scholarly journals Evaluating clinical impact of a shortened infusion duration for ramucirumab: a model-based approach

2021 ◽  
Vol 87 (5) ◽  
pp. 635-645
Author(s):  
Ling Gao ◽  
Yiu-Keung Lau ◽  
Ran Wei ◽  
Lisa O’Brien ◽  
Amanda Long ◽  
...  
Keyword(s):  
Infusion Rate ◽  
Time Course ◽  
Pharmacokinetic Profile ◽  
Sensitivity Analyses ◽  
Population Pharmacokinetic ◽  
Pharmacokinetic Data ◽  
Concentration Profiles ◽  
Increased Risk ◽  
The Impact ◽  
Infusion Duration

Abstract Purpose We investigated the impact of infusion duration (30 and 60 min) on the pharmacokinetic profile of ramucirumab using a population pharmacokinetic (PopPK) modeling approach. We also assessed the relationship between infusion rate and incidence of immediate infusion-related reactions (IRRs; occurring on the day of administration) using ramucirumab phase II/III study data. Methods The impact of different infusion durations (30 vs. 60 min) on the time-course of ramucirumab concentration profiles were evaluated using a PopPK model, established using ramucirumab pharmacokinetic data from 2522 patients. Logistic regression was used to evaluate the association between ramucirumab infusion rate and incidence of immediate IRRs in clinical trials. Results Ramucirumab time-course concentration profiles were equivalent following a 30- or 60-min infusion. In the pooled clinical study dataset, 254 of 3216 (7.9%) patients receiving ramucirumab experienced at least one immediate IRR (any grade). When grouped according to infusion rate quartile, the incidence of immediate IRRs (any grade or grade ≥ 3) was similar across quartiles; findings were confirmed in sensitivity analyses. The risk of immediate IRRs was not found to be associated with infusion rate based on multivariate logistic analysis. Conclusion Shortening the infusion duration of ramucirumab from 60 to 30 min has no impact on ramucirumab exposure. Analysis of trial data found no relationship between an increased risk of immediate IRRs and a faster infusion rate. Such a change in infusion duration is unlikely to affect the clinical efficacy or overall safety profile of ramucirumab.

Evaluating the clinical impact of a shortened infusion duration for ramucirumab: A population pharmacokinetic model-based approach.

2021 ◽  
Vol 39 (3_suppl) ◽  
pp. 191-191
Author(s):  
Paolo Abada ◽  
Yiu-Keung Lau ◽  
Ran Wei ◽  
Lisa O’Brien ◽  
Amanda Long ◽  
...  
Keyword(s):  
Infusion Rate ◽  
Population Pharmacokinetic Model ◽  
Pharmacokinetic Model ◽  
Study Data ◽  
Population Pharmacokinetic ◽  
Time Profiles ◽  
Concentration Time ◽  
Increased Risk ◽  
Grade 3 ◽  
Infusion Duration

191 Background: Ramucirumab is a human recombinant immunoglobin G1 monoclonal antibody (mAb) antagonist of vascular endothelial growth factor receptor-2. Ramucirumab dosed at 8 mg/kg every 2 weeks or 10 mg/kg every 3 weeks, either as monotherapy or in combination with chemotherapy, was initially studied with as an intravenous infusion over 60 minutes following premedication with a histamine-1 receptor antagonist. Lengthy intravenous infusions are inconvenient for patients and increase the workloads of nursing and administrative staff. Shortening the infusion duration of ramucirumab could therefore benefit both patients and healthcare professionals. The current analysis determined the impact such a change could have on the pharmacokinetic (PK) profile of ramucirumab. Additionally, the relationship between infusion rate and incidence of immediate infusion-related reactions (IRRs; occurring on the day of administration), common adverse events associated with mAb infusions, was assessed. Methods: A population pharmacokinetic model was established using concentration–time data collected from 2522 patients who received one of five different ramucirumab regimens involving an intravenous infusion over ~60 minutes in 17 clinical studies. The final PK model was used to simulate concentration–time profiles and exposure parameters following ramucirumab infusion durations of 30 vs 60 min. Phase II/III clinical study data from patients receiving ramucirumab were pooled to assess the association between ramucirumab infusion rate and incidence of immediate IRRs using multivariate logistic regression analysis. Results: Ramucirumab infusions of 30- and 60-min durations resulted in equivalent concentration–time profiles and, hence, equivalent systemic exposure to ramucirumab. Among 3216 patients receiving ramucirumab in phase II/III studies, 254 (7.9%) had at least one immediate any-grade IRR; 17 (0.5%) experienced grade ≥3 immediate IRRs. The incidence of immediate IRRs (any grade or grade ≥3) was similar across infusion rate quartiles. Under multivariate logistic analysis, infusion rate was not significantly associated with an increased risk of an immediate IRR (odds ratio per 1 mg/min increase 1.014, 95% confidence interval 0.999, 1.030; p=0.071). Conclusions: Administering ramucirumab using different infusion durations (30 vs 60 min) did not affect ramucirumab exposure. Analysis of clinical study data showed a faster infusion rate was not associated with an increased risk of immediate IRRs. It is considered unlikely that shortening the infusion duration of ramucirumab will impact its clinical efficacy or overall safety profile, and is now an option for administration in the U.S.

Body mass index and risk of all-cause mortality in normotensive and hypertensive adults: The Rural Chinese Cohort Study

2021 ◽  
pp. 1-25
Author(s):  
Qionggui Zhou ◽  
Xuejiao Liu ◽  
Yang Zhao ◽  
Pei Qin ◽  
Yongcheng Ren ◽  
...  
Keyword(s):  
Cohort Study ◽  
Population Based ◽  
Normal Weight ◽  
Sensitivity Analyses ◽  
Hypertension Status ◽  
Moderation Effect ◽  
Increased Risk ◽  
All Cause Mortality ◽  
Chinese Cohort ◽  
The Impact

Abstract Objective: The impact of baseline hypertension status on the BMI–mortality association is still unclear. We aimed to examine the moderation effect of hypertension on the BMI–mortality association using a rural Chinese cohort. Design: In this cohort study, we investigated the incident of mortality according to different BMI categories by hypertension status. Setting: Longitudinal population-based cohort Participants: 17,262 adults ≥18 years were recruited from July to August of 2013 and July to August of 2014 from a rural area in China. Results: During a median 6-year follow-up, we recorded 1109 deaths (610 with and 499 without hypertension). In adjusted models, as compared with BMI 22-24 kg/m2, with BMI ≤18, 18-20, 20-22, 24-26, 26-28, 28-30 and >30 kg/m2, the HRs (95% CI) for mortality in normotensive participants were 1.92 (1.23-3.00), 1.44 (1.01-2.05), 1.14 (0.82-1.58), 0.96 (0.70-1.31), 0.96 (0.65-1.43), 1.32 (0.81-2.14), and 1.32 (0.74-2.35) respectively, and in hypertensive participants were 1.85 (1.08-3.17), 1.67 (1.17-2.39), 1.29 (0.95-1.75), 1.20 (0.91-1.58), 1.10 (0.83-1.46), 1.10 (0.80-1.52), and 0.61 (0.40-0.94) respectively. The risk of mortality was lower in individuals with hypertension with overweight or obesity versus normal weight, especially in older hypertensives (≥60 years old). Sensitivity analyses gave consistent results for both normotensive and hypertensive participants. Conclusions: Low BMI was significantly associated with increased risk of all-cause mortality regardless of hypertension status in rural Chinese adults, but high BMI decreased the mortality risk among individuals with hypertension, especially in older hypertensives.

Gastrostomy Tubes Placed in Children With Neurologic Impairment: Associated Morbidity and Mortality

2021 ◽  
pp. 088307382110001
Author(s):  
Jody L. Lin ◽  
Joseph Rigdon ◽  
Keith Van Haren ◽  
MyMy Buu ◽  
Olga Saynina ◽  
...  
Keyword(s):  
Severe Pneumonia ◽  
Sensitivity Analyses ◽  
Tube Placement ◽  
Composite Outcome ◽  
Eligibility Criteria ◽  
Risk Of Death ◽  
Cox Proportional Hazard ◽  
Neurologic Impairment ◽  
Increased Risk ◽  
The Impact

Background: Gastrostomy tube (G-tube) placement for children with neurologic impairment with dysphagia has been suggested for pneumonia prevention. However, prior studies demonstrated an association between G-tube placement and increased risk of pneumonia. We evaluate the association between timing of G-tube placement and death or severe pneumonia in children with neurologic impairment. Methods: We included all children enrolled in California Children’s Services between July 1, 2009, and June 30, 2014, with neurologic impairment and 1 pneumonia hospitalization. Prior to analysis, children with new G-tubes and those without were 1:2 propensity score matched on sociodemographics, medical complexity, and severity of index hospitalization. We used a time-varying Cox proportional hazard model for subsequent death or composite outcome of death or severe pneumonia to compare those with new G-tubes vs those without, adjusting for covariates described above. Results: A total of 2490 children met eligibility criteria, of whom 219 (9%) died and 789 (32%) had severe pneumonia. Compared to children without G-tubes, children with new G-tubes had decreased risk of death (hazard ratio [HR] 0.47, 95% confidence interval [CI] 0.39-0.55) but increased risk of the composite outcome (HR 1.21, CI 1.14-1.27). Sensitivity analyses using varied time criteria for definitions of G-tube and outcome found that more recent G-tube placement had greater associated risk reduction for death but increased risk of severe pneumonia. Conclusion: Recent G-tube placement is associated with reduced risk of death but increased risk of severe pneumonia. Decisions to place G-tubes for pulmonary indications in children with neurologic impairment should weigh the impact of severe pneumonia on quality of life.

scholarly journals Real-world evidence on sodium-glucose cotransporter-2 inhibitor use and risk of Fournier’s gangrene

2020 ◽  
Vol 8 (1) ◽  
pp. e000985 ◽  
Author(s):  
Jeff Yufeng Yang ◽  
Tiansheng Wang ◽  
Virginia Pate ◽  
John B Buse ◽  
Til Stürmer
Keyword(s):  
Real World ◽  
Fournier’S Gangrene ◽  
Sensitivity Analyses ◽  
Standardized Mortality Ratio ◽  
Fournier's Gangrene ◽  
Diagnosis Codes ◽  
Sodium Glucose Cotransporter ◽  
Real World Evidence ◽  
Increased Risk ◽  
The Impact

BackgroundSodium-glucose cotransporter-2 inhibitors (SGLT2i) have been associated with increased occurrence of Fournier’s gangrene (FG), a rare but serious form of necrotizing fasciitis, leading to a warning from the Food and Drug Administration. Real-world evidence on FG is needed to validate this warning.MethodsWe used data from IBM MarketScan (2013–2017) to compare the incidence of FG among adult patients who initiated either SGLT2i, a dipeptidyl peptidase-4 inhibitor (DPP4i), or any non-SGLT2i antihyperglycemic medication. FG was defined using inpatient International Classification of Diseases, Ninth Edition and Tenth Edition diagnosis codes 608.83 and N49.3, respectively, combined with procedure codes for debridement, surgery, or systemic antibiotics. We estimated crude incidence rates (IRs) using Poisson regression, and crude and adjusted HRs (aHR) and 95% CIs using standardized mortality ratio-weighted Cox proportional hazards models. Sensitivity analyses examined the impact of alternative outcome definitions.ResultsWe identified 211 671 initiators of SGLT2i (n=93 197) and DPP4i (n=118 474), and 305 329 initiators of SGLT2i (n=32 868) and non-SGLT2i (n=272 461). Crude FG IR ranged from 3.2 to 3.8 cases per 100 000 person-years during a median follow-up of 0.51–0.58 years. Compared with DPP4i, SGLT2i initiation was not associated with increased risk of FG for any outcome definition, with aHR estimates ranging from 0.25 (0.04–1.74) to 1.14 (0.86–1.51). In the non-SGLT2i comparison, we observed an increased risk of FG for SGLT2i initiators when using FG diagnosis codes alone, using all diagnosis settings (aHR 1.80; 0.53–6.11) and inpatient diagnoses only (aHR 4.58; 0.99–21.21).ConclusionsNo evidence of increased risk of FG associated with SGLT2i was observed compared with DPP4i, arguably the most relevant clinical comparison. However, uncertainty remains based on potentially higher risk in the broader comparison with all non-SGLT2i antihyperglycemic agents and the rarity of FG.Trial registration numberEUPAS Register Number 30018.

scholarly journals Evaluating probiotics for the prevention of ventilator-associated pneumonia: a randomised placebo-controlled multicentre trial protocol and statistical analysis plan for PROSPECT

BMJ Open ◽  
2019 ◽  
Vol 9 (6) ◽  
pp. e025228 ◽  
Author(s):  
Jennie Johnstone ◽  
Diane Heels-Ansdell ◽  
Lehana Thabane ◽  
Maureen Meade ◽  
John Marshall ◽  
...  
Keyword(s):  
Statistical Analysis ◽  
Critically Ill ◽  
Critically Ill Patients ◽  
Controlled Trial ◽  
Statistical Analysis Plan ◽  
Hospital Length Of Stay ◽  
Sensitivity Analyses ◽  
Ventilator Associated Pneumonia ◽  
Increased Risk ◽  
The Impact

IntroductionVentilator-associated pneumonia (VAP) is the most common healthcare-associated infection in critically ill patients. Prior studies suggest that probiotics may reduce VAP and other infections in critically ill patients; however, most previous randomised trials were small, single centre studies. The Probiotics: Prevention of Severe Pneumonia and Endotracheal Colonization Trial (PROSPECT) aims to determine the impact of the probioticLactobacillus rhamnosusGG on VAP and other clinically important outcomes in critically ill adults.MethodsPROSPECT is a multicentre, concealed, randomised, stratified, blinded, controlled trial in patients ≥18 years old, anticipated to be mechanically ventilated ≥72 hours, in intensive care units (ICUs) in Canada, the USA and Saudi Arabia. Patients receive either 1×1010 colony forming units ofL. rhamnosusGG twice daily or an identical appearing placebo. Those at increased risk of probiotic infection are excluded. The primary outcome is VAP. Secondary outcomes are other ICU-acquired infections includingClostridioides difficileinfection, diarrhoea (including antibiotic-associated diarrhoea), antimicrobial use, ICU and hospital length of stay and mortality. The planned sample size of 2650 patients is based on an estimated 15% VAP rate and will provide 80% power to detect a 25% relative risk reduction.Ethics and disseminationThis protocol and statistical analysis plan outlines the methodology, primary and secondary analyses, sensitivity analyses and subgroup analyses. PROSPECT is approved by Health Canada (#9427-M1133-45C), the research ethics boards of all participating hospitals and Public Health Ontario. Results will be disseminated via academic channels (peer reviewed journal publications, professional healthcare fora including international conferences) and conventional and social media. The results of PROSPECT will inform practice guidelines worldwide.Trialregistration numberNCT02462590; Pre-results.

scholarly journals The Potential Role of Human Papillomavirus Infection in Bell's Palsy: A Hypothesis-Generating Study Based on a Nationwide Cohort

2021 ◽  
Vol 8 ◽  
Author(s):  
Kuan-Ying Li ◽  
Mei-Chia Chou ◽  
Renin Chang ◽  
Hei-Tung Yip ◽  
Yao-Min Hung ◽  
...  
Keyword(s):  
Human Papillomavirus ◽  
Index Date ◽  
Hpv Infection ◽  
Bell’S Palsy ◽  
Sensitivity Analyses ◽  
Chronic Obstructive ◽  
Bell's Palsy ◽  
Increased Risk ◽  
The Impact

Objective: Our purpose was to investigate whether people with a previous human papillomavirus (HPV) infection were associated with an increased risk of Bell's palsy (BP).Methods: By using Taiwan population-based data, patients aged > 18 years with HPV infection (n = 22,260) from 2000 to 2012 were enrolled and compared with control subjects who had never been diagnosed with an HPV infection at a 1:4 ratio matched by sex, age, index date, and co-morbidities (n = 89,040). The index date was the first date of HPV diagnosis. All the patients were tracked until the occurrence of BP. Cox proportional hazards regression was applied to estimate the hazard ratios (HRs) for the development of BP in both groups.Results: The HPV group had 1.25 [95% confidence interval (CI) = 1.03–1.51] times higher risk of BP compared with the non-HPV group after adjusting for sex, age, and co-morbidities. The association of HPV and BP was significant in the sensitivity analyses. In the subgroup analysis, the impact of HPV infection on the risk of BP was more pronounced in the elderly > 50 years [adjusted hazard ratio (aHR) =1.86; 95% CI = 1.37–2.52], hypertension (aHR = 1.65; 95% CI = 1.17–2.31), and chronic obstructive pulmonary disease (aHR = 2.14, 95% CI 1.333.43) subgroups.Conclusions: Patients with HPV infection have a higher risk of subsequent BP compared with non-HPV patients. More rigorous studies are needed to confirm if and how specific HPV genotypes are associated with BP and the possible role of vaccines in disease prevention.

scholarly journals 2389. Assessing the Time Course of Proton Pump Inhibitor Use and Clostridioides difficile Infection

2019 ◽  
Vol 6 (Supplement_2) ◽  
pp. S825-S825
Author(s):  
Katherine Panagos ◽  
Natalia Blanco ◽  
Surbhi Leekha ◽  
Erik von Rosenvinge ◽  
Emily Heil
Keyword(s):  
Proton Pump ◽  
Time Course ◽  
Conditional Logistic Regression ◽  
Academic Medical Center ◽  
Antibiotic Use ◽  
Clostridioides Difficile ◽  
Increased Risk ◽  
Significant Difference ◽  
Clostridioides Difficile Infection ◽  
The Impact

Abstract Background Proton pump inhibitors (PPIs) are a known risk factor for Clostridioides difficile infection (CDI) and recurrence, even in the absence of antibiotic use. No studies have specifically assessed the increased risk for CDI based on PPI duration, given that PPIs are frequently newly prescribed during hospitalizations and infrequently discontinued, even when CDI has occurred. The aim of this project was to assess the time course of PPI utilization and risk of CDI. Methods We conducted a retrospective matched case–control study comparing patients who developed CDI (cases) with patients who did not develop CDI (controls, matched on age, gender, date of admission and hospital location) from a cohort of patients with a C.difficile PCR test order from an academic medical center. Patient charts were reviewed for PPI use prior to the date of the positive test and whether the PPI was started in the hospital or as a home medication (>30d, 30–90d, 90–180d, >180d). The primary comparison was odds of PPI use between cases and controls using conditional logistic regression adjusted for antibiotic exposure (SAS 9.4, Cary, NC). Results A total of 348 patients were included in the study, 174 cases and 174 matched controls. 65% of patients in the study received a PPI, 85% a PPI or H2 blocker and 95% of patients received antibiotics during their admission. Patients on PPIs as home medications were not at an increased risk of CDI (OR = 1.08 (95% CI 0.60–1.93)) compared with those not on PPIs. Patients whose PPIs were initiated in the hospital were at increased risk of CDI compared with those not on PPIs (OR = 1.4 (95% CI 0.81–2.41)). No significant difference was observed across time periods of PPI use prior to admission and development of CDI. Conclusion Patients who started PPIs during inpatient stays were at a higher risk of developing CDI than patients not exposed to PPIs. However, PPI use was not found to be significantly associated with CDI in this analysis, regardless of the time or duration of PPI prescription. The results may be confounded by the high frequency of PPI use and concomitant antibiotic use in both cases and controls. Further study is needed to evaluate the impact of short-course PPI prescriptions in inpatient settings on CDI. Disclosures All authors: No reported disclosures.

scholarly journals 20. Cost-Effectiveness of Implementing 13-Valent Pneumococcal Conjugate Vaccine (Pcv13) for Adults Aged ≥19 Years with Underlying Conditions

2020 ◽  
Vol 7 (Supplement_1) ◽  
pp. S33-S33
Author(s):  
Miwako Kobayashi ◽  
Charles Stoecker ◽  
Wei Xing ◽  
Bo-Hyun Cho ◽  
Tamara Pilishvili
Keyword(s):  
Cost Effectiveness ◽  
Pneumococcal Disease ◽  
Clinical Decision Making ◽  
Vaccine Effectiveness ◽  
Sensitivity Analyses ◽  
Base Case ◽  
Case Scenario ◽  
Increased Risk ◽  
In Series ◽  
The Impact

Abstract Background In June 2019, the U.S. Advisory Committee on Immunization Practices changed the recommendation for routine PCV13 use in immunocompetent adults aged ≥65, including those with certain chronic medical conditions (CMC); PCV13 is now recommended based on shared clinical decision-making. Adults with CMC continue to be at increased risk for pneumococcal disease. We assessed the cost-effectiveness of adding PCV13 to the recommended PPSV23 dose for adults aged ≥19 years with CMC. Methods We used a probabilistic model following a cohort of 19-year-old U.S. adults. We used Monte Carlo simulation to estimate the impact on program, medical, and non-medical costs (in 2017 U.S. dollars [$] using the societal perspective), and pneumococcal disease burden when administering PCV13 in series with PPSV23. Table 1 shows vaccine effectiveness (VE) assumptions for the base case. We performed one-way sensitivity analyses assuming higher PCV13 VE against serotype 3 disease. Vaccine effectiveness assumptions by age group used for the base case Results In the base-case scenario, adding a dose of PCV13 upon CMC diagnosis cost $689,299 per QALY. Results of one-way sensitivity analyses are presented in Table 2. Base case and one-way sensitivity analyses of adding PCV13 at diagnosis of CMC Conclusion Adding PCV13 in series with PPSV23 for adults 19 years or older with CMC was not cost-saving. Results were sensitive to assumptions on PCV13 VE against serotype 3 disease. Disclosures All Authors: No reported disclosures

scholarly journals The risk of infections in adult patients with systemic lupus erythematosus: systematic review and meta-analysis

Rheumatology ◽  
2020 ◽  
Vol 60 (1) ◽  
pp. 60-72 ◽  
Author(s):  
José María Pego-Reigosa ◽  
Lindsay Nicholson ◽  
Nick Pooley ◽  
Sue Langham ◽  
Nina Embleton ◽  
...  
Keyword(s):  
Systematic Review ◽  
Herpes Zoster ◽  
General Population ◽  
Meta Analysis ◽  
Severe Infection ◽  
Infection Risk ◽  
Sensitivity Analyses ◽  
Healthy Controls ◽  
Increased Risk ◽  
The Impact

Abstract Objectives We conducted a systematic review and meta-analysis to determine the magnitude of infection risk in patients with SLE and evaluate the effect of general and SLE-related factors on infection risk. Methods We searched MEDLINE and Embase from inception to July 2018, screening for observational studies that evaluated infection risk in patients with SLE compared with the general population/healthy controls. Outcomes of interest included overall severe infection, herpes zoster infection/reactivation, opportunistic infections, pneumonia and tuberculosis. Random-effects models were used to calculate pooled risk ratios (RRs) for each type of infection. Sensitivity analysis assessed the impact of removing studies with high risk of bias. Results Eleven retrospective or prospective cohort studies were included in the meta-analysis: overall severe infection (n = 4), pneumonia (n = 6), tuberculosis (n = 3) and herpes zoster (n = 2). Pooled RRs for overall severe infection significantly increased for patients with SLE compared with the general population/healthy controls [RR 2.96 (95% CI 1.28, 6.83)]. Pooled RRs for pneumonia, herpes zoster and tuberculosis showed significantly increased risk compared with the general population/healthy controls [RR 2.58 (1.80, 3.70), 2.50 (2.36, 2.65) and 6.11 (3.61, 10.33), respectively]. Heterogeneity and evidence of publication bias were present for all analyses, except herpes zoster. Sensitivity analyses confirmed robustness of the results. Conclusion Patients with SLE have significantly higher risk of infection compared with the general population/healthy controls. Efforts to strengthen strategies aimed at preventing infections in SLE are needed. Protocol registration PROSPERO number: CRD42018109425.

scholarly journals Impact of gender, albumin, and CYP2C19 polymorphisms on valproic acid in Chinese patients: a population pharmacokinetic model

2020 ◽  
Vol 48 (8) ◽  
pp. 030006052095228
Author(s):  
Jinlin Guo ◽  
Yayu Huo ◽  
Fang Li ◽  
Yuanping Li ◽  
Zhaojun Guo ◽  
...  
Keyword(s):  
Valproic Acid ◽  
Population Pharmacokinetic Model ◽  
Pharmacokinetic Model ◽  
Volume Of Distribution ◽  
Chinese Patients ◽  
Population Pharmacokinetic ◽  
Pharmacokinetic Data ◽  
Mixed Effect ◽  
First Order ◽  
The Impact

Objective This prospective study aimed to establish the valproic acid (VPA) population pharmacokinetic model in Chinese patients and realise personalised medication on the basis of population pharmacokinetics. Methods The patients’ clinical information and VPA plasma concentrations were collected from The General Hospital of Taiyuan Iron & Steel (Group) Corporation (TISCO). Nonlinear mixed-effect modelling was used to build the population pharmacokinetic model. To characterise the pharmacokinetic data, a one-compartment pharmacokinetic model with first-order absorption and elimination was used. The first-order conditional estimation with η-ε interaction was applied throughout the model-developing procedure. The absorption rate constant (Ka) was fixed at 2.38 hour−1, and the impact of covariates on clearance and apparent volume of distribution were also explored. Medical records of 60 inpatients were reviewed prospectively and the objective function value (OFV) of the base model and final model were 851.813 and 817.622, respectively. Results Gender was identified as the covariate that had a significant impact on the volume of distribution, and albumin and CYP2C19 genotypes influenced clearance. Conclusion Bootstrap and VPC indicated that a reliable model had been developed that was based on the simulation results, and a simple-to-use dosage regimen table was created to guide clinicians for VPA drug dosing.

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