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Abstract
School-based mass drug administration (MDA) of Praziquantel (PZQ) is the global intervention strategy for elimination of schistosomiasis. Genetic variations in drug metabolizing enzymes and transporter proteins influences drug exposure and treatment outcomes, but data on PZQ pharmacokinetics and safety outcomes are scarce. We investigated the effect of pharmacogenetics variations on PZQ plasma concentrations and safety outcomes among 462 Rwandan schoolchildren who received single dose PZQ and albendazole in MDA. Genotyping for common functional variant alleles CYP3A4*1B, CYP3A5 (*3, *6, *7), CYP2C19 (*2, *3, *17), CYP2C9 (*2, *3) and CYP2J2*7 were done. Plasma concentration of PZQ, cis-4-OH-PZQ and trans-4-OH-PZQ were measured using LC/MS/MS. Active safety monitoring was done on days 1, 2, and 7 post-MDA. CYP2C9 and CYP2C19 genotypes were significantly associated with PZQ plasma concentrations and its cis- and trans-4-OH-PZQ/PZQ metabolic ratios (MR). CYP2C9*2 and CYP2C9*3 carriers had significantly higher PZQ concentration (p = 0.02), lower trans-4-OH-PZQ/PZQ (p < 0.001), and cis-4-OH-PZQ/PZQ (p = 0.02) MR. CYP2C19 (*2, *3) carriers had significantly higher plasma PZQ concentration than CYP2C19 *1/*1 and CYP2C19 *17 carriers (*1/*17 or *17/*17) (p < 0.001). CYP3A4 was significantly associated with cis-4-OH-PZQ MR (p = 0.04). Lower cis-4-OH-PZQ/PZQ MR (p < 0.0001) was a predictor of MDA-associated adverse events, but no significant association with genotypes were found. In conclusion, CYP2C9 and CYP2C19 genotypes significantly influence the plasma PZQ concentration and its MR. Lower cis-4-OH-PZQ/PZQ MR is significant predictor of adverse events following MDA.
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Details
1 Karolinska Institutet at Karolinska University Hospital, Division of Clinical Pharmacology, Department of Laboratory Medicine, Stockholm, Sweden (GRID:grid.24381.3c) (ISNI:0000 0000 9241 5705)
2 Karolinska Institutet at Karolinska University Hospital, Division of Clinical Pharmacology, Department of Laboratory Medicine, Stockholm, Sweden (GRID:grid.24381.3c) (ISNI:0000 0000 9241 5705); Rwanda Food and Drugs Authority, Kigali, Rwanda (GRID:grid.24381.3c)
3 Muhimbili University of Health and Allied Sciences, Department of Clinical Pharmacology, School of Medicine, Dar es Salaam, Tanzania (GRID:grid.25867.3e) (ISNI:0000 0001 1481 7466)
4 University of Rwanda, College of Medicine and Health Sciences, Kigali, Rwanda (GRID:grid.10818.30) (ISNI:0000 0004 0620 2260)
5 Rwanda Food and Drugs Authority, Kigali, Rwanda (GRID:grid.10818.30)
6 Rwanda Food and Drugs Authority, Kigali, Rwanda (GRID:grid.10818.30); University of Rwanda, College of Medicine and Health Sciences, Kigali, Rwanda (GRID:grid.10818.30) (ISNI:0000 0004 0620 2260)