Nancy Wedel

Preliminary evaluation of recombinant amino-terminal fragment of human bactericidal/permeability-increasing protein in children with severe meningococcal sepsis

BACKGROUND Meningococcal sepsis remains an important cause of morbidity and mortality. We hypothesised that children with severe meningococcaemia might benefit from inhibition of the inflammatory processes thought responsible for fulminant disease. rBPI21 is a recombinant, N-terminal fragment of human bactericidal/permeability-increasing protein, which kills meningococci and binds to and clears bacterial endotoxin, these being the primary inducers of the systemic inflammation. The aim of this study was to determine the safety and kinetics of rBPI21 in children with severe meningococcaemia and to make a preliminary assessment of clinical outcome. METHODS In this open-label, dose-escalation, phase I/II trial in severe meningococcaemia (Glasgow meningococcal prognostic septicaemia score [GMSPS] > or = 8), 26 patients aged 1-18 years, who had received their first dose of antibiotics no more than 8 hours earlier were given rBPI21 by infusion at total doses of 1.0, 2.0, and 4.0 mg/kg. FINDINGS The patients had significantly raised plasma concentrations of bacterial endotoxin and cytokines. Peak and steady state BPI concentrations were comparable with pharmacokinetic data in healthy adults. All complications were compatible with the expected pattern for severe meningococcal sepsis. Only one patient died. This outcome was found to compare favourably with a predicted mortality of > or = 30% by GMSPS, > or = 15% by plasma endotoxin values, > or = 28% by plasma interleukin-6 concentrations, 29-49% by severity of coagulopathy, and 20% (11/54) by comparison with recent historical patients consecutively treated in participating centres before this study. INTERPRETATION This, the first clinical trial or rBPI21, shows that rBPI21 can be safely administered to children with severe meningococcaemia and that the pharmacokinetics are consistent with patterns seen in healthy adults. Predicted mortality, on the basis of GMSPS, laboratory indices of inflammation and coagulopathy, and historical controls, was for between four and eight deaths. These findings have prompted a phase III randomised trial.

A Phase I Safety And Pharmacokinetic Study Of A Recombinant Amino Terminal Fragment Of Bactericidal/ Permeability-increasing Protein In Healthy Male Volunteers

A phase I pharmacokinetic and safety clinical trial of rBPI23, a recombinant amino terminal fragment of bactericidal/permeability-increasing protein, was conducted in healthy male volunteers. rBPI23 was administered as a 5 or 30 min infusion at doses of .1 to 1 mg/kg. The pharmacokinetics of rBPI23 in human subjects were described by a bi-exponential disposition function with evidence of concentration-dependent kinetics. The α half-life increased significantly with increasing dose, from 4–5 min at .1 mg/kg to 7–8 min at 1 mg/kg. The β half-life varied between 18 and 29 min regardless of dose and the clearance varied from 5 to 10 mL/min/kg. Very little, if any, of the administered rBPI23 was excreted intact in the urine. Electrocardiograms, ionized calcium concentration, prothrombin and partial prothrombin times, hematologic parameters, and blood chemistries remained normal. Furthermore, no antibody response to rBPI23 was observed in any of the subjects.

Plasma bactericidal/permeability-increasing protein concentrations in critically ill children with the sepsis syndrome.

Bactericidal/permeability-increasing protein (BPI) is a neutrophil azurophilic granule component that is bactericidal towards Gram-negative bacteria and inhibits lipopolysaccharide-mediated inflammatory responses. We conducted a prospective study to measure plasma BPI concentrations in 36 critically ill children with and without the sepsis syndrome. Plasma BPI concentrations ranged from 0.5 to 452 ng/ml. Patients with the sepsis syndrome had higher median plasma BPI concentrations than critically ill controls (5.1 v8. 1.8 ng/ml, P = 0.006). Patients with organ system failure had higher median plasma BPI concentrations than those with no organ system failure (4.5 v8. 1.3 ng/ml, P = 0.001). Plasma BPI concentrations were positively associated with pediatric risk of mortality score (P = 0.03, r8 = 0.4). These data provide the first clinical insights regarding the role of endogenous BPI production in critically ill children and suggest that BPI may play an important role in host defenses.

Randomized Placebo-controlled Study of E5 Monoclonal Antiendotoxin Antibody

Although many clinical investigations have been performed with monoclonal antibody products, few large multicenter trials have been reported. However, both scientific and regulatory rationales for such trials apply to monoclonal antibody products as well as other pharmaceuticals because conduct of blinded, randomized, concurrently controlled studies offers the best opportunity to study the safety and efficacy of new drugs.

Coagulopathy following major liver resection: the effect of rBPI21 and the role of decreased synthesis of regulating proteins by the liver.

This prospective study investigated the role of reduced hepatic synthesis of regulating proteins in coagulopathy after partial hepatectomy (PH) compared with major abdominal surgery (MAS) without involvement of the liver. Furthermore, we studied the effect of rBPI21, an endotoxin-neutralizing agent, on coagulopathy after PH was studied. Compared with MAS, PH resulted in significantly elevated levels of thrombin-antithrombin-III and plasmin-alpha2-antiplasmin complexes. Levels of antithrombin-3, alpha2-antiplasmin, fibrinogen, plasminogen, alpha2-macroglobulin (alpha2-M), and C1-inhibitor remained lower following PH. Treatment with rBPI21 led to significantly lower levels of tissue-type plasminogen activator (t-PA). Post-operative disseminated intravascular coagulation (DIC) was associated with significantly higher bilirubin and t-PA plasma levels and significantly lower levels of alpha2-M. This study indicates that PH induced hepatic failure results in decreased synthesis of hepatic regulating plasma proteins and subsequent activation of coagulation and fibrinolysis. Prevention of t-PA release by rBPI21 may have important clinical implications. Decreased availability of alpha2-M may be a factor in post-operative DIC.

Pharmacokinetics of a recombinant modified amino terminal fragment of bactericidal/permeability-increasing protein (rBPI21) in healthy volunteers.

Phase I pharmacokinetic and safety studies were conducted in healthy volunteers with rBPI21, a recombinant protein derived from the amino terminal domain of human bactericidal/permeability‐increasing protein. rBPI21 was administered as a 30‐minute infusion at doses of 0.25 to 4 mg/kg or as a 24‐ to 48‐hour infusion at doses of 2 to 8 mg/kg. For the 30‐minute infusions, the clearance of rBPI21 decreased with increasing dose from 8.4 mL/min/kg at 0.25 mg/kg to 3.3 mL/min/kg at 4 mg/kg. For rBPI21 infused over 24 to 48 hours the clearance was 10 to 11 mL/min/kg. The concentration‐time profile of rBPI21 was well described by a three‐compartmental model with parallel first‐order and Michaelis‐Menten (saturable) elimination. This model for the clearance of rBPI21 has been useful in estimating starting doses for therapeutic clinical trials.

916-91 Recombinant Endotoxin-binding Protein (rBPI23) Attenuates Endotoxin-induced Circulatory Changes in Humans

In the present study the protective effect of a recombinant endotoxin-binding protein rBPI23 on the circulatory changes in experimental endotoxemia in humans was investigated. In a controlled, blinded crossover study, eight volunteers were challenged twice with an intravenous bolus injection of endotoxin (40 EU/kg body weight), and concurrently received either rBPI23 (1 mg/kg) or placebo (human serum albumin, 0.2 mg/kg). Hemodynamic parameters were obtained non-invasively by means of M-mode, two-dimensional, and Doppler echocardiography. rBPI23 significantly reduced indices of the endotoxin-induced hyperdynamic circulation. rBPI23 treatment significantly reduced increase in cardiac index (P = 0.0156). rBPI23 treatment diminished the endotoxin-induced decrease in systemic vascular resistance index (P = 0.0304). rBPI23 did not prevent the endotoxin-induced rise in body temperature and systolic, diastolic and mean arterial pressure were not significantly different in the rBPI23- and placebo-treatment arm. Both treatment periods showed a small reduction in end diastolic and end systolic volumes. rBPI23 treatment slightly reduced the increase in M-mode ejection fraction and fractional shortening. These results indicate that rBPI23 is capable of attenuating the potentially deleterious circulatory effects of endotoxin in humans.