Background: Acetaminophen may improve renal function in patients with severe knowlesi malaria, particularly in those with acute kidney injury and haemolysis via inhibition of cell-free haemoglobin mediated oxidative kidney damage. The aim of this analysis was to assess the pharmacokinetic (PK) and pharmacodynamic (PD) effects of acetaminophen on renal function (creatinine), hepatotoxicity (alanine aminotransferase; ALT), fever clearance time and parasite clearance time among Malaysian patients with knowlesi malaria.
Methods: This PK/PD analysis was a pre-specified objective of the PACKNOW trial (1); an open-label, randomized, controlled trial of acetaminophen (500 mg or 1000 mg every 6 hours for 72 hours) vs no acetaminophen in Malaysian patients aged ³5 years with knowlesi malaria of any severity. Both sparsely and densely collected PK samples were used in the analysis. Creatinine, ALT, fever clearance time, and parasite clearance time were evaluated for up to 7 days after oral administration of acetaminophen. The population PK/PD models of acetaminophen were developed using a nonlinear mixed-effects modelling approach in NONMEM v7.4.
Results: A total of 372 patients were included in the PK/PD analyses, with 183 in the acetaminophen group and 189 in the control group. The PK of acetaminophen was best described by a two-compartment disposition model with first-order absorption, using a prior model previously published in falciparum malaria patients (2). Participants with more severe renal dysfunction at enrolment exhibited a greater reduction in creatinine from baseline, and higher acetaminophen concentrations were associated with a faster creatinine reduction rate, contributing to improved renal function. Acetaminophen exposure (AUC0-72H), age, and baseline ALT were significant covariates on the slope of ALT change over time. Acetaminophen administration reduced fever clearance time compared to controls. No significant association was observed between acetaminophen exposure and parasite clearance time.
Conclusions: Acetaminophen administered 6-hourly for 72 hours resulted in a faster creatinine reduction from baseline in Malaysian patients with knowlesi malaria. The greatest reduction was observed among those with more severe renal dysfunction at baseline. Although acetaminophen exposure is associated with increased ALT over time, no patients developed hepatotoxicity, and no serious adverse events were observed in the study population.
References:
(1) Cooper DJ, Grigg MJ, Plewes K, Rajahram GS, Piera KA, William T, et al. The Effect of Regularly Dosed Acetaminophen vs No Acetaminophen on Renal Function in Plasmodium knowlesi Malaria (PACKNOW): A Randomized, Controlled Trial. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 2022;75(8):1379-88.
(2) Wattanakul T, Teerapong P, Plewes K, Newton PN, Chierakul W, Silamut K, et al. Pharmacokinetic properties of intramuscular versus oral syrup paracetamol in Plasmodium falciparum malaria. Malaria journal. 2016;15:244.