Area Under Concentration-time Curve Research Articles

Protection of schisantherin A against dictamnine-induced hepatotoxicity: Pharmacokinetic insights.

Dictamnine (DIC), as the most abundant furoquinoline alkaloid ingredient of the herbal medicine Cortex Dictamni (CD), can induce severe liver injury. A previous study found that DIC-induced liver injury was initiated by cytochrome P4503A (CYP3A)-mediated metabolic activation and subsequent formation of adducts with cellular proteins. Schisantherin A (SchA) is the major lignan component of the herbal medicine Schisandra chinensis (SC). SC is frequently combined with CD used in numerous Chinese medicinal formulas for the treatment of eczema and urticaria. Furthermore, SC could protect against CD-induced hepatotoxicity. The objective of the study was to investigate the protective effect of SchA on DIC-induced hepatotoxicity based on pharmacokinetic interactions. The studies found that SchA exerted a protective effect on DIC-induced hepatotoxicity in a dose-dependent manner. Pharmacokinetic studies showed that pretreatment with SchA enhanced the area under concentration-time curve(AUC) and maximal concentration (Cmax ) values of DIC in the serum and liver tissue of mice, indicating that SchA could augment the accumulation of DIC in the circulation. In vitro metabolism assays with mouse liver microsomes (MLMs) showed that SchA reduced the production of DIC-glutathione (GSH) conjugate. In addition, SchA significantly reduced the excretion of DIC-GSH conjugate in the urine of mice and relieved hepatic GSH depletion induced by DIC. These results suggested that SchA could inhibit the metabolic activation of DIC in vitro and in vivo. In summary, our findings showed that the observed pharmacokinetic interactions might be attributable to the inhibition of the metabolism of DIC by SchA, which might be responsible for the protection of SchA against DIC-induced hepatotoxicity. Therefore, the development of a standardized combination of DIC and SchA may protect patients from DIC-induced liver injury.

Model-Informed Dosing Regimen of Ticagrelor in Chinese Patients With Acute Coronary Syndrome.

The exposure to ticagrelor (BRILINTA) is higher in the East Asian population compared with the White population, thus, East Asians have an increased risk of bleeding. We developed a population pharmacokinetic (PopPK) model of ticagrelor based on a randomized 3 × 3 crossover study in healthy subjects. The area under the concentration-time curve (AUC) of Chinese patients with acute coronary syndrome was simulated based on this model. Following this, eight machine learning (ML) methods were used to construct bleeding risk models. Variables included in the final bleeding risk model were age, hypertension, body weight, AUC, drinking status, calcium channel blockers, antidiabetic medications, β-blockers, peripheral vascular disease, diabetes, transient ischemic attack, sex, and proton pump inhibitor. In terms of F1 scores and area under the curve of receiver operating characteristic curve (ROC-AUC), the Random Forest model performed best among all models, with an F1 score of 0.73 and ROC-AUC of 0.81. Moreover, the PopPK model and ML algorithm were used to bridge the real-world data to build a bleeding risk prediction model based on drug exposure and clinical information. Using this model, a ticagrelor regimen that is associated with a lower risk of bleeding in individuals can be obtained. This model should be further validated prospectively in clinical settings.

Bioequivalence evaluation and blood concentration estimation of generic and branded tacrolimus in healthy subjects under fasting: A randomized, four-periods, two-sequences, complete repeated, crossover study

ObjectiveThe demand for generic tacrolimus is enormous. Our randomized trial was an open-label single-dose testing with four-periods and two-sequences; we aimed to evaluate the bioequivalence between a generic and branded tacrolimus by establishing their area under concentration-time curve (AUC) predictive equations. For better comparison, each tacrolimus served either as test vs. reference in sequence 1 or vice versa as reference vs. test in sequence 2. MethodsForty healthy subjects were randomized into two groups, namely a sequence 1 group (N = 20 in test-reference-test-reference) or sequence 2 (N = 20, reference-test-reference-test) received a test tacrolimus (Ruibeirong®; Chengdu Shengdi Medicine Co., Ltd.) and a reference tacrolimus (Astagraf XL®, Astellas Ireland Co., Ltd.) under the fasting condition with a wash-out period of ≥14 days between every two phases. Blood samples were collected sequentially until 120 h after oral administration of tacrolimus. ResultsA 95% upper confidence bound was −0.05% for the peak concentration (Cmax), −0.02% for the AUC from 0 to the last time point (AUC0-t), and − 0.02% for the AUC from 0 to infinity (AUC0-∞). The geometric least square means ratio (test/reference) with 90% of confidence interval (CI)) was 96.10% (90.58%–101.95%) for Cmax, 93.80% (88.52%–99.39%) for AUC0-t, and 94.34% (89.20%–99.77%) for AUC0-∞. Meanwhile, the ratio of within-subject standard deviation of test/reference (σWT/WR) with 90% CI was 0.66 (0.50–0.86) for Cmax, 0.73 (0.55–0.96) for AUC0-t, and 0.75 (0.57–0.98) for AUC0-∞. These results fulfilled the bioequivalence criteria by the Food and Drug Administration. Both products showed acceptable safety. Moreover, the AUC predictive equations (by linear regression plus limited sampling strategy) with 2–5 sampling time point showed the high performance (all R > 0.970, predictive error (PE) >0.5%, absolute PE <5.1%, which were interchangeable between test and reference products. ConclusionGeneric tacrolimus (Ruibeirong®) is bioequivalent to branded tacrolimus (Astagraf XL®) with tolerable safety, which AUC predictive equations work well and are interchangeable between the two products.

Improvements of Solubility and Bioavailability of Lutein Through Grafting with Hydrophilic Polyacrylic Acid

In this study, polyacrylic acid grafted lutein (PAA-g-lutein) was prepared by hydrophilic modification of lutein with polyacrylic acid (PAA) through Steglish esterification method. The unreacted lutein was loaded in micelles formed by self-assembly of graft copolymers in water to form composite nanoparticles. The bioaccessibility and bioavailability of lutein nanoparticles were studied by in vitro and in vivo digestion experiments. Compared with free lutein, the saturated solubility and bioaccessibility of lutein nanoparticles were increased by 78 times and 3.6 times, respectively. The pharmacokinetics results in the mice model showed that the maximum concentration (Cmax) and area under concentration-time curve (AUC) of plasma of mice were increased by 3.05 and 6.07 times with lutein nanoparticles compared with free lutein. Meanwhile, the prepared lutein nanoparticles also promoted the accumulation of lutein in the liver, mesenteric adipose, and eyeballs. These results indicate that graft copolymerization of lutein with water-soluble polymers to form nanoparticles is an effective method to promote the bioavailability of lutein in vivo. Moreover, this method is simple and applicable, and can also be used for the modification of other bioactive molecules.

High drug-loading and controlled-release hydroxyphenyl-polyacrylate adhesive for transdermal patch.

Long-acting transdermal drug delivery system (TDDS) requires high drug-loading and drug controlled-release. To simultaneously improve drug-polymer miscibility and realize drug controlled-release, this work aimed to develop a new pressure sensitive adhesive modified with hydroxyphenyl (HP-PSA) by introducing doubly ionic H-bond into drug-PSA interaction. Eight model drugs divided into R3N, R2NH and no N type were chosen to understand the characteristics of the HP-PSA and inner mechanism. The results showed that the doubly ionic H-bond between R3N and R2NH type drugs and HP-PSA, differing from the ionic bond and neutral H-bond, was a reversible and relatively strong interaction. It could significantly enhance their drug-loading by 1.5 to 7 times and control drug release rate to its 1/5 to 1/2 without altering its total release properties, outperforming the commercial Duro-Tak® 87-2510 and Duro-Tak® 87-2852 adhesives. According to the pharmacokinetics results, the high drug-loading patches based on HP-PSA achieved a sustainable plasma drug concentration avoiding burst release, and over 2 times area under concentration-time curve (AUC) as well as 6 times mean residence time (MRT) revealed its potential to realize long-acting drug delivery. Additionally, its safety and mechanical features were satisfied. The mechanism study showed that the repulsion of the ionic drugs in HP-PSA increased drug-loading, and the relatively strong interaction could also control drug release. The incomplete H-bond transfer determined its reversibility, thus making the drug release percentage up to that of non-functional PSA. In conclusion, the high drug-loading efficiency and drug controlled-release capacity of HP-PSA, as well as its unique interaction, would contribute to the development of TDDS. Moreover, the construction of the doubly ionic H-bond would provide further inspiration for various drug delivery systems in the non-polar environment.

Ivermectin inhibits ovine ABCG2-mediated in vitro transport of meloxicam and reduces its secretion into milk in sheep

The ATP-binding cassette transporter G2 (ABCG2) is an efflux protein involved in the bioavailability and secretion into milk of several compounds including anti-inflammatory drugs. The aim of this work was to determine the effect in sheep of an ABCG2 inhibitor, such as the macrocyclic lactone ivermectin, on the secretion into milk of meloxicam, a non-steroidal anti-inflammatory drug widely used in veterinary medicine, and recently reported as an ABCG2 substrate. In vitro meloxicam transport assays in ovine ABCG2-transduced cells have shown that ivermectin is an efficient inhibitor of in vitro transport of meloxicam mediated by ovine ABCG2, with a 75% inhibition in the transport ratio (24.85 ± 4.62 in controls vs 6.31 ± 1.37 in presence of ivermectin). In addition, the role of ovine ABCG2 in secretion into milk of meloxicam was corroborated using Assaf lactating sheep coadministered with ivermectin. Animals were administered subcutaneously with meloxicam (0.5 mg/kg) with or without ivermectin (0.2 mg/kg). No difference in plasma pharmacokinetic parameters was found between treatments. In the case of milk, a significant reduction in the area under concentration-time curve (AUC) (3.92 ± 0.66 vs 2.26 ± 1.52 μg·h/mL) and the AUC milk-to-plasma ratio (0.17 ± 0.03 vs 0.09 ± 0.06) was reported for ivermectin-treated animals compared to controls.

Preclinical Pharmacokinetics and Bioavailability of Oxypeucedanin in Rats after Single Intravenous and Oral Administration.

Oxypeucedanin, a furanocoumarin extracted from many traditional Chinese herbal medicines, has a variety of pharmacological effects. However, the independent pharmacokinetic characteristics and bioavailability of this compound remains elusive. In this study, a rapid, sensitive, and selective method using ultra-high performance liquid chromatography–tandem mass spectrometry (UPLC/MS/MS) was developed for evaluating the intravenous and oral pharmacokinetics of oxypeucedanin. After intravenous administration of oxypeucedanin (2.5, 5, and 10 mg/kg), and intragastric administration of oxypeucedanin (20 mg/kg), blood samples were collected periodically from the tail vein. The plasma concentration-time curves were plotted, and the pharmacokinetic parameters were calculated using a non-compartmental model analysis. After intravenous administration of oxypeucedanin (single dosing at 2.5, 5, and 10 mg/kg) to rats, the pharmacokinetics fit the linear kinetics characteristics, which showed that some parameters including average elimination half-life (T1/2Z of 0.61~0.66 h), mean residence time (MRT of 0.62~0.80 h), apparent volume of distribution (VZ of 4.98~7.50 L/kg), and systemic clearance (CLZ of 5.64~8.55 L/kg/h) are dose-independent and the area under concentration-time curve (AUC) increased in a dose-proportional manner. Single oral administration of oxypeucedanin (20 mg/kg) showed poor and slow absorption with the mean time to reach the peak concentration (Tmax) of 3.38 h, MRT of 5.86 h, T1/2Z of 2.94 h, and a mean absolute bioavailability of 10.26% in rats. These results provide critical information for a better understanding of the pharmacological effect of oxypeucedanin, which will facilitate its research and development.

Effects of Simvastatin on the Metabolism of Vonoprazan in Rats Both in vitro and in vivo.

PurposeTo study the potential drug–drug interactions between simvastatin and vonoprazan and to provide the scientific basis for rational use of them in clinical practice.MethodsAn incubation system was established with rat liver microsomes, and the main metabolite of vonoprazan M-I was detected by UPLC-MS/MS. The IC50 value of simvastatin was then calculated and its inhibitory mechanism against vonoprazan was also analyzed. Twelve SD rats were randomly divided into 2 groups, then they were given simvastatin or saline for 2 weeks continuously. On the day of the experiment, both groups were intragastrically administered with vonoprazan once, followed by the collection of blood at different time points. Then the plasma concentration of vonoprazan and M-I in rats were detected by UPLC-MS/MS.ResultsIn vitro experiments revealed that simvastatin could inhibit the metabolism of vonoprazan, and its inhibition type belonged to the mixed non-competitive and competitive inhibition model. In vivo experiments in rats demonstrated that the area under concentration time curve (AUC) of vonoprazan was decreased but the clearance (CLz/F) of it was increased in the simvastatin administrated group, as compared to those of the control group. However, M-I in simvastatin treated group exhibited the higher AUC and lower CLz/F values compared to those in the control group. These data indicated that multiple doses of simvastatin administration could reduce the plasma concentration of vonoprazan and accelerate its metabolic rate in rats.ConclusionSimvastatin could inhibit the metabolism of vonoprazan in vitro but multiple doses of simvastatin exhibited the opposite effect In vivo. Altogether, our data indicated that an interaction existed between simvastatin and vonoprazan and additional cares might be taken when they were co-administrated in clinic.

Imeglimin population pharmacokinetics and dose adjustment predictions for renal impairment in Japanese and Western patients with type 2 diabetes.

Imeglimin is an orally administered first‐in‐class drug to treat type 2 diabetes mellitus (T2DM) and is mainly excreted unchanged by the kidneys. The present study aimed to define the pharmacokinetic (PK) characteristics of imeglimin using population PK analysis and to determine the optimal dosing regimen for Japanese patients with T2DM and chronic kidney disease (CKD). Imeglimin plasma concentrations in Japanese and Western healthy volunteers, and patients with T2DM, including patients with mild to severe CKD with an estimated glomerular filtration rate (eGFR) greater than 14 ml/min/1.73 m2 were included in a population PK analysis. PK simulations were conducted using a population PK model, and the area under concentration‐time curve (AUC) was extrapolated with power regression analysis to lower eGFR. The influence of eGFR, weight, and age on apparent clearance and of dose on relative bioavailability were quantified by population PK analysis. Simulations and extrapolation revealed that the recommended dosing regimen based on the AUC was 500 mg twice daily (b.i.d.) for patients with eGFR 15–45 ml/min/1.73 m2, and 500 mg with a longer dosing interval was suggested for those with eGFR less than 15. Simulations revealed that differences in plasma AUCs between Japanese and Western patients at the same dose were mainly driven by a difference in the eGFR and that the plasma AUC after 1000 and 1500 mg b.i.d. in Japanese and Western patients, respectively, was comparable in the phase IIb studies. These results indicate suitable dosages of imeglimin in the clinical setting of T2DM with renal impairment.

Development and Validation of a Nomogram to Predict the Probability of Venous Thromboembolism in Patients with Epithelial Ovarian Cancer.

ObjectiveTo identify predictive factors and develop a nomogram to predict the probability of venous thromboembolism for epithelial ovarian cancer patients. Methods: Our study cohort was composed of 208 EOC patients who had received initial treatment in Sun Yat-sen Memorial Hospital from January 2016 to March 2020. Clinicopathological variables predictive of VTE were identified using univariate logistic analysis. A multivariate logistic regression model was used to select the predictive factors used for nomogram. The accuracy of nomogram was evaluated by the Concordance index (C-index), the area under the receiver–operator characteristic (ROC) curve, area under concentration-time curve (AUC) and the calibration curve. Results: Advancing age (hazard ratio [HR], 1.042; 95% confidence interval [CI], 1.000-1.085; P = .048), higher D-dimer level (HR, 1.144; 95%CI, 1.020-1.283; P = .022), lower PR immunohistochemical positive rate (HR, 0.186; 95%CI, 0.034-1.065; P = .059) and higher Ki67 immunohistochemical positive rate (HR, 4.502; 95%CI, 1.637-12.380; P = .004) were found to be independent risk factors for VTE, and were used to construct the nomogram. The C-index for VTE prediction of the nomogram was 0.75. Conclusions: We constructed and validated a nomogram able to quantify the risk of VTE for EOC patients, which can be applied in recognizing EOC patients with high risk of VTE.

Next generation risk assessment (NGRA): Bridging in vitro points-of-departure to human safety assessment using physiologically-based kinetic (PBK) modelling – A case study of doxorubicin with dose metrics considerations

Using the chemical doxorubicin (DOX), the objective of the present study was to evaluate the impact of dose metrics selection in the new approach method of integrating physiologically-based kinetic (PBK) modelling and relevant human cell-based assays to inform a priori the point of departure for human health risk. We reviewed the literature on the clinical consequences of DOX treatment to identify dosing scenarios with no or mild cardiotoxicity observed. Key concentrations of DOX that induced cardiomyocyte toxicity in vitro were derived from studies of our own and others. A human population-based PBK model of DOX was developed and verified against pharmacokinetic data. The model was then used to predict plasma and extracellular and intracellular heart concentrations of DOX under selected clinical settings and compared with in vitro outcomes, based on several dose metrics: Cmax (maximum concentration) or AUC (area under concentration-time curve) in free or total form of DOX. We found when using in vitro assays to predict cardiotoxicity for DOX, AUC is a better indicator. Our study illustrates that when appropriate dose metrics are used, it is possible to combine PBK modelling with in vitro-derived toxicity information to define margins of safety and predict low-risk human exposure levels.

Evidence for Establishing the Clinical Breakpoint of Cefquinome against Haemophilus Parasuis in China.

Haemophilus parasuis can cause high morbidity and mortality in swine. Cefquinome possesses excellent antibacterial activity against pathogens causing diseases of the respiratory tract. This study aimed to establish the clinical breakpoint (CBP) of cefquinome against H. parasuis and to monitor the resistance change. Referring to the minimum inhibitory concentration (MIC) distribution of cefquinome against 131 H. parasuis isolates, the MIC50 and MIC90 were determined to be 0.125 and 1 μg/mL, respectively. And the epidemiological cutoff (ECOFF) value was 1 μg/mL. HPS42 was selected as a representative strain for the pharmacodynamic (PD) experiment, pharmacokinetic (PK) experiment and clinical experiments. The PK/PD index values, area under concentration-time curve (AUC)/MIC, of the bacteriostatic, bactericidal, and bacterial elimination effects were 23, 41, and 51 h, respectively. The PK/PD cutoff was calculated as 0.125 μg/mL by Monte Carlo simulation (MCS), and the clinical cutoff was 0.25−4 μg/mL by WindoW. Combing these three values, the CBP of cefquinome against H. parasuis was found to be 1 μg/mL. In conclusion, this was the first study to integrate various cutoffs to establish the CBP in the laboratory. It is helpful to distinguish wild type H. parasuis and reduce the probability of treatment failure.

Population Pharmacokinetic, Pharmacogenetic, and Pharmacodynamic Analysis of Cyclophosphamide in Ethiopian Breast Cancer Patients.

Cyclophosphamide (CPA) containing chemotherapy regimen is the standard of care for breast cancer treatment in sub-Saharan Africa. Wide inter-individual variations in pharmacokinetics (PK) of cyclophosphamide (CPA) influence the efficacy and toxicity of CPA containing chemotherapy. Data on the pharmacokinetics (PK) profile of CPA and its covariates among black African patients is lacking. We investigated population pharmacokinetic/pharmacogenetic/pharmacodynamic (PK-PG-PD) of CPA in Ethiopian breast cancer patients. During the first cycle of CPA-based chemotherapy, the population PK parameters for CPA were determined in 267 breast cancer patients. Absolute neutrophil count was recorded at baseline and day 20 post-CPA administration. A population PK and covariate model analysis was performed using non-linear mixed effects modeling. Semi-mechanistic and empiric drug response models were explored to describe the relationship between the area under concentration-time curve (AUC), and neutrophil toxicity. One compartment model better described CPA PK with population clearance and apparent volume of distribution (VD) of 5.41 L/h and 46.5 L, respectively. Inter-patient variability in CPA clearance was 54.5%. Patients carrying CYP3A5*3 or *6 alleles had lower elimination rate constant and longer half-life compared to wild type carriers. CYP2C9 *2 or *3 carriers were associated with increased clearance of CPA. Patients who received 500 mg/m2 based CPA regimen were associated with a 32.3% lower than average clearance and 37.1% lower than average VD compared to patients who received 600 mg/m2. A 0.1 m2 unit increase in body surface area (BSA) was associated with a 5.6% increment in VD. The mean VD (33.5 L) in underweight group (BMI < 18.5 kg/m2) was significantly lower compared to those of overweight (48.1 L) or obese patients (51.9 L) (p < 0.001). AUC of CPA was positively correlated with neutropenic toxicity. In conclusion, we report large between-patient variability in clearance of CPA. CYP3A5 and CYP2C9 genotypes, BSA, BMI, and CPA dosage regimen influence PK of CPA. Plasma CPA exposure positively predicts chemotherapy-associated neutropenic toxicity.

Safety, PK and preliminary efficacy of talazoparib in Japanese patients with advanced solid tumors; Phase 1 Study

Abstract Background Talazoparib is a potent, orally bioavailable, small molecule poly (adenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibitor. The recommended dose (RD) of single-agent talazoparib in non-Japanese patients (pts) was determined as 1 mg/day [QD]. This ongoing Phase 1 study evaluated the safety, preliminary efficacy, and PK profile of single-agent talazoparib in Japanese pts with advanced solid tumors. Methods Primary endpoint was first-cycle dose limiting toxicity (DLT). The single dose and multiple-dose PK and anti-tumor activity were evaluated as secondary endpoints. Two dose levels (0.75 mg and 1 mg QD) of talazoparib were studied using modified 3 + 3 dose escalation scheme. Talazoparib was administered continuously with the cycle length of 28 days. Results A total of 9 pts (3 pts in 0.75 mg and 6 pts in 1 mg QD) with a variety of tumor types were enrolled. No DLT was reported in either dose levels. The most common treatment-related (TR) adverse events (AEs) were neutrophil count decreased, platelet count decreased and stomatitis (22.2%, 2 pts each). No grade 3 or more TRAEs were reported. Based on the preliminary PK analysis, the median time to reach maximum plasma concentration (Tmax) was ranging from 1.0 to 2.0 hours. Talazoparib was eliminated with terminal phase half-life ranging from 49 to 133 hours after single dose. The distributions of maximum plasma concentration (Cmax) and area under concentration-time curve (AUC) after single and multiple dose were within the range of those in non-Japanese pts. RD in Japanese pts was determined to be 1 mg QD. Conclusions No DLT was reported in Japanese pts who received up to 1 mg QD. Hematological toxicity was common AEs in Japanese pts as well as non-Japanese pts. RD in Japanese pts was determined as 1 mg QD. The PK profile in Japanese pts was comparable with that in non-Japanese pts. Now the study is expanding to evaluate the efficacy in Japanese pts with germline BRCA mutated advanced breast cancer.

Pharmacokinetics of High-Dose Propylene Glycol–Free Melphalan in Multiple Myeloma Patients Undergoing Autologous Hematopoietic Cell Transplantation

High-dose melphalan followed by autologous stem cell transplant (ASCT) is standard of care for eligible patients with multiple myeloma (MM). Evomela (propylene glycol–free melphalan HCl [PG-Free Mel]; Spectrum Pharmaceuticals, Irvine, CA) was approved by the US Food and Drug Administration as conditioning therapy for ASCT in MM in 2 daily 100-mg/m2 doses for a total dose of 200 mg/m2. In this phase II, open-label study PG-Free Mel (Evomela) conditioning was given at single dose of 200 mg/m2 on day −2 pre-ASCT to establish pharmacokinetic (PK) parameters and safety. Twenty-four patients (median age, 64 years) were enrolled between August 2016 and February 2017. Myeloablation followed by successful neutrophil engraftment occurred at a median of 10 days in all patients. Peak melphalan concentration was observed at 10 minutes after infusion, whereas there was considerable variation in the maximum plasma concentration (Cmax) and area under concentration time curve (AUC). Median Cmax was 7380 ng/mL (interquartile range [IQR], 6522 to 8027). Similarly, median AUC was 533,552 ng/mL∙min (IQR, 450,850 to 662,936). PG-Free Mel had an acceptable safety profile regardless of the exposure, with no mortality and an overall response rate of 96% and a very good partial response rate of 75%. In conclusion, although PG-Free Mel at a single dose of 200 mg/m2 was safe, considerable PK variability was observed with the highest quartile having an ~3-fold higher AUC than the first quartile, suggesting that strategies for higher targeted exposure could be explored in future trials to optimize clinical benefit.

Vancomycin Dosing and Monitoring: Critical Evaluation of the Current Practice.

After more than six decades of its use as the mainstay antibiotic for the treatment of multidrug-resistant Gram-positive bacterial infections, dosing and monitoring of vancomycin therapy have not been optimized. The current vancomycin therapeutic guidelines recommend empiric doses of 15-20mg/kg administered by intermittent infusion every 8-12h in patients with normal kidney function. Additionally, the guidelines recommend trough concentration of 15-20mg/L as a therapeutic goal for adult patients with severe infections. This review critically discusses the current guidelines considering the basic pharmacokinetics and pharmacodynamics of vancomycin and the recent published reports from clinical studies. More in-depth discussion will be focused on (1) providing evidence of advantages of administering vancomycin by continuous infusion compared to intermittent infusion; (2) revising the current practice of trough-only monitoring versus the area under concentration-time curve (AUC); and (3) assessing the current practice of weight-based dosing versus AUC-based dosing. Using the gathered information presented in this paper, two user-friendly and scientifically based dosing strategies are proposed to improve the efficiency of vancomycin dosing while avoiding the risk of nephrotoxicity and minimizing the cost of therapeutic drug monitoring.

Parallelogram based approach for in vivo dose estimation of genotoxic metabolites in humans with relevance to reduction of animal experiments

When employing metabolism studies of genotoxic compounds/metabolites and cancer tests for risk estimation, low exposure doses in humans are roughly extrapolated from high exposure doses in animals. An improvement is to measure the in vivo dose, i.e. area under concentration-time curve (AUC), of the causative genotoxic agent. In the present work, we propose and evaluate a parallelogram based approach for estimation of the AUC of genotoxic metabolites that incorporates in vitro metabolic data and existing knowledge from published in vivo data on hemoglobin (Hb) adduct levels, using glycidamide (GA) as a case study compound that is the genotoxic metabolite of acrylamide (AA). The estimated value of AUC of GA per AUC of AA from the parallelogram approach vs. that from Hb adduct levels measured in vivo were in good agreement; 0.087 vs. 0.23 in human and 1.4 vs. 0.53 in rat, respectively. The described parallelogram approach is simple, and can be useful to provide an approximate estimation of the AUC of metabolites in humans at low exposure levels for which sensitive methods for analyzing the metabolites are not available, as well as aid in reduction of animal experiments for metabolism studies that are to be used for cancer risk assessment.

Formulation and Pharmacokinetics of HSA-core and PLGA-shell Nanoparticles for Delivering Gemcitabine.

Gemcitabine-loaded core-shell nanoparticles (CSNPs), comprised of a cross-linked HSA-core and PLGA-shell, were prepared through a modified double emulsification method, and the processing parameters were systematically investigated. The optimized CSNPs had a particle size of 241±36.2nm and an encapsulation efficiency of 41.52%. The core-shell structure was characterized by optical microscope (OM), scanning electron microscopy (SEM), and transmission electron microscopy (TEM). The amorphous nature of the encapsulated drug was confirmed by differential scanning calorimetry (DSC) and X-ray diffraction (XRD). An in vitro release study demonstrated that the CSNPs had an improved sustained release profile controlled by erosion of materials in combination with drug diffusion. In vivo pharmacokinetics of CSNPs obtained a bigger area under concentration-time curve (AUC), t 1/2, and C max compared to free drug solution. The results suggest that HSA-PLGA-based CSNPs can be a promising carrier for the sustained release of gemcitabine.

Pharmacokinetics, Tissue Distribution, and Elimination of Three Active Alkaloids in Rats after Oral Administration of the Effective Fraction of Alkaloids from Ramulus Mori, an Innovative Hypoglycemic Agent.

In this study, we systematically investigated the plasma pharmacokinetics, tissue distribution, and elimination of three active alkaloids after oral administration of the effective fraction of alkaloids from Ramulus Mori (SZ–A)—an innovative hypoglycemic agent—in rats. Moreover, the influences of other components in SZ–A on dynamic process of alkaloids were explored for the first time. The results showed that 1-deoxynojirimycin (DNJ), fagomine (FGM) and 1,4-dideoxy-1,4-imino-d-arabinitol (DAB) exhibited nonlinear pharmacokinetics following oral administration of SZ–A (40–1000 mg/kg). The prolonged t1/2 and greater area under concentration-time curve (AUC) versus time (AUC0–t) of DNJ for SZ–A than for purified DNJ has been observed after both oral and intravenous administration. It was found that other components in SZ–A could enhance the absorption of DNJ through the intestinal barrier. The major distribution tissues of DNJ, FGM, and DAB were the gastrointestinal tract, liver, and kidney. Three alkaloids were mainly excreted into urine and feces, but less into bile. Interestingly, the excess excretion of FGM was revealed to be partly due to the biotransformation of other components in SZ–A via gut microbiota. These information provide a rational basis for the use of SZ–A in clinical practice.

Population pharmacokinetics and Bayesian estimation of tacrolimus exposure in Chinese liver transplant patients

Tacrolimus (TAC) is widely used as part of immunosuppressive regimens. There is great interindividual variation on the disposition of TAC. The aim of this study was to develop a population pharmacokinetic (PPK) model for Chinese liver transplant patients and evaluate genetic polymorphism and other possible factors on the PK parameters. The exposure of TAC is to be estimated through Bayesian modelling. A total of 47 sets of rich-time PK and 1234 conventional therapeutic drug monitoring (TDM) data were collected from 125 Chinese liver transplant patients. The pathophysiological data of these patients were recorded. CYP3A5*3 and ABCB1 genotypes were determined for each patient. The PPK model for TAC was established by nonlinear mixed-effects modelling (nonmem). The impact of pathophysiology and genotype on PPK parameters was evaluated. Bayesian estimators for the area under concentration-time curve (AUC) of TAC were validated. A two-compartment model with lag time was found to be the most suitable model for the pooled full PK and TDM data for Chinese liver transplant patients. The CL/F, V2 /F, Q/F, V3 /F, Ka and lag time were 17.4±0.81L/h, 165±44.1L, 54.9±25.8L/h, 594±87.5L, 0.51±0.095L/h and 1.57±0.34h. Post-operative day (POD), creatinine clearance (CLcr) and ABCB1 C3435T genotypes were found to have significant influences on CL/F (P<.01). ABCB1 C3435T genotypes showed a significant correlation with V2 /F (P<.01). C0 -C2 and C0 -C2 -C4 were shown to be suitable for the estimation of AUC in Chinese liver transplant patients. A PPK model for TAC was established successfully in Chinese liver transplant patients. POD, CLcr and ABCB1 C3435T genotypes were shown to have significant effects on CL/F. The AUC of TAC in Chinese liver transplant patients could be estimated through Bayesian modelling, based on which individualized immunosuppressive regimens can be designed.