Background CYP2C8 polymorphisms can impair the metabolism of the antimalarial amodiaquine and influence exposure to the key active metabolite desethylamodiaquine (DEAQ). CYP2C8*2 entailed to slow metabolism phenotype is the most frequent allele in Africa. Here we study the association between CYP2C8*2 carriage and DEAQ D7 drug level for repeated treatments. We conducted a retrospective study on achieved dried blood spot samples and drug level data from West African Network for Clinical Trials of Antimalarial Drugs (WANECAM I) conducted between October 2011 and December 2015 in Bougoula Hameau (Mali).

Methods We analyzed 206 samples and the related data from patients enrolled in artesunate-amodiaquine arm and actively followed for 2 years. DNA was extracted with QIAGEN kit. CYP2C8*2 status was determined by PCR-RFLP. We used DEAQ day 7 plasma concentration data previously measured by High Performance Liquid Chromatography. The set of outliers with extremely high day 7 DEAQ levels were additionally analyzed by Real time PCR for the presence of CYP2C8*3 and *4. Finally, we analysed the association between homozygous genotype, drug level and the timeframe between episodes.

Results Out of 206 patients, 153 patients (74.3%), 40 patients (19.4%) and 13 patients (6.3%) patients were respectively *1/*1, *1/*2 and the *2/*2. During the first treatment, there was no difference in D7 DEAQ drug level between the *1/*1 and *2/*2 groups. However, when retreatment was required less than 35 days after the first intervention, a more intense DEAQ accumulation was observed among *2/*2 carriers, relative to the first episode levels (D7, + 67%), compared with *1/*1 subjects (D7, +16%).

Conclusion We showed that repeated artesunate-amodiaquine administration inside a 35-day post-treatment frame leads to DEAQ accumulation, the effect being significantly higher in patients carrying the reduced function allele CYP2C8*2, suggesting an increased risk of overexposure and amodiaquine toxicity.