Quantitative Assessment of the in vivo Dissolution Rate to Establish a Modified IVIVC for Isosorbide Mononitrate Tablets.

A modified in vitro-in vivo correlation (IVIVC) of the oral solid dosage forms has been proposed as a linear correlation between in vitro and in vivo dissolution. Nevertheless, the analysis of in vivo dissolution is limited by the lack of available methods. In this proof-of-concept study, a novel pharmacokinetic (PK) model containing the in vivo dissolution process and its quantification was presented to directly estimate the in vivo dissolution rate constant (kd). The new model was validated with a hypothetical oral solution (kd â†’ +∞). The accuracy of the new method was clarified by comparing with the relatively true value of kd from the literature. Isosorbide mononitrate (ISMN) was used as a model drug to explore the practicability of the novel method. The dissolution capacities of ISMN reference and test tablets were discriminated by an improved in vitro dissolution method. Following the human PK studies, the kd values and corresponding in vivo dissolution profiles of two formulations were obtained using the novel method. Finally, a modified level A IVIVC between in vitro and in vivo dissolution of ISMN tablets was established, which is expected to guide the optimization of the tablet formulation containing ISMN.

Population Pharmacokinetics and Dosing Optimization of Gentamicin in Critically Ill Patients Undergoing Continuous Renal Replacement Therapy.

PURPOSE: Appropriate gentamicin dosing in continuous renal replacement therapy (CRRT) patients remains undefined. This study aimed to develop a population pharmacokinetic (PK) model of gentamicin in CRRT patients and to infer the optimal dosing regimen for gentamicin. METHODS: Fourteen CRRT patients dosed with gentamicin were included to establish a population PK model to characterize the variabilities and influential covariates of gentamicin. The pharmacokinetic/pharmacodynamic (PK/PD) target attainment and risk of toxicity for different combinations of gentamicin regimens (3-7 mg/kg q24h) and CRRT effluent doses (30-50 mL/h/kg) were evaluated by Monte Carlo simulation. The probability of target attainment (PTA) was determined for the PK/PD indices of the ratio of drug peak concentration/minimum inhibitory concentration (Cmax/MIC > 10) and the ratio of area under the drug concentration-time curve/MIC over 24 h (AUC0-24h/MIC > 100), and the risk of toxicity was estimated by drug trough concentration thresholds (1 and 2 mg/L). RESULTS: A one-compartment model adequately described the PK characteristics of gentamicin. Covariates including body weight, age, gender, and CRRT modality did not influence the PK parameters of gentamicin based on our dataset. All studied gentamicin regimens failed to achieve satisfactory PTAs for pathogens with an MIC ≥2 mg/L. A good balance of PK/PD target attainment and risk of toxicity (>2 mg/L) was achieved under 7 mg/kg gentamicin q24h and 40 mL/kg/h CRRT dose for an MIC ≤1 mg/L. CRRT dose intensity had a significant impact on the target attainment of AUC0-24h/MIC >100 and risk of toxicity. CONCLUSION: A combination of 7 mg/kg gentamicin q24h and 40 mL/kg/h CRRT dose might be considered as a starting treatment option for CRRT patients, and drug monitoring is required to manage toxicity.

Cost-effectiveness Analysis of Pembrolizumab Plus Axitinib Versus Sunitinib in First-line Advanced Renal Cell Carcinoma in China.

BACKGROUND AND OBJECTIVES: In first-line treatment of advanced renal cell carcinoma (aRCC), the KEYNOTE-426 study demonstrated a significant progression-free survival and overall survival for pembrolizumab plus axitinib in comparison with sunitinib. The objective of the current study was to evaluate the cost effectiveness of pembrolizumab plus axitinib versus sunitinib for previously untreated patients with aRCC in China. METHODS: A Markov model was used to estimate the costs and health outcomes of treatment of aRCC with sunitinib or pembrolizumab plus axitinib. Univariable and probabilistic sensitivity analyses were performed to determine the robustness of the model outcomes. Additional subgroup analyses were also performed. The primary outputs of the model included the total cost, life-years (LYs), quality-adjusted LYs (QALYs), and incremental cost-effectiveness ratio (ICER). RESULTS: Pembrolizumab plus axitinib provided an additional 2.461 LYs (1.650 QALYs). The total cost per patient was US$178,725 for pembrolizumab plus axitinib and US$87,693 for sunitinib. The ICER for pembrolizumab plus axitinib was US$55,185/QALY versus sunitinib. Sensitivity analyses found the results to be most sensitive to pembrolizumab cost and overall hazard ratio. The results of subgroup analyses showed that the ICER remained greater than US$32,000/QALY across the all patient subgroups. CONCLUSIONS: Pembrolizumab plus axitinib is not likely to be cost effective versus sunitinib for patients with previously untreated aRCC at a threshold value of US$29,306/QALY.

An effective and economical method for the storage of plasma samples using a novel freeze-drying device.

Biological samples, especially plasma samples, are conventionally stored under freezing conditions to maintain sample integrity prior to the detections of analytes. However, the storage of samples in a low-temperature environment is electric energy consuming, and the preparation of samples prior to analytes detection may be complicated. In this work, an effective and economical method was proposed to freeze-dry the samples using a novel device to allow subsequent storage of samples at ambient temperature. The sample preparations integrated in the new method are simple and easy to follow. Analytes were directly extracted with the extraction agent before sample injections. This new method was validated with quality control (QC) samples of levetiracetam and mycophenolic acid (MPA), and it was also applied to the pharmacokinetic (PK) studies of both drugs in healthy volunteers. When QC samples were stored and prepared with the new method, the detections of analytes were accurate and repeatable, and the analytes maintained stability for a long time. The PK studies of levetiracetam and MPA in healthy volunteers showed that the PK parameters of analytes stored with the new method were consistent with those stored with the conventional method. In conclusion, this effective and economical method is a practical option in reality and can play a big role in clinical and scientific drug researches.

Pharmacokinetic study of benfotiamine and the bioavailability assessment compared to thiamine hydrochloride.

Benfotiamine is a lipid-soluble thiamine precursor which can transform to thiamine in vivo and subsequently be metabolized to thiamine monophosphate (TMP) and thiamine diphosphate (TDP). This study investigated the pharmacokinetic profiles of thiamine and its phosphorylated metabolites after single- and multiple-dose administration of benfotiamine in healthy Chinese volunteers, and assessed the bioavailability of orally benfotiamine administration compared to thiamine hydrochloride. In addition, concentration of hippuric acid in urine which is produced in the transformation process of benfotiamine was determined. The results showed that thiamine and its phosphorylated metabolites exhibited different pharmacokinetic characteristics in plasma, blood and erythrocyte, and one-compartment model provided the best fit for pharmacokinetic profiles of thiamine. The transformation process of benfotiamine to thiamine produced large amount of hippuric acid. No accumulation of hippuric acid was observed after multiple-dose of benfotiamine. Compared to thiamine hydrochloride, the bioavailability of thiamine in plasma and TDP in erythrocyte after oral administration of benfotiamine were 1147.3 ± 490.3% and 195.8 ± 33.8%, respectively. The absorption rate and extent of benfotiamine systemic availability of thiamine were significantly increased indicating higher bioavailability of thiamine from oral dose of benfotiamine compared to oral dose of thiamine hydrochloride.