Pharmacokinetics and safety of TP10, soluble complement receptor 1, in infants undergoing cardiopulmonary bypass

Valvular and Congenital Heart Disease

Pharmacokinetics and safety of TP10, soluble complement receptor 1, in infants undergoing cardiopulmonary bypass Jennifer S. Li, MD,a,b Stephen P. Sanders, MD,a April E. Perry, RN,a Sandra S. Stinnett, DrPH,b James Jaggers, MD,c Paula Bokesch, MD,d Laurie Reynolds, PhD,e Rashid Nassar,a and Page A. W. Anderson, MDa Durham, NC, Cleveland, Ohio, and Richmond, Va

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 ⱕ60 ␮g/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 ␮g/mL and 160 ␮g/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 ␳ ⫺0.76, P ⫽ ⫺.016), and with total (␳ ⫺0.56, P ⫽ .047) and net (␳ ⫺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. (Am Heart J 2004;147:173– 80.)

Cardiopulmonary bypass (CPB) is essential for supporting patients during intracardiac surgery. CPB can result in a post-CPB syndrome that is characterized by increased vascular permeability, generalized edema, abnormal lung function and oxygenation, and impaired left ventricular systolic and diastolic function. This post-CPB syndrome affects up to 50% of infants after From the aDepartment of Pediatrics, Division of Cardiology, Duke University Medical Center, Durham, NC, bDuke Clinical Research Institute, Duke University Medical Center, Durham, NC, and cDepartment of Surgery, Duke University Medical Center, Durham, NC, dDepartment of Cardiothoracic Anesthesia, Cleveland Clinic, Cleveland, Ohio and eDepartment of Clinical Pharmacology, PPD Development, Richmond, Va. Guest Editor for this manuscript was James K. Kirklin, MD, University of Alabama, Birmingham, Ala. Submitted November 11, 2002; accepted July 21, 2003. Reprint requests: Jennifer S. Li, MD, Associate Professor, Duke University Medical Center, Erwin Road, Box 3090, Durham, NC 27710. E-mail: [email protected] 0002-8703/$ - see front matter © 2004, Elsevier Inc. All rights reserved. doi:10.1016/j.ahj.2003.07.004

repair of congenital heart disease and contributes to prolonged postoperative recovery and increased mortality.1–3 Activation of the complement kallikrein and other inflammatory host defense cascades may contribute to post-CPB syndrome. Complement cascade products have been shown to correlate with post-CPB organ dysfunction.1,2 TP10, soluble complement receptor 1, inhibits in vitro and in vivo C3 and C5 convertases, blocking activation of the 3 arms of the complement cascade at the level of C3 and C5 activation.4,5 TP10 reduces in vivo organ damage in adult animal models of reperfusion injury, organ transplantation, and cytokine-induced injury4 –10 and blunts the deleterious effects of CPB on organ function in the immature animal.11,12 The promising in vivo results in immature animals led us to use TP10 in infants undergoing CPB. We performed a phase I/II open-label prospective trial of TP10 to examine the relationship between adverse

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events and TP10 administration and pharmacokinetics of TP10 in infants. None of the adverse events were thought to be related to TP10. TP10 levels fell rapidly post-CPB. A 2-compartment model, based on these TP10 levels, was used to generate a dosing strategy for maintaining post-CPB TP10 levels in the infant. This dosing strategy should prove useful in a future phase III trial aimed at testing the efficacy of TP10 in decreasing the severity of post-CPB syndrome in infants requiring CPB.

were more complex (a 2- and a 3-compartment model) were fit to the data if warranted by the fitting criteria.14 The following criteria were used to determine the best model: weighted residual versus predicted plots, predicted and observed concentrations follow the same pattern, and the weighted residual sums of squares. Secondary criteria were the correlation coefficient and the CI of the estimated parameters. Various weighting schemes (uniform, 1/concentration, and 1/concentration2) were also evaluated.

Pharmacokinetic simulations

Methods Patient population Fifteen infants, ⬍1 year of age, were prospectively enrolled in this phase I/II open-label trial at Duke University Medical Center or the Cleveland Clinic. The acceptance criteria were: infant (ⱕ12 months of age) requiring cardiac surgery with the use of CPB who was expected to survive for the duration of the study. The study was approved by the institutional review board of each institution and informed consent was obtained from the patient’s parent or guardian.

TP10 administration and surgery TP10 (10 mg/kg) was administered as a 30-minute continuous infusion before cannulation for placement on CPB. The CPB protocol at the participating institutions was identical; aprotinin was not administered. Infants were given heparin (500 IU/kg), and arterial and venous cannulas were placed. TP10 was added to the CPB circuit (10 mg/100 mL prime solution) before placing the infant on bypass. Patients with transposition of the great arteries and hypoplastic left heart syndrome (HLHS) underwent repair or palliation on CPB with profound hypothermia to 18°C, during which time the heart was protected with cold blood cardioplegia. Modified ultrafiltration (MUF) was performed after removal from bypass.13

Data acquisition TP10 levels were measured pre- and post-CPB and pre- and post-MUF. C3a levels were measured pre-CPB and 12 hours and 24 hours post-CPB.4 Patient outcome parameters of fluid and blood products administration and loss, duration on mechanical ventilation, intensive care unit (ICU) stay, and hospital stay were recorded. The following laboratory values were obtained at 24 hours and 2, 3, and 5 days: complete blood count, differential white blood count, platelet count, partial thromboplastin time, prothrombin time, electrolytes, AST, ALT, BUN, creatinine, amylase, lipase, and total bilirubin (data not shown). TP10 antibody levels were measured at 7 and 14 days post-CPB.

Pharmacokinetic analysis Plasma concentration–time data for each patient were modeled using compartmental and noncompartmental methods for analysis with WinNonlin Professional for Windows (Version 3.0 Pharsight Corporation, Cary, NC). Actual blood sampling times were used in the model. A 1-compartment model was initially fit to the pharmacokinetic (PK) data. Models that

Based on the use of a 2-compartment model with a constant intravenous infusion, first-order output from the central compartment, and a weighting scheme of 1/concentration, the following compartmental PK parameters were estimated for each infant: K21 (1/h): rate constant for the drug leaving the peripheral compartment (compartment 2) and entering the central compartment (compartment 1) V1 (mL): volume of the central compartment (compartment 1) ␣ (1/h): hybrid rate constant during the absorption phase ␤ (1/h): hybrid rate constant during the elimination phase The following parameters were determined using noncompartmental analysis methods in WinNonlin: AUC(0 –t) (␮g 䡠 h/mL): area under the plasma concentration– time curve up to the last observed quantifiable concentration time CT (␮g/mL): observed concentration at the last quantifiable concentration time AUCinf (␮g 䡠 h/mL): area to infinity as AUC(0 –t) ⫹ CT/Kel Kel (1/h): apparent elimination rate constant determined by regression analysis of the log-linear segment of the plasma concentration–time curve Cmax (␮g/mL): maximum plasma concentration over the entire sampling phase, directly obtained from the experimental data of plasma concentration versus time curves, without interpolation Tmax (hours): time to attain Cmax T1/2 (hours): apparent elimination half-life calculated as 0.693/ Kel MRT (hours): mean residence time calculated as AUMC/AUC (where AUMC is that area under the moment curve from time zero to infinity) Cl (mL 䡠 h⫺1 䡠 kg⫺1) clearance calculated as Dose/AUCinf Vd (mL/kg): volume of distribution calculated as Cl/Kel Simulations were performed using the parameters estimated for each subject. Various dosing regimens were explored in order to determine an appropriate regimen to maintain plasma levels following CPB. A simulation was also performed using the mean PK parameters.

Statistical analysis Values are given as mean ⫾ SD, unless indicated otherwise. Spearman rank correlation coefficient (␳) was used to assess the correlation between TP10 concentration and clinical outcome parameters.

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Table I. Patient characteristics and outcomes Age cohort

Male (n) Survival Age at entry (d) Weight at entry (kg) ICU stay (h) Duration of mechanical ventilation (h) Hospital stay (d)

<1 Month (n ⴝ 4)

1–3 Months (n ⴝ 7)

4–12 Months (n ⴝ 4)

Total group (n ⴝ 15)

2 (50.0%) 100% 6.0 ⫾ 2.0 (7.0) 3.0 ⫾ 0.4 (2.9) 276 ⫾ 282 (159) 163 ⫾ 156 (128) 26.0 ⫾ 17.3 (16.0)

2 (28.6%) 100% 75.1 ⫾ 25.0 (72.0) 4.0 ⫾ 1.1 (3.6) 83 ⫾ 45 (92) 74 ⫾ 62 (72) 11.7 ⫾ 7.3 (12.0)

3 (75.0%) 100% 224.3 ⫾ 41.0 (207.5) 6.6 ⫾ 1.5 (6.3) 31 ⫾ 9 (30) 13 ⫾ 10 (11) 7.8 ⫾ 6.5 (5.5)

7 (46.7%) 100% 96.5 ⫾ 88.7 (72.0) 4.4 ⫾ 1.8 (3.6) 121 ⫾ 167 (92) 81 ⫾ 101 (37) 11.2 ⫾ 6.7 (12.0)

Values are mean ⫾ SD (median) unless otherwise indicated.

Results Patient characteristics and outcome parameters Fifteen infants fulfilled the criteria for acceptance in the study. Cardiac diagnoses and number of patients were: tetralogy of Fallot (TOF), 3; ventricular septal defect (VSD), 3; atrial septal defect (ASD), 2; hypoplastic left heart syndrome (HLHS), 3; transposition of the great arteries (TGA), 1; truncus arteriosus, 1; atrioventricular septal defect, 1; and atrial mass, 1. Characteristics of infants, grouped as neonates and 2 older age cohorts, as well as survival and the duration of ICU stay, mechanical ventilation, and hospital stay for the 3 groups are provided in Table I.

Safety All patients survived the 30-day trial and 1-month follow-up. No patient developed antibodies to TP10. The infants responded normally to treatment for adverse events.

Serious adverse events A total of 6 serious adverse events (SAEs) were reported in 4 patients. The events were considered either definitely unrelated or probably unrelated to study medication. Patient 1. This patient had HLHS and experienced 3 SAEs. SAE #1: After a stage I palliative procedure for HLHS, the patient was admitted to the pediatric ICU with bleeding from the chest drains. The activated clotting time was 246 seconds. The Eschmarck closing the chest became tight, ventilation became difficult, and blood pressure and oxygen saturation dropped. The

Eschmarck was removed, blood was evacuated from the anterior mediastinum, protamine was administered, blood was replaced intravenously, and the hypotension resolved. The patient was electively placed on a ventricular assist device. SAE#2: Four days after the administration of TP10 and surgery, and 24 hours after being taken off the ventricular assist device and the chest closed, the patient was diagnosed as having a sepsis-like syndrome with hypotension and was treated successfully with intravenous fluids, dopamine, epinephrine, and hydrocortisone. Antibiotics were given for possible sepsis. All cultures were negative. SAE#3: At home, 36 days post-CPB, the patient developed oral candidiasis, was admitted to the local hospital, and treated successfully with fluconazole. Patient 2. This patient had trisomy 21 and VSD. Just before discharge from the hospital, the patient developed respiratory difficulty, was intubated, and diagnosed with right lower lobe atelectasis. Otolaryngologic examination demonstrated subglottic stenosis requiring surgical repair. Patient 3. This patient underwent repair of truncus arteriosus type I requiring CPB for 145 minutes. Postoperatively, serum potassium determination of 5.1 mmol/L led to treatment with dextrose and insulin and a 10-hour period of peritoneal dialysis. Patient 4. This patient had low cardiac output after a stage I palliative procedure for HLHS. Inotropic support was maintained until chest closure and was increased at that time to maintain adequate cardiac output. The inotropic support was discontinued 3 days later.

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Figure 1

Plasma TP10 concentration–time curves after CPB and after MUF. The curve for each patient demonstrates a rapid fall in concentration during the first 12 hours post-CPB and a subsequent slower fall.

Figure 2

The pre- and post-MUF TP10 plasma concentrations (␮g/mL) for the 3 age groups. Pre-MUF (open bar), TP10 concentration measured in the patients at the end of CPB. Post-MUF (shaded bar), TP10 concentration measured in the patients after MUF and before decannulation. (Error bars indicate ⫾ SD).

Pharmacokinetics TP10 plasma concentration fell to ⱕ60 ␮g/mL by 12 hours after CPB (Figure 1). Area under the time– plasma concentration curve tended to be lower in age group 1 than in groups 2 and 3: group 1, 1760 ⫾ 433 ␮g 䡠 h/mL; group 2, 3737 ⫾ 1544 ␮g 䡠 h/mL; group 3, 3871 ⫾ 1634 ␮g 䡠 h/mL. TP10 plasma concentration was not affected by MUF: group 1, 81 ⫾ 29 ␮g/mL versus 96 ⫾ 24 ␮g/mL; group 2, 106 ⫾ 31 ␮g/mL versus 118 ⫾ 39 ␮g/mL; group 3, 106 ⫾ 13 ␮g/mL versus 120 ⫾ 20 ␮g/mL, pre-MUF versus post-MUF, respectively (Figure 2). A 2-compartment model with a weighting scheme of 1/concentration was chosen as the appropriate model based on the fitting criteria. The weighted residual versus predicted plots were uniform throughout, and the weighted residual sums of squares were lower for the majority of patients using the 2-compartment model. The correlation coefficients and the CIs also helped to confirm that the 2-compartment model with a weighting scheme of 1/concentration was the most appropriate (data not shown). TP10 plasma concentrations declined biphasically after CPB. The following results were obtained for pharmacokinetic parameters in a 2-compartment model: V1, 62.28 ⫾ 18.57 mL/kg; K21, 0.660 ⫾ 0.0759/h; ␣, 0.2958 ⫾ .2851/h; ␤, 0.118 ⫾ .0068/h. Results from noncompartmental analysis of the pharmacokinetic parameter values are shown in Table II. To determine a TP10 dosing that would maintain TP10 plasma concentrations between 100 ␮g/mL and 160 ␮g/mL, simulations were performed using a

2-compartment model, based on 2 sequential infusions during a period of 24 hours. The simulation began with an infusion of 10 mg/kg over 0.5 hours, similar to the pre-CPB dosing in this study. Three subjects (subject 7, 8, and 14) had plasma concentrations ⬎160 ␮g/mL after the first infusion. The second simulated infusion was then started and continued for 23.5 hours, using 4 different doses (10 mg/kg, 15 mg/kg, 20 mg/kg, and 25 mg/kg). Simulations were performed for each subject and for an average subject, using the pharmacokinetic parameters generated from the modeling. Based on the simulations, the 10 mg/kg infusion over 30 minutes followed by infusing 10 mg/kg over 23.5 hours appears to be the most appropriate dosing to reach the plasma concentration goal for the majority of the patients (Figure 3). For all the patients, plasma concentrations were maintained above 60 ␮g/mL during the second infusion.

TP10 plasma concentration correlation with clinical measures Complement activation was assessed by measuring C3a plasma concentration, which has been shown previously to increase with CPB.1,2,16 –18 C3a mean difference between pre-CPB and 24-hour post-CPB concentration was 433 ng/mL (P ⫽ .014, Wilcoxon signed rank test). The higher the TP10 concentration, the lower the ratio of 12-hour post-CPB to pre-CPB C3a levels (Figure 4, ␳ ⫺0.76, P ⫽ .016).

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Table II. Noncompartmental pharmacokinetic parameters*

Mean SD Min Median Max CV%

AUC(0-t) (␮g 䡠 h/ mL)

AUCinf (␮g 䡠 h/ mL)

3075 1660 1170 2487 6042 54.0

3512 1720 1427 3218 6461 49.0

MRT (h)

Cmax (␮g/ mL)

Tmax (h)

Kel (L/h)

T1/2 (h)

CI (mL 䡠 hⴚ1 䡠 kgⴚ1)

Vd (mL/ kg)

76.94 33.14 24.68 80.36 138.45 43.1

147.0 40.0 100.0 127.0 244.0 27.3

1.56 1.03 0.35 1.20 3.38 66.1

0.0119 0.0062 0.0052 0.0105 0.0280 52.1

71.38 30.97 24.73 66.14 134.07 43.4

3.591 1.761 1.545 3.144 7.028 49.0

331.9 162.8 142.2 298.8 711.1 49.1

*See Methods, Pharmacokinetics for definitions.

Figure 3

Figure 4

Simulation of TP10 plasma concentration for each patient in response to TP10 intravenous infusion of 10 mg/kg over 30 minutes pre-CPB, followed by intravenous infusion of 10 mg/kg over the following 23.5 hours. Thick line shows mean response.

TP10 concentration did not correlate significantly with age (␳ 0.33, P ⫽ .26 at 12 hours post-CPB; ␳ 0.18, P ⫽ .55 at 24 hours). An inverse correlation was found between TP10 plasma concentration at 24 hours after CPB and total fluid and blood product administration during the first 24 hours after CPB (␳ ⫺0.56, P ⫽ .047) and between TP10 plasma concentration and duration of mechanical ventilation (␳ ⫺0.56, P ⫽ .045, TP10 at 12 hours; ␳ ⫺0.47, P ⫽ .10, TP10 at 24 hours) (Figure 5). Further evaluation was done of the net difference in fluid and blood administered and that lost plus urine output (net fluid administration) over the first 24 hours after CPB in the patients from Duke University (n ⫽ 12 patients). The Cleveland Clinic patients (n ⫽ 3 patients) were excluded from this analysis due to the use of a different postoperative protocol for diuresis. Figure 6 shows a plot of net fluid administration corrected for body weight versus TP10 plasma concentration at 24 hours after CPB. One outlier is

Plot of the ratio of 12-hour post-CPB C3a concentration to pre-CPB C3a concentration as a function of 12-hour post-CPB TP10 concentration demonstrates a negative correlation (␳ ⫽ ⫺0.76, P ⫽ .016). The patients with the lowest TP10 concentration were the only ones in whom C3a increased 12 hours post-CPB.

plotted with a different symbol and omitted from the analysis. Net fluid administration was significantly and inversely related with TP10 concentration (␳ ⫺0.85, P ⫽ .0016) (Figure 6).

Discussion Post-CPB syndrome Advances in pediatric cardiac surgery, cardiology, cardiac anesthesia, and intensive care have improved survival for infants born with complex congenital

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Figure 5

2-fold to 3-fold greater in the affected infants than infants that showed no evidence of ventricular diastolic dysfunction.3,15 There are several pathways that activate the systemic inflammation attributed to the post-CPB syndrome including complement activation, kallikrein activation, endotoxin and cytokine release, and factor XIIa production. No therapy is yet available to prevent this syndrome. We hypothesized that TP10, a C3/C5 convertase inhibitor, may be protective against the contribution of complement activation to the post-CPB syndrome.

Complement activation, CPB, and inflammation

Duration of mechanical ventilation was inversely related to the area under the time–TP10 plasma concentration curve.

Figure 6

CPB massively activates the complement system.1,2,16 –18 This activation has been correlated with the post-CPB syndrome in children.1 Activation of this primitive host defense system yields products, including C3a, C5a, and C5b–9, that act directly as mediators of inflammation and cytotoxic agents and that amplify inflammation by enhancing chemotaxis and activation of leukocytes with their release of enzymes, reactive oxygen species, and eicosanoids.1,16,19,20 The inflammatory consequences of complement activation support the study of complement inhibitors to assess whether complement inhibition decreases the negative effects of CPB on organ function.

Complement receptor 1 and TP10

Relationship between net fluid administration and TP10 level at 24 hours. Net fluid administered (the net difference between fluid and blood administered and that lost plus urine, corrected per body weight) was inversely related to TP10 plasma concentration at 24 hours after CPB. The single outlier is plotted with a different symbol.

heart disease. Post-CBP multiorgan dysfunction, a significant contributor to post-CPB mortality and morbidity, is the remaining major barrier to successful cardiac surgery in infants. Seghaye et al reported a 54% incidence in neonates,3 and in our previous study 50% of neonates demonstrated post-CPB diastolic dysfunction that persisted for up to 3 weeks.15 The durations of mechanical assisted ventilation and of ICU stay were

Complement receptor 1 (CR1) is a membrane-bound inhibitor of C3 and C5 convertases. CR1 suppresses the normal ongoing low level of complement activation on the cell on which it is expressed, but CR1 expression is insufficient to inhibit complement activation that occurs on neighboring cells or surfaces. TP10, a soluble form of CR1, inhibits C3 and C5 convertases, while lacking the transmembrane and cytoplasmic domains of CR1. TP10 inhibits complement activation and decreases organ damage in animal models in which complement was activated by cobra venom, interleukin-2–induced lung injury, myocardial ischemia, organ reperfusion, and xenotransplantation of the lung and the heart.4 –10 Subsequent studies of TP10 in the neonatal and immature pig CPB model have yielded data that led us to investigate the use of TP10 in the infant exposed to CPB. Administration of TP10 protected against CPBinduced pulmonary hypertension11,12 and protected oxygenation and preserved in vivo left ventricular systolic and diastolic function.11 At the myofilament level, preservation of the relation between developed force and calcium concentration was found in the post-CPB TP10-treated heart.11 These data supported our study of TP10 in the infant exposed to CPB.

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TP10 and the infant We did not identify any safety issues in the infants exposed to TP10. Excessive blood loss in infants after CPB is extremely common, and the younger the patient, the greater the amount of blood loss.21 Low cardiac output state in HLHS patients after stage I palliation is common as reflected by 25% mortality after this procedure. After stage I palliation for HLHS, 16.7% of patients must be placed on an extracorporeal membrane oxygenator.22 Postoperative atelectasis in infants requiring intubation is also common, occurring in up to 21% of patients in a recent meta-analysis.23 Thus, SAEs often occur in infants undergoing palliation or repair of congenital cardiac defects. We cannot exclude, however, that some of these events may be related to systemic inflammation. This should be further elucidated with a phase III clinical trial.

Pharmacokinetics Based on our simulations, the 10 mg/kg dose over 30 minutes, followed by 10 mg/kg over 23.5 hours appears to be the most appropriate dose for maintaining a target plasma concentration of 60 ␮g/mL or greater in infants ⬍1 year of age. This concentration should reduce available hemolytic complement by ⬎80% over the first 24 hours after dosing. The results of the simulation analysis may underestimate the dose needed because it does not take into consideration the dose of TP10 administered in the CPB prime solution in the trial. Before a phase III trial is initiated, the effect of the suggested dosing regimen on TP10 levels needs to be established.

TP10 concentration correlations The findings in our study support the hypothesis that TP10 decreases CPB-induced complement activation. Previous studies have demonstrated that C3a levels, a measure of complement activation, increase in the pediatric patient in the first hours after CPB and then fall.1,2,17 We did not measure C3a levels at their peak. Our data do show (Figure 4) that C3a levels at 12 hours post-CPB relative to pre-CPB levels were lowest in infants in whom the TP10 concentration was highest, which suggests that high blood levels of TP10 inhibit complement activation effectively (eg, mean C3a at 12 hours relative to pre-CPB levels fell by a factor of 4.6 when TP10 concentration increased from 20 to 60 ␮g/mL). A potential beneficial effect of TP10 on clinical course is suggested by the inverse correlation between TP10 plasma concentration at 24 hours and fluid and blood administration over the first 24 hours post-CPB. Infants often require large volumes of fluid administration to maintain an adequate cardiac output after CPB because of a pathologic increase in vascular permeabil-

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ity. The inverse relationship suggests that TP10 protects against CPB-induced increase in complement activation and the pathologic increase in vascular permeability. Further studies will be required to assess the relationship between TP10 and these and other determinants of postoperative organ function such as oxygenation index, pulmonary artery pressure, and cardiac output. This phase I/II study is further limited by the heterogeneous patient cohort and the small number of patients, as is seen in other phase I/II studies. In summary, these promising results support the performance of a large multi-institutional clinical trial of TP10 in this patient population. A dosing regimen based on the analysis of TP10 metabolism in this study should prove useful in this future trial. The authors thank AVANT Immunotherapeutics, Needham, Mass, for providing the TP10, measuring the plasma concentrations of TP10 and C3a, and determining if TP10 antibodies became detectable in the patients’ serum.

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11. Chai PJ, Nassar R, Oakeley AE, et al. Soluble complement receptor 1 protects heart, lungs, and cardiac myofilament function from cardiopulmonary bypass damage. Circulation 2000;101:541– 6. 12. Gillinov AM, DeValeria PA, Winkelstein JA, et al. Complement inhibition with soluble complement receptor type 1 in cardiopulmonary bypass. Ann Thorac Surg 1993;55:619 –24. 13. Darling EM, Shearer IR, Nanry K, et al. Modified ultrafiltration in pediatric cardiopulmonary bypass. J Extracorporeal Tech 1994; 26:205–9. 14. Gibaldi M, Perrier D. Pharmacokinetics. 2nd ed. New York: Marcel Dekker, Inc; 1982. 15. Li JS, Bengur AR, Ungerleider RM, et al. Abnormal left ventricular filling after neonatal repair of congenital heart disease: association with increased mortality and morbidity. Am Heart J 1998;136: 1075– 80. 16. Miller BE, Levy JH. The inflammatory response to cardiopulmonary bypass. J Cardiothorac Vasc Anesth 1997;11:355– 66. 17. Steinberg JB, Kapelanski DP, Olsen JD, et al. Cytokine and complement levels in patients undergoing cardiopulmonary bypass. J Thorac Cardiovasc Surg 1993;106:1008 –16.

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18. Sonntag J, Da ¨ hnert I, Stiller B, et al. Complement and contact activation during cardiovascular operations in infants. Ann Thorac Surg 1998;65:525–31. 19. Moen O, Hogisen K, Fosse E, et al. Attenuation of changes in leukocyte surface markers and complement activation with heparincoated cardiopulmonary bypass. Ann Thorac Surg 1997;63:105–11. 20. Shandelya SML, Kuppusamy P, Herskowitz A, et al. Soluble complement receptor type 1 inhibits the complement pathway and prevents contractile failure in the post-ischemic heart: evidence that complement activation is required for neutrophil-mediated reperfusion injury. Circulation 1993;88:2812–26. 21. Williams GD, Bratton SL, Riley EC, et al. Association between age and blood loss in children undergoing open heart operations. Ann Thorac Surg 1998;66:870 – 6. 22. Charpie JR, Dekeon MK, Goldberg CS, et al. Postoperative hemodynamics after Norwood palliation for hypoplastic left heart syndrome. Am J Cardiol 2001;87:198 –202. 23. Flenady VJ, Gray PH. Chest physiotherapy for preventing morbidity in babies being extubated from mechanical ventilation. Cochrane Database of Systematic Reviews 2002(2):CD000283.