Physiologically-based pharmacokinetic modeling to predict the exposure and provide dosage regimens of Ustekinumab in pediatric patients with inflammatory bowel disease.

Ustekinumab (UST), a fully human immunoglobulin G1 κ monoclonal antibody, exhibiting high affinity for the p40 subunit shared by IL-12 and IL-23, which play key roles in the pathogenesis of inflammatory bowel disease (IBD). By scaling the physiologically-based pharmacokinetic modeling (PBPK) model of UST in adult patients with IBD, we aim to predict effective dosages for UST in pediatric patients, thereby offering a more practical dosing regimen for real-world applications. In this work, a PBPK model for UST in adult patients with IBD has been developed using PK-Sim and Mobi. Advanced ontogeny model has been incorporated to extrapolate the model to pediatric patients. The simulation results showed that the fold errors of the predicted and observed values of the area under the curve (AUC) and peak plasma concentration (Cmax) were between 0.79 and 1.73. For children aged 6-18, it is recommended to administer the drug per kilogram of body weight, at the model-recommended dose, to achieve a median AUC similar to that of the adult reference population post-administration. This comprehensive model construction enables us to comprehensively and extensively explore the pharmacokinetic characteristics of UST in pediatric patients of different age groups, providing robust support for clinical applications and personalized drug therapy.

Cardiac toxicity of brentuximab vedotin: a real-word disproportionality analysis of the FDA Adverse Event Reporting System (FAERS) database.

Brentuximab vedotin (BV) has obtained approval for the therapeutic management of classical Hodgkin lymphoma as well as systemic anaplastic large cell lymphoma. Given the inherent constraints of conventional clinical trials, the correlation between BV and cardiac adverse events (AEs) remains enigmatic. The objective of this investigation is to comprehensively assess cardiac AEs attributed to BV by employing advanced data mining techniques, utilizing the FDA Adverse Event Reporting System (FAERS). The indices for the assessment of disproportionality encompass the reporting odds ratio (ROR), the proportional reporting ratio, the information component, and the empirical Bayesian geometric mean. Employing these sophisticated metrics, we gauged the extent of disproportionate occurrences. The dataset was sourced from the FAERS from the first quarter of 2012 to first quarter of 2023, facilitating a comprehensive analysis of the potential correlation between BV and cardiac AEs. This scrutiny encompassed a comparative analysis of both cardiac and non-cardiac AEs. A total of 495 cases of BV's cardiac AEs were discerned, with the identification of 31 preferred terms (PTs). Among these, 8 PTs emerged as conspicuous signals of cardiac AEs, notably encompassing ventricular hypokinesia (ROR 7.59), tachyarrhythmia (ROR 7.06), sinus tachycardia (ROR 6.18), cardiopulmonary failure (ROR 4.44), pericardial effusion (ROR 4.32), acute coronary syndrome (ROR 4.02), cardiomyopathy (ROR 3.30), and tachycardia (ROR 2.76). The manifestation of severe outcomes demonstrates a discernible correlation with the cardiac AEs (P < 0.001). Our investigation furnishes invaluable insights for healthcare practitioners to proactively mitigate the incidence of BV-associated cardiac AEs.

Physiologically based pharmacokinetic modeling to predict maternal pharmacokinetics and fetal carbamazepine exposure during pregnancy.

Carbamazepine is an antiepileptic drug commonly used in pregnant women, during which the physiological changes may affect its efficacy. The aim of this study was to establish a physiologically based pharmacokinetic (PBPK) model of carbamazepine and its active metabolite carbamazepine-10,11-epoxide, and simulate maternal and fetal pharmacokinetic changes of carbamazepine and carbamazepine-10,11-epoxide in different trimesters and propose dose adjustment. We established pregnancy PBPK models for carbamazepine and carbamazepine-10,11-epoxide in PK-Sim® and Mobi® and validated the models with observed data from clinical reports. The placental transfer parameters obtained using different methods were also imported into the model and compared with the observed data to establish and validate fetal pharmacokinetic curves. The simulated results showed that mean steady-state trough plasma concentration of carbamazepine decreased by 27, 43.1, and 52 % during the first, second, and third trimesters, respectively. Therefore, to achieve an optimum therapeutic concentration, administering at least 1.4, 1.8, and 2.1 times the baseline dose of carbamazepine in the first, second, and third trimesters, respectively can be used as a dose reference. In conclusion, this study established and validated a pregnancy PBPK model of carbamazepine and carbamazepine-10,11-epoxide to assess exposure in pregnant women and fetuses, which provided a reference for the dosage adjustment of carbamazepine during pregnancy.

Physiologically-Based Pharmacokinetic Modeling of Anti-Tumor Necrosis Factor Agents for Inflammatory Bowel Disease Patients to Predict the Withdrawal Time in Pregnancy and Vaccine Time in Infants.

Anti-tumor necrosis factor (anti-TNF) agents are widely applied for patients with inflammatory bowel disease (IBD); however, the timing of the last dosing for IBD pregnancy and time to elimination in anti-TNF agent-exposed infants is controversial. This study aimed to determine the optimal timing for the last dosing of anti-TNF agents (infliximab, adalimumab, and golimumab) in pregnant women with IBD, as well as to investigate the recommended vaccine schedules for infants exposed to these drugs. A physiologically-based pharmacokinetic (PBPK) model of anti-TNF agents was built for adults and extrapolated to pregnant patients, fetuses, and infants. The PBPK models successfully predicted and verified the pharmacokinetics (PKs) of infliximab, adalimumab, and golimumab in pregnancy, fetuses, and infants. The predicted PK data were within two-fold of the observed data. The simulated results were used as timing advice. According to the dose of administration, the suggested timing of the last dosing for infliximab, adalimumab, and golimumab is successfully provided based on PBPK predictions. PBPK models indicated that, for infants, the advocated timing of vaccination is 12, 8, and 5 months after birth for infliximab, adalimumab, and golimumab, respectively. Our study illustrated that PBPK models can provide a valuable tool to predict the PKs of large macromolecules in pregnant women, fetuses, and infants, ultimately informing drug-treatment decisions for pregnancy and vaccination regimens for infants.

Physiologically based pharmacokinetic model combined with reverse dose method to study the nephrotoxic tolerance dose of tacrolimus.

Nephrotoxicity is the most common side effect that severely limits the clinical application of tacrolimus (TAC), an immunosuppressive agent used in kidney transplant patients. This study aimed to explore the tolerated dose of nephrotoxicity of TAC in individuals with different CYP3A5 genotypes and liver conditions. We established a human whole-body physiological pharmacokinetic (WB-PBPK) model and validated it using data from previous clinical studies. Following the injection of 1 mg/kg TAC into the tail veins of male rats, we developed a rat PBPK model utilizing the drug concentration-time curve obtained by LC-MS/MS. Next, we converted the established rat PBPK model into the human kidney PBPK model. To establish renal concentrations, the BMCL5 of the in vitro CCK-8 toxicity response curve (drug concentration range: 2-80 mol/L) was extrapolated. To further investigate the acceptable levels of nephrotoxicity for several distinct CYP3A5 genotypes and varied hepatic function populations, oral dosing regimens were extrapolated utilizing in vitro-in vivo extrapolation (IVIVE). The PBPK model indicated the tolerated doses of nephrotoxicity were 0.14-0.185 mg/kg (CYP3A5 expressors) and 0.13-0.155 mg/kg (CYP3A5 non-expressors) in normal healthy subjects and 0.07-0.09 mg/kg (CYP3A5 expressors) and 0.06-0.08 mg/kg (CYP3A5 non-expressors) in patients with mild hepatic insufficiency. Further, patients with moderate hepatic insufficiency tolerated doses of 0.045-0.06 mg/kg (CYP3A5 expressors) and 0.04-0.05 mg/kg (CYP3A5 non-expressors), while in patients with moderate hepatic insufficiency, doses of 0.028-0.04 mg/kg (CYP3A5 expressors) and 0.022-0.03 mg/kg (CYP3A5 non-expressors) were tolerated. Overall, our study highlights the combined usage of the PBPK model and the IVIVE approach as a valuable tool for predicting toxicity tolerated doses of a drug in a specific group.

Physiologically Based Pharmacokinetic Modeling Characterizes the Drug-Drug Interaction Between Saxagliptin and Rifampicin in Patients With Renal Impairment.

The aim of the present study is to develop physiologically based pharmacokinetic (PBPK) models for saxagliptin and its active metabolite, 5-hydroxy saxagliptin, and to predict the effect of coadministration of rifampicin, a strong inducer of cytochrome P450 3A4 enzymes, on the pharmacokinetics of saxagliptin and 5-hydroxy saxagliptin in patients with renal impairment. The PBPK models of saxagliptin and 5-hydroxy saxagliptin were developed and validated in GastroPlus for healthy adults with or without rifampicin and adults with varying renal functions. Then, the effect of renal impairment combined with drug-drug interaction on saxagliptin and 5-hydroxy saxagliptin pharmacokinetics was investigated. The PBPK models successfully predicted the pharmacokinetics. For saxagliptin, the prediction suggests that rifampin greatly weakened the effect of renal impairment on reducing clearance, and the inductive effect of rifampin on parent drug metabolism seems to be increased with an increase in the degree of renal impairment severity. For patients with the same degree of renal impairment, rifampicin would have a slightly synergistic effect on the increase of 5-hydroxy saxagliptin exposure compared with dosed alone. There is an unsignificant decline for the saxagliptin total active moiety exposure values in patients with the same degree of renal impairment. It seems that patients with renal impairment are unlikely to require additional dose adjustments when coadministered with rifampicin, compared with saxagliptin alone. Our study provides a reasonable approach to explore unknown DDI potential in renal impairment.

Pharmacokinetics and Comparative Bioavailability of Test or Reference Capecitabine and Discrepant Pharmacokinetics Among Various Tumors in Chinese Solid Cancer Patients.

The main objective of this study was to compare the pharmacokinetic (PK) bioequivalence of two capecitabine tablets and explore the different PK profiles of various tumors in Chinese patients with cancer. All 76 patients with a confirmed cancer diagnosis were included in this study. A single dose of 2000 mg of test or reference capecitabine (Xeloda, Hoffmann-La Roche) was orally administered postprandially. After 24 hours of washout, the patients were administered the test or the reference capecitabine alternately. PK samples were taken at the time of predose up to 6 hours postdose. Bioequivalence evaluation was performed using the geometric mean ratios of peak concentration in plasma (Cmax) , area under the concentration-time curve from time 0 to 6 h (AUC0-t) , and area under the concentration-time curve from time 0 to infinity (AUC0-∞ ) for capecitabine and 5-fluorouracil (5-FU). In this study, 90% confidence intervals of test/reference mean ratios of Cmax , AUC0-t , AUC0-∞ of capecitabine and 5-FU were in the range of 80%-125%. Both the test and reference capecitabine regimens were well tolerated in this study. Furthermore, we found that patients with esophageal-gastrointestinal cancers had higher exposure to capecitabine and a shorter time to Cmax (Tmax) than those with breast cancer. In conclusion, a single oral dose of 2000 mg of test capecitabine tablets after postprandial administration was bioequivalent to the reference drug.

Physiologically-Based Pharmacokinetic Modeling of Omalizumab to Predict the Pharmacokinetics and Pharmacodynamics in Pediatric Patients.

Omalizumab is widely used in clinical practice; however, knowledge gaps in the dosage of omalizumab for children aged 2-6 years with moderate-to-severe persistent allergic asthma have been identified. The aim of this study was to explore dosing regimens for moderately-to-severely allergic pediatric patients aged 2-6 years. The physiologically-based pharmacokinetic (PBPK) model of omalizumab was developed and verified in adult patients, extrapolated to pediatric patients, and simulated for omalizumab by adding two observation chambers (free IgE and total IgE). The simulation results showed that the fold errors of the predicted and observed values of the area under the curve (AUC) and peak plasma concentration (Cmax ) were between 0.5 and 2.0, and the average folding error and the absolute average folding error values for all concentration-time data points were 1.09 and 1.48, respectively. The PBPK model combined with pharmacokinetic/pharmacodynamic analysis of omalizumab demonstrated that both the model-derived dose and the original dose could control the average free IgE of 2-6-year-old children with moderate-to-severe allergic asthma below 25 ng/mL, and some of the model-derived doses were lower. This conclusion provides a basis for the selection of dosage in clinical practice reference.

Application of PBPK modeling in predicting maternal and fetal pharmacokinetics of levetiracetam during pregnancy.

Levetiracetam is currently being used to treat epilepsy in pregnant women. The plasma concentration of levetiracetam drops sharply during pregnancy, and the inability of pregnant women to maintain therapeutic concentrations can lead to seizures. This study aimed to predict the changes in fetal and maternal plasma exposure to levetiracetam during pregnancy and provide advice on dose adjustment. The physiology-based pharmacokinetics (PBPK) model was developed using PK-Sim and Mobi software, and validated following comparison of the observed plasma concentration and pharmacokinetic parameters. The levetiracetam PBPK model for mother and the fetus at various stages of pregnancy was successfully established and verified. Predictions indicated that the area under the steady-state concentration-time curve for levetiracetam decreased to 83, 62, and 67% of baseline values in the first, second, and third trimesters, respectively. Based on PBPK predictions, the recommended dose of levetiracetam is 1.2, 1.6, and 1.5 times the baseline dose in the first, second, and third trimesters, respectively, not exceeding 4000 mg/day in the third trimester due to fetal safety. The levetiracetam PBPK model for pregnancy was successfully developed and validated, and could provide alternative levetiracetam dosing regimens across the stages of pregnancy.

Application of Physiologically Based Pharmacokinetic Modeling to Predict Maternal Pharmacokinetics and Fetal Exposure to Oxcarbazepine.

Pregnancy is associated with physiological changes that may affect drug pharmacokinetics (PKs). The aim of this study was to establish a maternal-fetal physiologically based pharmacokinetic (PBPK) model of oxcarbazepine (OXC) and its active metabolite, 10,11-dihydro-10-hydroxy-carbazepine (MHD), to (1) assess differences in pregnancy, (2) predict changes in PK target parameters of these molecules following the current dosing regimen, (3) assess predicted concentrations of these molecules in the umbilical vein at delivery, and (4) compare different methods for estimating drug placental penetration. Predictions using the pregnancy PBPK model of OXC resulted in maternal concentrations within a 2-fold error, and extrapolation of the model to early-stage pregnancies indicated that changes in median PK parameters remained above target thresholds, requiring increased frequency of monitoring. The dosing simulation results suggested dose adjustment in the last two trimesters. We generally recommend that women administer ≥ 1.5× their baseline dose of OXC during their second and third trimesters. Test methods for predicting placental transfer showed varying performance, with the in vitro method showing the highest predictive accuracy. Exposure to MHD in maternal and fetal venous blood was similar. Overall, the above-mentioned models can enhance understanding of the maternal-fetal PK behavior of drugs, ultimately informing drug-treatment decisions for pregnant women and their fetuses.

Physiologically based pharmacokinetic modeling of daptomycin dose optimization in pediatric patients with renal impairment.

Background and Objective: Daptomycin is used to treat Gram-positive infections in adults and children and its dosing varies among different age groups. We focused on the pharmacokinetics of daptomycin in children with renal impairment, which has not been evaluated. Methods: A physiologically based pharmacokinetic (PBPK) model of daptomycin was established and validated to simulate its disposition in healthy populations and adults with renal impairment, along with a daptomycin exposure simulated in pediatric patients with renal impairment. Results: The simulated PBPK modeling results for various regimens of intravenously administered daptomycin were consistent with observed data according to the fold error below the threshold of 2. The Cmax and AUC of daptomycin did not differ significantly between children with mild-to-moderate renal impairment and healthy children. The AUC increased by an average of 1.55-fold and 1.85-fold in severe renal impairment and end-stage renal disease, respectively. The changes were more significant in younger children and could reach a more than 2-fold change. This scenario necessitates further daptomycin dose adjustments. Conclusion: Dose adjustments take into account the efficacy and safety of the drug; however, the steady-state Cmin of daptomycin may be above 24.3 mg/L in a few instances. We recommend monitoring creatine phosphokinase more than once a week when using daptomycin in children with renal impairment.

Development of Physiologically Based Pharmacokinetic Model for Pregabalin to Predict the Pharmacokinetics in Pediatric Patients with Renal Impairment and Adjust Dosage Regimens: PBPK Model of Pregabalin in Pediatric Patients with Renal Impairment.

Pregabalin (PGB) is widely used clinically; however, its pharmacokinetics (PK) has not been studied in pediatric patients with renal impairment (RI). To design optimized PGB regimens for pediatric patients with varying degrees of RI and predict exposure to PGB, physiologically based pharmacokinetic (PBPK) models of PGB were developed and verified, and its disposition was simulated in the healthy population and adults with RI. The simulated results from the PBPK models after single-dose and multi-dose administrations of PGB were consistent with the corresponding observed data based on the fold error values of less than 2. The area under curve ratios were 1.23 ± 0.06, 2.02 ± 0.10, 3.86 ± 0.21, and 9.92 ± 0.79 in pediatric patients with mild, moderate, severe, and end-stage RI, respectively. Based on the predictions for pediatric patients with moderate, severe, and end-stage RI, the maximum dose should not exceed 7, 3.5, and 1.4 mg/kg/day, respectively, among those weighing < 30 kg, and it should not exceed 5, 2.5, and 1 mg/kg/day, respectively, among those weighing > 30 kg. In conclusion, the developed PBPK model is a valuable tool for predicting PGB dosage for pediatric patients with RI.

Physiologically Based Pharmacokinetic Modeling and Dose Adjustment of Teicoplanin in Pediatric Patients With Renal Impairment.

The pharmacokinetics of teicoplanin differs in children as compared with adults, and especially in renally impaired pediatric patients. Inappropriate empirical antibacterial therapy may lead to treatment-related antibacterial resistance and increased toxicity, making adjustment of the dosage regimen essential. In the present study, physiologically based pharmacokinetic (PBPK) models were developed to define the appropriate dosage regimen for pediatric patients with differing renal function. Our PBPK models accurately predicted teicoplanin exposures in both adult and pediatric subjects after single and multiple intravenous infusions, with a <1.36-fold error between predicted and observed data, and all observed data were within minimal and maximal data of the corresponding population simulation. The area under the plasma concentration-time curve was predicted to increase 1.25-fold, 1.95-fold, and 2.82-fold in pediatric patients with mild, moderate, and severe renal impairment, respectively, relative to that of healthy children. Subsequently, the results of Monte Carlo simulations indicated that the recommended dosing of 12, 9.5, 6, and 4 mg/kg at 12-hour intervals would be appropriate in pediatric patients with normal renal function and in those with mild, moderate, and severe renal impairment, respectively, at a susceptible minimum inhibitory concentration <2 mg/L. In conclusion, our PBPK model with an incorporated Monte Carlo simulation can provide improved guidance on dosing in pediatric patients with differing renal function and provide a basis for precision therapy with teicoplanin.

Ceftaroline Dosage Optimized for Pediatric Patients With Renal Impairment Using Physiologically Based Pharmacokinetic Modeling.

Ceftaroline fosamil is a fifth-generation cephalosporin approved as a treatment for adults and children with community-acquired bacterial pneumonia and acute bacterial skin and skin structure infections. However, its pharmacokinetics have not been fully evaluated in children with renal impairment. This study aimed to propose proper ceftaroline dosages optimized for the renally impaired pediatric population using physiologically based pharmacokinetic (PBPK) modeling. A PBPK model of ceftaroline was established and verified to simulate its disposition in the healthy population and renally impaired adults and to predict the exposure in renally impaired pediatric patients. Consistency was confirmed between simulated and observed data after intravenous administration of various ceftaroline regimens; fold errors were within the 2-fold error range. Among 6-year-old children, healthy subjects had 1.5-fold, 2-fold, and 2.6-fold lower areas under the plasma concentration-time curve (AUCs) than the moderate, severe, and end-stage renally impaired patient groups, respectively; among 1-year-old children, healthy subjects had 1.5-fold, 2.1-fold, and 2.5-fold lower AUCs than the respective renally impaired patient groups; among 1-month-old children, healthy subjects had 1.5-fold, 1.8-fold, and 2.2-fold lower AUCs than the respective renally impaired patient groups. The proposed dosage should be adjusted to 8, 6, and 5 mg/kg every 8 hours for patients aged ≥2 years to <18 years (≤33 kg) with moderate, severe, and end-stage renal impairment, respectively; 5, 4, and 3 mg/kg every 8 hours for patients aged 2 months to <2 years with moderate, severe, and end-stage renal impairment, respectively; 4, 3.5, and 2.5 mg/kg every 8 hours for patients 0 to <2 months of age with moderate, severe, and end-stage renal impairment, respectively. Furthermore, pharmacodynamic investigations demonstrated that adequate antimicrobial effects were attained at the proposed doses in 3 age groups. Hence, our PBPK model can be an effective tool to support ceftaroline dosage proposals for renally impaired pediatric patients.

Dosage Adjustment for Ceftazidime in Pediatric Patients With Renal Impairment Using Physiologically Based Pharmacokinetic Modeling.

Physiologically based pharmacokinetic (PBPK) modeling has unique advantages in investigating the pharmacokinetics of drugs in special populations. Our aim is to design optimized dosing regimens for ceftazidime in renally-impaired pediatric patients using PBPK modeling. Models for healthy and renally-impaired adults were developed, verified, and adapted for children to predict ceftazidime exposure in pediatric patients with varying degrees of renal impairment, capturing age- and weight-related pharmacokinetic changes. We derived a dosage-adjusted regimen for renally-impaired children based on pharmacokinetic data and evaluated the pharmacodynamics of ceftazidime. The PBPK models adequately predicted ceftazidime exposures in populations after single- and multi-dose administrations, with fold error values within 1.1 between simulated and observed data. In moderate, severe, and end-stage renally-impaired pediatric patients, the areas under the plasma concentration-time curves (AUCs) were 1.87-fold, 3.56-fold, and 6.19-fold higher, respectively, than in healthy children when treated with the same dose of 50 mg/kg. Pharmacodynamic verification indicated that the recommended doses of 28, 15, and 8 mg/kg administered three times daily (every 8 h) to pediatric patients with moderate, severe, and end-stage renal disease, respectively, were sufficient to attain the target of maintaining the free plasma concentration at or above minimum inhibitory concentration (MIC) during 70% of the dosing interval (70% fT > MIC: nearly 100% target attainment for susceptible MIC of 4 mg/L and >70% for intermediate MIC of 8 mg/L). Our PBPK model can be an effective tool to support dosing recommendations in pediatric patients with different degrees of renal impairment.

Application of physiologically based pharmacokinetic modeling to predict the pharmacokinetics of telavancin in obesity with renal impairment.

PURPOSE: U.S. Food and Drug Administration (FDA) recommended telavancin dosing is based on total body weight (TBW) but lacks adjusted regimens for obese subjects with varying renal function. Our aim was to develop a physiologically based pharmacokinetic (PBPK) model of telavancin to design optimized dosing regimens for obese patients with hospital-acquired pneumonia (HAP) and varying renal function. METHODS: The PBPK model was verified using clinical pharmacokinetic (PK) data of telavancin in healthy populations with varying renal function and obese populations with normal renal function. Then, the PBPK model was applied to predict the PK in obese HAP patients with renal impairment (RI). RESULTS: The fold error values of PK parameters (AUC, Cmax, Tmax) were all within 1.5. The telavancin AUC0-inf was predicted to increase 1.07-fold in mild RI, 1.23-fold in moderate RI, 1.41-fold in severe RI, and 1.57-fold in end-stage renal disease (ESRD), compared with that in obese HAP with normal renal function. The PBPK model combined with Monte Carlo simulations (MCS) suggested that dose adjustment based on a 750-mg-fixed dose could achieve effectiveness with reduced risk of toxicity, compared with current TBW-based dosing recommendations. CONCLUSION: The PBPK simulation proposed that using TBW-based regimen in obesity with RI should be avoided. Dose recommendations in obesity from the PBPK model are 750 mg daily for normal renal function and mild RI, 610 mg daily for moderate RI, 530 mg daily for severe RI, and 480 mg daily for ESRD.

Population pharmacokinetics of azathioprine active metabolite in patients with inflammatory bowel disease and dosage regimens optimisation.

Azathioprine is a first-line drug used to maintain the remission of inflammatory bowel disease (IBD). As a prodrug, azathioprine is metabolised to produce active 6-thioguanine nucleotides (6-TGN). There are large individual variations in the pharmacokinetics/pharmacodynamics of 6-TGN in patients with IBD. Here, we aimed to develop a model to quantitatively investigate factors that affect 6-TGN pharmacokinetics to formulate a dosage guideline for azathioprine. Data were collected prospectively from 100 adult patients with IBD who were receiving azathioprine. Patients were genotyped for two single-nucleotide polymorphisms (TPMT*3C c.719A > G and NUDT15 c.415C > T). Using high-performance liquid chromatography, we measured 156 steady-state trough concentrations of 6-TGN within the range 0.09 to 1.16 mg/L (ie 133-1733 pmol per 8 × 108 RBC). The covariates analysed included sex, age, body-weight, laboratory tests and concomitant medications. A population pharmacokinetic model was established using "non-linear mixed-effects modelling" software and the "first-order conditional estimation method with interaction." Body-weight, TPMT*3C polymorphisms and co-therapy with mesalazine were found to be important factors influencing the clearance of 6-TGN. A dosage guideline for azathioprine was developed based on the PPK model that enables individualised azathioprine dosing in adult patients with different body-weights, TPMT*3C genotypes and co-administration with mesalazine.

The use of methylprednisolone in COVID-19 patients: A propensity score matched retrospective cohort study.

PURPOSE: To evaluate the efficacy and safety of methylprednisolone in treating the coronavirus disease 2019 (COVID-19) patients. METHODS: A retrospective cohort study was conducted, and all COVID-19 patients were recruited who were admitted to the Yichang Third People's Hospital from February 1st to March 31st, 2020. One-to-one propensity score matching (PSM) was used for minimizing confounding effects. The primary outcome was hospital mortality, with the secondary outcomes being the time needed for a positive SARS-CoV-2 nucleic acid test to turn negative and the length of hospital stay. RESULTS: Totaling 367 patients with COVID-19 hospitalized at the Yichang Third People's Hospital were identified, of whom 276 were mild or stable COVID-19, and 67 were serious or critically ill. Among them, 255 patients were treated using methylprednisolone, and 188 did not receive any corticosteroid-related treatment. After PSM, no statistically significant difference was found in the baseline characteristics between the two groups. Regarding the outcomes, there also were no statistically significant difference between the two groups. Patients without the use of methylprednisolone were more quickly to obtain negative results of their nasopharyngeal swab tests of SARS-CoV-2 nucleic acid after treatment, compared to those receiving methylprednisolone. CONCLUSION: Methylprednisolone could not improve the prognosis of patients with COVID-19, and the efficacy and safety of the use of methylprednisolone in patients with COVID-19 still remain uncertain, thus the use of corticosteroids clinically in patients with COVID-19 should be with cautions.

CircRNA SMARCC1 Sponges MiR-140-3p to Regulate Cell Progression in Colorectal Cancer.

PURPOSE: Our objective was to investigate the effect of circSMARCC1 on the developmental and biological behavior of colorectal cancer (CRC). MATERIALS AND METHODS: The expression of circSAMRCC1 and miR-140-3p in CRC tissues and cell lines (SW620, HCT116, HT29 and SW480) and a normal cell line (NCM460) was detected using qRT-PCR. The expression levels of circSMARCC1 and its linear subtype were detected. Fluorescence in situ hybridization was performed for the evaluation of the localization of circSAMRCC1 and miR-140-3p in the SW620 cell line. The effects of circSAMRCC1 and miR-140-3p on cell proliferation were investigated using CCK8 and colony formation assays, respectively. The effects of circSAMRCC1 and miR-140-3p on cell migration and invasion were determined using Transwell assay. The binding relationship between circSMARCC1 and miR-140-3p was further assessed by bioinformatics, ChIRP analysis and double luciferase reporter assay. RESULTS: The expression of circSAMRCC1 in the CRC tissues and four cell lines is significantly increased, and circSMARCC1 and miR-140-3p are negatively correlated with expression level in the tissue. The downregulation of circSMARCC1 decreased CRC cell viability and suppressed metastasis in vitro and Inhibition of protein (MMP-2, MMP-9, VEGF) expression. miR-140-3p is downregulated in CRC tissues; miR-140-3p mimics inhibited SW620 cell viability, migration and invasion, and miR-140-3p inhibitors reversed the the effect of circSMARCC1 downregulation on cell proliferation, migration and invasion in CRC cells. CONCLUSION: circSMARCC1 competitively combined with miR-140-3p and functioned through a circSMARCC1/miR-140-3p/MMPs axis as a CRC carcinogen, demonstrating its potential as a biomarker for CRC treatment.

A Physiologically Based Pharmacokinetic Model of Ertapenem in Pediatric Patients With Renal Impairment.

Ertapenem is a widely used antibiotic; however, its pharmacokinetics has not been fully evaluated in children with renal impairment. A physiologically based pharmacokinetic (PBPK) model of ertapenem was established and validated to simulate its disposition in the healthy population and adults with renal impairment, as well as to predict the exposure in pediatric patients with renal impairment. The simulated PBPK modeling results and the observed data of ertapenem after intravenous administration of various regimens were consistent according to the fold error values of less than 2. Furthermore, %T > MIC of ertapenem was evaluated using the PBPK model. The Cmax was not significantly changed in pediatric patients with renal impairment compared to healthy children. However, the AUC was 1.42-fold, 1.84-fold, 2.37-fold, and 3.52-fold higher in mild, moderate, severe renal impairment, and end-stage renal disease, respectively, than that in healthy children and the doses of ertapenem were reduced to 13 mg/kg b.i.d, 9 mg/kg b.i.d, 6 mg/kg b.i.d, and 5 mg/kg b.i.d, respectively. The probability of achieving 40%T > MIC (MIC ≤ 4 µg/mL) was nearly 100% throughout the recommended dosing interval. In conclusion, our model can be used as a tool to generate better predictions for the most effective ertapenem dosing in pediatric patients.