Impact of target-mediated drug disposition on hetrombopag pharmacokinetics and pharmacodynamics in Chinese healthy subjects and patients with chronic idiopathic thrombocytopenic purpura.

AIMS: The pharmacokinetics (PK) of hetrombopag were found to be nonlinear across evaluated dose ranges. The aim of this study was to develop a mechanism-based population pharmacokinetic/pharmacodynamic (PopPK/PD) model and to provide a reasonable expected therapeutic dose for a future confirmatory clinical study of hetrombopag. METHODS: Nonlinear mixed-effects modelling was performed using pooled 2168 hetrombopag concentrations and 1526 platelet counts from 72 healthy subjects and 32 chronic idiopathic thrombocytopenic purpura (ITP) patients from two phase I studies and one phase II study. The final model was evaluated via goodness-of-fit plots, visual predictive check and nonparametric bootstrap. Simulations from the validated PopPK/PD model were used to devise an expected therapeutic dose for later confirmatory clinical study. RESULTS: The pharmacokinetic data of hetrombopag were well described by a modified target-mediated drug disposition (TMDD) model with dual sequential first-order absorption. Mean parameter estimates (interindividual variability) were CL/F 7.66 L/h (63.5%), Vc /F 30.0 L (77.2%) and Kdeg 0.693/h (87.1%). The pharmacodynamic profile was well described by a five-compartment lifespan model with four-transit and one-platelet compartments. Simulation results suggested that chronic ITP patients following 10 mg once-daily hetrombopag would able to achieve an ideal platelet count level (50-200 × 109 /L). CONCLUSION: TMDD was the primary reason leading to nonlinear PK profile of hetrombopag. Our PK/PD modelling and simulation results support 10 mg once-daily as the recommended therapeutic dose for chronic ITP patients in subsequent confirmatory clinical study of hetrombopag.

Carbohydrates Used in Polymeric Systems for Drug Delivery: From Structures to Applications.

Carbohydrates, one of the most important compounds in living organisms, perform numerous roles, including those associated with the extracellular matrix, energy-related compounds, and information. Of these, polymeric carbohydrates are a class of substance with a long history in drug delivery that have attracted more attention in recent years. Because polymeric carbohydrates have the advantages of nontoxicity, biocompatibility, and biodegradability, they can be used in drug targeting, sustained drug release, immune antigens and adjuvants. In this review, various carbohydrate-based or carbohydrate-modified drug delivery systems and their applications in disease therapy have been surveyed. Specifically, this review focuses on the fundamental understanding of carbohydrate-based drug delivery systems, strategies for application, and the evaluation of biological activity. Future perspectives, including opportunities and challenges in this field, are also discussed.

Association Between Genetic Polymorphisms of Metabolic Enzymes and Azathioprine-Induced Myelosuppression in 1,419 Chinese Patients: A Retrospective Study.

The aim of this study was to investigate the correlation between genetic polymorphisms of azathioprine-metabolizing enzymes and adverse reactions of myelosuppression. To this end, a retrospective analysis was performed on 1,419 Chinese patients involving 40 different diseases and 3 genes: ITPA (94C>A), TPMT*3 (T>C), and NUDT15 (415C>T). Strict inclusion and exclusion criteria were established to collect the relative cases, and the correlation between azathioprine and myelosuppression was evaluated by adverse drug reaction criteria. The mutation rates of the three genes were 29.32, 3.73, and 21.92% and grades I to IV myelosuppression occurred in 54 (9.28%) of the 582 patients who took azathioprine. The highest proportion of myelosuppression was observed in 5 of the 6 (83.33%) patients carrying the NUDT15 (415C>T) TT genotype and 12 of the 102 (11.76%) patients carrying the NUDT15 (415C>T) CT genotype. Only the NUDT15 (415C>T) polymorphism was found to be associated with the adverse effects of azathioprine-induced myelosuppression (odds ratio [OR], 51.818; 95% CI, 5.280-508.556; p = 0.001), which suggested that the NUDT15 (415C>T) polymorphism could be an influencing factor of azathioprine-induced myelosuppression in the Chinese population. Epistatic interactions between ITPA (94C>A) and NUDT15 (415C>T) affect the occurrence of myelosuppression. Thus, it is recommended that the genotype of NUDT15 (415C>T) and ITPA (94C>A) be checked before administration, and azathioprine should be avoided in patients carrying a homozygous NUDT15 (415C>T) mutation. This study is the first to investigate the association between genetic polymorphisms of these three azathioprine-metabolizing enzymes and myelosuppression in a large number of cases with a diverse range of diseases.