A semiphysiological population pharmacokinetic model of agomelatine and its metabolites in Chinese healthy volunteers

Aims: Agomelatine is an antidepressant for major depressive disorders. It undergoes extensive first-pass hepatic metabolism and displays irregular absorption profiles and large interindividual variability (IIV) and interoccasion variability of pharmacokinetics. The objective of this study was to characterize the complex pharmacokinetics of agomelatine and its metabolites in healthy subjects. Methods: Plasma concentration-time data of agomelatine and its metabolites were collected from a 4-period, cross-over bioequivalence study, in which 44 healthy subjects received 25 mg agomelatine tablets orally. Nonlinear mixed effects modelling was used to characterize the pharmacokinetics and variability of agomelatine and its metabolites. Deterministic simulations were carried out to investigate the influence of pathological changes due to liver disease on agomelatine pharmacokinetics. Results: A semiphysiological pharmacokinetic model with parallel first-order absorption and a well-stirred liver compartment adequately described the data. The estimated IIV and interoccasion variability of the intrinsic clearance of agomelatine were 130.8% and 28.5%, respectively. The IIV of the intrinsic clearance turned out to be the main cause of the variability of area under the curve-based agomelatine exposure. Simulations demonstrated that a reduction in intrinsic clearance or liver blood flow, and an increase in free drug fraction had a rather modest influence on agomelatine exposures (range: -50 to 200%). Portosystemic shunting, however, substantially elevated agomelatine exposure by 12.6-109.1-fold. Conclusions: A semiphysiological pharmacokinetic model incorporating first-pass hepatic extraction was developed for agomelatine and its main metabolites. The portosystemic shunting associated with liver disease might lead to significant alterations of agomelatine pharmacokinetics, and lead to substantially increased exposure

A novel random forest integrative approach based on endogenous CYP3A4 phenotype for predicting tacrolimus concentrations and dosages in Chinese renal transplant patients.

WHAT IS KNOWN AND OBJECTIVE(#br)Personalized treatment with tacrolimus has remained a challenge. The present study aimed to evaluate the potential of an integrative approach to predict individual tacrolimus concentrations and dosages based on endogenous CYP3A4 phenotype, CYP3A5 genotype and clinical variables.(#br)METHODS(#br)A random forest (RF) algorithm which incorporated an endogenous CYP3A4 phenotype (assessed by urinary ratio of 6β-hydroxycortisol and 6β-hydroxycortisone to cortisol and cortisone), CYP3A5*3 genotype and other clinical determinants of tacrolimus disposition was performed in 182 medically stable renal transplant recipients.(#br)RESULTS AND DISCUSSION(#br)The results suggested that endogenous CYP3A4 phenotype was the most important determinant of tacrolimus concentrations and dose requirements. RF models provided high goodness of fit (R2 ) with .92 and .95 for the prediction of tacrolimus trough concentrations and dosages, respectively, as well as high predictability (Q2 ) with 0.63 and 0.70, respectively. Significant correlations existed between experimental and predictive data.(#br)WHAT IS NEW AND CONCLUSION(#br)In summary, endogenous CYP3A4 phenotype is a critical biomarker for the determination of tacrolimus disposition. This predictive RF approach based on CYP3A4 biomarker with the combination of CYP3A5*3 genotype and other clinical variables can be used for predicting tacrolimus concentrations and dosages, which may serve as a useful tool in individualized tacrolimus dosing

A novel method to estimate the absorption rate constant for two-compartment model fitted drugs without intravenous pharmacokinetic data

The in vivo performances of most drugs after extravascular administration are fitted well with the two-compartment pharmacokinetic (PK) model, but the estimation of absorption rate constant (ka) for these drugs becomes difficult during unavailability of intravenous PK data. Herein, we developed a novel method, called the direct method, for estimating the ka values of drugs without using intravenous PK data, by proposing a new PK parameter, namely, maximum apparent rate constant of disposition (kmax). The accuracy of the direct method in ka estimation was determined using the setting parameters (k12, k21, and k10 values at high, medium, and low levels, respectively) and clinical data. The results showed that the absolute relative error of ka estimated using the direct method was significantly lower than that obtained using both the Loo-Riegelman method and the statistical moment method for the setting parameters. Human PK studies of telmisartan, candesartan cilexetil, and tenofovir disoproxil fumarate indicated that the ka values of these drugs were accurately estimated using the direct method based on good correlations between the ka values and other PK parameters that reflected the absorption properties of drugs in vivo (Tmax, Cmax, and Cmax/AUC0-t). This novel method can be applied in situations where intravenous PK data cannot be obtained and is expected to provide valuable support for PK evaluation and in vitro-in vivo correlation establishment

A Literature Review on High-Performance Photocatalysts for Sustainable Cancer Therapy

Since cancer is a serious threat to public health worldwide, the development of novel methods and materials for treating cancer rapidly and thoroughly is of great significance. This review summarizes the mechanism and application of photocatalytic materials used to kill cancer cells. The photosensitivity and toxicological properties of several common photcatalysts used in anti-cancer treatment are discussed in detail. The ideal photocatalyst must possess the following characteristics: a highly stable production of active oxygen species and high selectivity to cancer cells without causing any damage to healthy tissues. This work concluded the existing photocatalytic materials used to treat cancer, as well as the current challenges in the application of cancer therapy. We aim to provide a basis for the development of new photocatalytic anti-cancer materials with high stability and selectivity while maintaining high photodynamic reaction performance

A Literature Review on High-Performance Photocatalysts for Sustainable Cancer Therapy

Since cancer is a serious threat to public health worldwide, the development of novel methods and materials for treating cancer rapidly and thoroughly is of great significance. This review summarizes the mechanism and application of photocatalytic materials used to kill cancer cells. The photosensitivity and toxicological properties of several common photcatalysts used in anti-cancer treatment are discussed in detail. The ideal photocatalyst must possess the following characteristics: a highly stable production of active oxygen species and high selectivity to cancer cells without causing any damage to healthy tissues. This work concluded the existing photocatalytic materials used to treat cancer, as well as the current challenges in the application of cancer therapy. We aim to provide a basis for the development of new photocatalytic anti-cancer materials with high stability and selectivity while maintaining high photodynamic reaction performance.</jats:p

Population pharmacokinetics and dosing considerations of daptomycin in critically ill patients undergoing continuous renal replacement therapy

Abstract Objectives The dosing regimen of daptomycin for critically ill patients undergoing continuous renal replacement therapy (CRRT) remains controversial. The goal of this study was to provide guidance for optimal daptomycin therapy in CRRT patients with Staphylococcus aureus infections. Methods Individual concentration data of 32 CRRT subjects pooled from previously published studies were used to construct the population pharmacokinetic model for daptomycin. Model-based simulations were performed to evaluate the efficacy and risk of toxicity for daptomycin doses of 4, 6 and 8 mg/kg, q24h or q48h, under CRRT doses of 25, 30 and 35 mL/h/kg. Efficacy was assessed by the bacteriostatic and bactericidal AUC/MIC targets and drug exposure-based efficacy references. Toxicity was estimated by safety exposure references and the trough concentration threshold. Results A two-compartment model adequately described the pharmacokinetics of daptomycin. Efficacy analysis demonstrated that q48h dosing is associated with an extremely low probability of bactericidal target attainment on every second day after dosing and q24h dosing is preferred for a high probability of bactericidal target attainment. Toxicity evaluation showed that 8 mg/kg q24h has a high probability for reaching the toxicity-related concentration threshold, while 6 mg/kg q24h gives a satisfactory risk–benefit balance. The studied CRRT doses had a limited impact on efficacy and a CRRT dose of 30–35 mL/h/kg may lower the risk of toxicity. Conclusions The model predicted that the combination of 6 mg/kg q24h daptomycin dose and CRRT dose of 30–35 mL/h/kg would achieve the best balance of efficacy and safety. </jats:sec