Pharmacokinetics of C1-inhibitor protein in patients with acute myocardial infarction

• Published in: Clinical pharmacology and therapeutics 2002-11, Vol.72 (5), p.498-504
• Main Authors: Diris, Jart H. C., Hermens, Wim Th, Hemker, Pieter W., Lagrand, Wim K., Hack, C. Erik, Dieijen‐Visser, Marja P.
• Format: Article
• Language: English
• Subjects: Adult; Aged; Aged, 80 and over; Complement C1 Inactivator Proteins - pharmacokinetics; Complement C1 Inhibitor Protein; Female; Humans; Male; Middle Aged; Myocardial Infarction - drug therapy; Myocardial Infarction - metabolism
• ISSN: 0009-9236; 1532-6535
• DOI: 10.1067/mcp.2002.129320

Objectives 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. Clinical Pharmacology & Therapeutics (2002) 72, 498–504; doi: 10.1067/mcp.2002.129320