Pharmacokinetic properties of intramuscular versus oral syrup paracetamol in Plasmodium falciparum malaria.
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.
['Wattanakul|Thanaporn|T|', 'Teerapong|Pramote|P|', 'Plewes|Katherine|K|', 'Newton|Paul N|PN|', 'Chierakul|Wirongrong|W|', 'Silamut|Kamolrat|K|', 'Chotivanich|Kesinee|K|', 'Ruengweerayut|Ronnatrai|R|', 'White|Nicholas J|NJ|', 'Dondorp|Arjen M|AM|', 'Tarning|Joel|J|']
D000082:Acetaminophen D000284:Administration, Oral D000293:Adolescent D000328:Adult D000962:Antimalarials D058633:Antipyretics D001682:Biological Availability D018592:Cross-Over Studies D005260:Female D006207:Half-Life D006801:Humans D007273:Injections, Intramuscular D016778:Malaria, Falciparum D008297:Male D008875:Middle Aged D055815:Young Adult
Pharmacokinetics Intramuscular Paracetamol Falciparum malaria Antipyretic NONMEM Randomized crossover trial