Fetal and neonatal rats paracetamol dosage and the perinatal human setting: Lost in translation?

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 profiles. This is even already the case within human neonates (10-fold variability in size, 0.5 to 5 kg). Interspecies scaling should be applied to predict pharmacokinetic parameters between animal and human and is commonly used for the selection of first-inhuman-dose. This is further elaborated in the FDA guideline which reported an algorithmic selection process of maximum recommended starting dose (MRSD) for adults based on animal toxicology data and administered dose. The conversion is commonly based on a normalisation (allometry) of dosage to Body Surface Area (BSA) or weight. Another approach, when adequate data are available, is to use earlier reported species-specific PK parameters (especially clearance) to determine dosing to reach target concentrations. Applying these concepts, studies in rats commonly use a paracetamol dose range of 100–400 mg/kg instead of the sub therapeutic dose (5–15 mg/kg) currently evaluated. Similar to the human setting, ontogeny should be further considered in the developing, juvenile animal. Similar to the human perinatal setting, we encourage researchers working with juvenile animal models to document not only dose and effect, but also exposure to make observations as useful as possible.
Our second concern is the continuous exposure to paracetamol throughout fetal rat life and infancy. Although such a study design may result in more recognizable effects, it also makes it difficult to translate this to the human setting. In clinical practice, paracetamol is mostly used on indication (i.c. to treat pain or fever), but not continuously throughout pregnancy and infancy. Besides, as illustrated for morphine in juvenile rats, both the indication (e.g. inflammatory pain) and morphine exposure modulated the long-term behavioral effects. This situation is also applicable for this study, where rats were exposed to paracetamol, without an indication.
In conclusion, animal experimental studies are very valuable to provide mechanistic evidence, including safety aspects in juvenile animals. However, translation to the human infant necessitates careful consideration of dose, effect, and exposure (concentration, duration) through multidisciplinary collaboration.