Publication: Pharmacokinetic properties of intramuscular versus oral syrup paracetamol in Plasmodium falciparum malaria
Issued Date
2016
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eng
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Mahidol University
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BioMed Central
Bibliographic Citation
Malar J. Vol. 15, (2016), 244
Suggested Citation
Thanaporn Wattanakul, Pramote Teerapong, Plewes, Katherine, Newton, Paul N., Wirongrong Chierakul, Kamolrat Silamut, Kesinee Chotivanich, Ronnatrai Ruengweerayut, White, Nicholas J., Dondorp, Arjen M., Tarning, Joel Pharmacokinetic properties of intramuscular versus oral syrup paracetamol in Plasmodium falciparum malaria. Malar J. Vol. 15, (2016), 244. doi:10.1186/s12936-016-1283-9 Retrieved from: https://repository.li.mahidol.ac.th/handle/20.500.14594/2746
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Title
Pharmacokinetic properties of intramuscular versus oral syrup paracetamol in Plasmodium falciparum malaria
Abstract
Background: Fever is an inherent symptom of malaria in both adults and children. Paracetamol (acetaminophen) is
the recommended antipyretic as it is inexpensive, widely available and has a good safety profile, but patients may not
be able to take the oral drug reliably. A comparison between the pharmacokinetics of oral syrup and intramuscular
paracetamol given to patients with acute falciparum malaria and high body temperature was performed.
Methods: A randomized, open-label, two-treatment, crossover, pharmacokinetic study of paracetamol dosed orally
and intramuscularly was conducted. Twenty-one adult patients with uncomplicated falciparum malaria were randomized
to receive a single 600 mg dose of paracetamol either as syrup or intramuscular injection on day 0 followed
by a single dose administered by the alternative route on day 1. Paracetamol plasma concentrations were quantified
frequently and modelled simultaneously using nonlinear mixed-effects modelling. The final population pharmacokinetic
model was used for dose optimization simulations. Relationships between paracetamol concentrations with
temperature and parasite half-life were investigated using linear and non-linear regression analyses.
Results: The population pharmacokinetic properties of paracetamol were best described by a two-compartment
disposition model, with zero-order and first-order absorption for intramuscular and oral syrup administration, respectively.
The relative bioavailability of oral syrup was 84.4 % (95 % CI 68.2–95.1 %) compared to intramuscular administration.
Dosing simulations showed that 1000 mg of intramuscular or oral syrup administered six-hourly reached therapeutic
steady state concentrations for antipyresis, but more favourable concentration–time profiles were achieved
with a loading dose of 1500 mg, followed by a 1000 mg maintenance dose. This ensured that maximum therapeutic
concentrations were reached rapidly during the first 6 h. No significant relationships between paracetamol concentrations
and temperature or parasite half-life were found.
Conclusions: Paracetamol plasma concentrations after oral syrup and intramuscular administration in patients with
acute falciparum malaria were described successfully by a two-compartment disposition model. Relative oral bioavailability
compared to intramuscular dosing was estimated as 84.4 % (95 % CI 68.2–95.1 %). Dosing simulations showed
that a loading dose followed by six-hourly dosing intervals reduced the time delay to reach therapeutic drug levels
after both routes of administration. The safety and efficacy of loading dose paracetamol antipyretic regimens now
needs to be established in larger studies.