Pharmacokinetic properties of intramuscular versus oral syrup paracetamol in Plasmodium falciparum malaria

Abstract

BackgroundFever 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.MethodsA 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.ResultsThe 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.ConclusionsParacetamol 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.

Temperature Dependence of Plasmodium falciparum Erythrocytic Stage Development

“…Paracetamol (acetaminophen) is the recommended antipyretic therapy as it is safe, inexpensive, and widely available. 33 However, paracetamol has been associated with a prolonged parasite clearance time, which our study suggests could be, to some extent, explained by increased survival in normothermia. 5 A more recent randomized controlled trial did not show a difference in parasite clearance between patients treated with or without paracetamol.…”

A study on parental perspectives towards childhood fever

“…A study which compared the pharmacokinetics of oral paracetamol versus intramuscular paracetamol given to patients with acute falciparum malaria with high fever revealed that both methods were able to achieve mean steady state therapeutic drug levels in serum. 14 During the dengue fever season, the physician must avoid unnecessary intramuscular injections in managing febrile episodes. Unnecessary intramuscular injections can be associated with local complications such as pain swelling or abscess formation.…”

Formulation and evaluation of an Anti-pyretic (Paracetamol) syrup for Paediatric

“…This work, in conjunction with the latest reports on the mechanism of action of Paracetamol, trying to point out that it is not a panacea devoid of side effects, and indeed, especially when is taken regularly and in large doses (> 4 g/day), there is a risk of serious side effects [7].…”