title: Pharmacokinetics and safety of TP10, soluble complement receptor 1, in infants undergoing cardiopulmonary bypass.
abstract: BACKGROUND
  Increase in vascular permeability and multiorgan dysfunction after cardiopulmonary bypass (CPB) are barriers to successful cardiac surgery in infants. Complement inhibition with TP10, a C3/C5 convertase inhibitor (AVANT Immunotherapeutics, Needham, Mass), blunts post-CPB organ dysfunction in the neonatal pig. Methods and results The pharmacokinetics and safety of TP10 in infants (age <1 year, n = 15) undergoing CPB were examined in a phase I/II open-label prospective trial. TP10 (10 mg/kg) was given intravenously before CPB and also added (10 mg/100 mL prime volume) to the CPB circuit. TP10 plasma levels correlated with C3a levels and measures of clinical course. All infants survived. No adverse events were attributed to TP10. TP10 plasma concentration fell to < or =60 microg/mL 12 hours after CPB. A 2-compartment model was fit to the TP10 blood levels as a function of time. Based on this model, an initial dose of 10 mg/kg over 0.5 hours followed by 10 mg/kg over 23.5 hours is the most appropriate for maintaining TP10 concentration between 100 microg/mL and 160 microg/mL for 24 hours after CPB. C3a was lower 12 hours after CPB than before CPB and still lower 24 hours after CPB. TP10 concentration was inversely correlated with the 12-hour post-CPB to pre-CPB ratio of C3a (Spearman rho -0.76, P = -.016), and with total (rho -0.56, P =.047) and net (rho -0.85, P =.0016) fluid and blood product administration/kg >24 hours after CPB.
  
  
  CONCLUSIONS
  TP10 administration to infants appears safe. Pharmacokinetic analysis generated an optimal dosing strategy to achieve effective TP10 levels for 24 hours after CPB. In the infant, TP10 appears to decrease CPB-induced complement activation and protect vascular function. These results support a phase III trial of TP10 in infants requiring CPB.
authors.affiliation: Department of Pediatrics, Division of Cardiology, Duke University Medical Center, Durham, NC 27710, USA. li000001@mc.duke.edu
authors.forename: Jennifer S
authors.initials: JS
authors.lastname: Li
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Sanders
authors.forename: April E
authors.initials: AE
authors.lastname: Perry
authors.forename: Sandra S
authors.initials: SS
authors.lastname: Stinnett
authors.forename: James
authors.initials: J
authors.lastname: Jaggers
authors.forename: Paula
authors.initials: P
authors.lastname: Bokesch
authors.forename: Laurie
authors.initials: L
authors.lastname: Reynolds
authors.forename: Rashid
authors.initials: R
authors.lastname: Nassar
authors.forename: Page A W
authors.initials: PA
authors.lastname: Anderson
mesh_terms: D002199:Capillary Permeability; D002315:Cardiopulmonary Bypass / Q000009:adverse effects*; D003169:Complement Inactivator Proteins / Q000009:adverse effects / Q000493:pharmacokinetics*; D005260:Female; D006330:Heart Defects, Congenital / Q000097:blood* / Q000601:surgery; D006801:Humans; D007223:Infant; D008297:Male; D011446:Prospective Studies; D011951:Receptors, Complement / Q000378:metabolism*; D018709:Statistics, Nonparametric; D013577:Syndrome
chemical_list: D003169:Complement Inactivator Proteins; D011951:Receptors, Complement; C082885:soluble complement inhibitor 1