Population Pharmacokinetic Estimates Suggest Elevated Clearance and Distribution Volume of Desethylamodiaquine in Pediatric Patients with Sickle Cell Disease Treated with Artesunate-Amodiaquine

Abstract

BackgroundThere is limited information on the safety or efficacy of currently recommended antimalarial drugs in patients with sickle cell disease (SCD), a population predisposed to worse outcomes if affected by acute malaria. Artesunate-amodiaquine (ASAQ) is the first-line treatment for uncomplicated malaria (UM) in many malaria-endemic countries and is also used for treatment of UM in SCD patients. There is, however, no information to date, on the pharmacokinetics (PK) of amodiaquine or artesunate or the metabolites of these drugs in SCD patients.ObjectivesThis study sought to determine the PK of desethylamodiaquine (DEAQ), the main active metabolite of amodiaquine, among paediatric SCD patients with UM treated with artesunate-amodiaquine (ASAQ).MethodsPlasma concentration-time data (median DEAQ levels) of SCD children (n = 16) was initially compared with those of concurrently recruited non-SCD paediatric patients with acute UM (n = 13). A population PK modelling approach was then used to analyze plasma DEAQ concentrations obtained between 64 and 169 hours after oral administration of ASAQ in paediatric SCD patients with acute UM (n = 16). To improve PK modeling, DEAQ concentration-time data (n = 21) from SCD was merged with DEAQ concentration-time data (n = 169) of a historical paediatric population treated with ASAQ (n = 103) from the same study setting.ResultsThe median DEAQ concentrations on days 3 and 7 were comparatively lower in the SCD patients compared to the non-SCD patients. A two-compartment model best described the plasma DEAQ concentration-time data of the merged data (current SCD data and historical data). The estimated population clearance of DEAQ was higher in the SCD patients (67 L/h, 21% relative standard error (RSE) compared with the non-SCD population (15.5 L/h, 32% RSE). The central volume of distribution was larger in the SCD patients compared with the non-SCD patients (4400 L, 43% RSE vs. 368 L, 34% RSE).ConclusionsThe data shows a tendency towards lower DEAQ concentration in SCD patients and the exploratory population PK estimates suggest altered DEAQ disposition in SCD patients with acute UM. These findings, which if confirmed, may reflect pathophysiological changes associated with SCD on DEAQ disposition, have implications for therapeutic response to amodiaquine in SCD patients. The limited number of recruited SCD patients and sparse sampling approach however, limits extrapolation of the data, and calls for further studies in a larger population.

The Role of Clinical Pharmacology in Chemotherapy of Multidrug‐Resistant Plasmodium falciparum

“…There is limited information on the safety, efficacy, or PK of antimalarial drugs in SCD. One population‐based PK modeling suggests altered desethylamodiaquine disposition in SCD children 175 . This calls for further studies due to concerns of potential therapeutic effects of amodiaquine and other antimalarial drugs in SCD patients.…”

The effect of sickle cell genotype on the pharmacokinetic properties of artemether-lumefantrine in Tanzanian children

“…This may represent depressed reticuloendothelial (splenic) function ( Pearson et al, 1979 ) but it could also result from effects of SCD on artemisinin pharmacokinetics ( Sugiarto et al, 2018 ). There are few data on the disposition of longer half-life ACT partner drugs in either SCD or SCT, but SCD has been associated with reduced desethylamodiaquine exposure in children with acute malaria treated with artesunate-amodiaquine ( Adjei et al, 2019 ). This finding is consistent with the accelerated clearance of morphine, suggesting the need for higher doses in the management of SCD vaso-occlusive crises ( Darbari et al, 2011 ).…”