Relative Bioavailability of Orally Dispersible Tablet Formulations of Levo‐ and Racemic Praziquantel: Two Phase I Studies

Bagchus, Wilhelmina; Bezuidenhout, Deon; Harrison-Moench, Eleanor; Kourany-Lefoll, Elly; Wolna, Peter; Yalkinoglu, Oezkan

doi:10.1111/cts.12601

Cited by 24 publications

(24 citation statements)

References 18 publications

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“…In order to investigate the PZQ enantioselective pharmacokinetic behavior previously hypothesized (Bagchus et al, 2019), selected aspects of its in vitro metabolism were explored. First, metabolite identification in in vitro systems of increasing biological complexity was addressed, i.e.…”

Section: Discussionmentioning

confidence: 99%

“…The simulated oral clearance for R-PZQ was significantly in under-predicted all cases, in both racemic and R-PZQ ODT formulations (data not shown). The inability to recover in vivo clearance from in vitro data, the erratic shapes of the PK profiles (Bonate et al, 2018), multiple peaks, the large PK variability and the unexplained dose non-linearity of the observed PK (Bagchus et al, 2019) made PBPK model building and parameterization challenging.…”

Section: Downloaded Frommentioning

confidence: 99%

“…Considering the recommendations from Research and Training in Tropical Diseases on switching to an enantiomerically pure formulation of the active form R-PZQ (WHO, 2007), one goal of the Pediatric Praziquantel Consortium was to clinically compare racemic (rac-PZQ) vs pure R-PZQ formulations (WHO, 2010), with the expectation that an enantiomeric pure formulation will result in a smaller orally disintegrating tablet (ODT) with less bitter taste, as inactive S-PZQ mainly contributes to unpleasant taste (Meyer et al, 2009). One outcome of the subsequent clinical study was that the administration of enantiomerically pure R-PZQ (20 mg/kg) resulted in 40% of relative bioavailability when compared to rac-PZQ (40 mg/kg total, containing 20 mg/kg of R-PZQ) (Bagchus et al, 2019). This could be indicative of enantiomerenantiomer interactions and thus in vitro investigations were triggered.…”

Section: Introductionmentioning

confidence: 99%

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Insights into Praziquantel Metabolism and Potential Enantiomeric Cytochrome P450–Mediated Drug-Drug Interaction

et al. 2020

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The active enantiomer R-Praziquantel (PZQ) shows clinically a lower relative exposure when administered enantiomerically pure compared to a racemic form. We investigated the hypothesis that enantiomer-enantiomer interactions on CYP enzymes could explain this observation and aimed to further deepen the understanding of PZQ metabolism. Firstly, in an in vitro metabolite profiling study, the formation of multiple metabolites per CYP, together with an observed interconversion of cis-4'-OH-PZQ to trans-4'-OH-PZQ in human hepatocytes, pointed out the inadequacy of measuring metabolite formation in kinetic studies. Thus, a substrate depletion approach to study PZQ enantiomeric interactions was applied. Secondly, an abundant CYP 3A4 metabolite found in previous studies was structurally characterized. Thirdly, substrate depletion methodologies were applied to determine CYP enzyme kinetics of PZQ and to further estimate enantiomer-enantiomer inhibitory parameters. A competitive inhibition between PZQ enantiomers for CYP2C9, 2C19, 3A4 and 3A5 was revealed. Analyses considering the clearance of only one or both enantiomers provided comparable enantiomer-enantiomer inhibition estimates. To conclude, this paper provides new insights into PZQ metabolic profile to enable a better understanding of enantioselective PK using substrate depletion-based methods. Significance Statement In this study, enantiomer-enantiomer interactions of praziquantel on CYP metabolizing enzymes are investigated via substrate depletion measurement using modelling methods. Together with new insights into the praziquantel metabolism, this work provides a novel dataset to understand its pharmacokinetics.

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Section: Discussionmentioning

confidence: 99%

Section: Downloaded Frommentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Insights into Praziquantel Metabolism and Potential Enantiomeric Cytochrome P450–Mediated Drug-Drug Interaction

et al. 2020

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“…As with the rodent models, the relative exposure of PZQ was compared using t 1/2 , T max , C max , and AUC values, with 13 papers containing human PK data sets [51][52][53][54][55][56][57][58][59][60][61][62][63].…”

Section: Human Studies: Pk and Pzq Efficacymentioning

confidence: 99%

Drug metabolism and pharmacokinetics of praziquantel: A review of variable drug exposure during schistosomiasis treatment in human hosts and experimental models

Zdesenko

Mutapi

2020

PLoS Negl Trop Dis

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Schistosomiasis control is heavily reliant on the drug praziquantel (PZQ), which is used as preventive chemotherapy as part of national helminth control strategies. Given the heavy reliance on PZQ for mass drug administration, there has been considerable research on the potential of parasites developing resistance to the drug, resulting in decreased drug efficacy. However, there have been comparatively fewer studies of other factors that can potentially alter PZQ efficacy. Here, we investigate whether host PZQ metabolism contributes towards variable cure rates. We evaluate factors that can influence the metabolism of PZQ and the resultant effect on the efficacy of PZQ treatment to determine factors that potentially influence an individual's response to the drug. The literature search was directed at published studies from three online databases: Web of Science, PubMed, and EMBASE. The search terms for the review comprised of ([praziquantel OR PZQ] AND [schistosom* OR bilharzia] AND [pharmaco*]) and included studies evaluating PZQ metabolism. Publications were categorised into pharmacokinetics, drug-drug interactions, pharmacogenetics, and metabolite analysis. Forty publications describing human and experimental studies fitted the inclusion criteria and were subjected to data extraction and analysis. The analyses showed that variable exposure to PZQ was associated with alterations in the liver's capacity to metabolise PZQ and observed drug-drug interactions. Other factors influencing the efficacy of PZQ were brand, formulation, and co-administered food. Although some work has been performed on metabolite identification, there was minimal information on PZQ's metabolic pathway, and no pharmacogenetics studies were identified. The study indicated that in both human and experimental studies alterations in the liver's capacity to metabolise PZQ as well as drug-drug interactions affected systemic levels of PZQ that could result in variable cure rates. The study confirmed previous findings of higher antischistosomal activity of (R)-PZQ enantiomer when administered alone compared to the racemate at the same dose as well as improved efficacy when the drug is administered with food. The study also highlighted PLOS NEGLECTED TROPICAL DISEASES

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“…PZQ (Figure 1) is currently used in the racemic form, even though the pharmacological activity is mainly driven by the (R)-enantiomer [9][10][11][12], which also has a much higher bioavailability [13]. Moreover, (S)-PZQ (the inactive enantiomer) has been recognized as being responsible for the bitter taste [14] and worsened side effects [15,16].…”

Section: Introductionmentioning

confidence: 99%

Mechanochemical Formation of Racemic Praziquantel Hemihydrate with Improved Biopharmaceutical Properties

et al. 2020

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Praziquantel (PZQ) is the first-line drug used against schistosomiasis, one of the most common parasitic diseases in the world. A series of crystalline structures including two new polymorphs of the pure drug and a series of cocrystals of PZQ have been discovered and deposited in the Cambridge Structural Database (CSD). This work adds to the list of multicomponent forms of PZQ a relevant example of a racemic hemihydrate (PZQ-HH), obtainable from commercial PZQ (polymorphic Form A) through mechanochemistry. Noteworthy, the formation of the new hemihydrate strongly depends on the initial polymorphic form of PZQ and on the experimental conditions used. The new PZQ-HH has been fully characterized by means of HPLC, Differential Scanning Calorimetry (DSC), Thermogravimetric Analysis (TGA), Hot-Stage Microscopy (SEM), Powder X-Ray Diffraction (PXRD), Scanning Electron Microscopy (SEM), FT-IR, polarimetry, solid-state NMR (SS-NMR), solubility and intrinsic dissolution rate (IDR), and in vitro tests on Schistosoma mansoni adults. The crystal structure was solved from the powder X-ray diffraction pattern and validated by periodic-DFT calculations. The new bioactive hemihydrate was physically stable for three months and showed peculiar biopharmaceutical features including enhanced solubility and a double intrinsic dissolution rate in water in comparison to the commercially available PZQ Form A.

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Relative Bioavailability of Orally Dispersible Tablet Formulations of Levo‐ and Racemic Praziquantel: Two Phase I Studies

Cited by 24 publications

References 18 publications

Insights into Praziquantel Metabolism and Potential Enantiomeric Cytochrome P450–Mediated Drug-Drug Interaction

Insights into Praziquantel Metabolism and Potential Enantiomeric Cytochrome P450–Mediated Drug-Drug Interaction

Drug metabolism and pharmacokinetics of praziquantel: A review of variable drug exposure during schistosomiasis treatment in human hosts and experimental models

Mechanochemical Formation of Racemic Praziquantel Hemihydrate with Improved Biopharmaceutical Properties

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