Safety and Pharmacokinetics of Paracetamol Following Intravenous Administration of 5 g During the First 24 h with a 2-g Starting Dose

Abstract

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.

Estradiol and Weight Are Covariates of Paracetamol Clearance in Young Women

“…These data were reported by Gregoire et al [16], independently from our data. We hereby aimed to quantify inter-individual pharmacokinetic differences between women at delivery and non-pregnant women, either exposed or not to OCs.…”

“…1 year postpartum, as well as 8 female controls with no OCs) via ELISA with electro-chemiluminescence (MODULAR® ANALYTICS E-170; Roche/Hitachi) by the clinical laboratory of University Hospitals Leuven. Estradiol and progesterone observations in the cohort of Gregoire et al [16] were not available, but all these women were on OCs.…”

“…In addition, 8 female controls using no OCs were also enrolled, to whom a 2-gram paracetamol loading dose was administered, and blood samples were collected, handled and stored as described for postpartum women. Finally, and as mentioned earlier, raw data of similar observations (a single 2-gram intravenous paracetamol loading dose, with observations at 1, 2, 4 and 6 h) in 14 healthy female volunteers were provided by Gregoire et al [16]. …”

Peri‐operative use of paracetamol

“…None of the 132 patients who received 2 g displayed elevated aminotransferases at 48 h post dose. Gregoire et al [77] confirmed that in patients with no risk factors, a 2 g loading dose leading to a total of 5 g in the first 24 h of treatment gives plasma concentrations well below the toxic threshold, with no accumulation. Blood samples taken 72 h after the initial dose showed no clinically significant increases in any of the measured parameters (aminotransferases, gamma-glutamyl transpeptidase (cGT), bilirubin).…”

“…An initial enlarged dose will provide higher plasma concentrations [77,78], although whether this leads to superior analgesia is not clear. Piguet et al [78] showed a close correlation between plasma concentration and analgesic effect, demonstrating the absence of ceiling effect in healthy volunteers with intravenous doses of up to 2 g, but clinical studies have produced conflicting results.…”