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Background and Objective: Although acetaminophen is frequently used during pregnancy, little is known about fetal acetaminophen pharmacokinetics. Acetaminophen safety evaluation has typically focused on hepatotoxicity, while other events (fetal ductal closure/constriction) are also relevant. We aimed to develop a fetal–maternal physiologically based pharmacokinetic (PBPK) model (f-m PBPK) to quantitatively predict placental acetaminophen transfer, characterize fetal acetaminophen exposure, and quantify the contributions of specific clearance pathways in the term fetus. Methods: An acetaminophen pregnancy PBPK model was extended with a compartment representing the fetal liver, which included maturation of relevant enzymes. Different approaches to describe placental transfer were evaluated (ex vivo cotyledon perfusion experiments, placental transfer prediction based on Caco-2 cell permeability or physicochemical properties [MoBi®]). Predicted maternal and fetal acetaminophen profiles were compared with in vivo observations. Results: Tested approaches to predict placental tr

BACKGROUND and OBJECTIVE Paracetamol is the most used analgesic in older people. The physiological changes occurring with ageing influence the pharmacokinetics of paracetamol and its variability. A population pharmacokinetic analysis to describe the pharmacokinetics of intravenous paracetamol in fit older people was performed. Thereafter, simulations were conducted to illustrate target attainment and variability of paracetamol exposure following current dosing regimens (1000 mg q6h, q8h) using steady-state concentration (Css-mean) of 10 mg/L as target for effective analgesia. DESIGN and METHODS A population pharmacokinetic-analysis, using NONMEM 7.2, was performed based on 601 concentrations of paracetamol from 30 fit

BACKGROUND and OBJECTIVE: Paracetamol is the most used analgesic in older people. The physiological changes occurring with ageing influence the pharmacokinetics of paracetamol and its variability. A population pharmacokinetic analysis to describe the pharmacokinetics of intravenous paracetamol in fit older people was performed. Thereafter, simulations were conducted to illustrate target attainment and variability of paracetamol exposure following current dosing regimens (1000 mg q6h, q8h) using steady-state concentration [Css-mean] of 10 mg/L as target for effective analgesia. DESIGN and METHODS: A population pharmacokinetic-analysis. using N0NMEM 7.2. was performed based on 601 concentrations of paracetamol from 30 fit older people (median age = 77.3 years [61.8-88.5], body weight = 79 kg 160-107)1. All had received an intravenous paracetamol dose of 1000 mg - over 15 min - after elective knee surgery. RESULTS: A two-compartment pharmacokinetic-model best described the data. Volume of distribution of paracetamol increased exponentially with body weight. Clearance was not influenced by any covariate. Simulations of the standardized dosing regimens resulted in a Css-mean of 9.2 mg/L Iq6h) and 7.2 mg/L Iq8h|. Variability in paracetamol pharmacokinetics resulted in a Css-mean above 5.4 (q6h| and 4.1 mg/L (q8h) in 90%. and above 15.5 Iq6h) and 11.7 mg/L Iq8h) in 10% of the population. CONCLUSION: The target concentration was achieved in the average patient with 1000 mg q6h, while q8h resulted in underdosing for the majority of the population. Due to large unexplained interindividual variability in paracetamol pharmacokinetics a relevant proportion of the fit older people remained either under- or overexposed.

Background and Objective: Little is known about acetaminophen (paracetamol) pharmacokinetics during pregnancy. The aim of this study was to develop a physiologically based pharmacokinetic (PBPK) model to predict acetaminophen pharmacokinetics throughout pregnancy. Methods: PBPK models for acetaminophen and its metabolites were developed in non-pregnant and pregnant women. Physiological and enzymatic changes in pregnant women expected to impact acetaminophen pharmacokinetics were considered. Models were evaluated using goodness-of-fit plots and by comparing predicted pharmacokinetic profiles with in vivo pharmacokinetic data. Predictions were performed to illustrate the average concentration at steady state (Css,avg) values, used as an indicator for efficacy, of acetaminophen achieved following administration of 1000 mg every 6 h. Furthermore, as a measurement of potential hepatotoxicity, the molar dose fraction of acetaminophen converted to N-acetyl-p-benzoquinone imine (NAPQI) was estimated. Results: PBPK models successfully predicted the pharmacokinetics of acetaminophen and its metabolites in non-pregnant and pregnant women. Predictions resulted in the lowest Css,avg in the third trimester (median [interquartile range]: 4.5 [3.8–5.1] mg/L), while Css,avg was 6.7 [5.9–7.4], 5.6 [4.7–6.3], and 4.9 [4.1–5.5] mg/L in non-pregnant, first trimester, and second trimester populations, respectively. Assuming a constant raised cytochrome P450 2E1 activity throughout pregnancy, the molar dose fraction of acetaminophen converted to NAPQI was highest during the first trimester (median [interquartile range]: 11.0% [9.1–13.4%]), followed by the second (9.0% [7.5–11.0%]) and third trimester (8.2% [6.8–10.1%]), compared with non-pregnant women (7.7% [6.4–9.4%]). Conclusion: Acetaminophen exposure is lower in pregnant than in non-pregnant women, and is related to pregnancy duration. Despite these findings, higher dose adjustments cannot be advised yet as it is unknown whether preg

Paracetamol is the most commonly used analgesic in older people, and is mainly dosed according to empirical dosing guidelines. However, the pharmacokinetics and thereby the effects of paracetamol can be influenced by physiological changes occurring with ageing. To investigate the steps needed to reach more evidence-based paracetamol dosing regimens in older people, we applied the concepts used in the paediatric study decision tree. A search was performed to retrieve studies on paracetamol pharmacokinetics and safety in older people (> 60 years) or studies that performed a (sub) analysis of pharmacokinetics and/or safety in older people. Of 6088 articles identified, 259 articles were retained after title and abstract screening. Further abstract and full-text screening identified 27 studies, of which 20 described pharmacokinetics and seven safety. These studies revealed no changes in absorption with ageing. A decreased (3.9–22.9%) volume of distribution (Vd) in robust older subjects and a further decreased Vd (20.3%) in frail older compared with younger subjects was apparent. Like Vd, age and frailty decreased paracetamol clearance (29–45.7 and 37.5%) compared with younger subjects. Due to limited and heterogeneous evidence, it was difficult to draw firm and meaningful conclusions on changed risk for paracetamol safety in older people. This review is a first step towards bridging knowledge gaps to move to evidence-based paracetamol dosing in older subjects. Remaining knowledge gaps are safety when using therapeutic dosages, pharmacokinetics changes in frail older people, and to what extent changes in paracetamol pharmacokinetics should lead to a change in dosage in frail and robust older people.

We congratulate Blecharz-Klin et al. with their research on the effects of perinatal paracetamol exposure in rats on the resulting modulation of neurotransmitters in different regions of the central nervous system. Paracetamol is an over the counter (OTC) compound and is very commonly used for mild to moderate pain or fever, during pregnancy, in neonates and infants, because of its high safety profile. However, a possible association- not equal to causality- between paracetamol used during pregnancy and long-term safety, including neurologic disorders (e.g. autism, Attention Deficit Hyperactivity Disorder (ADHD)), in later childhood has been reported. The results of this association type of studies should be interpreted with care, because of limitations like selection bias, self-report assessment and lack of data on prenatal doses. The European Medicines Agency (EMA) and Food and Drug Administration (FDA) examined those studies and concluded that clinical relevance of these possible associations is still unknown, leading to no advice changes. The research of Blecharz-Klin et al. provides data on pathophysiological mechanisms between paracetamol exposure and subsequent modulation of neurotransmitters in different regions of the brain. As clinical pharmacologists-with a specific interest in human perinatal pharmacology- we would like to add two concerns related to cross species translation of these animal studies to the human setting. First, the dosages selected in the rat experiments were harmonized to the currently used doses applied in the human neonate. However -across species- harmonized doses (mg/kg) do not simply translate to similar paracetamol concentration time pr