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BACKGROUND and OBJECTIVE Paracetamol is the most used analgesic in older people. The physiological changes occurring with ageing influence the pharmacokinetics of paracetamol and its variability. A population pharmacokinetic analysis to describe the pharmacokinetics of intravenous paracetamol in fit older people was performed. Thereafter, simulations were conducted to illustrate target attainment and variability of paracetamol exposure following current dosing regimens (1000 mg q6h, q8h) using steady-state concentration (Css-mean) of 10 mg/L as target for effective analgesia. DESIGN and METHODS A population pharmacokinetic-analysis, using NONMEM 7.2, was performed based on 601 concentrations of paracetamol from 30 fit

BACKGROUND and OBJECTIVE: Paracetamol is the most used analgesic in older people. The physiological changes occurring with ageing influence the pharmacokinetics of paracetamol and its variability. A population pharmacokinetic analysis to describe the pharmacokinetics of intravenous paracetamol in fit older people was performed. Thereafter, simulations were conducted to illustrate target attainment and variability of paracetamol exposure following current dosing regimens (1000 mg q6h, q8h) using steady-state concentration [Css-mean] of 10 mg/L as target for effective analgesia. DESIGN and METHODS: A population pharmacokinetic-analysis. using N0NMEM 7.2. was performed based on 601 concentrations of paracetamol from 30 fit older people (median age = 77.3 years [61.8-88.5], body weight = 79 kg 160-107)1. All had received an intravenous paracetamol dose of 1000 mg - over 15 min - after elective knee surgery. RESULTS: A two-compartment pharmacokinetic-model best described the data. Volume of distribution of paracetamol increased exponentially with body weight. Clearance was not influenced by any covariate. Simulations of the standardized dosing regimens resulted in a Css-mean of 9.2 mg/L Iq6h) and 7.2 mg/L Iq8h|. Variability in paracetamol pharmacokinetics resulted in a Css-mean above 5.4 (q6h| and 4.1 mg/L (q8h) in 90%. and above 15.5 Iq6h) and 11.7 mg/L Iq8h) in 10% of the population. CONCLUSION: The target concentration was achieved in the average patient with 1000 mg q6h, while q8h resulted in underdosing for the majority of the population. Due to large unexplained interindividual variability in paracetamol pharmacokinetics a relevant proportion of the fit older people remained either under- or overexposed.