Objectives: To characterize the pharmacokinetics of L-NG-methylarginine in patients with septic shock.
Methods: This was an international, uncontrolled, open-label study of L-NG-methylarginine (546C88) therapy given to 32 patients with septic shock. It was conducted in hospital-based intensive care units that admit general surgical and medical patients. Patient cohorts received an infusion of L-NG-methylarginine at fixed dose rates of 1, 2.5, 5, 10, and 20 mg/kg/h for up to 8 hours. The 5 dosing regimens were administered sequentially to separate groups of patients.
Results: Of the 32 patients studied, 23 received complete 8-hour infusions. In the other 9 patients, the infusion was terminated prematurely within the first 1/2 to 4 hours. Median clearance of L-NG-methylarginine averaged 485 mL/h/kg for the 1 and 2.5 mg/kg/h dosing cohorts combined but decreased to 283, 181, and 98 mL/h/kg for the 5, 10, and 20 mg/kg/h dosing cohorts, respectively. Median renal clearance was similar at 9 to 26 mL/h for the 1, 2.5, and 5 mg/kg/h dosing cohorts but increased to 156 and 284 mL/h for the 10 and 20 mg/kg/h dosing cohorts, respectively. Median steady-state volume of distribution was similar in all 5 dosing cohorts, averaging 0.66 to 0.82 L/kg.
Conclusions: The 80% decrease in clearance from 485 to 98 mL/h/kg with the increase in dose suggests that a predominant metabolic pathway(s) of L-NG-methylarginine, accounting for at least 80% of clearance, is becoming progressively saturable in association with L-NG-methylarginine infusion rates > or = 5 mg/kg/h. Therefore the use of L-NG-methylarginine infusion rates > or = 5 mg/kg/h are typically expected to result in progressive inhibition of nitric oxide synthase activity. Consequently, patient hemodynamics should be monitored closely to avoid an excessive increase in vasomotor tone, which would be manifest by either an increase in mean arterial pressure or a decrease in cardiac output. The infusion rates of conventional vasopressor(s) (eg, norepinephrine [BAN, noradrenaline]) or L-NG-methylarginine or both may need to be reduced accordingly.