The pharmacokinetics of a high intravenous dose of paracetamol after caesarean delivery: the effect of gestational age.

CONTEXT: Pregnancy affects intravenous paracetamol pharmacokinetics, but there are no studies on covariates of intravenous paracetamol pharmacokinetics around delivery.
OBJECTIVES: To document the impact of gestational age at delivery on pharmacokinetics of a high intravenous dose of paracetamol.
DESIGN: 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.
SETTING: Single, tertiary perinatal care centre. PATIENTS: 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). MAIN OUTCOME MEASURES: Individual paracetamol pharmacokinetics.
RESULTS: 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)].
CONCLUSION: 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. TRIAL REGISTRATION: EudraCT 2010-020164-37.