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

2019 ◽  
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.

scholarly journals Pregnancy-Related Effects on Nelfinavir-M8 Pharmacokinetics: a Population Study with 133 Women

2006 ◽  
Vol 50 (6) ◽  
pp. 2079-2086 ◽  
Author(s):  
Déborah Hirt ◽  
Jean-Marc Treluyer ◽  
Vincent Jullien ◽  
Ghislaine Firtion ◽  
Hélène Chappuy ◽  
...  
Keyword(s):  
Population Study ◽  
Time Course ◽  
Plasma Concentrations ◽  
Elimination Rate ◽  
Concomitant Administration ◽  
Individual Characteristics ◽  
Individual Treatment ◽  
Therapeutic Drug ◽  
Population Pharmacokinetic ◽  
Linear Absorption

ABSTRACT A relationship between nelfinavir antiretroviral efficacy and plasma concentrations has been previously established. As physiological changes associated with pregnancy have a large impact on the pharmacokinetics of many drugs, a nelfinavir population study with women was developed, and the large intersubject variability was analyzed in order to optimize individual treatment schedules for this drug during pregnancy. A population pharmacokinetic model was developed in order to describe the concentration time course of nelfinavir and its metabolite M8 in pregnant and nonpregnant women. Individual characteristics, such as age, body weight, and weeks of gestation or delivery, which may influence nelfinavir-M8 pharmacokinetics were investigated. Data from therapeutic drug monitoring in 133 women treated with nelfinavir were retrospectively analyzed with NONMEM. Nelfinavir pharmacokinetics was described by a one-compartment model with linear absorption and elimination and M8 produced from the nelfinavir central compartment. Mean pharmacokinetic estimates and the corresponding intersubject percent variabilities for a nonpregnant woman were the following: absorption rate, 0.83 h−1; absorption lag time, 0.85 h; apparent nelfinavir elimination clearance (CL10/F), 35.5 liters/h (50%); apparent volume of distribution (V/F), 596 liters (118%); apparent formation clearance to M8 (CL1M/F), 0.65 liters/h (69%); and M8 elimination rate constant (k M0), 3.3 h−1 (59%). During pregnancy, we observed significant increases in nelfinavir (44.4 liters/h) and M8 (5 h−1) elimination but unchanged nelfinavir transformation clearance to M8, suggesting an induction of CYP3A4 but no effect on CYP2C19. Apparent nelfinavir clearance and volume showed a twofold increase on the day of delivery, suggesting a decrease in bioavailability on this day. The M8 elimination rate was increased by concomitant administration of nonnucleoside reverse transcriptase inhibitors. A trough nelfinavir plasma concentration above 1 mg/liter was previously shown to improve the antiretroviral response. The Bayesian individual pharmacokinetic estimates suggested that the dosage should not be changed in pregnant women but may be doubled on the day of delivery.

scholarly journals 1319. Pharmacokinetics of Ceftolozane/Tazobactam in Patients with Burns

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)

Histologic Evaluation Using the Robarts Histopathology Index in Patients With Ulcerative Colitis in Deep Remission and the Association of Histologic Remission With Risk of Relapse

2022 ◽  
Author(s):  
Jin Park ◽  
Soo Jin Kang ◽  
Hyuk Yoon ◽  
Jihye Park ◽  
Hyeon Jeong Oh ◽  
...  
Keyword(s):  
Ulcerative Colitis ◽  
Proportional Hazards Model ◽  
Characteristic Curve ◽  
Multivariable Analysis ◽  
Fecal Calprotectin ◽  
Cox Proportional Hazards ◽  
Cox Proportional Hazards Model ◽  
Clinical Relapse ◽  
Endoscopic Remission ◽  
Risk Of Relapse

Abstract Background This study prospectively evaluated the risk of relapse according to the status of histologic activity in patients with ulcerative colitis (UC) who achieved deep remission. Methods Patients with UC in clinical remission (partial Mayo score ≤1) and endoscopic remission (ulcerative colitis endoscopic index of severity ≤1) were enrolled. Rectal biopsies were performed in patients, and histologic remission was defined as a Robarts histopathology index of ≤3. Receiver-operating characteristic curve analysis was conducted to determine fecal calprotectin cutoff values for histologic remission. The cumulative risk of relapse was evaluated using the Cox proportional hazards model. Results Among the 187 patients enrolled, 82 (43.9%) achieved histologic remission. The best cutoff value of fecal calprotectin for predicting histologic remission was 80 mg/kg (area under the curve of 0.646, sensitivity of 74%, and specificity of 61%). Among 142 patients who were followed up for &gt;3 months, 56 (39.4%) showed clinical relapse during a median of 42 weeks. The risk of relapse was lower in patients with histologic remission than in those with histologic activity (P = .026). In multivariable analysis, histologic remission (hazard ratio [HR], 0.551; 95% confidence interval [CI], 0.316-0.958; P = .035), elevated C-reactive protein levels (HR, 3.652; 95% CI, 1.400-9.526; P = .008), and history of steroid use (HR, 2.398; 95% CI, 1.196-4.808; P = .014) were significantly associated with clinical relapse. Conclusions In patients with UC who achieved clinical and endoscopic remission, histologic remission was independently associated with a lower risk of clinical relapse.

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

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.

Cetuximab (Cet) clearance and survival in patients (pts) with metastatic colorectal cancer (mCRC).

2017 ◽  
Vol 35 (4_suppl) ◽  
pp. 699-699
Author(s):  
Di Maria Jiang ◽  
Hao-Wen Sim ◽  
Lillian L. Siu ◽  
Jeremy David Shapiro ◽  
Geoffrey Liu ◽  
...  
Keyword(s):  
Progression Free Survival ◽  
Compartment Model ◽  
Phase Iii ◽  
Population Pharmacokinetic ◽  
Mean Values ◽  
Clinical Variables ◽  
Disease Characteristics ◽  
Exposure Response ◽  
Trough Blood ◽  
Grade 3

699 Background: Cet, a monoclonal antibody against EGFR, is a standard therapy for pts with RAS wild-type (WT) mCRC. Limited previous data suggest that Cet clearance correlates with progression-free survival (PFS). We performed a population pharmacokinetic (pop-pK) analysis of Cet in pts who participated in the randomized phase III NCIC CO.20 trial in KRAS WT mCRC patients. Methods: Standard Cet doses ± brivanib were administered. Using intermittent trough blood samples, pop-pK analysis was conducted to evaluate different models. Pts were divided into quartiles according to clearance parameters to assess the exposure-response relationship to response rate (RR), PFS and overall survival (OS). Clinical variables including demographic, laboratory, disease characteristics and co-administration of brivanib were evaluated as co-variates on Cet clearance. Results: In 701 pts, Cet elimination was best described as a one-compartment model with a non-linear saturable elimination process (defined by Vmax and Km). Mean values (± standard deviation) for pop-pk parameters were 2.7 ± 0.5 L/m2 for V, 2.5 ± 0.3 mg/h/m2 for Vmax, and 101.0 ± 0.05 mg/L/m2 for Km. Grouped into quartiles, Vmax and Km were significantly associated with OS, but not RR or PFS. The median OS for pts in the lowest quartile of Vmax was 12.0 ms versus (vs.) 6.9 ms for pts in the highest quartile ( p< 0.001), while the median OS was 11.6 ms in the highest Km quartile vs. 6.9 ms in the lowest Km quartile ( p< 0.001). When compared to the quartile with the combination of highest Vmax and lowest Km, pts in the quartile with the lowest Vmax and highest Km had longer PFS (5.0 vs. 3.7 ms, HR 0.75 (95% confidence interval (CI) 0.58-0.98, p= 0.032) and OS (11.7 vs. 6.6 ms, HR 0.59 (95% CI, 0.45-0.77, p< 0.001). Pts in the lower Vmax and higher Km quartiles also experienced less grade 3 toxicity. Neither clinical variables nor brivanib administration were associated with Cet clearance parameters. Conclusions: For KRAS WT mCRC, standard Cet dosing is not optimal for all pts. Pts with slower Cet clearance have significantly improved PFS and OS. Further studies are needed to optimize Cet doses based on individual pK assessments, and to identify novel factors associated with clearance.

Population Pharmacokinetic (PK) Modeling of Hydroxyurea for Therapeutic Drug Monitoring Applications in Children and Adolescents with Sickle Cell Disease

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2136-2136
Author(s):  
Pawel Wiczling ◽  
Robert I. Liem ◽  
Julie A. Panepinto ◽  
Uttam Garg ◽  
Susan M. Abdel-Rahman ◽  
...  
Keyword(s):  
Therapeutic Drug Monitoring ◽  
Sickle Cell ◽  
Drug Monitoring ◽  
Drug Exposure ◽  
Oral Drug ◽  
Therapeutic Drug ◽  
Population Pharmacokinetic ◽  
Average Dose ◽  
Intersubject Variability ◽  
Exposure Response

Abstract Abstract 2136 Introduction: Sickle cell anemia (SCA) is an inherited disorder of abnormal hemoglobin synthesis. Hydroxyurea (HU) is the only disease modifying agent available for use in patients with SCA. Clinically, HU has been shown to decrease pain, number of transfusions, and development of acute chest syndrome as well as improve life expectancy in adults with SCA. Although HU is increasingly utilized to treat children with SCA, drug exposure-response relationships and therapeutic drug monitoring are not well characterized in the pediatric population. The exposure-response relationships of HU are currently being evaluated as is the potential role of therapeutic drug monitoring. Objective: The objective of this study was to develop a population pharmacokinetic (PK) model sufficient to describe HU disposition in serum and urine following oral drug administration in pediatric patients. Such a model is required for exploring concentration-effect relationships in children with SCA taking HU. Methods: PK was determined in 20 subjects (mean age 10.5 yr, range 5–17 yr) with SCA either as a single dose (SD, n=6, average dose 17.4 mg/kg) or at steady state (SS, n=14, average daily dose 25.5 mg/kg). Blood and urine samples for HU assay were taken throughout the 24 hour period post HU administration. HU was quantitated by a validated gas chromatography–mass spectrometry (GC-MS) method. Population nonlinear mixed-effect modeling was done using NONMEM software. Measured HU concentrations at specific sampling time points were compared to model predicted area under the curves (AUCs) to find the most predictive relationship. Results: A one-compartment model with first-order absorption and two elimination pathways (metabolic and renal) was used. The mean absorption rate constant differed for children < 8.5 years of age (19.5 h−1) as compared to those ≥ 8.5 years of age (2.1 h−1) and demonstrated high intersubject variability (76%). The population apparent volume of distribution (V/F) was 21.3 L (for an average weight patient of 30.7 kg) with an intersubject variability of 24.7%. The apparent renal (CLu/F) and metabolic (CLm/F) clearance was 3.47 L/hr and 3.52 L/hr, respectively, with the same between subject variability of 42%. Significant relationships (p<0.005) between both CL/F and V/F and body weight were found with these parameters increasing by 2.96% and 2.49%, respectively, for every kilogram difference from the median weight. Significant linear correlations were apparent between the plasma HU concentration at 0.75, 1, 1.5, 2, 4, and 6 hours post-dose; the most significant (p<0.01, r2 =0.71) occurring at 1.5 hours. Conclusion: In children with SCA, a population PK model parameterized from a classical PK study of HU was successful in describing HU disposition in plasma and urine. Data from the model also demonstrated that HU plasma concentrations at 1.5 or 2 hours after an oral dose of the drug were especially predictive of systemic drug exposure (as reflected by AUC). Data from this study also suggest that there may be age related differences in absorption rates. Further studies are warranted to confirm this finding. Disclosures: Off Label Use: Hydroxyurea is not labeled for use in children.

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

2018 ◽  
Vol 62 (12) ◽  
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.)

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

Pharmaceutics ◽  
2019 ◽  
Vol 11 (5) ◽  
pp. 224 ◽  
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.

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

1996 ◽  
Vol 14 (5) ◽  
pp. 1581-1588 ◽  
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.

scholarly journals Pharmacokinetics of Enfuvirtide in Patients Treated in Typical Routine Clinical Settings

2006 ◽  
Vol 50 (2) ◽  
pp. 667-673 ◽  
Author(s):  
Hartmut Stocker ◽  
Charlotte Kloft ◽  
Nele Plock ◽  
Antje Breske ◽  
Guido Kruse ◽  
...  
Keyword(s):  
Compartment Model ◽  
Volume Of Distribution ◽  
Time Profile ◽  
Therapeutic Drug ◽  
Clinical Settings ◽  
Serum Samples ◽  
Linear Absorption ◽  
Percentile Curves ◽  
Population Pk ◽  
Liquid Chromatography Tandem Mass

ABSTRACT Therapeutic drug monitoring (TDM) is gaining importance for improving the success of antiretroviral treatment in human immunodeficiency virus-infected patients. However, enfuvirtide (ENF) concentrations are not regularly determined. The objective of this work was to study the pharmacokinetics (PK) of ENF in patients treated in routine clinical settings, to develop a population PK model describing the concentration-time profile, and to establish PK reference values. A liquid chromatography-tandem mass spectrometry method was developed and applied to serum samples submitted for TDM. A two-compartment model with linear absorption and elimination was fitted to 329 concentrations from 131 patients. The PK model was used for simulations resulting in percentile curves for ENF levels for the full dosing interval. The model predicted that a median concentration of 1,968 ng/ml would be reached 12 h after administration of 90 mg of ENF, and 23% and 58% of patients are expected to have concentrations below 1,000 ng/ml and 2,200 ng/ml, respectively. Both values have been proposed as cutoffs for virological efficacy. The median maximum concentration of drug in serum (C max) of 3,943 ng/ml, predicted for 3 h after drug administration, is lower than the C max reported previously. We found an enormous interpatient variability at every time point, with concentration spectrums covering >1 log and 52% and 123% interindividual variabilities in the typical clearance and volume of distribution, respectively, in contrast to preexisting PK data. In summary, ENF levels are lower and more variable than expected. Many patients may achieve insufficient concentrations. Further covariate analysis in the population PK model might help to identify factors influencing the variability in ENF concentrations.

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