Paracetamol and its metabolites in children and adults with spinal muscular atrophy - a population pharmacokinetic model

Abstract

Aims: The aim of the study was to investigate whether differences in paracetamol pharmacokinetics (PK) between spinal muscular atrophy (SMA) patients and healthy controls (HC) could be attributed to specific clinical covariates.

Methods: Nonlinear mixed-effects modelling (NONMEM 7.4) was used to develop a population PK model, explore covariates for paracetamol and its metabolites and perform simulations.

Results: With body weight as allometric scaling in the model, SMA disease resulted in a 58% (95% confidence interval [CI]: 20%-130%) increase in the volume of distribution for paracetamol and its metabolites compared to healthy controls. Decreased plasma myoglobin and plasma bilirubin concentrations, seen in SMA patients, resulted in a higher paracetamol leftover clearance (SMA, median: 13.30 L/h/70 kg, 95% CI: 9.14-18.29%; HC, median: 4.05 L/h/70 kg, 95% CI: 3.38-8.83%) and a shift from slower sulfate formation clearance (SMA, median: 8.78 L/h/70 kg, 95% CI: 7.22-9.61%; HC, median: 9.30 L/h/70 kg, 95% CI: 8.42-10.15%) and faster oxidative metabolites elimination clearance (SMA, median: 3.74 L/h/70 kg, 95% CI: 3.31-4.72%; HC, median: 3.25 L/h/70 kg, 95% CI: 2.87-3.92%). Simulations revealed that in SMA patients, higher bodyweight was associated with increased exposure to paracetamol and its metabolites.

Conclusions: The differences in PK between SMA patients and healthy controls could be explained by body weight and the disease itself. SMA patients should be dosed cautiously, ensuring doses do not exceed the recommended body weight adjusted limit.

Keywords: SMA; metabolites; paracetamol; pharmacokinetic.

FIGURE 1

Schematic illustration of the structural pharmacokinetic model for paracetamol and its metabolites in plasma. All formation and renal clearances were modelled as first‐order processes. CL _pg , CL _ps , CL _pox represent, respectively, formation (hepatic) clearances for paracetamol‐glucuronide, paracetamol‐sulfate and paracetamol‐oxidative metabolites. CL _P , CL _gluc , CL _sulf , CL _ox represent, respectively, leftover clearance for paracetamol, elimination clearances of paracetamol‐glucuronide, paracetamol‐sulfate and paracetamol‐oxidative metabolites. V _pcm , V _gluc , V _sulf , V _ox represent, respectively, volumes of distribution for paracetamol, paracetamol‐glucuronide, paracetamol‐sulfate and paracetamol‐oxidative metabolites.

FIGURE 2

Model‐based simulation of the concentrations over time for plasma paracetamol and its metabolites in SMA patients with different body weight in steady state with the dosage of 1000 mg. (A) Paracetamol concentration–time profile; (B) paracetamol‐glucuronide concentration–time profile; (C) paracetamol‐sulfate concentration–time profile; (D paracetamol‐oxidative metabolites concentration–time profile. Concentrations are presented as median (solid line) and 90% prediction interval (dashed line). HC, healthy controls; SMA, spinal muscular atrophy.

FIGURE 3

Model‐based simulation of plasma paracetamol and its metabolites in 70 kg SMA patients with different myoglobin in steady state with the dosage of 1000 mg. (A) Paracetamol concentration–time profile; (B) paracetamol‐glucuronide concentration–time profile; (C) paracetamol‐sulfate concentration–time profile; (D) paracetamol‐oxidative metabolites concentration–time profile. Solid line representing median value and dashed line representing 90% prediction interval. HC, healthy controls; SMA, spinal muscular atrophy; MYO, myoglobin.

FIGURE 4

Model‐based simulation of plasma paracetamol and its metabolites in 70 kg SMA patients with different bilirubin in steady state with the dosage of 1000 mg. (A) Paracetamol concentration–time profile; (B) paracetamol‐glucuronide concentration–time profile; (C) paracetamol‐sulfate concentration–time profile; (D) paracetamol‐oxidative metabolites concentration–time profile. Solid line representing median value and dashed line representing 90% prediction interval. HC, healthy controls; SMA, spinal muscular atrophy; BILI, bilirubin.