Disposition of Intravenous Paracetamol in Young Women

Disposition of Intravenous Paracetamol in Young Women, Including During Pregnancy, in Postpartum or When on Oral Contraceptives

Compared to early postpartum (10-15 weeks) observations, paracetamol clearance was significantly higher (21.1 vs 11.7 l.h-1, + 80 %) at delivery. This higher clearance was due to a disproportional increase in glucuronidation (11.6 vs 4.76 l.h-1, + 144 %), a proportional increase in oxidation clearance (4.95 vs 2.77 l.h-1, 78 %) and primary renal clearance (1.15 vs 0.75 l.h-1, 53 %) [KUlo et al, Int J Obstet Anesth]. 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.

Based on a pooled analysis, investigators 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.

Study Overview

• Status: Completed
• Conditions: Pain
• Intervention / Treatment: Drug: intravenous paracetamol (acetaminophen)

Detailed Description

This study aims to perform a pooled analysis of:

1. Paracetamol PK data recently published in 47 pregnant women. In these cases, iv paracetamol was administered q6h after delivery (caesarean) for 24 h. 8 were recruited a second time for an additional single dose pK study in postpartum (Kulo et al, Br J Clin Pharmacol 2013).
2. The PK data as initially published by Gregoire et al, but limited to female volunteers, all on oral contraceptives (n=14) (Gregoire et al, Clin Pharm Ther 2007)
3. A dataset in 8 young women not on oral contraceptives, iv paracetamol, single dose.

• Study Type: Observational
• Enrollment (Actual): 69

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 45 years (Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: Female

• Sampling Method: Non-Probability Sample

Study Population

Pooled analysis of different cohorts of young women who all underwent PK study on paracetamol disposition after iv paracetamol administration.

Description

Inclusion Criteria:

1. informed consent
2. for patients (pregnant women at delivery), there has to be a clinical indication (post caesarean analgesia, NPO) to administer iv paracetamol.

Exclusion Criteria:

1. intolerance to paracetamol
2. withdrawal of informed consent.

Study Plan

How is the study designed?

Number of groups / cohorts

3

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
at delivery; women who underwent cesarean at delivery, and needed iv paracetamol as part of multimodal analgesia. In these cases, paracetamol was administered q6h (2g loading dose, 1g q6h for 24 h), and blood and urine samples were collected to describe paracetamol disposition at delivery.	Drug: intravenous paracetamol (acetaminophen); paracetamol disposition in young women, exploring the impact of covariates (pregnancy, postpartum, oral contraceptives) in this population.; Other Names: Perfusalgan, paracetamol Fresenius,
postpartum; a subgroup of 8 women initially included in at delivery, underwent a second PK study 2-3 months postpartum and another PK study about 1 year after delivery. This PK study was based on a single iv paracetamol administration (2 g), and blood and urine samples were collected to describe paracetamol disposition in postpartum	Drug: intravenous paracetamol (acetaminophen); paracetamol disposition in young women, exploring the impact of covariates (pregnancy, postpartum, oral contraceptives) in this population.; Other Names: Perfusalgan, paracetamol Fresenius,
healthy female volunteers; a group of 8 young healthy women not on oral contraceptives underwent a single PK study (2 g intravenous paracetamol) and blood and urine samples were collected to described paracetamol disposition in healthy female volunteers, not on oral contraceptives. Raw data as published by Gregoire et al (Clin Pharm Ther 2007) were available in 14 young women, all on contraceptives.	Drug: intravenous paracetamol (acetaminophen); paracetamol disposition in young women, exploring the impact of covariates (pregnancy, postpartum, oral contraceptives) in this population.; Other Names: Perfusalgan, paracetamol Fresenius,

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
paracetamol disposition in young women: total clearance and metabolite specific clearance estimates	pooled analysis of plasma and urine paracetamol and paracetamol metabolite data published in literature in young women following iv paracetamol administration. Samples (plasma and urine) will be collected in the 24 h time interval after initiation of intravenous paracetamol administration (time interval of the PK study)	24 h is the maximal time frame of this pharmacokinetic study (PK is the outcome measured

Collaborators and Investigators

• Sponsor: Universitaire Ziekenhuizen KU Leuven
• Investigators: Principal Investigator: karel allegaert, MD, PhD, Universitaire Ziekenhuizen KU Leuven

Publications and helpful links

General Publications

• Beleyn B, Vermeersch S, Kulo A, Smits A, Verbesselt R, de Hoon JN, Van Calsteren K, Allegaert K. Estradiol and weight are covariates of paracetamol clearance in young women. Gynecol Obstet Invest. 2014;77(4):211-6. doi: 10.1159/000358394. Epub 2014 Mar 25.
• Kulo A, Peeters MY, Allegaert K, Smits A, de Hoon J, Verbesselt R, Lewi L, van de Velde M, Knibbe CA. Pharmacokinetics of paracetamol and its metabolites in women at delivery and post-partum. Br J Clin Pharmacol. 2013 Mar;75(3):850-60. doi: 10.1111/j.1365-2125.2012.04402.x.
• Gregoire N, Hovsepian L, Gualano V, Evene E, Dufour G, Gendron A. Safety and pharmacokinetics of paracetamol following intravenous administration of 5 g during the first 24 h with a 2-g starting dose. Clin Pharmacol Ther. 2007 Mar;81(3):401-5. doi: 10.1038/sj.clpt.6100064.

Study record dates

Study Major Dates

• Study Start: June 1, 2010
• Primary Completion (Actual): December 1, 2010
• Study Completion (Actual): April 1, 2015

Study Registration Dates

• First Submitted: October 19, 2015
• First Submitted That Met QC Criteria: October 27, 2015
• First Posted (Estimate): October 29, 2015

Study Record Updates

• Last Update Posted (Estimate): October 29, 2015
• Last Update Submitted That Met QC Criteria: October 27, 2015
• Last Verified: October 1, 2015

More Information

Terms related to this study

• Keywords: pharmacokinetics; pregnancy; oral contraceptives; oestradiol
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Analgesics, Non-Narcotic; Antipyretics; Acetaminophen
• Other Study ID Numbers: ML6563