Population pharmacokinetics, dosing optimization and clinical outcomes of biapenem in patients with sepsis.

Introduction: Biapenem is a carbapenem antibiotic widely used in Asia, can be used for the treatment of adults and children with infections due to susceptible bacteria. Although biapenem is utilized in the treatment of a diverse range of bacterial infections, current pharmacokinetic data in the context of septic populations remain limited. Consequently, our research aims to evaluate the pharmacokinetics and efficacy of biapenem within a septic population to optimize biapenem therapy. Methods: In this study, we characterized the pharmacokinetics of biapenem in septic patients using a population pharmacokinetic (PPK) approach. The clinical PK data to develop the PPK model were obtained from 317 septic patients admitted to Nanjing Drum Tower Hospital between 2018 and 2022. All patients were randomized to the modeling and validation cohorts at a 3:1 ratio, with PPK modeling and validation performed utilizing the NONMEM software. Results: The model found to best describe the available data was a two-compartment PPK model with first-order elimination characterized by the parameters clearance (CL), central volume (V1), peripheral volume (V2), and intercompartmental clearance (Q). A covariate analysis identified that creatinine clearance (CLCR) was a significant covariate influencing biapenem CL, while blood urea nitrogen (BUN) was a significant covariate influencing biapenem Q. Accoding to the clinical outcome analyses, 70% of the time that the free antimicrobial drug concentration exceeds the MIC (fT >MIC) is associated with favourable clinical outcomes. The PPK model was then used to perform Monte Carlo simulations to evaluate the probability of attaining 70% fT >MIC. Conclusions: A final PPK model of biapenem was established for patients with sepsis. The current daily dosage regimen of 1.2 g may insufficient to achieve 70% fT >MIC in septic patients. The dosage regimen of 600 mg every 6 h appears to be the optimal choice.

Vancomycin: An analysis and evaluation of eight population pharmacokinetic models for clinical application in general adult population.

INTRODUCTION: Based on the recent guidelines for vancomycin therapeutic drug monitoring (TDM), the area under the curve to minimum inhibitory concentration ratio was to be employed combined with the usage of population pharmacokinetic (popPK) model for dosing adaptation. Yet, deploying these models in a clinical setting requires an external evaluation of their performance. OBJECTIVES: This study aimed to evaluate existing vancomycin popPK models from the literature for the use in TDM within the general patient population in a clinical setting. METHODS: The models under external evaluation were chosen based on a review of literature covering vancomycin popPK models developed in general adult populations. Patients' data were collected from Charles-Le Moyne Hospital (CLMH). The external evaluation was performed with NONMEM® (v7.5). Additional analyses such as evaluating the impact of number of samples on external evaluation, Bayesian forecasting, and a priori dosing regimen simulations were performed on the best performing model. RESULTS: Eight popPK models were evaluated with an independent dataset that included 40 patients and 252 samples. The model developed by Goti and colleagues demonstrated superior performance in diagnostic plots and population predictive performance, with bias and inaccuracy values of 0.251% and 22.7%, respectively, and for individual predictive performance, bias and inaccuracy were -4.90% and 12.1%, respectively. When limiting the independent dataset to one or two samples per patient, the Goti model exhibited inadequate predictive performance for inaccuracy, with values exceeding 30%. Moreover, the Goti model is suitable for Bayesian forecasting with at least two samples as prior for the prediction of the next trough concentration. Furthermore, the vancomycin dosing regimen that would maximize therapeutic targets of area under the curve to minimum inhibitory concentration ratio (AUC24/MIC) and trough concentrations (Ctrough) for the Goti model was 20 mg/kg/dose twice daily. CONCLUSION: Considering the superior predictive performance and potential for Bayesian forecasting in the Goti model, future research aims to test its applicability in clinical settings at CLMH, both in a priori and a posteriori scenario.

Profiling antibody epitopes induced by mRNA-1273 vaccination and boosters.

Background: Characterizing the antibody epitope profiles of messenger RNA (mRNA)-based vaccines against SARS-CoV-2 can aid in elucidating the mechanisms underlying the antibody-mediated immune responses elicited by these vaccines. Methods: This study investigated the distinct antibody epitopes toward the SARS-CoV-2 spike (S) protein targeted after a two-dose primary series of mRNA-1273 followed by a booster dose of mRNA-1273 or a variant-updated vaccine among serum samples from clinical trial adult participants. Results: Multiple S-specific epitopes were targeted after primary vaccination; while signal decreased over time, a booster dose after >6 months largely revived waning antibody signals. Epitope identity also changed after booster vaccination in some subjects, with four new S-specific epitopes detected with stronger signals after boosting than with primary vaccination. Notably, the strength of antibody responses after booster vaccination differed by the exact vaccine formulation, with variant-updated mRNA-1273.211 and mRNA-1273.617.2 booster formulations inducing significantly stronger S-specific signals than a mRNA-1273 booster. Conclusion: Overall, these results identify key S-specific epitopes targeted by antibodies induced by mRNA-1273 primary and variant-updated booster vaccination.

Optimal Once-Daily Busulfan Administration in Pediatric Patients: A Simulation-Based Investigation of Intravenous Infusion Times.

Purpose: Pediatric patients receiving hematopoietic stem cell transplantation undergo regular administration of intravenous busulfan as a conditioning regimen. Once-daily regimen of busulfan has been proposed as a more convenient alternative to the traditional regimen, but it may increase the risk of toxicity such as veno-occlusive disease (VOD). The study aims to evaluate the pharmacokinetics (PKs) of once-daily regimens and investigate appropriate intravenous infusion times to reduce the risk of toxicity. Patients and methods: Once-daily busulfan dosing regimens for pediatric patient were reviewed and selected including EMA- and FDA-based once-daily dosing regimens. We generated busulfan PK data of virtual pediatric patients using a previously developed population PK model. PK profiles and proportion of patients achieving the referenced maximum concentration (Cmax) and exposure to busulfan were used to evaluate the appropriateness of both infusion time and dosing regimens. Results: Predicted PK profiles and exposure of busulfan showed relatively similar distributions for all once-daily dosing regimens. Most patients exceeded the referenced Cmax possibly associated with a high risk of VOD with all once-daily regimens when applied with 3 hours of infusion. Conclusion: While intravenous infusion of once-daily busulfan is typically administered over 3 hours, our findings emphasize the necessity of considering sufficient infusion times to ensure safe drug utilization and prevent toxicity, which will aid in optimal busulfan use in pediatric oncology.

Latamoxef dosing regimen adjustments and pharmaceutical care in pediatrics.

Latamoxef is a semi-synthetic, broad-spectrum oxacephem antibiotic used primarily to treat infectious diseases, but the adverse drug reactions, such as the risk of fatal bleeding, once caused physicians to use it less frequently. However, with the rise of antibiotic-resistant bacterial strains, latamoxef is being used again to treat infectious diseases, especially in pediatrics. The pharmacokinetic parameters of latamoxef are highly variable, given the changes in body composition, organ maturation, and development that occurs in pediatrics. Therefore, an appropriate dosing regimen is essential. Latamoxef dosing optimization in pediatrics should adequately account for current body weight, postnatal age, postmenstrual age, and different minimum inhibitory concentration (MIC) values. In addition, attention should also be paid to some of the adverse reactions associated with latamoxef, such as coagulation disorders and bleeding risks, disulfiram-like reactions, as well as hypersensitivity and anaphylactic shock. This review summarizes the dosing regimens and some key points of pharmaceutical care for latamoxef in pediatrics in order to provide a better reference for its application in clinical practice.

Prediction of drug-drug interactions between roflumilast and CYP3A4/1A2 perpetrators using a physiologically-based pharmacokinetic (PBPK) approach.

This study aimed to develop a physiologically-based pharmacokinetic (PBPK) model to predict changes in the pharmacokinetics (PK) and pharmacodynamics (PD, PDE4 inhibition) of roflumilast (ROF) and ROF N-oxide when co-administered with eight CYP3A4/1A2 perpetrators. The population PBPK model of ROF and ROF N-oxide has been successfully developed and validated based on the four clinical PK studies and five clinical drug-drug interactions (DDIs) studies. In PK simulations, every ratio of prediction to observation for PK parameters fell within the range 0.7 to 1.5. In DDI simulations, except for tow peak concentration ratios (Cmax) of ROF with rifampicin (prediction: 0.63 vs. observation: 0.19) and with cimetidine (prediction: 1.07 vs. observation: 1.85), the remaining predicted ratios closely matched the observed ratios. Additionally, the PBPK model suggested that co-administration with the three perpetrators (cimetidine, enoxacin, and fluconazole) may use with caution, with CYP3A4 strong inhibitor (ketoconazole and itraconazole) or with dual CYP3A41A2 inhibitor (fluvoxamine) may reduce to half-dosage or use with caution, while co-administration with CYP3A4 strong or moderate inducer (rifampicin, efavirenz) should avoid. Overall, the present PBPK model can provide recommendations for adjusting dosing regimens in the presence of DDIs.

Selexipag for the Treatment of Pediatric Pulmonary Hypertension: A Systematic Review.

PURPOSE: To systematically evaluate the safety, dosing regimen, and efficacy of selexipag for pediatric patients with pulmonary hypertension (PH). METHODS: A literature search of the electronic databases of PubMed, Embase, Web of Science, Cochrane Library, and Google Scholar was performed from inception through February 28, 2023. Two reviewers independently searched and evaluated the quality of the studies and pooled data when appropriate. Full-text articles of studies of children diagnosed with PH and treated with selexipag were eligible. Pediatric patients with PH were classified into 2 groups: the add-on therapy group, in which selexipag was used as a third therapy in addition to the baseline treatment, and the transition therapy group, in which patients were switched from parenteral prostacyclin analogs to selexipag. FINDINGS: Fourteen studies involving 58 pediatric patients with PH were included. All studies were either case reports or case series. Overall, 30 and 28 patients were in the add-on and transition therapy groups, respectively. In both groups, selexipag was initially administered as 50-200 µg twice daily and titrated to a tolerated dosage of 200-1,600 µg twice daily. Prostacyclin analogs were simultaneously weaned for patients in the transition group. In the add-on therapy group, 16 patients (80.0%) were at low risk of the World Health Organization functional class (WHO FC I/II), 12 (76.9%) were at low risk of the 6-minute walk distance (6MWD; >350 m), and 21 (95.5%) were at low risk of the pulmonary vascular resistance index (PVRi; <20 WU/m2). Furthermore, N-terminal pro-brain natriuretic peptide and mean pulmonary arterial pressure were significantly improved. More than 70% of patients experienced common tolerable side effects, such as headache, nausea, and diarrhea. In the transition therapy group, 5 patients (55.6%) were at low risk according to WHO FC I/II, 6 (66.7%) were at low risk according to 6MWD, and 14 (87.5) were at low risk according to PVRi; however, selexipag had no significant effect on their hemodynamic parameters. Additionally, more than 80% of patients experienced no side effects. IMPLICATIONS: Selexipag as add-on therapy or for transition from prostacyclin analogs may have a favorable safety profile and potential efficacy for pediatric patients with PH. Further high-quality evidence of the efficacy and safety of selexipag for the treatment of pediatric PH is warranted.

Prediction of trough concentration and ALK occupancy in plasma and cerebrospinal fluid using physiologically based pharmacokinetic modeling of crizotinib, alectinib, and lorlatinib.

Backgrounds: Brain metastases occur in approximately 30% of patients with non-small-cell lung cancer (NSCLC). Therefore, the free drug concentration in cerebrospinal fluid (CSF) is strongly associated with the clinical efficacy. Purpose: The present study aimed to develop physiologically based pharmacokinetic (PBPK) models that can predict the steady-state trough concentration (Ctrough) in plasma and CSF, as well as anaplastic lymphoma kinase (ALK) occupancy (AO), for three inhibitors: crizotinib (CRI), alectinib (ALE), and lorlatinib (LOR). Methods: To achieve this, population PBPK models were successfully developed and validated using multiple clinical pharmacokinetics (PK) and drug-drug interaction (DDI) studies, both in healthy subjects and patients. Results: The prediction-to-observation ratios for plasma AUC, Cmax, and Ctrough in heathy subjects and patients ranged between 0.5 and 2.0. In addition, PK profiles of CRI, ALE, and LOR in CSF aligned well with observed data. Moreover, the AUC and Cmax ratios of the three inhibitors when co-administered with CYP3A4 inhibitors/inducers also matched with clinically observed values. Utilizing PK thresholds for effective plasma Ctrough and AO values on wild-type and four ALK mutations in plasma and CSF, PBPK models were then combined with the mean and 95% confidence interval to predict optimal dosing regimens. Conclusions: Overall, these PBPK models provide valuable insights into determining appropriate dosing regimens for the three ALK inhibitors, understanding their effectiveness in brain metastasis therapy, and analyzing the underlying mechanisms of on-target resistance.

Supporting patients in the transition to the revised pexidartinib dosing regimen: perspectives from the multidisciplinary clinical and allied health professional team.

Pexidartinib is a colony-stimulating factor-1 receptor inhibitor approved in the United States for treatment of adult patients with symptomatic tenosynovial giant cell tumor (TGCT) associated with severe morbidity or functional limitations and not amenable to improvement with surgery. Because of the risk of severe and potentially fatal hepatotoxicity, pexidartinib is only available through a Risk Evaluation and Mitigation Strategy (REMS) program. Pexidartinib pharmacokinetics are influenced by the fat content of meals: compared with the fasted state, consuming a high-fat meal with pexidartinib increases pexidartinib absorption by 100%; a low-fat meal increases absorption by approximately 60%. Pexidartinib was initially authorized to be taken at 800 mg/day on an empty stomach; therefore, if this same dose of pexidartinib is taken with food, there is a risk of overexposure and potential toxicity. To reduce the risk of hepatotoxicity and improve patient compliance, pexidartinib has undergone a revised dosing regimen, from 800 mg/day (400 mg twice daily) fasted to 500 mg/day (250 mg twice daily) with a low-fat meal (approximately 11-14 g of total fat). The objective of this report is to educate clinical and allied health professionals on the revised dosing regimen and the importance of patient compliance with a low-fat meal. Healthcare professionals need to understand the rationale for the switch from pexidartinib dosing on an empty stomach to dosing with a low-fat meal and how meal composition and timing influence pharmacokinetics. Finally, we provide guidance for the healthcare team of prescribing providers, nurses, pharmacists, and dietitians who are caring for patients with TGCT on pexidartinib. It is important for healthcare providers to deliver consistent messaging on the low-fat meal requirement and help patients fit pexidartinib into their regular meal schedules. Consulting a dietitian may be helpful for patients, especially those with complex dietary needs. We provide an overview of the roles and responsibilities of each healthcare professional and outline steps to best support patients, including key questions and answers related to the revised dosing regimen. This report provides the information necessary to guide the multidisciplinary team caring for patients with TGCT and to support them through the pexidartinib dosing regimen change.

Optimization of the dosage regimen of zoledronic acid with a kinetic-pharmacodynamic model and exposure-response analysis.

Purpose: In order to support the dose optimization of zoledronic acid, the kinetic-pharmacodynamic model and exposure-response analysis were used to describe the changes in bone mineral density in different doses of zoledronic acid and establish the relationship between dose and acute phase reaction. Methods: Data were extracted from literature in accessible public databases. The kinetic-pharmacodynamic model was developed based on the above data using the NONMEM package to estimate parameters describing the relationship between the dose of zoledronic acid and bone mineral density. Exposure-response analysis was developed to establish the relationship between dose and acute phase reaction. Model evaluation was performed using goodness-of-fit, coefficient of variation (CV%). And sensitivity analyses were performed to assess the necessity of related parameters. Then the established model was used to simulate the changes of bone mineral density under different administration regimens, and the literature data was verified. Results: The kinetic-pharmacodynamic model successfully described zoledronic acid dose and change of bone mineral density in osteoporosis patients, with coefficient of variation of most less than 71.5%. The exposure-response analysis showed the incidence of acute phase reaction is dose-dependent. The bone mineral density was simulated based on the developed kinetic-pharmacodynamic model. And the simulated change of bone mineral density and the incidence of acute phase reaction could be helpful to propose a dosage regimen. Conclusion: Overall, the kinetic-pharmacodynamic model described changes of bone mineral density in different doses of zoledronic acid in vivo. And, the model and the exposure-response analysis also showed to provide the assessment of dose-response relationship for zoledronic acid.

Assessing the Effects of Changing Patterns of Inhaled Corticosteroid Dosing and Adherence with Fluticasone Furoate and Budesonide on Asthma Management.

INTRODUCTION: Pharmacological asthma management focuses on the use of inhaled corticosteroid (ICS)-containing therapies, which reduce airway inflammation and provide bronchoprotection, improving symptom control and reducing exacerbation risk. ICS underuse due to poor adherence is common, leading to poor clinical outcomes including increased risk of mortality. This article reviews efficacy versus systemic activity profiles for various adherence patterns and dosing regimens of fluticasone furoate (FF)-containing and budesonide (BUD)-containing asthma therapies in clinical trials and real-world studies. METHODS: We performed a structured literature review (1 January 2000-3 March 2022) and mathematical modelling analysis of FF-containing and BUD-containing regular daily dosing in patients with mild-to-severe asthma, as-needed BUD/formoterol (FOR) in mild asthma, and BUD/FOR maintenance and reliever therapy (MART) dosing in moderate-to-severe asthma, to assess efficacy (bronchoprotection) and systemic activity (cortisol suppression) profiles of dosing patterns of ICS use in multiple adherence scenarios. RESULTS: A total of 22 manuscripts were included in full-text review and 18 in the model simulations. Focusing on FF-containing or BUD-containing treatments at comparable adherence rates, regular daily FF or FF/vilanterol (VI) dosing provided more prolonged bronchoprotection and fewer systemic effects than daily BUD, daily BUD/FOR, or BUD/FOR MART dosing, especially in low adherence scenarios. In model simulations and the real-world setting, FF/VI generally provided longer bronchoprotection, lower systemic activity, and greater clinical benefits over BUD/FOR as well as consistently higher adherence. CONCLUSION: In this literature review and modelling analysis, FF/VI was found to show clinical advantages on asthma control over BUD/FOR. These findings have implications for helping clinicians select the most suitable inhaled therapy for their patients with asthma.

A new dosing regimen of ropeginterferon alfa-2b is highly effective and tolerable: findings from a phase 2 study in Chinese patients with polycythemia vera.

Ropeginterferon alfa-2b represents a new-generation pegylated interferon-based therapy and is administered every 2-4 weeks. It is approved for polycythemia vera (PV) treatment in the United States and Europe with a starting dose of 100 µg (50 µg for patients receiving hydoxyurea) and intra-patient dose titrations up to 500 µg at 50 µg increments, which took approximately 20 or more weeks to reach a plateau dose level. This study aimed to assess ropeginterferon alfa-2b at an alternative dosing regimen with a higher starting dose and quicker intra-patient dose titrations, i.e., the 250-350-500 µg schema, in 49 Chinese patients with PV with resistance or intolerance to hydroxyurea. The primary endpoint of the complete hematologic response rate at treatment weak 24 was 61.2%, which was notably higher than 43.1% at 12 months with the approved dosing schema. The JAK2V617F allele burden decreased from baseline to week 24 (17.8% ± 18.0%), with one patient achieving a complete molecular response. Ropeginterferon alfa-2b was well-tolerated and most adverse events (AEs) were mild or moderate. Common AEs included alanine aminotransferase and aspartate aminotransferase increases mostly at grade 1 or 2 levels. Patients did not present with jaundice or significant bilirubin level increase. No grade 4 or 5 AEs occurred. Seven patients (14.3%) experienced reversible, drug-related grade 3 AEs. No AEs led to treatment discontinuation. Ropeginterferon alfa-2b at the 250-350-500 µg regimen is highly effective and well-tolerated and can help patients achieve greater and rapid complete hematologic and molecular responses.Clinical Trial Registration: This trial is registered at ClinicalTrials.gov (Identifier: NCT05485948) and in China (China National Medical Products Administration Registration Number: CTR20211664).

Towards a population pharmacokinetic/pharmacodynamic model of anti-VEGF therapy in patients with age-related macular degeneration.

PURPOSE: To develop a population pharmacokinetic/pharmacodynamic model (popPKPD) of intravitreal bevacizumab treatment for neovascular age-related macular degeneration (nAMD) patients to learn about the PK/PD relationship and utilise it for dosing regimen decisions on future nAMD patients. METHODS: The Greater Manchester Avastin for Neovascularisation (GMAN) randomised clinical trial data was retrospectively utilised, and the best-corrected visual acuity (BCVA) and central macular retinal thickness (CRT, measured by optical coherence tomography) were the PD inputs to the model. Using the nonlinear mixed-effects method, the best PKPD structural model was investigated, and the clinical significance of the two different dosing treatment regimens (as-needed versus routine) was evaluated. RESULTS: A structural model to describe the change of BCVA from the baseline of nAMD patients was successfully obtained based on the turnover PD model concept (drug stimulates the "visual acuity response production"). The popPKPD model and simulation indicate that the routine regimen protocol improves patient visual outcome compared to the as-needed protocol. For the change in CRT, the turnover structural PKPD model was too demanding to fit to the given clinical data. CONCLUSIONS: This is the first popPKPD attempt in nAMD treatment that shows the potential of this strategy to understand/inform the dosing regimen. Clinical trials with richer PD data will provide the means to build more robust models.

Optimal dosing regimen of biapenem based on population pharmacokinetic/pharmacodynamic modelling and Monte Carlo simulation in patients with febrile neutropenia and haematological malignancies.

In the current study, a population pharmacokinetic (PPK) model was developed for biapenem in patients with febrile neutropenia (FN) and haematological malignancies. Through Monte Carlo simulation, optimal administration regimens were suggested based on the developed PPK model. In a prospective, single-centre, open-label study, 174 plasma samples from 120 Chinese patients with FN and haematological malignancies were analysed by chromatography, and PK parameters were analysed by NONMEM. The drug clearance process was influenced by crucial covariates, namely creatinine clearance (CLCR) and concomitant posaconazole (POS). The ultimate PPK model was as follows: CL (L/h)=29.81 × (CLCR/121.38)0.806 × (1-POS × 0.297); volume of distribution (L)=114. For the target of ≥40% fT>minimum inhibitory concentration (MIC) (duration that the plasma level exceeds the MIC of the causative pathogen) and achieving the probability of target attainment ≥90%, the PK/pharmacodynamic breakpoint was 2 mg/L for the 2.4 g/day dosing regimen consisting of 600 mg q6h and 800 mg q8h. The breakpoint was 1 mg/L for the 1.2 g/day dosing regimen consisting of 300 mg q6h and 600 mg q12h. Empirical therapy would benefit from utilizing higher dosages and extended infusion durations. Therefore, it is suggested that patients with symptoms that are strongly suggestive of Pseudomonas aeruginosa or Acinetobacter baumannii infection may be suitable for combined treatment with other antibacterial drugs.

Development and Validation of Physiologically Based Pharmacokinetic Model of Levetiracetam to Predict Exposure and Dose Optimization in Pediatrics.

Levetiracetam (Lev) is an antiepileptic drug that has been increasingly used in the epilepsy pediatric population in recent years, but its pharmacokinetic behavior in pediatric population needs to be characterized clearly. Clinical trials for the pediatric drug remain difficult to conduct due to ethical and practical factors. The purpose of this study was to use the physiologically based pharmacokinetic (PBPK) model to predict changes in plasma exposure of Lev in pediatric patients and to provide recommendations for dose adjustment. A PBPK model of Lev in adults was developed using PK-Sim® software and extrapolated to the entire age range of the pediatric population. The model was evaluated using clinical pharmacokinetic data. The results showed the good fit between predictions and observations of the adult and pediatric models. The recommended doses for neonates, infants and children are 0.78, 1.67 and 1.22 times that of adults, respectively. Moreover, at the same dose, plasma exposure in adolescents was similar to that of adults. The PBPK models of Lev for adults and pediatrics were successfully developed and validated to provide a reference for the rational administration of drugs in the pediatric population.

Pharmacokinetics of intravenous daptomycin in Japanese pediatric patients: Pharmacokinetic comparisons supporting dosing recommendations in Japanese pediatric patients.

INTRODUCTION: The pharmacokinetics (PK) of daptomycin has not been previously characterized in Japanese pediatric patients with complicated skin and soft tissue infections (cSSTI) or bacteremia. An aim of the study includes evaluation of PK of daptomycin in Japanese pediatric patients and an appropriateness of the age-specific, weight-based dosing regimens in Japanese pediatric patients based on PK comparison with Japanese adult patients. METHODS: The phase 2 trial enrolled Japanese pediatric patients (age 1-17 years) with cSSTI (n = 14) or bacteremia (n = 4) caused by gram-positive cocci in order to evaluate safety, efficacy and PK. The Phase 3 trial in Japanese adult patients (SSTI n = 65, septicemia/right-sided infective endocarditis (RIE) n = 7) was referred to for PK comparison between adult and pediatric. Daptomycin concentrations in plasma were analyzed by reverse-phase high-performance liquid chromatography (HPLC). PK parameters were determined using non-compartmental analysis in Japanese pediatric and Japanese adult patients. The exposures in Japanese pediatric patients were graphically compared with those in Japanese adult patients. The relationship between daptomycin exposures and creatine phosphokinase (CPK) elevation was explored visually. RESULTS: Following administration of the age-specific, weight-based dosing regimens, daptomycin exposures were overlapping across age groups in pediatric patients with cSSTI with similar observations based on clearance. The distribution of individual exposure in Japanese pediatric patients was overlapping with that in Japanese adult patients. No apparent relationship between daptomycin exposures and CPK elevation in Japanese pediatric patients was observed. CONCLUSIONS: The results suggested that the age-specific, weight-based dosing regimens are considered to be appropriate in Japanese pediatric patients.

Dose adjustment not required for contezolid in patients with moderate hepatic impairment based on pharmacokinetic/pharmacodynamic analysis.

Objective: Contezolid is an oxazolidinone antimicrobial agent newly approved for treatment of Gram-positive bacterial infections. It is primarily metabolized by the liver. This study aimed to assess whether it is required to adjust the dose of contezolid in patients with moderate hepatic impairment for clinicians to use the drug more rationally. Methods: A single-center, open-label, parallel-group study was conducted to compare the pharmacokinetic (PK) parameters of contezolid and its metabolite M2 between the patients with moderate hepatic impairment and healthy controls with normal liver function after oral administration of 800 mg contezolid tablets. Monte Carlo simulation was performed to calculate the probability of target attainment (PTA) and cumulative fraction of response (CFR) of contezolid based on the PK and pharmacodynamic data. Results: Oral treatment with 800 mg contezolid tablets was safe and well tolerated in both the patients with moderate hepatic impairment and healthy controls. Moderate hepatic impairment did not result in substantial difference in the area under the concentration-time curve from 0 to 24 h (AUC0-24h, 106.79 vs. 97.07 h µg/mL) of contezolid even though lower maximum concentration (Cmax, 19.03 vs. 34.49 µg/mL) compared with healthy controls. The mean cumulative amount excreted in urine from 0 to 48 h (Ae0-48h) and renal clearance (CLR) of contezolid did not show significant difference between the two groups. Moderate hepatic impairment was associated with lower Cmax, slightly lower AUC and Ae0-48h of M2 compared to the healthy controls. fAUC/MIC was the best PK/PD index to predict the clinical efficacy of contezolid. Monte Carlo simulation results indicated that at the proposed fAUC/MIC target value of 2.3, the dosing regimen of oral contezolid 800 mg q12h could achieve satisfactory PTA and CFR (both >90%) for the target pathogen (methicillin-resistant S. aureus, MIC ≤4 mg/L) in patients with moderate hepatic impairment. Conclusion: Our preliminary data suggest that dose adjustment is not required for contezolid in patients with moderate hepatic impairment. Clinical Trial Registration: https://chinadrugtrials.org.cn, identifier: CTR20171377.

Population pharmacokinetics of levornidazole in healthy subjects and patients, and sequential dosing regimen proposal using pharmacokinetic/pharmacodynamic analysis.

Although sequential treatment with levornidazole has been used for anaerobic infection in clinical practice, there is no evidence-based dosing regimen. This study aimed to evaluate the pharmacokinetics (PK) of levornidazole in healthy subjects and patients, and to propose an evidence-based sequential dosing regimen by pharmacokinetic/pharmacodynamic (PK/PD) analysis. A population PK model was built using the data of 116 Chinese subjects, including 88 healthy young subjects, 12 healthy elderly subjects, and 16 patients with intra-abdominal anaerobic infection. PK/PD analysis was performed combining the minimum inhibitory concentration (MIC) values of levornidazole against 375 anaerobic strains. Four sequential dosing regimens (500 mg q12h, 1000 mg loading dose followed by 500 mg q12h, 750 mg q24h, and 1000 mg q24h) were evaluated in terms of cumulative fraction of response (CFR) and probability of target attainment (PTA) by Monte Carlo simulation. The concentration data of levornidazole and its active metabolites were described adequately by two- and one-compartment models, respectively. Body weight was identified as a significant covariate of levornidazole clearance. Simulations showed that satisfactory PTA (>90%) was achieved for the four dosing regimens when MIC ≤1 mg/L. Considering the simulation results, patients' safety and compliance, levornidazole 750 mg intravenous infusion q24h for 2 days followed by 750 mg oral dose q24h for 5 days was optimal for Bacteroides spp. with an identified MIC ≤1 mg/L.

Recombinant human thrombopoietin (rhTPO) of different dosing regimens for refractory/relapsed primary immune thrombocytopenia: a multicenter, randomized controlled trial and pharmacokinetics study.

Recombinant human TPO (rhTPO) is effective for refractory/relapsed primary immune thrombocytopenia (ITP), but optimal dosing regimen remains elusive. In this multicenter, randomized, controlled trial, a total of 282 adult ITP patients (mean age 47.3 years; 82 men) with a platelet count ≤30 × 109/L or >30 × 109/L with active bleeding randomly received a once daily (QD) subcutaneous injection of 7500 U (n = 64) or 15000 U rhTPO for 14 injections, or 15000 U or 30000 U rhTPO once every other day (QOD) for 7 injections. The primary outcomes included change from baseline in platelet count and total response rate (TRR) on day 14. On day 14, the median increase of platelet count from baseline was the highest in the 15000-U QD group (167.5 × 109/L, interquartile range [IQR] 23.0-295.0 × 109/L), followed by the 30000-U QOD group (57.5 × 109/L, IQR 9.0-190.0 × 109/L) (ANCOVA P < .001; P = .266 with baseline count as a covariate). The TRR on day 14 was also the highest in the 15000-U QD group (63.2%), followed by the 30000-U QOD group (59.7%). The rate of grade 3 and above adverse events did not differ among the four groups. There were no new safety concerns. All 4 regimens are safe and well-tolerated. The 30000-U QOD regimen is practically indistinguishable in efficacy to the 15000-U QD regimen.

What is the context? Relative thrombopoietin deficiency is implicated in primary immune thrombocytopenia (ITP), which is characterized by increased platelet destruction and impaired megakaryopoiesis.Patients who are innately unresponsive to or have relapsed after glucocorticoid treatment have limited treatment options.Recombinant human thrombopoietin (rhTPO) improves treatment response of primary ITP patients when added to high-dose dexamethasone.What is new? This trial sought to identify an optimal dosing regimen of rhTPO for patients who had failed or relapsed after glucocorticoid therapy.Of the 4 regimens, once daily 15000 U rhTPO for 14 injections yielded the greatest median increase in platelet count (167.5 × 10⁹/L) from baseline and attained the highest total response rate on day 14 (63.2%).30000 U rhTPO once every other day for 7 injections was effective in rapidly increasing platelet counts in the first 7 days.All 4 regimens were safe and well-tolerated.What is the impact? The 30000 U rhTPO once every other day regimen may offer an effective and safe regimen with less frequent injections, but future trials with longer follow-up are needed.

Population pharmacokinetic model and dosing optimization of vancomycin in hematologic malignancies with neutropenia and augmented renal clearance.

AIM: Data on the pharmacokinetics (PK) and area under the curve (AUC)-based dosing strategy of vancomycin (VCM) in hematologic malignancies are limited. According to our preliminary narrative review, only a few population PK analyses in hematologic malignancies have been performed. Therefore, we aimed to develop a population PK model, investigate the factors influencing VCM PK, and propose an optimal dosing regimen for hematologic malignancies. METHODS: A retrospective study was conducted in patients with underlying hematologic malignancies treated with VCM. A total of 148 patients were enrolled for population PK modeling. Simulation analyses were performed to identify dosing regimens achieving a target exposure of AUC0-24 of 400-600 mg h/L at the steady-state. RESULTS: The VCM PK data were best described with a one-compartment model. Significant covariates included creatinine clearance (Ccr), diagnosis of acute myeloid leukemia (AML) and neutropenia on VCM clearance (CL), and body weight (WT) on the volume of distribution (Vd). The typical values of CL and Vd were 3.09 L/h (normalized to Ccr value of 90 mL/min) and 122 L/70 kg, respectively. Concerning the effect on VCM dosing, AML patients required 15% higher doses than non-AML patients, independently of renal function. In contrast, for neutropenic patients, only those with augmented renal clearance (ARC, Ccr value ≥ 130 mL/min) required a 10% dose increase compared to non-neutropenic patients. CONCLUSION: AML patients with neutropenia and ARC represent a critical population with a higher risk of VCM underexposure. Thus, individualized dosing adjustment and therapeutic drug monitoring are strongly recommended.