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

Evaluation of Pharmacokinetic Drug–Drug Interactions: A Review of the Mechanisms, In Vitro and In Silico Approaches

Pharmacokinetic drug–drug interactions (DDIs) occur when a drug alters the absorption, transport, distribution, metabolism or excretion of a co-administered agent. The occurrence of pharmacokinetic DDIs may result in the increase or the decrease of drug concentrations, which can significantly affect the drug efficacy and safety in patients. Enzyme-mediated DDIs are of primary concern, while the transporter-mediated DDIs are less understood but also important. In this review, we presented an overview of the different mechanisms leading to DDIs, the in vitro experimental tools for capturing the factors affecting DDIs, and in silico methods for quantitative predictions of DDIs. We also emphasized the power and strategy of physiologically based pharmacokinetic (PBPK) models for the assessment of DDIs, which can integrate relevant in vitro data to simulate potential drug interaction in vivo. Lastly, we pointed out the future directions and challenges for the evaluation of pharmacokinetic DDIs

Evaluation of a Modified Flow-Through Method for Predictive Dissolution and In Vitro/In Vivo Correlations of Immediate Release and Extended Release Formulations

The present study evaluated the ability of a modified flow-through method for predicting in vivo performance of immediate release (IR) and extended release (ER) formulations. In vitro dissolution of two model drugs, paracetamol IR tablets and felodipine ER tablets, was investigated under tuned conditions using the modified flow-through method and compared with the compendial quality control (QC) basket method. The in vivo absorption properties of paracetamol IR tablets and felodipine ER tablets were investigated in healthy volunteers. In vitro-in vivo correlation (IVIVC) analysis was performed based on the obtained in vitro and in vivo data. Our results demonstrated that the compendial QC method was not able to reflect in vivo actual absorption, while satisfactory discriminatory power and comparable in vitro dissolution/in vivo absorption were achieved for both paracetamol IR tablets and felodipine ER tablets by the modified flow-through method. This study indicated that the modified flow-through method is a potential tool to reflect in vivo performance of the IR and ER formulations

Association between Polymorphisms in Vascular Endothelial Growth Factor Gene and Response to Chemotherapies in Colorectal Cancer: A Meta-Analysis

<div><p>Background</p><p>Some studies have investigated the effects of polymorphisms in the vascular endothelial growth factor (VEGF) gene on responsiveness to chemotherapy for colorectal cancer (CRC) and have shown inconclusive results.</p><p>Methods</p><p>Eligible studies that assessed the associations between polymorphisms in the VEGF gene and response to chemotherapy in CRC were searched in the PubMed, Embase and Medline databases until November 2014. Odds ratios (OR) and 95% confidence intervals (CIs) were used to evaluate the associations, using Review Manager software, version 5.3. Stratified analysis was also conducted.</p><p>Results</p><p>In the overall analysis, a significant association with responsiveness to chemotherapy in CRC was identified in CC vs. CA of the VEGF -2578 C/A polymorphism (OR = 1.40, 95% CI 1.00-1.97, P = 0.05) and in CC+CT vs. TT of the VEGF -460 C/T polymorphism (OR = 0.71, 95% CI 0.53-0.96, P = 0.02). In subgroup analysis, a significant association was found in excluding anti-angiogenic agent subgroup in three comparison models of the VEGF -2578 C/A polymorphism and another three genetic models of the VEGF -460 C/T C/A polymorphism.</p><p>Conclusions</p><p>CC vs. CA of the VEGF -2578 C/A polymorphism and CC+CT vs. TT of the VEGF -460 C/T polymorphism might be predictive factors of responsiveness to chemotherapy in CRC. However, single-nucleotide polymorphisms in the VEGF gene lacked sufficient predictive ability to determine whether patients with CRC should add anti-angiogenic agents to their chemotherapy regimens.</p></div