The Use of Physiologically Based Pharmacokinetic Modelling in Assessing Drug–drug Interactions Associated with Antimalarial Treatment in Paediatrics Co-infected with Tuberculosis: A Case Study with Lumefantrine and Rifampicin.
Olusola Olafuyi(1), Michael Coleman(2) and Raj K. S. Badhan(1,2)
1. Aston Healthy Research Group, Aston Pharmacy School, Aston University, Birmingham, B4 7ET, United Kingdom. 2. Aston Pharmacy School, Aston University, Birmingham, B4 7ET, United Kingdom.
Objectives: Drug-drug interactions (DDIs) between the antimalarial–Artemether/lumefantrine (AL) and anti-tuberculosis (TB) or antiretorvirals are likely. This DDI impact in children is unknown. Physiological based pharmacokinetic (PBPK) modelling technique can be used to describe the pharmacokinetics of drugs where clinical data is either unavailable or limited. This study aims to investigate the impact of AL co-administered with anti-TB drugs in paediatrics using physiological based pharmacokinetic (PBPK) modelling techniques.
Methods: Oral PK profiles as well as physico-chemical data of AL was collated from literature and used to develop adult oral PK models in the presence and absence of interactions with ketoconazole on SimCYP®. These models were validated with published clinical data. Paediatric oral DDI with rifampicin and isoniazid where then simulated followed by prediction of paediatric dose evaluations of AL in the presence of DDI with anti-tuberculosis drugs.
Results: Cmax and AUClast of artemether and lumefantrine (include the lumefantrine day-7 concentrations) were within 2-folds of published clinical data. In children, the model-predicted mean artemether plasma concentration for 20mg dose (293.5 ± 98.6 µg/mL) and 40mg dose (221.3 µg/mL ± 104.5 µg/mL) were within the 2-fold of the literarture reported plasma concentrations for the 20mg dose (150 ± 206 µg/mL) and 40mg dose (196 ± 204 µg/mL). Also the day 7 lumefantrine concentrations 389.7 [0.1-7544] ng/ml were predicted within 2-folds of reported clinical studies 367 [0.12-768] ng/ml. The DDI in the presence of a combination of rifampicin and isoniazid significantly reduced the Cmax and AUC to give a Cmax ratio and area under concentration time profile curve ratio (AUCr) of 0.21 and 0.22 respectively while for the lumefantrine day 7 concentrations the same DDI resulted in Cmax ratio and AUCr of 0.41 and 0.40 respectively significantly falling below the 280ng/ml threshold. An adapted AL 7-day dosage regimen resulted in between 63% and 75% of subjects attaining the 280ng/ml day 7 concentration target.
Conclusions: AL concentrations decreases significantly in presence of interaction with anti-tuberculosis (TB) regimen (rifampicin and isoniazid). An increase in dosing frequency increased the percentage of subjects within the 280ng/ml Cd7 target. An increase AL dosing frequency to a 7-day regimen from the regular 3-day regimen may overcome the impact of DDI in most TB co-infected malaria patients between 2 and 5 years old.
References:
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