Pharmacokinetics Of Intravenous Paracetamol Research Articles

Population Pharmacokinetics of Intravenous Paracetamol and Its Metabolites in Extreme Preterm Neonates in the Context of Patent Ductus Arteriosus Treatment.

Our aim was to describe the pharmacokinetics of paracetamol and its metabolites in extreme preterm neonates in the context of patent ductus arteriosus treatment. Factors associated with inter-individual variability and metabolic pathways were studied. The association between drug exposure and clinical outcomes were investigated. Preterm neonates of 23-26 weeks' gestational age received paracetamol within 12 h after birth. Plasma concentrations of paracetamol and its metabolites were measured throughout 5 days of treatment. Clinical success was defined as ductus closure on two consecutive days or at day 7. Aspartate aminotransferase and alanine aminotransferase levels were used as surrogates for liver damage. Data from 30 preterm neonates were available for pharmacokinetic analysis. Paracetamol pharmacokinetics were described using a two-compartment model with significant positive effects of weight on clearance and of birth length on peripheral compartment volume. Paracetamol was mainly metabolised into sulphate (89%) then glucuronide (6%), and the oxidative metabolic pathway was reduced (4%). The glucuronidation pathway increased with gestational age, whereas the sulfation pathway decreased. No difference was observed in drug exposure between successful and unsuccessful patients. No increase in aspartate aminotransferase and alanine aminotransferase levels were observed during treatment, and no association was found with either paracetamol or oxidative metabolite exposures. The relative proportions of the metabolic pathways were characterised with gestational age. In the range of observed drug exposures, no association was found with clinical response or liver biomarkers. These findings may suggest that paracetamol concentrations were within the range that already guarantee a maximum effect on ductus closure.

Population Pharmacokinetic Modeling in the Presence of Missing Time-Dependent Covariates: Impact of Body Weight on Pharmacokinetics of Paracetamol in Neonates.

Body weight is the primary covariate in pharmacokinetics of many drugs and dramatically changes during the first weeks of life of neonates. The objective of this study is to determine if missing body weights in preterm and term neonates affect estimates of model parameters and which methods can be used to improve performance of a population pharmacokinetic model of paracetamol. Data for our analysis were obtained from previously published studies on the pharmacokinetics of intravenous paracetamol in neonates. We adopted a population model of body weight change in neonates to implement three previously introduced methods of handling missing covariates based on data imputation, likelihood function modification, and full random effects modeling. All models were implemented in NONMEM 7.4, and population parameters were estimated using the FOCE method. Our major finding was that missing body weights minimally affect population estimates of pharmacokinetic parameters but do affect the covariate relationship parameters, particularly the one describing dependence of clearance on body weight. None of the tested methods changed estimates of between-subject variability nor impacted the predictive performance of the model. Our analysis shows that a modeling approach towards handling missing covariates allows borrowing information gathered in various studies as long as they target the same population. This approach is particularly useful for handling time-dependent missing covariates.

Population pharmacokinetics of intravenous paracetamol in critically ill patients with traumatic brain injury

PurposeHigh-dose paracetamol (6 g/day) is a low-cost intervention that may prevent pyrexia. The purpose of this study was to describe the pharmacokinetics of high-dose intravenous paracetamol, in patients with traumatic brain injury (TBI). Materials and methodsA clinical pharmacokinetic study in adult patients with TBI was performed as a sub-study to a prospective, phase 2B, randomized placebo-controlled study (PARITY). Patients received 1 g of intravenous paracetamol or 0.9% sodium chloride every 4 h for 72 h. ResultsAll patients were included in the pharmacokinetic sub-study. The mean age, weight and area under the concentration-time curve for the sampled dosing interval were 34.5 yr, 82.3 kg and 39.9 ± 19.8 mg.h/L, respectively. The concentrations observed in the study patients were well below the threshold of toxicity and there was no evidence of accumulation of paracetamol. Paracetamol clearance was found to be high and variable (25.7 L.h−1, coefficient of variation (CV) 40.9%), and a wide range of volume of distribution observed (27.6 L, CV 30.6%). A relationship between lower Glasgow coma scores and higher clearance of paracetamol was observed. ConclusionDue to altered pharmacokinetics, patients experiencing severe TBI may require a higher dose of paracetamol to achieve drug exposure that results in preventing pyrexia.

O-15 Population pharmacokinetic modelling of paracetamol and its two major metabolites after cardiac surgery in children with and without down syndrome

<h3>Background</h3> Nearly half of children with Down Syn-drome (DS) who undergo cardiac surgery, receive parac-etamol as part of their post-operative pain treatment (Fudge et al., 2010). Differences have been reported in paracetamol metabolism in children with or without DS (Griener et al., 1990). The aim of the study was to deter-mine the population pharmacokinetics of intravenous paracetamol after cardiac surgery and the elimination through the major metabolic pathways in two groups of children – those with and those without DS. <h3>Methods</h3> The model was based on 483 plasma sam-ples from 30 children of whom 17 (median age 176 days [92-300] and bodyweight 6.1 kg [4.2–12.9]) had DS and 13 (median age 204 days [105-944] and bodyweight 5.9 kg[4.0–8.2]) did not. All received three paracetamol dos-es of 7.5 mg/kg (&lt;10 kg) or 15 mg/kg (&gt;10 kg) at 8 hour-ly intervals. Population pharmacokinetic modelling for paracetamol, paracetamol-sulfate and paracetamol-glu-curonide was performed using NONMEM 7.2. One, two and three compartment models were evaluated and the influence of different covariates such as age, bodyweight, cardiopulmonary bypass time and DS was investigated. Model selection criteria were statistical significant de-crease in objective function and evaluation of diagnostic plots. <h3>Results</h3> All compounds were best described with a one-compartment model, in which clearance (Cl) in-creased linearly with bodyweight. Volume of distribution (Vd) was not statistical significantly influenced by any covariates. The population value [relative standard er-ror] for paracetamol Cl and Vd were (27.6 ml/min/6.1 kg [22%]) and (7560 ml/6.1 kg [19%]) respectively. For parac-etamol-sulfate and paracetamol-glucuronide Cl and Vd were 23 [29%] and 1590 [33%], and 68.1 [25%] and 5330 [7%] respectively. DS did not have a statistically significant influence on any model parameter for any of the com-pounds. <h3>Conclusion</h3> Population pharmacokinetic analysis re-vealed that bodyweight influenced clearance of parac-etamol, paracetamol-sulfate and paracetamol-glucuro-nide in children from 3–36 months of age. However, no statistically significant differences in any of the pharma-cokinetic parameters of paracetamol between children with and without DS after cardiac surgery were observed. As paracetamol is also metabolised through cytochrome P450 2E1 oxidation, the following step will be to incorpo-rate these metabolites in this model to evaluate potential differences in paracetamol metabolism between children with or without DS.

Covariates of intravenous paracetamol pharmacokinetics in adults.

BackgroundPharmacokinetic estimates for intravenous paracetamol in individual adult cohorts are different to a certain extent, and understanding the covariates of these differences may guide dose individualization. In order to assess covariate effects of intravenous paracetamol disposition in adults, pharmacokinetic data on discrete studies were pooled.MethodsThis pooled analysis was based on 7 studies, resulting in 2755 time-concentration observations in 189 adults (mean age 46 SD 23 years; weight 73 SD 13 kg) given intravenous paracetamol. The effects of size, age, pregnancy and other clinical settings (intensive care, high dependency, orthopaedic or abdominal surgery) on clearance and volume of distribution were explored using non-linear mixed effects models.ResultsParacetamol disposition was best described using normal fat mass (NFM) with allometric scaling as a size descriptor. A three-compartment linear disposition model revealed that the population parameter estimates (between subject variability,%) were central volume (V1) 24.6 (55.5%) L/70 kg with peripheral volumes of distribution V2 23.1 (49.6%) L/70 kg and V3 30.6 (78.9%) L/70 kg. Clearance (CL) was 16.7 (24.6%) L/h/70 kg and inter-compartment clearances were Q2 67.3 (25.7%) L/h/70 kg and Q3 2.04 (71.3%) L/h/70 kg. Clearance and V2 decreased only slightly with age. Sex differences in clearance were minor and of no significance. Clearance, relative to median values, was increased during pregnancy (FPREG = 1.14) and decreased during abdominal surgery (FABDCL = 0.715). Patients undergoing orthopaedic surgery had a reduced V2 (FORTHOV = 0.649), while those in intensive care had increased V2 (FICV = 1.51).ConclusionsSize and age are important covariates for paracetamol pharmacokinetics explaining approximately 40% of clearance and V2 variability. Dose individualization in adult subpopulations would achieve little benefit in the scenarios explored.

The pharmacokinetics of a high intravenous dose of paracetamol after caesarean delivery

Pregnancy affects intravenous paracetamol pharmacokinetics, but there are no studies on covariates of intravenous paracetamol pharmacokinetics around delivery. To document the impact of gestational age at delivery on pharmacokinetics of a high intravenous dose of paracetamol. Pharmacokinetic study in women shortly after caesarean delivery. This study is an alternative analysis of a previously published study, using the same cohort but with added participants. Single, tertiary perinatal care centre. Of 36 patients recruited, pharmacokinetics analysis was performed in 34. Shortly following caesarean delivery, women received a loading dose (2 g) of intravenous paracetamol and four (at 1, 2, 4 and 6 h) plasma samples were collected. Of these 36 women, 28 had already been reported, but without further discrimination between preterm and term delivery, or any other covariate. Individual pharmacokinetic profiles were calculated assuming a linear one-compartment model with instantaneous input, first-order output. Covariates of between individual variability (preterm vs. term, maternal disease vs. healthy, twin vs. singleton pregnancy) of individual pharmacokinetics within this cohort were explored (Mann-Whitney U-test). Individual paracetamol pharmacokinetics. Mean (SD) paracetamol clearance was 22.4 l h(-1) (9.3) or - when corrected for body surface area - 11.5 l h(-1) m(-2) (4.0). No significant effects of twin pregnancy (n = 8) or maternal co-morbidity (n = 3) were observed, but mean clearance after preterm delivery (n = 12, <37 weeks gestational age) was significantly higher [13.8 (5.7) vs. 10.2 l h(-1) m(-2) (1.9), P = 0.028] compared with term delivery (n = 22). Similarly, there was a difference in mean distribution volume [0.83 (0.25) vs. 0.69 l kg(-1) (0.1), P = 0.037], resulting in the absence of differences in median elimination half-life [112 (28) vs. 119 min (19)]. Women who underwent a preterm caesarean delivery had a higher paracetamol clearance compared with term delivery. These pharmacokinetic differences illustrate the relevance of performing pharmacokinetic studies at delivery. We encourage clinicians to perform similar studies for other drugs administered in this group. EudraCT 2010-020164-37.

Does pregnancy affects loading dose pharmacokinetics of intravenous paracetamol?

s and Programme: EUROANAESTHESIA 2011: The European Anaesthesiology Congress: Obstetric Anaesthesia

The pharmacokinetics of intravenous paracetamol in neonates: size matters most

BackgroundThe aim was to describe intravenous paracetamol pharmacokinetics, determine major covariates and suggest a dosing regimen for (pre)term neonates.MethodsA population pharmacokinetic analysis of 943 paracetamol observations from 158 neonates (27–45...

Pharmacokinetics of Intravenous Paracetamol in Elderly Patients

Intravenous paracetamol (N-acetyl-paraminophenol, acetaminophen) is a widely used nonopioid analgesic which has become popular in the treatment of pain in many patient groups, including the elderly. Although intravenous paracetamol has been studied widely in clinical analgesia studies, there is little information on its pharmacokinetics in the elderly. We designed this study to determine the pharmacokinetics of intravenous paracetamol in very old patients and to compare them with that of younger patients. We also considered the effect of adenosine triphosphate-binding cassette G2 protein (ABCG2) genotype and renal function on paracetamol pharmacokinetics in these patients. We compared the pharmacokinetics of intravenous paracetamol in four groups of ten patients, aged 20-40, 60-70, 70-80 and 80-90 years, undergoing orthopaedic surgery. Paracetamol 1000 mg was given by infusion over 15 minutes. Plasma concentrations of paracetamol and its glucuronide and sulphate conjugates were measured for 24 hours with a high-performance liquid chromatographic method and ABCG2 genotype was determined. Glomerular filtration rate (GFR) was estimated from age, sex and serum creatinine of the patient. In the group aged 80-90 years, the mean value of the area under the plasma concentration-time curve extrapolated to infinity (AUC(∞)) of paracetamol was 54-68% higher than in the two youngest groups. Paracetamol clearance showed a statistically significant dependence on age group, whereas volume of distribution during elimination and elimination half-life were associated with age group and sex, respectively. Based on mean AUC(∞) of paracetamol glucuronide and paracetamol sulphate, the oldest patients had 1.3- to 1.5-fold greater exposure to these metabolites than patients aged 20-40 years. ABCG2 genotype did not affect paracetamol pharmacokinetics. There was a linear correlation between the values of AUC(∞) of paracetamol, its glucuronide and sulphate metabolites and GFR. Age and sex are important factors affecting the pharmacokinetics of paracetamol. The higher the age of the patient, the higher is the exposure to paracetamol. Female sex is associated with increased paracetamol concentrations but ABCG2 genotype does not seem to affect paracetamol pharmacokinetics. Trial registration number (EudraCT): 2006-001917-14.

Intravenous paracetamol pharmacokinetics in neonates: a pooled analysis

The aim of this study was to describe paracetamol pharmacokinetics in neonates, to determine its covariates and suggest a dosing regimen for neonates (28 to 44 weeks postmenstrual age (PMA)).

Efficacy and pharmacokinetics of intravenous paracetamol in the critically ill patient

Introduction: Paracetamol (PCM) is a drug with analgesic and antipyretic properties. Despite its frequent use, little is known about its efficacy and pharmacokinetics (PK) when intravenously administered in the critically ill patient. A previous study suggests that therapeutic concentrations are not always reached [1]. The primary aim of this open-label, multiple-dose study was to evaluate intravenous PCM therapy in critically ill, secondary aim was to study the PK of intravenous PCM. Methods: Ventilated patients needing PCM treatment according to our ICU protocol (1 g PCM intravenously four times daily) were eligible for inclusion. Excluded were those with severe liver failure and those treated with PCM on the time of admission to the ICU. Blood samples were collected at 0, 30, 60, 180 and 300 minutes after the first and, if possible, the fifth and 21st doses. A computerized model was used to estimate population PK. Results: Nineteen patients were included of which 13 were male, with a mean APACHE IV score of 94.8. No antipyretic effect could be measured in any of the patients. PK parameters have been calculated for all patients after the first PCM dose. The half-life was 2.2 hours, the volume of distribution was 1.03 l/kg, and the clearance was 0.33 l/kg/hour. Data from 15 patients could be analysed after the fifth dose and from five patients after the 21st dose. The PK of intravenous PCM in our population show a biphasic profile (Figure 1). One hour after the dose, the mean serum concentration level was below the therapeutic level. In 18 out of 19 patients serum concentration dropped below 5 mg/ml before the next dose, resulting in a lack of build-up of a suitable therapeutic level of PCM after multiple dosages. Conclusions: The recommended dose of 1 g intravenous PCM four times daily is not sufficient to achieve a therapeutic effect in critically ill patients. This can be explained by the low serum levels reached. These results warrant the development of an adequate dosing scheme for intravenous PCM followed by a large clinical trial studying the effects and safety of this regimen in critically ill patients.

Effect of cardiopulmonary bypass on the pharmacokinetics of intravenous paracetamol (propacetmol hydrochloride)

Effect of cardiopulmonary bypass on the pharmacokinetics of intravenous paracetamol (propacetmol hydrochloride)

Pharmacokinetics of intravenous paracetamol in children and adolescents under major surgery

The aim of this study was to describe the pharmacokinetics of paracetamol (acetaminophen) and to get primary information on its metabolism after first indicated intravenous administration of paracetamol in children and adolescents undergoing major surgery. About 4 weeks after the last chemotherapy, seven children and adolescents (five osteosarcoma, two Ewing tumors) received paracetamol infusion (median: 15.0 mg/kg) for analgesia. Sparse serum (37 samples; 4-7 per patient) and urine samples (27 samples; 0-15 per patient) were analyzed for paracetamol, paracetamol-glucuronide, paracetamol-sulfate, paracetamol-mercapturate and paracetamol-cysteine using capillary electrophoresis. Nonlinear mixed-effect models were used to describe the pharmacokinetics of paracetamol in plasma. Pharmacokinetics of paracetamol after intravenous administration was best described by a two-compartment model with clearance of 13.2 l/h per 70 kg (between-subject variability: 30%), intercompartmental clearance of 45.7 l/h per 70 kg (both parameters standardized to a 70-kg person using allometric "1/4 power models"), central volume of distribution of 13.2 l per 70 kg (between-subject variability: 71%) and peripheral volume of distribution of 33.0 l per 70 kg. Paracetamol, the glucuronide- and sulfate conjugates as well as cysteine and mercapturic acid conjugates, both products of oxidative pathways of paracetamol, were excreted in urine. Surgery, with all its potential influencing factors, together with chemotherapy given about 4 weeks previously do not seem to have a major impact on the pharmacokinetic behavior and the between-subject variability of paracetamol after intravenous administration.