Despite the widespread use of praziquantel (PZQ) for schistosomiasis, little is known about how genetic differences influence its plasma levels and treatment outcomes. This study examined the relationship between pharmacogenetic variations and both drug exposure and therapeutic response in Tanzanian school-aged children infected with Schistosoma mansoni. A total of 340 participants received a single PZQ dose. Stool samples were analyzed using the Kato-Katz technique, and treatment success was evaluated three weeks later. Adverse events were monitored within four hours of drug administration. Plasma concentrations of PZQ and its metabolite trans-4-OH-PZQ were measured four hours post-dose using UPLC-MS/MS, and genotyping for CYP3A4*1B, CYP3A5 (*3, *6, *7), CYP2C19 (*2, *3, *17), and CYP2C9 (*2, *3) was performed by real-time PCR. Participants had a median age of 12 years (range 7–17). Variations in CYP2C19 were significantly linked to PZQ plasma levels and the metabolic ratio (trans-4-OH-PZQ/PZQ). Specifically, carriers of CYP2C19 (*2, *3) exhibited higher PZQ concentrations than those with CYP2C19 *1/*1 or 17 (ultra-rapid metabolizers) (p = 0.04), while the metabolic ratio was elevated in CYP2C1917 carriers compared to CYP2C19 (*2, *3) (p = 0.01). No genotype significantly influenced treatment efficacy or overall adverse events, although baseline infection intensity and CYP3A5 genotype predicted drug-related side effects. These findings demonstrate that CYP2C19 polymorphisms meaningfully affect PZQ pharmacokinetics and metabolism, underscoring for the first time the clinical relevance of pharmacogenetic variability in schistosomiasis management.
