Pharmacokinetics of C1-inhibitor protein in patients with acute myocardial infarction.
OBJECTIVE
C1-inhibitor protein (C1-INH) purified from pooled human plasma is used for the treatment of patients with hereditary angioedema. Recently, the beneficial effects of high-dose C1-INH treatment on myocardial ischemia or reperfusion injury have been reported in various animal models and in humans. We investigated the pharmacokinetic behavior of C1-INH in patients with acute myocardial infarction to calculate the amount of C1-INH required for optimal efficacy.


METHODS
Twenty-two patients received an intravenous loading dose, followed by 48 hours of continuous infusion of C1-INH. Changes in the endogenous production of C1-INH were evaluated in 16 control patients with acute myocardial infarction. A 2-compartment model was used to estimate the fractional catabolic rate constant (FCR), transcapillary escape rate constant (TER), and extravascular return rate constant (ERR) of C1-INH. Software designed to analyze and fit measured data to unknown parameters in a system of differential equations was used to fit the experimental data against the 3-parameter model.


RESULTS
With fixed TER and ERR values (0.014 h(-1) and 0.018 h(-1), respectively), 20 of the 22 cases yielded well-determined FCR values, and simultaneous fitting resulted in a median FCR of 0.011 h(-1) (95% confidence interval, 0.010 to 0.012 h(-1)) versus 0.025 h(-1) as reported in healthy control patients. Simultaneous estimation of TER, ERR, and FCR demonstrated weakly defined TER and ERR values, whereas the median FCR value remained unchanged. The use of a 2-compartment model resulted in a significantly better fit compared with the 1-compartment model. Physiologic explanations are offered for discrepancies in the literature.


CONCLUSIONS
Dose calculation of C1-INH in patients treated with massive doses of C1-INH requires turnover parameters that differ from those found in healthy subjects, possibly because of suppression of continuous C1-INH consumption by target proteases.
Diris
Jart H C
JH
Department of Clinical Chemistry, University Hospital Maastricht, and Cardiovascular Research Institute Maastricht, University of Maastricht, Amsterdam. J.Diris@groupwise.azm.nl
Hermens
Wim Th
WT
Hemker
Pieter W
PW
Lagrand
Wim K
WK
Hack
C Erik
CE
van Dieijen-Visser
Marja P
MP
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D003174:Complement C1 Inactivator Proteins / Q000493:pharmacokinetics*; D050718:Complement C1 Inhibitor Protein; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009203:Myocardial Infarction / Q000188:drug therapy* / Q000378:metabolism
D003174:Complement C1 Inactivator Proteins; D050718:Complement C1 Inhibitor Protein