Estradiol and Weight Are Covariates of Paracetamol Clearance in Young Women

Beleyn, Bjorn; Vermeersch, Steve; Kulo, Aida; Smits, Anne; Verbesselt, René; Hoon, Jan N. de; Calsteren, Kristel Van; Allegaert, Karel

doi:10.1159/000358394

Cited by 5 publications

(17 citation statements)

References 23 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Has recently been confirmed and may be driven by oestradiol [49]. In the current pooled analysis, we were unable to show that sex was a covariate.…”

Section: Discussioncontrasting

confidence: 61%

Covariates of intravenous paracetamol pharmacokinetics in adults

et al. 2014

View full text Add to dashboard Cite

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.

show abstract

“…Has recently been confirmed and may be driven by oestradiol [49]. In the current pooled analysis, we were unable to show that sex was a covariate.…”

Section: Discussioncontrasting

confidence: 61%

Covariates of intravenous paracetamol pharmacokinetics in adults

et al. 2014

View full text Add to dashboard Cite

show abstract

“…There are data suggesting that women taking steroid oral contraceptives have an increased glucuronidation of acetaminophen of up to 50%, consistent with observations that both pregnancy and oral contraceptives use has effect on intravenous acetaminophen disposition . This may be driven by oestradiol . Clearance in pregnant women is increased, but by a reduced magnitude than in early reports, which did not account for appropriate size scaling .…”

Section: Discussionmentioning

confidence: 64%

“…27,28 This may be driven by oestradiol. 29 Clearance in pregnant women is increased, but by a reduced magnitude than in early reports, which did not account for appropriate size scaling. 30 Those authors were unable to show that sex was a covariate.…”

Section: Population Parameter Estimationsmentioning

confidence: 69%

Acetaminophen pharmacokinetics in severely obese adolescents and young adults

Hakim

Anderson

Walia

et al. 2018

Pediatric Anesthesia

View full text Add to dashboard Cite

Background Intravenous acetaminophen is commonly administered as an adjunctive to opioids during major surgical procedures, but neither the correct pharmacokinetic size descriptor nor the dose is certain in severely obese adolescents undergoing bariatric surgery. Methods Adolescents, 14‐20 years of age, with a body mass index (BMI) ≥95th percentile for age and sex or BMI ≥40 kg·m−2, presenting for laparoscopic or robotic assisted or vertical sleeve gastrectomy were administered intravenous acetaminophen (1000 mg) following completion of the surgical procedure. Venous blood was drawn for acetaminophen assay at eight time points, starting 15 minutes after completion of the infusion and up to 12 hours afterward. Time‐concentration data profiles were analyzed using nonlinear mixed effects models. Parameter estimates were scaled to a 70‐kg person using allometry. Normal fat mass was used to assess the impact of obesity on pharmacokinetic parameters. Results The study cohort comprised 11 female patients, age 17 SD 2 years with a weight of 125 SD 19 kg and a mean BMI of 46 SD 5 kg·m−2. The plasma acetaminophen serum concentration was 17 (SD 4) μg·mL−1 at 10‐20 minutes after completion of the infusion and 5 (SD 6) μg·mL−1 at 80‐100 minutes. A two‐compartment model, used to investigate pharmacokinetics, estimated clearance 10.6 (CV 72%) L·h·70 kg−1, intercompartment clearance 37.3 (CV 63%) L·h·70 kg−1, central volume of distribution 20.4 (CV 46%) L·70 kg−1, and peripheral volume of distribution 16.8 (CV 42%) L·70 kg−1. Clearance was best described using total body weight. Normal fat mass with a parameter that accounts for fat mass contribution (Ffat) of 0.88 best described volumes. Conclusion Current recommendations of acetaminophen to a maximum dose of 1000 mg resulted in serum concentrations below detection limits in all patients within 2 hours after administration. Dose is better predicted using total body mass with allometric scaling.

show abstract

“…This was an open-label, 3-period PK study (at delivery, early, and late postpartum) conducted from August 2010 to March 2013 (EudraCT Number 2010-020164-37) [ 6 , 11 , 16 ]. The study documents (study protocol, informed consent, subsequent amendments) were reviewed and approved by the local Ethics Committee of the University Hospitals Leuven.…”

Section: Methodsmentioning

confidence: 99%

“…This increase in glucuronidation clearance may in part be driven by oestradiol, and may explain within and between individual differences in paracetamol metabolism (e.g. oral contraceptives, follicular vs luteal phase, postpartum, pregnancy, or duration of pregnancy) in young women [ 6 , 8 , 9 , 11 – 14 ]. Based on a pooled analysis, we aimed to further explore the impact of these covariates on paracetamol metabolism based on plasma and urine collections in women at delivery, in postpartum (early, or late) and healthy volunteers, either or not on oral contraceptives (OC) following intravenous (iv) paracetamol administration [ 6 , 11 , 15 ].…”

Section: Introductionmentioning

confidence: 99%

Paracetamol pharmacokinetics and metabolism in young women

et al. 2015

View full text Add to dashboard Cite

BackgroundThere is relevant between individual variability in paracetamol clearance in young women. In this pooled study, we focused on the population pharmacokinetic profile of intravenous paracetamol metabolism and its covariates in young women.MethodsPopulation PK parameters using non-linear mixed effect modelling were estimated in a pooled dataset of plasma and urine PK studies in 69 young women [47 at delivery, 8/47 again 10–15 weeks after delivery (early postpartum), and 7/8 again 1 year after delivery (late postpartum), 22 healthy female volunteers with or without oral contraceptives].ResultsPopulation PK parameters were estimated based on 815 plasma samples and 101 urine collections. Compared to healthy female volunteers (reference group) not on oral contraceptives, being at delivery was the most significant covariate for clearance to paracetamol glucuronide (Factor = 2.03), while women in early postpartum had decreased paracetamol glucuronidation clearance (Factor = 0.55). Women on contraceptives showed increased paracetamol glucuronidation clearance (Factor = 1.46). The oestradiol level did not further affect this model. Being at delivery did not prove significant for clearance to paracetamol sulphate, but was higher in pregnant women who delivered preterm (<37 weeks, Factor = 1.34) compared to term delivery and non-pregnant women. Finally, clearance of unchanged paracetamol was dependent on urine flow rate.ConclusionsCompared to healthy female volunteers not on oral contraceptives, urine paracetamol glucuronidation elimination in young women is affected by pregnancy (higher), early postpartum (lower) or exposure to oral contraceptives (higher), resulting in at least a two fold variability in paracetamol clearance in young women.

show abstract

Estradiol and Weight Are Covariates of Paracetamol Clearance in Young Women

Cited by 5 publications

References 23 publications

Covariates of intravenous paracetamol pharmacokinetics in adults

Covariates of intravenous paracetamol pharmacokinetics in adults

Acetaminophen pharmacokinetics in severely obese adolescents and young adults

Paracetamol pharmacokinetics and metabolism in young women

Contact Info

Product

Resources

About