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.

Keywords: Antipyretic; Falciparum malaria; Intramuscular; NONMEM; Paracetamol; Pharmacokinetics; Randomized crossover trial.

Fig. 1

Patient flow diagram. After enrolment to the studies, patients admitted to Mae Sot Hospital had blood collected prior to paracetamol administration followed by timed blood collections. Group 1 received oral syrup paracetamol (PO) on day 0 then intramuscular paracetamol (IM) on day 1; Group 2 received intramuscular paracetamol on day 0 then oral syrup paracetamol on day 1. One patient in Group 1 did not receive the intramuscular dose of paracetamol on day 1 due to self-discharge from the hospital; one patient from Group 2 did not receive oral paracetamol on day 1 as the patient received multiple doses of paracetamol during the study period. All patients were included in the pharmacokinetic analysis

Fig. 2

Goodness-of-fit diagnostics of the final population pharmacokinetic model for paracetamol in patients with falciparum malaria. a observed concentrations plotted against population predictions, b observed concentrations plotted against individually predicted concentrations, c conditionally weighted residual plotted against time after dose, and d conditionally weighted residual plotted against population predictions. Observations are represented by black circles, solid black lines represents the line of identity or zero line, and the local polynomial regression fitting for all observations is represented by the dashed black line. The observed paracetamol concentrations, population predictions and individual predictions were transformed into their logarithms (base 10)

Fig. 3

Visual predictive check of the final population pharmacokinetic model for paracetamol in patients with falciparum malaria stratified by route of drug administration. a Intramuscular administration and b oral syrup administration. Open circles observed data points; solid lines 5th, 50th and 95th percentiles of the observed data; shaded area 95 % confidence intervals of the simulated 5th, 50th and 95th percentiles (n = 2000)

Fig. 4

Simulations from the final population pharmacokinetic model for paracetamol. The lower and upper dashed lines represent the therapeutic plasma concentration range of paracetamol for fever control (10–20 mg/l) [23, 24]. Upper panel population mean plasma concentration–time profiles after intramuscular (IM) administration of a study dosing regimen; 600 mg every 4 h, b normal dosing regimen; 1000 mg every 6 h and c modified dosing regimen; 1500 mg loading dose followed by 1000 mg every 6 h. Lower panel population mean plasma concentration–time profiles after oral syrup (PO) administration of d study dosing regimen; 600 mg every 4 h, e normal dosing regimen; 1000 mg every 6 h and f modified dosing regimen; 1500 loading followed by 1000 mg every 6 h