeast or anti-FXIII antibodies. After 5 daily doses of rFXIII, accumulation indices indicated a 3 to 4fold accumulation of rFXIII in plasma. The elimination half-life, estimated for rFXIII as the heterotetramer, ranged from 228-346 hours for the 10U/kg dose group and 167-197 hours for the 25U/kg dose group. The safety, pharmacokinetic, and immunogenic profile of rFXIII suggests it may have potential use in patients with congenital or acquired FXIII deficiency.

Preclinical safety and pharmacokinetics of recombinant human factor XIII.

Factor XIII (FXIII) is a thrombin-activated protransglutaminase responsible for fibrin clot stabilization and longevity. Deficiency in FXIII is associated with diffuse bleeding and wound-healing disorders in humans. This report summarizes results from several studies conducted in adult cynomolgus monkeys (M. fascicularis) to evaluate the safety and pharmacokinetics of recombinant human factor XIII A(2) dimer (rFXIII). Intravenous slow bolus injection of rFXIII resulted in the expected formation of the heterotetramer rA(2)cnB(2), prolonged circulating half-life (5-7 days), and increased plasma transglutaminase activity. Recombinant FXIII was well tolerated as a single dose up to 20 mg/kg rFXIII (2840 U/kg), as repeated daily doses up to 6 mg/kg (852 U/kg) for 14 days, and as 3 repeated doses of 8 mg/kg (1136 U/kg) separated by 14 days. Overt toxicity occurred after a single intravenous injection of = 22.5 mg/kg rFXIII (3150 U/kg), or with 2 doses of = 12.5 mg/kg (1775 U/kg) administered within 72 hours. The rFXIII-mediated toxicity was expressed as an acute systemic occlusive coagulopathy. Evaluation of plasma samples from dosed animals demonstrated formation of cross-linked fibrin/fibrinogen oligomers and higher-order protein aggregates, which are hypothesized to be responsible for the observed vessel occlusion and associated embolic sequelae. These results demonstrate that rFXIII-mediated toxicity results from exaggerated pharmacological activity of the molecule at supraphysiological concentrations. The absence of observed toxicological effect with repeated intravenous doses up to 8 mg/kg (1136 U/kg) was used to support an initial clinical dose range of 0.014 to 0.35 mg/kg (2-50 U/kg).