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

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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1540. A Population Pharmacokinetic Model for Vancomycin in Korean Patients Receiving Extracorporeal Membrane Oxygenation Therapy: A Prospective Study

Open Forum Infectious Diseases ◽

10.1093/ofid/ofz360.1404 ◽

2019 ◽

Vol 6 (Supplement_2) ◽

pp. S562-S562

Author(s):

Younghee Jung ◽

Dong-Hwan Lee ◽

Hyoung Soo Kim

Keyword(s):

Extracorporeal Membrane Oxygenation ◽

Creatinine Clearance ◽

Compartment Model ◽

Volume Of Distribution ◽

Population Pharmacokinetic ◽

Test Model ◽

Mixed Effect ◽

Korean Patients ◽

Membrane Oxygenation ◽

Population Pk

Abstract Background There is no literature on population pharmacokinetics (PK) of vancomycin in Korean patients receiving extracorporeal membrane oxygenation (ECMO) therapy. The aim of this study was to develop a population PK model for vancomycin in Korean ECMO patients. Methods We prospectively enrolled adult patients who were undergoing ECMO and receiving vancomycin from July 2018 to April 2019. After initial dose of vancomycin was administrated, serial blood samples (seven to nine times per patient) were drawn before the next dose. A population PK model for vancomycin was developed using a nonlinear mixed-effect modeling. Age, sex, creatinine clearance, and body weight were tested as potential covariates in the model. Model selection was based on log-likelihood test, model diagnostic plots, and clinical plausibility. Results Fourteen patients were included over the period. Ten received venovenous, three venoarterial, and one both type ECMO. Eleven were men and the median age was 54 (interquartile range 45–66.3). Mean estimated glomerular filtration rate (eGFR) was 69 ± 46 mL/minute/1.73m2 by the modification of diet in renal disease equation. A total of 123 vancomycin concentrations from the patients were included in the analysis. The population PK of vancomycin was best described by a two-compartment model with a proportional residual error model. The typical value (%between-subject variability) for total clearance was estimated to be 4.33 L/h (21.6%), central volume of distribution was 9.22 L, the intercompartmental clearance was 10.75 L/hr (34.9%) and the peripheral volume of distribution was 19.6 L (26.6%). The proportional residual variability was 8.81%. Creatinine clearance significantly influenced vancomycin clearance (CL). The proposed equation to estimate vancomycin clearance in Korean ECMO patients was CL = 4.33 + 0.199 × (eGFR – 56). Conclusion A two-compartment population PK model successfully describes vancomycin PK profiles in Korean ECMO patients. The model could be used to optimize the dosing regimen if more data become available from currently ongoing clinical study. Disclosures All authors: No reported disclosures.

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Optimization of flucloxacillin dosing regimens in critically ill patients using population pharmacokinetic modelling of total and unbound concentrations

Journal of Antimicrobial Chemotherapy ◽

10.1093/jac/dkaa187 ◽

2020 ◽

Vol 75 (9) ◽

pp. 2641-2649

Author(s):

Nynke G L Jager ◽

Reinier M van Hest ◽

Jiao Xie ◽

Gloria Wong ◽

Marta Ulldemolins ◽

...

Keyword(s):

Protein Binding ◽

Critically Ill ◽

Critically Ill Patients ◽

Binding Capacity ◽

Compartment Model ◽

Therapeutic Drug ◽

Population Pharmacokinetic ◽

Population Pk ◽

Non Linear ◽

Dosing Regimens

Abstract Background Initial appropriate anti-infective therapy is associated with improved outcomes in patients with severe infections. In critically ill patients, altered pharmacokinetic (PK) behaviour is common and known to influence the achievement of PK/pharmacodynamic targets. Objectives To describe population PK and optimized dosing regimens for flucloxacillin in critically ill patients. Methods First, we developed a population PK model, estimated between-patient variability (BPV) and identified covariates that could explain BPV through non-linear mixed-effects analysis, using total and unbound concentrations obtained from 35 adult critically ill patients treated with intermittent flucloxacillin. Second, we validated the model using external datasets from two different countries. Finally, frequently prescribed dosing regimens were evaluated using Monte Carlo simulations. Results A two-compartment model with non-linear protein binding was developed and validated. BPV of the maximum binding capacity decreased from 42.2% to 30.4% and BPV of unbound clearance decreased from 88.1% to 71.6% upon inclusion of serum albumin concentrations and estimated glomerular filtration rate (eGFR; by CKD-EPI equation), respectively. PTA (target of 100%fT>MIC) was 91% for patients with eGFR of 33 mL/min and 1 g q6h, 87% for patients with eGFR of 96 mL/min and 2 g q4h and 71% for patients with eGFR of 153 mL/min and 2 g q4h. Conclusions For patients with high creatinine clearance who are infected with moderately susceptible pathogens, therapeutic drug monitoring is advised since there is a risk of underexposure to flucloxacillin. Due to the non-linear protein binding of flucloxacillin and the high prevalence of hypoalbuminaemia in critically ill patients, dose adjustments should be based on unbound concentrations.

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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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Evaluation of the Adequacy of WHO Revised Dosages of the First-Line Antituberculosis Drugs in Children with Tuberculosis Using Population Pharmacokinetic Modeling and Simulations

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00008-18 ◽

2018 ◽

Vol 62 (9) ◽

Cited By ~ 9

Author(s):

Yasuhiro Horita ◽

Abdullah Alsultan ◽

Awewura Kwara ◽

Sampson Antwi ◽

Antony Enimil ◽

...

Keyword(s):

Compartment Model ◽

World Health ◽

Population Pharmacokinetic ◽

Optimal Dosage ◽

Nonlinear Mixed Effects Models ◽

First Line ◽

Time Curve ◽

Drug Concentrations ◽

Target Values ◽

Population Pk

ABSTRACTOptimal doses for antituberculosis (anti-TB) drugs in children have yet to be established. In 2010, the World Health Organization (WHO) recommended revised dosages of the first-line anti-TB drugs for children. Pharmacokinetic (PK) studies that investigated the adequacy of the WHO revised dosages to date have yielded conflicting results. We performed population PK modeling using data from one of these studies to identify optimal dosage ranges. Ghanaian children with tuberculosis on recommended therapy with rifampin (RIF), isoniazid (INH), pyrazinamide (PZA), and ethambutol (EMB) for at least 4 weeks had blood samples collected predose and at 1, 2, 4, and 8 hours postdose. Drug concentrations were determined by validated liquid chromatography-mass spectrometry methods. Nonlinear mixed-effects models were applied to describe the population PK of those drugs using MonolixSuite2016R1 (Lixoft, France). Bayesian estimation was performed, the correlation coefficient, bias, and precision between the observed and predicted areas under the concentration-time curve (AUCs) were calculated, and Bland-Altman plots were analyzed. The population PK of RIF and PZA was described by a one-compartment model and that for INH and EMB by a two-compartment model. Plasma maximum concentration (Cmax) and AUC targets were based on published results for children from India. The lowest target values for pediatric TB patients were attainable at the WHO-recommended dosage schedule for RIF and INH, except forN-acetyltransferase 2 non-slow acetylators (rapid and intermediate acetylators) in the lower-weight bands. However, higher published adult targets were not attainable for RIF and INH. The targets were not achieved for PZA and EMB. (This study has been registered at ClinicalTrials.gov under identifier NCT01687504.)

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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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Real Life Population Pharmacokinetics Modelling of Eight Factors VIII in Patients with Severe Haemophilia A: Is It Always Relevant to Switch to an Extended Half-Life?

Pharmaceutics ◽

10.3390/pharmaceutics12040380 ◽

2020 ◽

Vol 12 (4) ◽

pp. 380 ◽

Cited By ~ 2

Author(s):

Quentin Allard ◽

Zoubir Djerada ◽

Claire Pouplard ◽

Yohann Repessé ◽

Dominique Desprez ◽

...

Keyword(s):

Half Life ◽

Random Effect ◽

Real Life ◽

Compartment Model ◽

Central Compartment ◽

Peripheral Compartment ◽

Population Pharmacokinetic ◽

Severe Haemophilia ◽

Fviii Activity ◽

Data Files

We retrospectively analysed the data files of 171 adults and 87 children/adolescents with severe haemophilia, except for 14 patients (moderate; minor) (1), to develop a global population pharmacokinetic (PK) model for eight factors VIII (FVIII) that could estimate individual PK parameters for targeting the desired level of FVIII activity (FVIII:C); and (2) to compare half-life (HL) in patients switching from a standard half-life (SHL) to an extended half-life (EHL) and evaluate the relevance of the switch. One-stage clotting assay for the measurement of FVIII activity (FVIII:C, IU/mL) was used for population PK modelling. The software, Monolix version 2019R1, was used for non-linear mixed-effects modelling. A linear two-compartment model best described FVIII:C. The estimated PK parameters (between-subject variability) were: 2640 mL (23.2%) for volume of central compartment (V1), 339 mL (46.8%) for volume of peripheral compartment (V2), 135 mL/h for Q (fixed random effect), and 204 mL/h (34.9%) for clearance (Cl). Weight, age, and categorical covariate EHL were found to influence Cl and only weight for V1. This model can be used for all of the FVIII cited in the study. Moreover, we demonstrated, in accordance with previous studies, that Elocta had longer half-life (EHL) than SHL (mean ratio: 1.48) as compared to Advate, Factane, Kogenate, Novoeight, and Refacto.

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Nemonoxacin Dosage Adjustment in Patients with Severe Renal Impairment Based on Population Pharmacokinetic and Pharmacodynamic Analysis

10.22541/au.161167889.97008719/v1 ◽

2021 ◽

Author(s):

Yi Li ◽

Jianda Lu ◽

Yue Kang ◽

Xiaoyong Xu ◽

Xin Li ◽

...

Keyword(s):

Renal Impairment ◽

Severe Renal Impairment ◽

Compartment Model ◽

Central Compartment ◽

Peripheral Compartment ◽

Population Pharmacokinetic ◽

Healthy Controls ◽

Dosing Regimen ◽

Open Label ◽

Optimal Dosing

Aims: To optimize the dosing regimen in patients with severe renal impairment based on population pharmacokinetic/pharmacodynamic (PPK/PD) analysis. Methods: The pharmacokinetics and safety of nemonoxacin was evaluated in a single-dose, open-label, nonrandomized, parallel-group study after single oral dose of 0.5 g nemonoxacin capsule in 10 patients with severe renal impairment and 10 healthy controls. Both blood and urine samples were collected within 48 hours after admission and determined the concentrations. A PPK model was built using nonlinear mixed effects modelling. The probability of target attainment (PTA) and the cumulative fraction of response (CFR) against S. Pneumoniae and S. aureus was calculated by Monte Carlo simulation. Results: The data best fitted to a two-compartment model, from which the PPK parameters were estimated, including clearance (8.55 L/h), central compartment volume (80.8 L), and peripheral compartment volume (50.6 L). The accumulative urinary excretion was 23.4±6.5% in severe renal impairment patients and 66.1±16.8% in healthy controls. PPK/PD modeling and simulation of 4 dosage regimens found that nemonoxacin 0.5 g q48h was the optimal dosing regimen in severe renal impairment patients, evidenced by higher PTA (92.7%) and CFR (>99%) at nemonoxacin MIC ≤ 1 mg/L against S. pneumoniae and S. aureus. The alternative regimens (0.25 g q24h; loading dose 0.5 g on Day 1 followed by 0.25 g q24h) were insufficient to cover the pathogens even if MIC ≤ 0.5 mg/L. Conclusion: An extended dosing interval (0.5 g q48h) may be appropriate for optimal efficacy of nemonoxacin in case of severe renal impairment.

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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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A Population Pharmacokinetic and Exposure–Response Model of Golimumab for Targeting Endoscopic Remission in Patients With Ulcerative Colitis

Inflammatory Bowel Diseases ◽

10.1093/ibd/izz144 ◽

2019 ◽

Cited By ~ 1

Author(s):

Erwin Dreesen ◽

Wannee Kantasiripitak ◽

Iris Detrez ◽

Sebastian Stefanović ◽

Séverine Vermeire ◽

...

Keyword(s):

Ulcerative Colitis ◽

Characteristic Curve ◽

Compartment Model ◽

Therapeutic Drug ◽

Population Pharmacokinetic ◽

Linear Absorption ◽

Necrosis Factor Alpha ◽

Predictive Values ◽

Exposure Response ◽

Endoscopic Remission

Abstract Background Unlike other anti–tumor necrosis factor alpha antibodies, golimumab does not deliver on its promise of effectiveness for treating patients with ulcerative colitis. We investigated the value of therapeutic drug monitoring for optimizing golimumab therapy. Methods We analyzed the golimumab pharmacokinetics data of 56 patients with moderate to severe ulcerative colitis. Induction and maintenance golimumab concentrations (296 venipuncture, 414 serum) were used to develop a population pharmacokinetic model. Exposure–response relationships were analyzed using the data of 40/56 patients with available endoscopy data. Receiver operating characteristic curve analysis was performed, and an exposure–response Markov model was developed, linking golimumab exposure to probabilities of transitioning between Mayo endoscopic subscore (MES) states from baseline to week (w)14. Results Golimumab pharmacokinetics was best described by a 2-compartment model with linear absorption and elimination. Antibodies to golimumab and previous biological therapy reduced golimumab exposure. Still, interindividual pharmacokinetic variability (IIVPK) remained largely unexplained. Endoscopic remission (ER; MESw14 ≤ 1) was achieved in 14/40 (35%) patients. Golimumab serum trough concentration thresholds of 7.4 mg/L (w6) and 3.2 mg/L (w14) predicted ER at w14 (positive predictive values [pv+] 83% and 91%, pv- 82% and 67%, respectively). The 3.2-mg/L target predicted 38% and 44% chances of achieving ER in patients with MESbaseline of 3 and 2, respectively. Conclusions Personalized, model-based induction dosing aiming at here-established target concentrations may account for IIVPK and thus provide patients with more equal chances of achieving ER. As <50% of patients attained the exposure targets, higher golimumab induction dosing requires investigation to secure its future in clinical practice.

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Lack of relationship between systemic exposure for the component drug of the fluorouracil, epirubicin, and 4-hydroxycyclophosphamide regimen in breast cancer patients.

Journal of Clinical Oncology ◽

10.1200/jco.1996.14.5.1581 ◽

1996 ◽

Vol 14 (5) ◽

pp. 1581-1588 ◽

Cited By ~ 54

Author(s):

M Sandström ◽

A Freijs ◽

R Larsson ◽

P Nygren ◽

M L Fjällskog ◽

...

Keyword(s):

Breast Cancer ◽

Cancer Patients ◽

Half Life ◽

Systemic Exposure ◽

Compartment Model ◽

Pharmacokinetic Parameters ◽

Therapeutic Drug ◽

Population Pharmacokinetic ◽

Breast Cancer Patients ◽

Nonlinear Elimination

PURPOSE The aim of this study was to investigate the covariance between the pharmacokinetics of the three components of the FEC regimen, epirubicin (EPI), fluorouracil (5-FU), and the cyclophosphamide (CP) metabolite 4-hydroxycyclophosphamide (4-OHCP), in breast cancer patients. PATIENTS AND METHODS Data from 21 women were collected over a total of 35 cycles. 5-FU (300 to 600 mg/m2) and CP (300 to 600 mg/m2) were administered as bolus injections, whereas EPI (15 to 60 mg/m2) was administered either as a bolus injection or as an infusion. The pharmacokinetics of the component drugs were monitored using a limited sampling scheme. Population pharmacokinetic models for each of the three drugs were developed using the program NONMEM. RESULTS The data for 5-FU were best described by a one-compartment model with nonlinear elimination, where the maximal rate of elimination (Vmax) and the concentration at which the elimination was half-maximal (Km) were 105 mg/L.h and 27 mg/L, respectively. EPI concentration-time profiles showed a triexponential decline, with a mean terminal half-life of 24 hours and a clearance (CL) of 59 L/h. The elimination of 4-OHCP was monoexponential, with a mean half-life of 7 hours. The interindividual coefficients of variation (CVs) in CL were 30%, 22%, and 41% for 5-FU, EPI, and 4-OHCP, respectively. The corresponding values for intrapatient course-to-course variability in CL were 11%, 8%, and 27%. No significant correlation in any of the pharmacokinetic parameters between the drugs was found. CONCLUSION Individualization of dosing of the FEC regimen using therapeutic drug monitoring and attempts to find concentration-response relationships may be successful, but requires that the exposure of all three drugs is considered simultaneously.

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