Dataset Information

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

ABSTRACT: Orally dispersible tablet (ODT) formulations of levo praziquantel (L-PZQ) and racemic PZQ (rac-PZQ) are being developed to treat schistosomiasis in preschool-aged children. Two crossover studies (N = 32 and 36, respectively) assessed the relative bioavailability of these ODTs vs. Cysticide in adults. Bioavailability for L-PZQ of ODT rac-PZQ and Cysticide at 40 mg/kg was comparable (L-PZQ area under the concentration-time curve from zero to infinity (AUC0-? ) test/reference ratio (90% confidence interval (CI)): 96% (84-111%)), whereas relative bioavailability of ODT L-PZQ 20 mg/kg was ~40% that of Cysticide 40 mg/kg (test/reference: 40% (35-46%)). AUC0-? and peak plasma concentration (Cmax ) were highly variable in both studies. For both ODTs, L-PZQ AUC0-? showed greater than dose-proportional increase over the ranges tested and a significant food effect. Safety was comparable among formulations. The lower bioavailability of ODT L-PZQ, as well as the high variability and nondose-proportionality of pharmacokinetic (PK) parameters, highlighted the need for a dedicated pediatric dose-finding study for the selection of the most appropriate formulation and dose (L-PZQ ODT or rac-PZQ ODT).

SUBMITTER: Bagchus WM

PROVIDER: S-EPMC6342245 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

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

Bagchus Wilhelmina Maria WM Bezuidenhout Deon D Harrison-Moench Eleanor E Kourany-Lefoll Elly E Wolna Peter P Yalkinoglu Oezkan O

Clinical and translational science 20181221 1

Orally dispersible tablet (ODT) formulations of levo praziquantel (L-PZQ) and racemic PZQ (rac-PZQ) are being developed to treat schistosomiasis in preschool-aged children. Two crossover studies (N = 32 and 36, respectively) assessed the relative bioavailability of these ODTs vs. Cysticide in adults. Bioavailability for L-PZQ of ODT rac-PZQ and Cysticide at 40 mg/kg was comparable (L-PZQ area under the concentration-time curve from zero to infinity (AUC<sub>0-∞</sub> ) test/reference ratio (90% ...[more]

PMID: 30536632

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Project description:OBJECTIVE:Galunisertib (LY2157299 monohydrate), an inhibitor of the transforming growth factor ? (TGF?) pathway, is currently under investigation in several clinical trials involving multiple tumor types. The primary objective of this study was to assess relative bioavailability of two new galunisertib formulations developed using the roller compaction (RC) dry-milled (RCD) and RC slurry-milled (RCS) processes, compared with the existing formulation developed using the high-sheer wet granulation (HSWG) process. The secondary objective was to report the safety profile after a single dose of the three formulations. METHODS:Patients with advanced or metastatic cancer were enrolled into this single-center, 3-period, 6-sequence crossover study. Patients were assigned sequentially to 1 of 6 sequences in blocks of 6 to ensure that all 6 sequences have the same number of completers. A patient entering a sequence received a different galunisertib formulation as a single 150 mg dose orally during each of the 3 periods. Each period was separated from the next by a washout interval of at least 48 hours. Pharmacokinetic (PK) parameters, including area under curve (AUC) and Cmax, were computed using standard non-compartmentalized methods of analysis. For comparison of exposures between formulations, log-transformed AUC and Cmax values were analyzed using a linear mixed-effects model. Safety assessments included adverse event monitoring, physical examinations, and laboratory tests. RESULTS:Of the 14 patients who entered and completed the study, 13 patients were included in the final statistical analysis. AUC(0-tlast), AUC(0-48 h), and AUC(0-?) for the RC formulations and the HSWG formulation were similar. Cmax was reduced by approximately 22% and tmax was longer by at least 1.00 h for the RCD and RCS formulations compared with the HSWG formulation. The RC formulations demonstrated a safety profile after a single dose similar to the HSWG formulation. CONCLUSIONS:In this relative bioavailability study comparing galunisertib formulations after a single dose, RCD and RCS formulations had similar exposure and safety profile compared with the HSWG formulation.

Dataset Information

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

Publications

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

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