Paracetamol (Acetaminophen) and Metabolites Population Pharmacokinetics Model in children and adults with Spinal Muscular Atrophy
Qiaolin Zhao (1,3), Marie Mostue Naume (2,7), Sissel Sundell Haslund-Krog (4), Thomas Krag (2), Brenda C.M.de Winter (1,3), Karoline Lolk Revsbeck (2), John Vissing (2), Helle Holst (4), Morten Hylander Møller (5), Morten Dunø (6), Christina Engel Høi-Hansen (7), Alfred Peter Born (7), Per Bo Andersen (4), Mette Cathrine Ørngreen (2,7)
1 Department of Hospital Pharmacy, Erasmus University Medical Center Rotterdam, Rotterdam, the Netherlands; 2 Copenhagen Neuromuscular Center, Department of Neurology, University hospital of Copenhagen, Rigshospitalet; 3 Rotterdam Clinical Pharmacometrics Group; 4 Department of Clinical Pharmacology, Bispebjerg Hospital; 5 Department of Intensive Care, University hospital of Copenhagen, Rigshospitalet; 6 Department of clinical genetics, University hospital of Copenhagen, Rigshospitalet; 7 Department of Pediatric and Adolescent medicine, University hospital of Copenhagen, Rigshospitalet; *Note: Qiaolin Zhao and Marie Mostue Naume are both first authors.
Introduction: Spinal muscular atrophy (SMA) is neuromuscular disorder characterized by progressive muscular weakness and low skeletal muscle mass. Paracetamol is part of multimodal analgesia treatment in patients with SMA. Paracetamol is metabolized by the liver and the majority of its metabolites are glucuronide and sulfate. There is only a small portion of paracetamol excreted in urine as unchanged paracetamol or conjugated by cytochrome P450 CYP2E1 to a toxic metabolite, NAPQI. NAPQI is further conjugated by glutathione (GSH) to neutral metabolites and excreted in the urine as cysteine and mercapturic acid. Several case studies have reported children and adults with SMA and other muscular wasting disorders developing acute liver failure after therapeutic doses of paracetamol[1-3]. We suspect that patients with SMA have a lower concentration of GSH, due to low muscle mass and malnutrition. Thus, children and adults with SMA may have increased risk of paracetamol toxicity. There is no published study investigating the pharmacokinetics (PK) of paracetamol in the SMA population.
Objectives: The aim of this study is to compare the differences in PK of plasma paracetamol, paracetamol-glucuronide, paracetamol-sulphate, paracetamol-oxidative metabolites, between SMA patients and healthy controls. We want to explore the separate contributions of the different metabolic pathways and assess the influence of physiologic covariates on paracetamol pharmacokinetics.
Methods: In this study, we collected 1764 plasma samples for paracetamol and its metabolites from 11 healthy adults, 6 adults with SMA and 6 children with SMA. Non-linear mixed-effects modeling (NONMEM) was used to develop a population pharmacokinetic model and perform a covariate analysis[4-5]. Bootstrap was used to validate the final model. Total CL was calculated to compare the PK differences between SMA patients and healthy controls. Simulations were performed to investigate the impact of significant covariates on the exposure of paracetamol and its metabolites and compare the differences of the paracetamol and metabolites exposures in SMA patients and healthy controls.
Results: A one-compartment model with first-order absorption, lag time and allometric scaling best described the paracetamol and its metabolites in the population. Population PK parameters included Ka (2.84 1/h), lag time (0.153 h), volume of distribution (V) for paracetamol (63.5 L/70kg), unchanged paracetamol clearance (CL) (8.16 L/h/70kg), V for glucuronide (11.43 L/70kg), glucuronide formation CL (6.37 L/h/70kg), glucuronide elimination CL (5.69 L/h/70kg), V for sulfate (11.43 L/70kg), sulfate formation CL (8.43 L/h/70kg), sulfate elimination CL (20.4 L/h/70kg), V for oxidative metabolites (11.43 L/70kg), oxidative metabolites formation CL (0.203 L/h/70kg), oxidative metabolites elimination CL (3.72 L/h/70kg). IIV was included on Ka, V for paracetamol, unchanged paracetamol CL, glucuronide formation CL, sulfate formation CL, and oxidative metabolites elimination CL. The V of SMA patients was 1.58-fold higher than healthy controls. Myoglobin was a significant covariate on unchanged paracetamol CL and bilirubin was a significant covariate on sulfate formation CL and oxidative metabolites elimination CL. SMA patients have lower total CL (L/h) (17.795 for children with SMA, 19.274 for adults with SMA, 23.127 for healthy controls) when compared with healthy controls. Oxidative metabolites elimination CL (L/h/70kg) is higher in SMA patients than that in healthy controls after corrected by 70kg body weight (3.679 for children with SMA, 3.878 for adults with SMA, 3.308 for healthy controls).
Conclusions: This is the first description of population PK of oral paracetamol intake in patients with SMA. Simulations from the model showed that SMA patients have lower exposure of paracetamol and its metabolites than healthy controls, which can be explained by low body weight. From simulation, we can also see higher bilirubin is accompanied by higher exposure to the oxidative metabolites in SMA patients. As oxidative metabolites are involved in paracetamol’s toxic pathway, we should be cautious about SMA patients’ bilirubin value when they are given paracetamol as analgesia treatment.
References:
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