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Paracetamol plasma and cerebrospinal fluid pharmacokinetics in children
B J Anderson1, N H Holford, G A Woollard
1Paediatric Intensive Care Department, Auckland Children's Hospital, New Zealand.
Insights
Paracetamol
Area of Science:
- Pediatric Pharmacology
- Neuroscience
- Pharmacokinetics
Background:
- Paracetamol (acetaminophen) provides central antipyretic and analgesic effects.
- Peak effects occur 1-2 hours after peak plasma concentrations.
- Understanding drug distribution to the central nervous system is crucial.
Purpose of the Study:
- To investigate the pharmacokinetic relationship between plasma and cerebrospinal fluid (CSF) paracetamol in children.
- To determine how quickly paracetamol concentrations equilibrate between plasma and CSF.
Main Methods:
- Population pharmacokinetic analysis using NONMEM and MKMODEL.
- Measurement of paracetamol concentrations in plasma and CSF via ventricular drains in nine children.
- Dose administered: 40 mg/kg nasogastric paracetamol.
Main Results:
- NONMEM estimates: clearance 10.21 L/h, volume of distribution 67.11 L, absorption rate constant 0.77 h⁻¹.
- CSF concentrations lagged behind plasma concentrations.
- CSF/plasma partition coefficient was 1.18, with an equilibration half-time of 0.72 hours.
Conclusions:
- Higher CSF paracetamol concentrations suggest lower free water in plasma.
- CSF kinetics may better reflect the effect site than plasma.
- Optimal timing for paracetamol administration in children is 1-2 hours before expected pain or fever.
Aims:
Paracetamol has a central action for both antipyresis and analgesia. Maximum temperature decrease and peak analgesia are reported at 1-2 h after peak plasma paracetamol concentration. We wished to determine the relationship between plasma and cerebrospinal fluid (CSF) pharmacokinetics in children.
Methods:
Concentration-time profiles in plasma and CSF after nasogastric paracetamol 40 mg kg(-1) were measured in nine children who had indwelling ventricular drains. Estimation of population pharmacokinetic parameters was made using both a standard two-stage population approach (MKMODEL) and a nonlinear mixed effect model (NONMEM). Results were standardized to a 70 kg person using an allometric power model.
Results:
Both approaches gave similar estimates. NONMEM parameter estimates were clearance 10.21 h(-1) (CV 47%), volume of distribution 67.11 (CV 58%) and absorption rate constant 0.77 h(-1) (CV 49%). Cerebrospinal fluid concentrations lagged behind those of plasma. The equilibration half time was 0.72 h (CV 117%). The CSF/plasma partition coefficient was 1.18 (CV 8%).
Conclusions:
Higher concentrations in the CSF probably reflect the lower free water volume of plasma. The CSF equilibration half time suggests that CSF kinetics approximate more closely to the effect compartment than plasma, but further time is required for paracetamol to exert its effects. Effect site concentrations equilibrate slowly with plasma. Paracetamol should be given 1-2 h before anticipated pain or fever in children.