Fig 1.
The molecular structure of the two PZQ enantiomers.
The (R)-praziquantel has the hydrogen atom (H) pointing down from the chiral center. The (S)-praziquantel has the hydrogen atom (H) pointing up from the chiral center. PZQ, praziquantel.
Fig 2.
Comparison of the percentage WBR in an infected mouse model when dosing racemic PZQ or a single enantiomer.
The data for this graph were extracted from two papers in this review and evaluated to assess the WBR-dose response [49, 50]. The relationship between WBR and drug formulation was found to be significantly different (*P < 0.01, **P < 0.001) for each PZQ dose based on the results of the independent samples Kruskal-Wallis Test. PZQ, praziquantel; WBR, worm burden reduction.
Fig 3.
The mean AUC values extracted from the included studies against the PZQ dose of each of the PZQ enantiomers in HNV.
The PZQ enantiomers were measured after a racemic PZQ dose or the (R)-PZQ dosed alone. These data were extracted from multiple papers in this review, separated by PZQ enantiomer, and the AUC was averaged for each dose and plotted on a graph for analysis [51–54]. Using a linear regression model, the difference in AUC between (R)-PZQ and (S)-PZQ in humans was found to be statistically significant (P < 0.05). AUC, area under the curve; HNV, healthy normal volunteers; PZQ, praziquantel.
Fig 4.
The mean AUC values extracted from the included studies against PZQ dose of (R)-PZQ [I, II], (S)-PZQ [III, IV], and the major metabolite (R)-trans-4-OH-PZQ [V, VI] at 20, 40, and 60 mg/kg.
The data are extracted from Kovac and colleagues [56], which investigated S. mansoni and S. haematobium infected PSAC (●) and SAC (○) treated with PZQ. The AUC values were then plotted against the dose of PZQ administered for further analysis. P < 0.05 was considered statistically significant; a: significant difference between SAC and PSAC for the same dose and analyte, b: significant difference between S. haematobium and S. mansoni for the same dose, age group, and analyte, and c: significant difference between (R)-PZQ and (S)-PZQ for the same dose, age group, and species. AUC, area under the curve; PSAC, preschool-aged children; PZQ, praziquantel; SAC, school-aged children.
Fig 5.
The DDIs identified by the review, and the resultant effect on PZQ exposure.
The in vivo model and “Drug B” are listed as well as the overall effect of the drug combination on exposure of PZQ. The effect of the drug combination on PZQ efficacy in rodents was calculated based on the percentage change in WBR of each drug alone in comparison to the combined action (S9 Table) [73–83]. The effect of the drug combination on PZQ efficacy in humans was calculated based on the percentage change in AUC of each drug alone in comparison to the combined action (S10 Table) [54, 59, 84–86]. AUC, area under the curve; DDI, drug–drug interaction; PZQ, praziquantel; WBR, worm burden reduction.
Fig 6.
Each bar represents the percentage change in AUC during the drug combination in comparison to PZQ alone. The effect of the drug combination is listed above the bar chart, with ±20% representing the boundaries of no effect due to interindividual variation [87]. The data were extracted from five papers [54, 59, 84–86], compiled in S10 Table, analysed to create percentage change in AUC and then plotted to aid further analysis. ABZ, albendazole; AUC, area under the curve; BIC, bicarbonate; CHQ, chloroquine; CIM, cimetidine; DDI, drug–drug interaction; GLUC, glucose; KTZ, ketoconazole; PZQ, praziquantel.
Fig 7.
A comprehensive map of PZQ metabolites extracted and combined from studies that focused on the metabolite analysis of PZQ.
I: 8-OH-PZQ [89], II: 4-OH-PZQ [28, 53], III: X-OH-PZQ [84], IV: O-PZQ [28], V:O-PZQ [28], VI: O-PZQ [28], VII: O-PZQ [28], VIII: O-PZQ [28], IX: (-2H)-O-PZQ [28], X: (-2H)-O-PZQ [28], XI/XII: O2-PZQ [28], XIII: O2-PZQ [28], G1: Gluc-PZQ [28], G2/G3: Gluc-O-PZQ [28], G4: (-2H)-Gluc-O-PZQ [28]. The chemical structures and metabolite map were created using ChemDraw Prime v16.0. Gluc, glucuronide; PZQ, praziquantel.
Fig 8.
The favourable formation of trans-4-OH-PZQ compared to the cis-4-OH-PZQ isomer created from pharmacokinetic data by Nleya and colleagues [84].
The equatorial position points upwards and the axial position points downwards. The chemical structures were created using ChemDraw Prime v16.0. PZQ, praziquantel.