POS0070 POPULATION PHARMACOKINETICS OF INFLIXIMAB IN CHILDREN WITH JUVENILE IDIOPATHIC ARTHRITIS

Background:Higher dosage regimes for Infliximab (IFX) have been described to be effective in partial- or non-responding adults and children with rheumatic disease and appear to be safe (1,2). To optimize IFX treatment in juvenile idiopathic arthritis (JIA) patients, therapeutic drug monitoring (TDM) might be beneficial. To support routine TDM of IFX and dose regimen optimization in JIA patients, more in-depth knowledge of the pharmacokinetic (PK) variability of IFX is needed. Ultimately, as soon as the optimal therapeutic drug ranges will be known, PK model-based simulation can be used to individualize drug dosing recommendations. Individual dosages may be adjusted by taking specific patient characteristics into account that explain inter-patient variability in pharmacokinetics (PK). Inter-patient variability can be quantified and investigated by the population approach.Objectives:Our hypothesis is that optimizing dosage and frequency of IFX administration for individual patients will improve treatment outcome. In this current study, the population PK for IFX are described for JIA patients.Methods:Data including IFX trough concentrations and anti-IFX antibodies of 27 JIA patients on IFX maintenance treatment were retrieved from electronic charts. Three population pharmacokinetic models from literature were validated for our dataset using nonlinear-mixed effects modeling program NONMEM (3,4,5). A novel population pharmacokinetic model was developed based on our study data.Results:A total of 65 obtained blood samples after a median of 32 days after the last IFX infusion (IQR 28-42) were analyzed. The three published models underpredicted the observed trough concentrations. A newly developed one compartment model best described the IFX serum concentration over time data in JIA patients (see Figure 1).Conclusion:Our study shows a novel and the first PK model for IFX in JIA patients. Our main finding was that a one- compartment model best described the IFX serum concentration over time data. Predictive performance of the known models from literature was insufficient for our patient data. Our data also show that different PK models are needed for different age categories (children or adults) and in different diseases.References:[1]Nozaki Y et al. Infliximab dose adjustment can improve the clinical and radiographic outcomes of rheumatoid arthritis patients: REVIVE study results. Biologics. 2018.[2]Tambralli A et al. High doses of infliximab in the management of juvenile idiopathic arthritis. J Rheumatol. 2013.[3]Fasanmade AA et al. Pharmacokinetic properties of infliximab in children and adults with Crohn’s disease: a retrospective analysis of data from 2 phase III clinical trials. Clin Ther. 2011.[4]Xu Z et al. Population pharmacokinetics of infliximab in patients with ankylosing spondylitis. J Clin Pharmacol. 2008.[5]Ternant D et al. Relationship between inflammation and infliximab pharmacokinetics in rheumatoid arthritis. Br J Clin Pharmacol. 2014.Table 1.Patient characteristicsN=27 patientsWeight (kg)52 [40 – 62]BSA1.6 [1.3 – 1.8]Age (years)14 [11 – 17]Male, N (%)6 (22%)CRP (mg/L)0.5 [0.2 – 0.7]WBC count6.5 [5.6 –7.5]Antibodies-to-IFX1 (4%)Dose (mg)300 [200-400]Dose (mg/kg)5.4 [4.9 -7.0]Hemoglobine (mmol/L)7.9 [7.5 -8.2]ESR (mm/h)5 [5-8]Uveitis3 (11%)Disclosure of Interests:None declared.

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1319. Pharmacokinetics of Ceftolozane/Tazobactam in Patients with Burns

Open Forum Infectious Diseases ◽

10.1093/ofid/ofaa439.1501 ◽

2020 ◽

Vol 7 (Supplement_1) ◽

pp. S670-S671

Author(s):

Ronald G Hall ◽

Jotam Pasipanodya ◽

William C Putnam ◽

John Griswold ◽

Sharmila Dissanaike ◽

...

Keyword(s):

Human Plasma ◽

Kidney Injury ◽

Compartment Model ◽

Pharmacokinetic Parameters ◽

Therapeutic Drug ◽

Population Pharmacokinetic ◽

Parameter Estimates ◽

Population Parameter ◽

Full Thickness ◽

Severe Burns

Abstract Background Antimicrobial dosing in moderate/severe burns patients is complicated due to the potential unpredictable hyperdynamic pathophysiologic states including 1) hypoproteinemia, 2) acute kidney injury and 3) onset of septicemia. Therefore, distribution assumptions about the population pharmacokinetic (PopPK) profiles of either endogenous or xenobiotic pharmacophores in this patient population can lead to biased parameter estimates. In order to prevent potential bias an agnostic nonparametric adaptive grid approach to describe ceftolozane/tazobactam (C/T) PopPK profiles in patients with partial- and full-thickness burns was employed. Methods A human clinical PK study in burn patients was conducted using the standard approved dose of C/T (2 grams/1 gram). A single intravenous dose was administered over 60 minutes. Whole blood was obtained pre-dose and at 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 16, and 24 hours following the start of infusion. LC-MS/MS bioanalytical methods were developed, validated and employed to determine C/T concentrations in human plasma. PopPK were modeled using Pmetrics package for R. One-, two- and three-compartment models were examined and compared. The influence of several parameters, including %body surface area burns, creatinine clearance (CrCL), weight, albumin and age were tested. Results The bioanalytical method for determination of C/T in human plasma met all recommended criteria of the LC-MS/MS. Five males and one female (ages 24 to 66 years), contributed 148 plasma PK samples. The female had 35% partial-thickness burns. The males had full-thickness burns ranging from 27 to 66%. The median CrCL was 104 mL/min (range 73-148 mL/min). Two-compartment model with absorption (Ka) from compartment 1 to 2 and elimination from compartment 2 (Ke), with nonlinear interactions between C/T elimination and CrCL best described the data. Figure A show that bias was minimal. Importantly, both drugs exhibited marked variability for both volume and elimination (Table), since volume was bimodally distributed (Figure B). A) Observation-versus-Prediction; B) Estimated Ke, V and Ka population parameter densities Summary of pharmacokinetic parameters Conclusion C/T exhibited high variability surpassing that observed with severe infections, suggesting that dose adjustment and/or may be therapeutic drug monitoring may be needed to balance target attainment from dose-related toxicities. Disclosures Ronald G. Hall, II, PharmD, MSCS, Medical Titan Group (Grant/Research Support)Merck (Research Grant or Support)

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Population pharmacokinetic modeling and dosing simulations of tobramycin in pediatric patients with cystic fibrosis

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00737-21 ◽

2021 ◽

Author(s):

Antonin Praet ◽

Laurent Bourguignon ◽

Florence Vetele ◽

Valentine Breant ◽

Charlotte Genestet ◽

...

Keyword(s):

Cystic Fibrosis ◽

Dose Adjustment ◽

Total Body Weight ◽

Compartment Model ◽

Therapeutic Drug ◽

Population Pharmacokinetic ◽

Time Curve ◽

Population Pharmacokinetic Modeling ◽

Two Compartment Model ◽

Total Body

Initial dosing and dose adjustment of intravenous tobramycin in cystic fibrosis children is challenging. The objectives of this study were to develop nonparametric population pharmacokinetic (PK) models of tobramycin in children with CF to be used for dosage design and model-guided therapeutic drug monitoring. We performed a retrospective analysis of tobramycin PK data in our CF children center. The Pmetrics package was used for nonparametric population PK analysis and dosing simulations. Both the maximal concentration over the MIC (Cmax/MIC) and daily area under the concentration-time curve to the MIC (AUC 24 /MIC) ratios were considered as efficacy target. Trough concentration (Cmin) was considered as the safety target. A total of 2884 tobramycin concentrations collected in 195 patients over 9 years were analyzed. A two-compartment model including total body weight, body surface area and creatinine clearance as covariates best described the data. A simpler model was also derived for implementation into the BestDose software to perform Bayesian dose adjustment. Both models were externally validated. PK/PD simulations with the final model suggest that an initial dose of tobramycin of 15 to 17.5 mg/kg/day was necessary to achieve Cmax/MIC ≥ 10 values for MIC values up to 2 mg/L in most patients. The AUC 24 /MIC target was associated with larger dosage requirements and higher Cmin. A daily dose of 12.5 mg/kg would optimize both efficacy and safety target attainment. We recommend to perform tobramycin TDM, model-based dose adjustment, and MIC determination to individualize intravenous tobramycin therapy in children with CF.

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β-Lactam Dosage Regimens in Septic Patients with Augmented Renal Clearance

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.02534-17 ◽

2018 ◽

Vol 62 (9) ◽

Cited By ~ 15

Author(s):

Alexandra Jacobs ◽

Fabio Silvio Taccone ◽

Jason A. Roberts ◽

Frédérique Jacobs ◽

Frederic Cotton ◽

...

Keyword(s):

Creatinine Clearance ◽

Renal Clearance ◽

Total Body Clearance ◽

Therapeutic Drug ◽

Population Pharmacokinetic ◽

Augmented Renal Clearance ◽

Drug Concentrations ◽

Trough Concentrations ◽

Total Body ◽

Body Clearance

ABSTRACTAugmented renal clearance is commonly observed in septic patients and may result in insufficient β-lactam serum concentrations. The aims of this study were to evaluate potential correlations between drug concentrations or total body clearance of β-lactam antibiotics and measured creatinine clearance and to quantify the need for drug dosage adjustments in septic patients with different levels of augmented renal clearance. We reviewed 256 antibiotic measurements (512 drug concentrations) from a cohort of 215 critically ill patients who had a measured creatinine clearance of ≥120 ml/min and who received therapeutic drug monitoring of meropenem, cefepime, ceftazidime, or piperacillin from October 2009 until December 2014 at Erasme Hospital. Population pharmacokinetic (PK) analysis of the data was performed using the Pmetrics software package for R. Fifty-five percent of drug concentrations showed insufficient β-lactam serum concentrations to treat infections due toPseudomonas aeruginosa. There were significant, yet weak, correlations between measured creatinine clearance and trough concentrations of meropenem (r= −0.21,P= 0.01), trough concentrations of piperacillin (r= −0.28,P= 0.0071), concentrations at 50% of the dosage interval (r= −0.41,P< 0.0001), and total body clearance of piperacillin (r= 0.39,P= 0.0002). Measured creatinine clearance adequately explained changes in drug concentrations in population pharmacokinetic models for cefepime, ceftazidime, and meropenem but not for piperacillin. Therefore, specific PK modeling can predict certain β-lactam concentrations based on renal function but not on absolute values of measured creatinine clearance, easily available for clinicians. Currently, routine therapeutic drug monitoring is required to adjust daily regimens in critically ill patients receiving standard dosing regimens.

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Evaluating the Relationship between Vancomycin Trough Concentration and 24-Hour Area under the Concentration-Time Curve in Neonates

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01647-17 ◽

2018 ◽

Vol 62 (4) ◽

pp. e01647-17 ◽

Cited By ~ 10

Author(s):

Sheng-Hsuan Tseng ◽

Chuan Poh Lim ◽

Qi Chen ◽

Cheng Cai Tang ◽

Sing Teang Kong ◽

...

Keyword(s):

Steady State ◽

Trough Concentration ◽

Therapeutic Drug ◽

Population Pharmacokinetic ◽

Time Curve ◽

Content Type ◽

Concentration Time ◽

Vancomycin Trough ◽

Trough Concentrations ◽

The Relationship

ABSTRACT Bacterial sepsis is a major cause of morbidity and mortality in neonates, especially those involving methicillin-resistant Staphylococcus aureus (MRSA). Guidelines by the Infectious Diseases Society of America recommend the vancomycin 24-h area under the concentration-time curve to MIC ratio (AUC24/MIC) of >400 as the best predictor of successful treatment against MRSA infections when the MIC is ≤1 mg/liter. The relationship between steady-state vancomycin trough concentrations and AUC24 values (mg·h/liter) has not been studied in an Asian neonatal population. We conducted a retrospective chart review in Singapore hospitals and collected patient characteristics and therapeutic drug monitoring data from neonates on vancomycin therapy over a 5-year period. A one-compartment population pharmacokinetic model was built from the collected data, internally validated, and then used to assess the relationship between steady-state trough concentrations and AUC24. A Monte Carlo simulation sensitivity analysis was also conducted. A total of 76 neonates with 429 vancomycin concentrations were included for analysis. Median (interquartile range) was 30 weeks (28 to 36 weeks) for postmenstrual age (PMA) and 1,043 g (811 to 1,919 g) for weight at the initiation of treatment. Vancomycin clearance was predicted by weight, PMA, and serum creatinine. For MRSA isolates with a vancomycin MIC of ≤1, our major finding was that the minimum steady-state trough concentration range predictive of achieving an AUC24/MIC of >400 was 8 to 8.9 mg/liter. Steady-state troughs within 15 to 20 mg/liter are unlikely to be necessary to achieve an AUC24/MIC of >400, whereas troughs within 10 to 14.9 mg/liter may be more appropriate.

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Population pharmacokinetics of dolutegravir: influence of drug–drug interactions in a real-life setting

Journal of Antimicrobial Chemotherapy ◽

10.1093/jac/dkz217 ◽

2019 ◽

Vol 74 (9) ◽

pp. 2690-2697 ◽

Cited By ~ 3

Author(s):

Catalina Barcelo ◽

Manel Aouri ◽

Perrine Courlet ◽

Monia Guidi ◽

Dominique L Braun ◽

...

Keyword(s):

Drug Interactions ◽

Plasma Concentrations ◽

Real Life ◽

Therapeutic Drug ◽

Population Pharmacokinetic ◽

Genetic Barrier ◽

Good Tolerability ◽

Standard Dosage ◽

Real Life Setting ◽

Trough Concentrations

Abstract Objectives Dolutegravir is widely prescribed owing to its potent antiviral activity, high genetic barrier and good tolerability. The aim of this study was to characterize dolutegravir’s pharmacokinetic profile and variability in a real-life setting and to identify individual factors and co-medications affecting dolutegravir disposition. Methods A population pharmacokinetic model was developed using NONMEM®. Relevant demographic factors, clinical factors and co-medications were tested as potential covariates. Simulations based on the final model served to compare expected dolutegravir concentrations under standard and alternative dosage regimens in the case of drug–drug interactions. Results A total of 620 dolutegravir plasma concentrations were collected from 521 HIV-infected individuals under steady-state conditions. A one-compartment model with first-order absorption and elimination best characterized dolutegravir pharmacokinetics. Typical dolutegravir apparent clearance (CL/F) was 0.93 L/h with 32% between-subject variability, the apparent volume of distribution was 20.2 L and the absorption rate constant was fixed to 2.24 h−1. Older age, higher body weight and current smoking were associated with higher CL/F. Atazanavir co-administration decreased dolutegravir CL/F by 38%, while darunavir modestly increased CL/F by 14%. Rifampicin co-administration showed the largest impact on CL/F. Simulations suggest that average dolutegravir trough concentrations are 63% lower after 50 mg/12h with rifampicin compared with a standard dosage of 50 mg/24h without rifampicin. Average trough concentrations after 100 mg/24h and 100 mg/12h with rifampicin are 92% and 25% lower than the standard dosage without rifampicin, respectively. Conclusions Patients co-treated with dolutegravir and rifampicin might benefit from therapeutic drug monitoring and individualized dosage increase, up to 100 mg/12 h in some cases.

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Use of Pharmacokinetic and Pharmacodynamic Principles To Determine Optimal Administration of Daptomycin in Patients Receiving Standardized Thrice-Weekly Hemodialysis

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01224-10 ◽

2011 ◽

Vol 55 (4) ◽

pp. 1677-1683 ◽

Cited By ~ 16

Author(s):

Nimish Patel ◽

Katie Cardone ◽

Darren W. Grabe ◽

Shari Meola ◽

Christopher Hoy ◽

...

Keyword(s):

Staphylococcus Aureus ◽

Monte Carlo ◽

Body Weight ◽

Infective Endocarditis ◽

Population Model ◽

Area Under The Curve ◽

Compartment Model ◽

Population Pharmacokinetic ◽

Exposure Profile ◽

Trough Concentrations

ABSTRACTThis study identified optimal daptomycin dosing for patients receiving thrice-weekly hemodialysis (HD). Twelve adult patients on HD received daptomycin at 6 mg/kg of body weight intravenously (i.v.) one time; plasma and dialysate samples were collected over 3 days. A 2-compartment model with separate HD and non-HD clearance terms was fit to the data. A series of 9,999-subject Monte Carlo simulations (MCS) was performed to identify HD dosing schemes providing efficacy and toxicity profiles comparable to those obtained for MCS employing the daptomycin population pharmacokinetic (PK) model derived from patients in theStaphylococcus aureusbacteremia-infective endocarditis (SAB-IE) study. For efficacy, we selected the HD dosing scheme which generated an area-under-the-curve (AUC) exposure profile comparable to that for the SAB-IE population model. For toxicity, we selected HD dosing schemes that minimized trough concentrations of ≥24.3 mg/liter. Separate HD dosing schemes were developed for each FDA-approved regimen and for two weekly interdialytic periods (48 and 72 h). Administration of the same parent daptomycin dose intra-HD and post-HD resulted in AUC, maximum concentration of drug in serum (Cmax), andCminvalues most comparable to those for SAB-IE simulations for the 48-hour interdialytic period. In contrast, all candidate HD dosing schemes provided AUC48-72values that were at least 50% lower than the SAB-IE AUC48-72values. Increasing the parent dose by 50% provided more comparable AUC48-72values while maintaining acceptableCminvalues. Administration of the daptomycin parent dose intra-HD or post-HD was optimal for the 48-h interdialytic period. For the 72-h interdialytic period, clinicians should consider increasing the dose by 50% to achieve more comparable AUC48-72values.

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Population Pharmacokinetic Model and Limited Sampling Strategies for Personalized Dosing of Levofloxacin in Tuberculosis Patients

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01092-18 ◽

2018 ◽

Vol 62 (12) ◽

Cited By ~ 6

Author(s):

Simone H. J. van den Elsen ◽

Marieke G. G. Sturkenboom ◽

Natasha van't Boveneind-Vrubleuskaya ◽

Alena Skrahina ◽

Tjip S. van der Werf ◽

...

Keyword(s):

Linear Regression ◽

Multiple Linear Regression ◽

Compartment Model ◽

Performance Criteria ◽

Therapeutic Drug ◽

Population Pharmacokinetic ◽

Sampling Strategies ◽

Tuberculosis Patients ◽

Limited Sampling ◽

Poppk Model

ABSTRACT Levofloxacin is an antituberculosis drug with substantial interindividual pharmacokinetic variability; therapeutic drug monitoring (TDM) could therefore be helpful to improve treatment results. TDM would be more feasible with limited sampling strategies (LSSs), a method to estimate the area under the concentration curve for the 24-h dosing interval (AUC0–24) by using a limited number of samples. This study aimed to develop a population pharmacokinetic (popPK) model of levofloxacin in tuberculosis patients, along with LSSs using a Bayesian and multiple linear regression approach. The popPK model and Bayesian LSS were developed using data from 30 patients and externally validated with 20 patients. The LSS based on multiple linear regression was internally validated using jackknife analysis. Only clinically suitable LSSs (maximum time span, 8 h; minimum interval, 1 h; 1 to 3 samples) were tested. Performance criteria were root-mean-square error (RMSE) of <15%, mean prediction error (MPE) of <5%, and r2 value of >0.95. A one-compartment model with lag time best described the data while only slightly underestimating the AUC0–24 (mean, −7.9%; standard error [SE], 1.7%). The Bayesian LSS using 0- and 5-h postdose samples (RMSE, 8.8%; MPE, 0.42%; r2 = 0.957) adequately estimated the AUC0–24, with a mean underestimation of −4.4% (SE, 2.7%). The multiple linear regression LSS using 0- and 4-h postdose samples (RMSE, 7.0%; MPE, 5.5%; r2 = 0.977) was internally validated, with a mean underestimation of −0.46% (SE, 2.0%). In this study, we successfully developed a popPK model and two LSSs that could be implemented in clinical practice to assist TDM of levofloxacin. (This study has been registered at ClinicalTrials.gov under identifier NCT01918397.)

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Population pharmacokinetics of daptomycin in patients with bone and joint infection: minimal effect of rifampicin co-administration and confirmation of a sex difference

Journal of Antimicrobial Chemotherapy ◽

10.1093/jac/dkab006 ◽

2021 ◽

Author(s):

Romain Garreau ◽

Romain Bricca ◽

Marie-Claude Gagnieu ◽

Sandrine Roux ◽

Anne Conrad ◽

...

Keyword(s):

Joint Infection ◽

Compartment Model ◽

Volume Of Distribution ◽

Individual Variability ◽

Therapeutic Drug ◽

Marginal Effect ◽

Bone And Joint Infection ◽

Two Compartment Model ◽

Central Volume ◽

Trough Concentrations

Abstract Background Daptomycin is increasingly used in the treatment of bone and joint infection (BJI), but its pharmacokinetics (PK) and dosage requirements have not been thoroughly investigated in this indication. Daptomycin may be co-administered with rifampicin, which raises questions about a potential drug interaction. Objectives To investigate the population PK and dosage requirements of daptomycin in patients with BJI, and examine the influence of rifampicin co-administration. Methods A population approach was used to analyse PK data from patients who received daptomycin in our regional reference for BJI. We examined the influence of available covariates, including rifampicin co-administration on daptomycin PK. Simulations performed with the final model investigated the influence of dosages and covariates on PTA for both efficacy and safety. Results A total of 1303 daptomycin concentrations from 183 patients were analysed. A two-compartment model best described the data. Significant intra-individual variability was observed. Daptomycin clearance was influenced by renal function and sex, with females having a 26% lower typical clearance than males. Central volume of distribution (V1) was influenced by body weight, age, sex and rifampicin co-administration. Typical V1 was 11% lower in patients who were co-administered rifampicin. In PK/PD simulations, sex influenced the probability of AUC24/MIC target attainment, while rifampicin had a marginal effect. Conclusions A daptomycin dosage of 8 mg/kg/24 h in women and 10 mg/kg/24 h in men should optimize efficacy but may lead to excessive trough concentrations in many patients, especially in women. Therapeutic drug monitoring appears necessary for precision dosing of daptomycin.

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1532. Population Pharmacokinetic (PPK) Modeling and Simulation of Long-Acting (LA) Cabotegravir (CAB) to Inform Strategies Following Dosing Interruptions in HIV-1-Infected Subjects

Open Forum Infectious Diseases ◽

10.1093/ofid/ofz360.1396 ◽

2019 ◽

Vol 6 (Supplement_2) ◽

pp. S558-S558 ◽

Cited By ~ 1

Author(s):

Kelong Han ◽

Mark Baker ◽

Parul Patel ◽

David Margolis ◽

William Spreen ◽

...

Keyword(s):

Modeling And Simulation ◽

Compartment Model ◽

Population Pharmacokinetic ◽

Strand Transfer ◽

Phase 3 ◽

Once Daily ◽

Minimal Impact ◽

Treatment And Prevention ◽

Trough Concentrations ◽

Hiv 1

Abstract Background CAB is an integrase strand transfer inhibitor under investigation as an injectable LA formulation for the treatment and prevention of HIV, and as a tablet formulation as an oral lead-in (OLI) and bridging treatment for dose interruptions. The monthly injection regimen of CAB LA and rilpivirine (RPV) LA was noninferior to standard oral therapy in maintaining HIV-1 suppression in Phase 3 trials. PPK modeling and simulation was used to inform strategies for managing dosing interruptions. Methods A 2-compartment model with first-order oral and LA absorption and elimination adequately described the data from 1,647 healthy (28%) and HIV-infected (72%) adult subjects in 16 studies. Gender was a significant covariate on LA absorption; therefore, simulations of 5,000 virtual subjects were performed using a 4:1 male:female ratio to ensure 1,000 representative females and covariate sampling with replacement from the analysis dataset. One- to 12-week delays in dosing of the second, third, and fourth injection were simulated, and predicted troughs were compared with the 5th percentile (0.65 μg/mL) of trough concentrations following the first injection in Phase 3. Simulations of 1–2 months of oral bridging with CAB 30 mg once daily from time of a missed injection until CAB LA dosing resumed were performed, with the median Cmax (13.1 μg/mL) observed following oral CAB 60mg once daily in Phase 2b as an upper reference. Results Proportions of subjects predicted to achieve target plasma CAB trough concentrations are shown by length of delay and injection visit in Table 1. Oral bridging with CAB 30mg once daily starting at the time of a planned missed injection is predicted to provide exposures within ranges observed in clinical studies (Figure 1). Conclusion Dosing delays of up to one week appear to have minimal impact, but the effect is more likely to become problematic with longer delays, particularly in the first few months of dosing. Oral bridging provides therapeutic and safe exposures for planned interruptions in LA dosing. Regardless of use of oral bridging, simulations support resuming CAB LA dosing for interruptions <1 month (<2 months between injections) and reinitiating CAB LA with a loading dose and subsequent monthly injections for interruptions ≥ 1 month (≥ 2 months between injections). Disclosures All authors: No reported disclosures.

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Application of Pharmacometrics in Pharmacotherapy: Open-Source Software for Vancomycin Therapeutic Drug Management

Pharmaceutics ◽

10.3390/pharmaceutics11050224 ◽

2019 ◽

Vol 11 (5) ◽

pp. 224 ◽

Cited By ~ 1

Author(s):

Soo Hyeon Bae ◽

Dong-Seok Yim ◽

Hyemi Lee ◽

Ae-Ryoung Park ◽

Ji-Eun Kwon ◽

...

Keyword(s):

Open Source ◽

Open Source Software ◽

Compartment Model ◽

Therapeutic Drug ◽

Peripheral Compartment ◽

Population Pharmacokinetic ◽

Drug Management ◽

Korean Patients ◽

Population Pk ◽

R Shiny

The population pharmacokinetic (PK) parameters that are implemented in therapeutic drug management (TDM) software were generally obtained from a Western population and might not be adequate for PK prediction with a Korean population. This study aimed to develop a population PK model for vancomycin using Korean data to improve the quality of TDM for Korean patients. A total of 220 patients (1020 observations) who received vancomycin TDM services were included in the dataset. A population PK analysis was performed using non-linear mixed effects modeling, and a covariate evaluation was conducted. A two-compartment model with first-order elimination best explained the vancomycin PK, with estimates of 2.82 L/h, 31.8 L, 11.7 L/h, and 75.4 L for CL, V1, Q, and V2, respectively. In the covariate analysis, weight correlated with the volume of the peripheral compartment, and creatinine clearance, hemodialysis, and continuous renal replacement therapy treatments contributed to the clearance of vancomycin. The results show the clear need to optimize the PK parameters used for TDM in Korean patients. Specifically, V1 should be smaller for Korean patients, and renal replacement therapies should be considered in TDM practice. This final model was successfully applied in R shiny as open-source software for Koreans.

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