scholarly journals Concentration–response model of rilpivirine in a cohort of HIV-1-infected naive and pre-treated patients

2019 ◽  
Vol 74 (7) ◽  
pp. 1992-2002 ◽  
Author(s):  
Nadège Néant ◽  
Caroline Solas ◽  
Naïm Bouazza ◽  
Minh Patrick Lê ◽  
Yazdan Yazdanpanah ◽  
...  
Keyword(s):  
Plasma Concentration ◽  
Plasma Concentrations ◽  
Pharmacodynamic Model ◽  
People Living With Hiv ◽  
Good Precision ◽  
Response Relationship ◽  
Final Model ◽  
Trough Plasma Concentration ◽  
Hiv 1 ◽  
Trough Plasma

Abstract Background Rilpivirine is widely prescribed in people living with HIV. Although trough plasma concentrations have been associated with virological response, the drug pharmacodynamics remain incompletely characterized. Objectives To develop the first pharmacodynamic model of rilpivirine in order to establish the rilpivirine concentration–response relationship for future treatment optimization. Methods A retrospective observational study was conducted in patients receiving the once-daily rilpivirine/tenofovir disoproxil fumarate/emtricitabine regimen. Individual rilpivirine trough plasma concentrations over time were predicted using a previous pharmacokinetic model. An established susceptible, infected, recovered model was used to describe HIV dynamics without assuming disease steady-state. Population analysis was performed with MONOLIX 2018 software. Simulations of the viral load evolution as a function of time and rilpivirine trough plasma concentration were performed. Results Overall, 60 naive and 39 pre-treated patients were included with a follow-up ranging from 2 to 37 months. The final model adequately described the data and the pharmacodynamic parameters were estimated with a good precision. The population typical value of rilpivirine EC50 was estimated at 65 ng/mL. A higher infection rate constant of CD4 cells for HIV-1 was obtained in pre-treated patients. Consequently, the time to obtain virological suppression was longer in pre-treated than in naive patients. Conclusions The concentration–response relationship of rilpivirine was satisfactorily described for the first time using an original population pharmacodynamic model. Simulations performed using the final model showed that the currently used 50 ng/mL rilpivirine trough plasma concentration efficacy target might need revision upwards, particularly in pre-treated patients.

scholarly journals Risk Factors for a Low Linezolid Trough Plasma Concentration in Acute Infections

2013 ◽  
Vol 57 (4) ◽  
pp. 1913-1917 ◽  
Author(s):  
Laura Morata ◽  
Marta Cuesta ◽  
Jhon F. Rojas ◽  
Sebastian Rodriguez ◽  
Merce Brunet ◽  
...  
Keyword(s):  
Risk Factors ◽  
Steady State ◽  
Plasma Concentration ◽  
Plasma Concentrations ◽  
Time Curve ◽  
Content Type ◽  
Acute Infections ◽  
Trough Plasma Concentration ◽  
Dependent Activity ◽  
Trough Plasma

ABSTRACTLinezolid is an antibiotic with time-dependent activity, and both the percentage of time that plasma concentrations exceed the MIC and the area under the concentration-time curve over 24 h in the steady state divided by the MIC (AUC24/MIC ratio) are associated with clinical response. The aim of this study was to analyze the linezolid trough plasma concentration (Cmin) and to determine factors associated with aCmin< 2 mg/liter and other clinically relevant thresholds. Characteristics of 78 patients receiving 600 mg/12 h of linezolid with aCmindetermination at the steady state and within the first 10 days of treatment were retrospectively reviewed. Concentrations were measured using high-pressure liquid chromatography. Univariate and multivariate analysis were performed to identify risk factors of lowCmin. A total of 29.5% of patients had aCmin< 2 mg/liter. The percentage was significantly higher in patients with an estimated glomerular filtration (eGF) > 80 ml/min, in intensive care unit (ICU) patients, and in patients with an infection due toStaphylococcus aureus. The independent predictors ofCmin< 2 mg/liter were an eGF > 80 ml/min (odds ratio [OR], 10; 95% confidence interval [CI], 2.732 to 37.037;P= 0.001) and infection due toS. aureus(OR, 5.906; 95% CI, 1.651 to 21.126;P= 0.006). A linezolidCminof <2 mg/liter was found in 29.5% of cases, and the risk was significantly higher among those with an eGF > 80 ml/min and in infections due toS. aureus. In patients with severe sepsis, a loading dose or continuous infusion and drug monitoring could improve the pharmacodynamic parameters associated with linezolid efficacy.

scholarly journals High-Trough Plasma Concentration of Afatinib Is Associated with Dose Reduction

Cancers ◽  
2021 ◽  
Vol 13 (14) ◽  
pp. 3425
Author(s):  
Takayuki Takahashi ◽  
Hideyuki Terazono ◽  
Takayuki Suetsugu ◽  
Hideki Sugawara ◽  
Junko Arima ◽  
...  
Keyword(s):  
Plasma Concentration ◽  
Adverse Effects ◽  
Dose Reduction ◽  
Roc Curve ◽  
High Performance ◽  
Kinase Inhibitor ◽  
Plasma Concentrations ◽  
Laboratory Data ◽  
Trough Plasma Concentration ◽  
Trough Plasma

Afatinib is used to treat non-small-cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutation as a second-generation EGFR-tyrosine kinase inhibitor (TKI). Early prediction of adverse effects based on the pharmacokinetics of afatinib enables support for quality of life (QOL) in patients with no change in efficacy. We examined the pharmacokinetic relationship between trough plasma concentration and adverse effects and evaluated the utility of measuring the trough plasma concentration of afatinib as the first EGFR-TKI treatment for NSCLC in a prospective multicenter study. Twenty-four patients treated with afatinib were enrolled in this study. All blood samples were collected at the trough point, and plasma concentrations were measured using high-performance liquid chromatography–tandem mass spectrometry. Logistic regression analysis for the dose reduction of afatinib was performed, and the receiver operating characteristic (ROC) curve was plotted. Although all patients started afatinib at 40 mg/day, plasma concentrations were variable, and mean and median trough plasma concentrations were 32.9 ng/mL and 32.5 ng/mL in this study, respectively. Minimum and maximum trough plasma concentrations were 10.4 ng/mL and 72.7 ng/mL, respectively. This variability was speculated to involve personal parameters such as laboratory data. However, no patient characteristics or laboratory data examined correlated with the trough plasma concentration of afatinib, except albumin. Albumin showed a weak correlation with plasma concentration (r = 0.60, p = 0.009). The trough plasma concentration of afatinib was significantly associated with the dose reduction of afatinib (p = 0.047). The area under the ROC curve (AUC) for the trough plasma concentration of afatinib was 0.81. The cut-off value was 21.4 ng/mL. The sensitivity and specificity of the cut-off as a risk factor were 0.80 and 0.75. In summary, the trough plasma concentration of afatinib was associated with continued or reduced dosage because of the onset of several adverse effects, and a threshold was seen. Adverse effects not only lower QOL but also hinder continued treatment. Measuring plasma concentrations of afatinib appears valuable to predict adverse effects and continue effective therapy.

Imatinib Plasma Concentration and Sokal Risk Score Are Independently Prognostic for Complete Cytogenetic Response (CCyR) in Patients with Chronic-Phase Chronic Myeloid Leukemia (CML-CP).

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1935-1935 ◽  
Author(s):  
Richard A. Larson ◽  
Brian J. Druker ◽  
Francois Guilhot ◽  
Stephen G. O’Brien ◽  
Tillman Krahnke ◽  
...  
Keyword(s):  
Plasma Level ◽  
Odds Ratio ◽  
Risk Group ◽  
Plasma Concentrations ◽  
Laboratory Data ◽  
Risk Level ◽  
Stepwise Logistic Regression ◽  
Final Model ◽  
Trough Levels ◽  
Trough Plasma

Abstract Background: In the International Randomized Study of Interferon and STI571 (IRIS), 553 patients (pts) with newly diagnosed CML-CP were randomized to receive imatinib (IM) 400 mg/d. The 5-year analysis of these pts showed that first-line IM yielded an estimated 87% cumulative CCyR rate and an estimated 89% overall survival (OS) and was generally well tolerated (Druker et al, NEJM 2006). We analyzed the IM pharmacokinetic (PK) exposure and evaluated its effect on efficacy and safety parameters. Methods: Pts were grouped into quartiles according to IM trough plasma concentrations at steady state (day 29 of therapy; Q1 &lt;647 ng/mL, Q2+Q3, and Q4 &gt;1170 ng/mL). Adverse events (AEs) and discontinuations as well as CCyR (0% Ph+) rates were summarized based on these groups. A multivariate analysis was performed using stepwise logistic regression to examine whether IM plasma levels are prognostic for ability to achieve a CCyR independently of Sokal risk group, patient demographics, and laboratory data. Criteria for inclusion of variables into the statistical model was a P&lt;0.15, and a P&lt;0.05 was required for variables to remain in the final model. Results: Of 351 pts for whom PK samples were available, 105 (30%) have discontinued imatinib therapy: 41% of pts with low IM trough levels (Q1), 28% in Q2-Q3, and 23% in Q4. “Unsatisfactory therapeutic effect” was the most frequently cited reason for discontinuation in 18%, 15%, and 8% of pts in Q1, Q2-Q3, and Q4, respectively. Fluid retention, rash, myalgia, and anemia were more frequent relevant AEs, of any grade, among pts in Q4 vs Q1 group (76% vs 53%, 51% vs 32%, 30% vs 20% and 20% vs 8%, respectively), but these events did not translate into significantly higher discontinuations due to AEs. Muscle cramps, diarrhea, abdominal pain, headache, and hemorrhage were less frequent among pts with highest IM trough levels vs those with the lowest, suggesting that some AEs may be disease related. Overall, CCyR rates were 76% in pts with lowest IM trough levels (Q1), 85% in pts with intermediate levels (Q2-Q3), and 92% in pts with the highest trough levels (Q4) (P=0.013, Fisher’s exact test). Of pts with both Sokal risk and PK sample available, 50% were in the low risk group, 32% in the intermediate, and 18% in the high risk group; their CCyR rates were 94%, 84%, and 73%, respectively (P=0.002). Within each Sokal group, the prognostic effect of IM trough levels was most apparent in pts of intermediate risk, among whom 64% achieved CCyR in Q1 vs 94% in Q4 (P=0.015). Of all the evaluated prognostic variables, only Sokal risk and IM trough plasma level were prognostic for ability to achieve a CCyR. Based on the final multivariate model, for an increase by one Sokal risk level, the odds ratio of achieving a CCyR was 0.55 (95% CI, 0.32–0.93, P=0.027), while an increase by 250 ng/mL in IM trough yielded an odds ratio of 1.77 (1.22–2.56, P=0.003). No other factors met the selection criteria to remain in the final model. Conclusion: These results suggest that achieving an adequate IM plasma level is important for a good clinical response. Monitoring of IM plasma concentrations should be encouraged in patients with poor response.

Association Between CYP3A4 Polymorphisms, Trough Imatinib Plasma Concentration and Cytogenetic Response in Chronic Phase Chronic Myeloid Leukemia (CML-CP)

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3788-3788 ◽  
Author(s):  
Vikram Gota ◽  
Anupam Sharma ◽  
Amey Paradkar ◽  
Anand Patil ◽  
Navin Khattry ◽  
...  
Keyword(s):  
Plasma Concentration ◽  
Roc Curve ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Molecular Response ◽  
Complete Cytogenetic Response ◽  
Trough Plasma Concentration ◽  
Pcr Rflp ◽  
Trough Levels ◽  
Trough Plasma

Abstract Abstract 3788 Introduction: Imatinib mesylate has demonstrated excellent efficacy as first-line therapy for treatment of chronic phase chronic myelogenous leukemia (CML-CP). The drug has a high inter-patient variability in pharmacokinetics (PK), and several factors are presumed to influence its PK. Imatinib is a substrate of CYP3A4 and CYP3A5 enzymes. However, the clinical significance of its metabolism on pharmacokinetics and therapeutic response is still unclear. Significantly higher in vivo CYP3A activity was reported recently in patients achieving complete molecular response than those who did not in a small cohort study. Several investigators in the past have tried to optimize imatinib dosing based on trough levels after the fourth treatment week. Picard S et al (Blood, 2007) showed that threshold plasma concentration of 1002 ng/ml on day 29 was associated with higher incidence of major molecular response. The primary objective of this study was to evaluate the association between CYP3A4 polymorphisms, trough plasma concentration of imatinib on day 8 and day 29 of treatment, and cytogenetic response. The secondary objective was to evaluate the potential of early (day 8) trough level monitoring to discriminate between responders and non-responders. Methods: All patients received standard 400 mg OD dose of imatinib. A single blood sample was collected on day 8 and day 29 prior to imatinib dosing for the determination of trough plasma concentration. Imatinib level was determined using High Performance Liquid Chromatography (HPLC). Cytogenetic response was assessed at 3 monthly intervals by Fluorescence In Situ Hybridization (FISH). Complete cytogenetic response (CCR) was defined as 0% of Philadelphia chromosome–positive cells in the bone marrow aspirate. Pharmacogenetic sample was collected from each patient at the beginning of the study to look for CYP3A4 polymorphism. Genotyping was carried out for *4 (rs55951658), *5 (rs55901263) and *18 (rs28371759) variants by PCR-RFLP technique. About 10% samples were chosen randomly for direct sequencing to confirm the PCR-RFLP findings. Median imatinib concentration in the CCR and non CCR groups was compared using non-parametric Mann-Whitney test. Receiver Operating Characteristic (ROC) curve analysis was performed to assess the discrimination potential of trough imatinib plasma levels for complete cytogenetic response (CCR). Results: Ninety eight patients were enrolled on this study, 70 males and 28 females. The median age was 33 years (Range 6 – 71 years). High interpatient variability in the trough concentration of imatinib was observed (Coefficient of variation = 64% and 56% for day 8 and day 29 respectively). However, none of the patients were found to have *4, *5 or *18 variant alleles. Genotype–PK or genotype-response association could not be evaluated as a result. Data on cytogenetic response at 12 months was available for 75 patients (60 CCR, 15 without CCR), 46 of whom also had trough imatinib levels measured on day 8 and day 29 (36 CCR, 10 without CCR). Median day 8 and day 29 trough concentrations were not significantly different in the group with CCR (1.71 and 1.91 μg/mL respectively) and the group without (1.31 and 1.64 μg/mL respectively). Regarding the discrimination potential of trough levels for CCR, day 8 concentrations failed to discriminate between responders and non-responders, whereas for the Day 29 levels, the area under the ROC curve (AUC) was 0.554, with best sensitivity (75%) and specificity (61%) at plasma threshold of 1.69 μg/mL. Conclusion: In this cohort of patients, common CYP3A4 variants did not contribute to the high inter-patient variability of imatinib levels. Early monitoring on Day 8 failed to discriminate responders from non-responders. Day 29 levels are a better predictor of complete cytogenetic response as shown in previous studies. Disclosures: No relevant conflicts of interest to declare.

A sensitive liquid chromatography-tandem mass spectrometry method for monitoring the caspofungin trough plasma concentration and its association with caspofungin efficacy in intensive-care-unit patients

RSC Advances ◽  
2015 ◽  
Vol 5 (127) ◽  
pp. 104806-104814 ◽  
Author(s):  
Qianting Yang ◽  
Taotao Wang ◽  
Jiao Xie ◽  
Lu Chen ◽  
Yan Wang ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Intensive Care Unit ◽  
Intensive Care ◽  
Plasma Concentration ◽  
Tandem Mass ◽  
Spectrometry Method ◽  
Trough Plasma Concentration ◽  
Chromatography Tandem Mass Spectrometry ◽  
Liquid Chromatography Tandem Mass ◽  
Trough Plasma

LC-MS/MS method for monitoring the caspofungin trough plasma concentration and its association efficacy in intensive-care-unit patients.

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