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Variabiliteit in farmacokinetiek van intraveneuze paracetamol bij gezonde ouderen

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Abstract
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 (Cssmean) 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 older people (median age = 77.3 years [61.8- 88.5], body weight = 79 kg [60-107]). 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 (q6h) and 7.2 mg/L (q8h). 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 (q6h) and 11.7 mg/L (q8h) 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.
Keywords
paracetamol, ageing, older people, geriatric, pharmacokinetics, variability

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MLA
Mian, Paola et al. “Variabiliteit in Farmacokinetiek Van Intraveneuze Paracetamol Bij Gezonde Ouderen.” Nederlands Platform voor Farmaceutisch Onderzoek 4 (2019): a1713. Print.
APA
Mian, Paola, van Esdonk , M., de Winter, B., Spriet, I., Tibboel, D., Petrovic, M., Allegaert, K., et al. (2019). Variabiliteit in farmacokinetiek van intraveneuze paracetamol bij gezonde ouderen. Nederlands Platform voor Farmaceutisch Onderzoek, 4, a1713.
Chicago author-date
Mian, Paola, Michiel van Esdonk , Brenda de Winter, Isabel Spriet, Dick Tibboel, Mirko Petrovic, Karel Allegaert, and Birgit Koch. 2019. “Variabiliteit in Farmacokinetiek Van Intraveneuze Paracetamol Bij Gezonde Ouderen.” Nederlands Platform Voor Farmaceutisch Onderzoek 4: a1713.
Chicago author-date (all authors)
Mian, Paola, Michiel van Esdonk , Brenda de Winter, Isabel Spriet, Dick Tibboel, Mirko Petrovic, Karel Allegaert, and Birgit Koch. 2019. “Variabiliteit in Farmacokinetiek Van Intraveneuze Paracetamol Bij Gezonde Ouderen.” Nederlands Platform Voor Farmaceutisch Onderzoek 4: a1713.
Vancouver
1.
Mian P, van Esdonk M, de Winter B, Spriet I, Tibboel D, Petrovic M, et al. Variabiliteit in farmacokinetiek van intraveneuze paracetamol bij gezonde ouderen. Nederlands Platform voor Farmaceutisch Onderzoek. 2019;4:a1713.
IEEE
[1]
P. Mian et al., “Variabiliteit in farmacokinetiek van intraveneuze paracetamol bij gezonde ouderen,” Nederlands Platform voor Farmaceutisch Onderzoek, vol. 4, p. a1713, 2019.
@article{8625359,
  abstract     = {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 (Cssmean) 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 older people (median age = 77.3 years [61.8- 88.5], body weight = 79 kg [60-107]). 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 (q6h) and 7.2 mg/L (q8h). 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 (q6h) and 11.7 mg/L (q8h) 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.},
  author       = {Mian, Paola and van Esdonk , Michiel and de Winter, Brenda and Spriet, Isabel and Tibboel, Dick and Petrovic, Mirko and Allegaert, Karel and Koch, Birgit},
  journal      = {Nederlands Platform voor Farmaceutisch Onderzoek},
  keywords     = {paracetamol,ageing,older people,geriatric,pharmacokinetics,variability},
  title        = {Variabiliteit in farmacokinetiek van intraveneuze paracetamol bij gezonde ouderen},
  volume       = {4},
  year         = {2019},
}