[Pharmacokinetic evaluation of linezolid in patients with major thermal injuries]. / Pharmacocinétique du linézolide chez des patients souffrant de brûlures sévères.

The aims of this multicentre open-label study was to evaluate the pharmacokinetics of linezolid in patients with burn injury above 20 % BSA and to compare them with healthy volunteers, matched in age, sex and weight. After a single 600 mg IV dose of linezolid, multiple blood and urine samples were taken from subjects, in order to determine linezolid concentrations, using a HPLC assay. C(max) and volume of distribution at steady state were not different between the two groups. Values describing clearance were altered in burns, leading to a reduction by half in AUC in these patients (42.5 versus 98.1 mghL(-1)). The enhancement of clearance was due to which of non renal clearance (323+/-191 versus 80.4+/-27.5 mLmin(-1)). We conclude that pharmacokinetics of linezolid are altered in burn patients, in a magnitude sufficient that linezolid concentration may be subtherapeutic in some patients and we suggest that the dosage interval may need to be decreased in this patient population.

Pharmacokinetic evaluation of linezolid in patients with major thermal injuries.

AIMS: To evaluate the pharmacokinetics of linezolid following its administration in patients with major thermal injuries and in a group of healthy volunteers. METHODS: In an open-label, multicentre design with two parallel groups, a group of patients with major thermal injuries (>20% body area) and a group of age-, sex- and weight-matched healthy volunteers, subjects received a single 600 mg intravenous dose of linezolid. Serial blood and urine collections were made and the concentrations of linezolid in these samples were determined by HPLC. Non-compartmental analyses were used to describe the pharmacokinetic disposition of linezolid. RESULTS: C(max) concentrations and the volume of distribution at steady state (V(ss)) were not statistically different (P > 0.05) between the two groups of subjects. In contrast, values describing clearance [elimination rate constant (k(el)), t(1/2) and mean residence time (MRT)] were significantly different (P < 0.05) in patients with thermal injuries compared with volunteers, which lead to an approximate reduction by half in AUC(0-infinity) from 98.1 mg.h/L (volunteers) to 42.5 mg.h/L (patients). Although renal clearance was similar in the two groups (24.7 +/- 23 versus 30.6 +/- 14.3 mL/min; P = 0.156), non-renal clearance was substantially increased (323 +/- 191 versus 80.4 +/- 27.5 mL/min) in the patients with thermal injuries, though this difference did not achieve statistical significance (P = 0.063). CONCLUSIONS: The pharmacokinetics of linezolid are altered in patients with major thermal injuries, mainly as a result of increased non-renal clearance. These changes are of sufficient magnitude that linezolid concentrations may be sub-therapeutic in some patients and we suggest that the dosage interval may need to be decreased in this patient population.

Safety and pharmacokinetics of paracetamol following intravenous administration of 5 g during the first 24 h with a 2-g starting dose.

Intravenous (i.v.) paracetamol is used as 1-g infusions with a maximal daily dose of 4 g/day. However, a higher initial analgesic dose could be of interest in the immediate postoperative period when the pain is maximal. The purpose of the present study was to determine in healthy subjects the safety and the pharmacokinetics of i.v. paracetamol, starting with a 2-g dose, followed by 1-g doses every 6 h, leading to a total of 5 g the first 24 h. This was an open-label, single-sequence study. The paracetamol pharmacokinetic profile was assessed in 26 subjects after both the 2-g starting dose and the 1-g doses. Safety, especially hepatotoxicity, was evaluated up to 72 h after the initial 2-g dose. Following the first 15-min i.v. administration of paracetamol 2 g, plasma concentrations ranged from 67.9+/-21.8 mug/ml (peak plasma concentration (C(max)) at the end of infusion) to 6.2+/-2.3 mug/ml (trough plasma concentration (C(min)) measured just before the next infusion) without any C(max) in the toxic range for any subject. After the repeated 1-g infusions, the plasma concentrations were approximately 35% lower than that measured after 2 g, showing the absence of accumulation. No clinical adverse events related to the drug administration nor clinically relevant changes in laboratory parameters, including biochemical signs of hepatotoxicity, were reported. After i.v. administration of paracetamol 2-g starting dose and 5 g during the first 24 h, the pharmacokinetics of paracetamol remain unchanged, with concentrations far below the toxic threshold. Overall, these results demonstrate that the i.v. administration of a 2-g starting dose of paracetamol, followed by three i.v. administrations of 1 g during the first 24 h is safe in healthy subjects.