Pharmacokinetics of prednisolone in children: an open-label, randomised, two-treatment cross-over trial investigating the bioequivalence of different prednisolone formulations in children with airway disease

Introduction: One in three Danish children under 3 years of age experience asthma-like symptoms, and one-third will later be diagnosed with asthma. Oral prednisolone is used in various formulations to treat acute asthma. However, the potential differences in bioequivalence between these formulations have never been examined in children despite interchangeable use in clinical practice. Methods and analysis: An open-label, randomised, two-treatment cross-over trial investigating the bioequivalence of different prednisolone formulations in children with airway disease. The included patients (6 months-11 years of age) are admitted to the Department of Paediatric and Adolescent Medicine Nordsjællands University Hospital, Hillerød, with asthma or asthma-like symptoms. The primary objective is to assess the bioequivalence between different prednisolone formulations herein area under the concentration time curve, Cmax and Tmax using saliva samples. The secondary objectives are to evaluate tolerability (five-point face scale), adverse events and severity of the disease. If the patient has an intravenous access for other purposes, the saliva samples will be validated with plasma samples. A total of 66 evaluable patients are needed according to European Medicines Agency Guideline on bioequivalence. Ethics and dissemination: Traditional pharmacokinetic trials are burdensome due to the extent of blood samples necessary to capture the time-dependant drug profile. Saliva sampling is far more acceptable for paediatric patients. In addition, this trial adheres to standard dosing strategies. No additional venepunctures are performed, and no additional prednisolone doses are administered. Guidelines for paediatric bioequivalence trials are warranted

Pharmacokinetics and Safety of Prolonged Paracetamol Treatment in Neonates: An Interventional Cohort Study

Aims To investigate the pharmacokinetics and safety of prolonged paracetamol use (\u3e72 h) for neonatal pain. Methods Neonates were included if they received paracetamol orally or intravenously for pain treatment. A total of 126 samples were collected. Alanine aminotransferase and bilirubin were measured as surrogate liver safety markers. Paracetamol and metabolites were measured in plasma. Pharmacokinetic parameters for the parent compound were estimated with a nonlinear mixed-effects model. Results Forty-eight neonates were enrolled (38 received paracetamol for \u3e72 h). Median gestational age was 38 weeks (range 25–42), and bodyweight at inclusion was 2954 g (range 713–4750). Neonates received 16 doses (range 4–55) over 4.1 days (range 1–13.8). The median (range) dose was 10.1 mg/kg (2.9–20.3). The median oxidative metabolite concentration was 14.6 μmol/L (range 0.12–113.5) and measurable \u3e30 h after dose. There was no significant difference (P \u3e .05) between alanine aminotransferase and bilirubin measures at \u3c72 h or \u3e72 h of paracetamol treatment or the start and end of the study. Volume of distribution and paracetamol clearance for a 2.81-kg neonate were 2.99 L (% residual standard error = 8, 95% confidence interval 2.44–3.55) and 0.497 L/h (% residual standard error = 7, 95% confidence interval 0.425–0.570), respectively. Median steady-state concentration from the parent model was 50.3 μmol/L (range 30.6–92.5), and the half-life was 3.55 h (range 2.41–5.65). Conclusion Our study did not provide evidence of paracetamol-induced liver injury nor changes in metabolism in prolonged paracetamol administration in neonates

Acetaminophen treatment in children and adults with spinal muscular atrophy:a lower tolerance and higher risk of hepatotoxicity

Acute liver failure has been reported sporadically in patients with spinal muscular atrophy (SMA) and other neuromuscular disorders with low skeletal muscle mass receiving recommended dosages of acetaminophen. It is suggested that low skeletal muscle mass may add to the risk of toxicity. We aimed to describe the pharmacokinetics and safety of acetaminophen in patients with SMA. We analyzed acetaminophen metabolites and liver biomarkers in plasma from SMA patients and healthy controls (HC) every hour for six or eight hours on day 1 and day 3 of treatment with therapeutic doses of acetaminophen. Twelve patients with SMA (six adults and six children) and 11 HC participated in the study. Adult patients with SMA had significantly lower clearance of acetaminophen compared to HC (14.1 L/h vs. 21.5 L/h). Formation clearance of acetaminophen metabolites, glucuronide, sulfate, and oxidative metabolites were two-fold lower in the patients compared to HC. The liver transaminases and microRNAs increased nine-fold in one adult SMA patient after two days of treatment. The other patients and HC did not develop abnormal liver biomarkers. In this study, patients with SMA had lower clearance and slower metabolism of acetaminophen, and one patient developed liver involvement. We recommend giving 15 mg/kg/dose to SMA adults (with a maximum of 4000 mg/day) and monitoring standard liver biomarkers 48 h after first-time treatment of acetaminophen.</p

Pharmacokinetics and Safety of Prolonged Paracetamol Treatment in Neonates: An Interventional Cohort Study

Aims To investigate the pharmacokinetics and safety of prolonged paracetamol use (\u3e72 h) for neonatal pain. Methods Neonates were included if they received paracetamol orally or intravenously for pain treatment. A total of 126 samples were collected. Alanine aminotransferase and bilirubin were measured as surrogate liver safety markers. Paracetamol and metabolites were measured in plasma. Pharmacokinetic parameters for the parent compound were estimated with a nonlinear mixed-effects model. Results Forty-eight neonates were enrolled (38 received paracetamol for \u3e72 h). Median gestational age was 38 weeks (range 25–42), and bodyweight at inclusion was 2954 g (range 713–4750). Neonates received 16 doses (range 4–55) over 4.1 days (range 1–13.8). The median (range) dose was 10.1 mg/kg (2.9–20.3). The median oxidative metabolite concentration was 14.6 μmol/L (range 0.12–113.5) and measurable \u3e30 h after dose. There was no significant difference (P \u3e .05) between alanine aminotransferase and bilirubin measures at \u3c72 h or \u3e72 h of paracetamol treatment or the start and end of the study. Volume of distribution and paracetamol clearance for a 2.81-kg neonate were 2.99 L (% residual standard error = 8, 95% confidence interval 2.44–3.55) and 0.497 L/h (% residual standard error = 7, 95% confidence interval 0.425–0.570), respectively. Median steady-state concentration from the parent model was 50.3 μmol/L (range 30.6–92.5), and the half-life was 3.55 h (range 2.41–5.65). Conclusion Our study did not provide evidence of paracetamol-induced liver injury nor changes in metabolism in prolonged paracetamol administration in neonates

Pharmacokinetics and Safety of Prolonged Paracetamol Treatment in Neonates: An Interventional Cohort Study

Aims To investigate the pharmacokinetics and safety of prolonged paracetamol use (\u3e72 h) for neonatal pain. Methods Neonates were included if they received paracetamol orally or intravenously for pain treatment. A total of 126 samples were collected. Alanine aminotransferase and bilirubin were measured as surrogate liver safety markers. Paracetamol and metabolites were measured in plasma. Pharmacokinetic parameters for the parent compound were estimated with a nonlinear mixed-effects model. Results Forty-eight neonates were enrolled (38 received paracetamol for \u3e72 h). Median gestational age was 38 weeks (range 25–42), and bodyweight at inclusion was 2954 g (range 713–4750). Neonates received 16 doses (range 4–55) over 4.1 days (range 1–13.8). The median (range) dose was 10.1 mg/kg (2.9–20.3). The median oxidative metabolite concentration was 14.6 μmol/L (range 0.12–113.5) and measurable \u3e30 h after dose. There was no significant difference (P \u3e .05) between alanine aminotransferase and bilirubin measures at \u3c72 h or \u3e72 h of paracetamol treatment or the start and end of the study. Volume of distribution and paracetamol clearance for a 2.81-kg neonate were 2.99 L (% residual standard error = 8, 95% confidence interval 2.44–3.55) and 0.497 L/h (% residual standard error = 7, 95% confidence interval 0.425–0.570), respectively. Median steady-state concentration from the parent model was 50.3 μmol/L (range 30.6–92.5), and the half-life was 3.55 h (range 2.41–5.65). Conclusion Our study did not provide evidence of paracetamol-induced liver injury nor changes in metabolism in prolonged paracetamol administration in neonates