Population Pharmacokinetics and Pharmacodynamics of Artemether-Lumefantrine in Malaria Patients with Haematological Comorbidities in Three Nigerian States

Haematological comorbidities including sickle cell disease, iron deficiency anaemia, and helminth-associated anaemia are prevalent in malaria-endemic Nigerian populations and may alter artemether-lumefantrine pharmacokinetics by affecting drug absorption, protein binding, and erythrocyte-drug interaction, with implications for treatment efficacy and toxicity. This research characterises the population pharmacokinetics and pharmacodynamics of AL in malaria patients with and without haematological comorbidities in Rivers, Ogun, and Kano States. A multi-centre pharmacokinetic-pharmacodynamic study will enrol 300 uncomplicated falciparum malaria patients stratified by haematological status into sickle cell trait or disease, iron deficiency anaemia, and haematologically normal groups. Serial plasma sampling over 72 hours after AL dosing will be performed for artemether, dihydroartemisinin, and lumefantrine quantification by LC-MS/MS. Non-linear mixed-effects modelling using NONMEM will develop population PK models. PD endpoints including day-3 parasite clearance, 28-day cure rate, and post-treatment haemoglobin recovery will be modelled against PK-derived exposure metrics. Genetic polymorphisms in CYP3A4, CYP2C8, and ABCB1 will be evaluated as covariates. Monte Carlo simulation will identify optimal dosing strategies for comorbid subgroups. Original contributions include the first population PK-PD model for AL incorporating haematological comorbidities in Nigerian patients, a novel theoretical framework for comorbidity-driven dosing individualisation, and evidence-based dosing recommendations for sickle cell and anaemic malaria patients. Keywords: artemether-lumefantrine, pharmacokinetics, pharmacodynamics, sickle cell, malaria treatment