scholarly journals Exposure-Response Analyses for Tafenoquine after Administration to Patients with Plasmodium vivax Malaria

2015 ◽  
Vol 59 (10) ◽  
pp. 6188-6194 ◽  
Author(s):  
David Tenero ◽  
Justin A. Green ◽  
Navin Goyal
Keyword(s):  
Plasmodium Vivax ◽  
Regression Tree ◽  
Classification And Regression Tree ◽  
Radical Cure ◽  
Pivotal Phase ◽  
Time Curve ◽  
Content Type ◽  
Cart Analysis ◽  
Exposure Response ◽  
Time To Relapse

ABSTRACTTafenoquine (TQ), a new 8-aminoquinoline with activity against all stages of thePlasmodium vivaxlife cycle, is being developed for the radical cure of acuteP. vivaxmalaria in combination with chloroquine. The efficacy and exposure data from a pivotal phase 2b dose-ranging study were used to conduct exposure-response analyses for TQ after administration to subjects withP. vivaxmalaria. TQ exposure (i.e., area under the concentration-time curve [AUC]) and region (Thailand compared to Peru and Brazil) were found to be statistically significant predictors of clinical response based on multivariate logistic regression analyses. After accounting for region/country, the odds of being relapse free at 6 months increased by approximately 51% (95% confidence intervals [CI], 25%, 82%) for each 25-U increase in AUC above the median value of 54.5 μg · h/ml. TQ exposure was also a significant predictor of the time to relapse of the infection. The final parametric, time-to-event model for the time to relapse, included a Weibull distribution hazard function, AUC, and country as covariates. Based on the model, the risk of relapse decreased by 30% (95% CI, 17% to 42%) for every 25-U increase in AUC. Monte Carlo simulations indicated that the 300-mg dose of TQ would provide an AUC greater than the clinically relevant breakpoint obtained in a classification and regression tree (CART) analysis (56.4 μg · h/ml) in more than 90% of subjects and consequently result in a high probability of being relapse free at 6 months. This model-based approach was critical in selecting an appropriate phase 3 dose. (This study has been registered at ClinicalTrials.gov under registration no. NCT01376167.)

scholarly journals Establishment of an AUC0–24 Threshold for Nephrotoxicity Is a Step towards Individualized Vancomycin Dosing for Methicillin-Resistant Staphylococcus aureus Bacteremia

2017 ◽  
Vol 61 (5) ◽  
Author(s):  
R. Chavada ◽  
N. Ghosh ◽  
I. Sandaradura ◽  
M. Maley ◽  
S. J. Van Hal
Keyword(s):  
Staphylococcus Aureus ◽  
Regression Tree ◽  
Kidney Injury ◽  
Classification And Regression Tree ◽  
Time Curve ◽  
Methicillin Resistant ◽  
Content Type ◽  
Cart Analysis ◽  
Vancomycin Trough ◽  
Trough Concentrations

ABSTRACT Unlike vancomycin trough concentrations, data on the utility of vancomycin pharmacokinetic (PK) parameters, namely, the area under the concentration-time curve from 0 to 24 h (AUC0–24), in predicting acute kidney injury (AKI) are limited. Our aim was to investigate this relationship in patients receiving vancomycin therapy for methicillin-resistant Staphylococcus aureus bacteremia (MRSA-B). A single-center retrospective observational cohort study involving 127 consecutive MRSA-B patients was conducted to examine the incidence of AKI (defined as serum creatinine of ≥0.5 mg/liter and a 50% increase from baseline) and vancomycin exposure parameters associated with nephrotoxicity. Bayesian estimation was used to predict individual vancomycin AUC0–24. All patients received vancomycin monotherapy for a minimum of 14 days following the diagnosis of MRSA-B. AKI was observed in 15.7% of patients (20/127). Clinical characteristics were similar between patients with and without AKI. At steady state, higher vancomycin trough concentrations were associated with AKI (17.2 mg/liter versus 13.1 mg/liter; P = 0.003). A vancomycin AUC0–24 threshold for AKI of >563 mg · h/liter was detected by classification and regression tree (CART) analysis; patients with exposures above this threshold were significantly more likely to experience AKI than patients with lower vancomycin exposures (40% [8/20] versus 11.2% [12/107]; P = 0.002). This parameter remained an independent predictor of AKI on multivariate logistic regression (odds ratio [OR], 5.07; 95% confidence interval [CI], 1.57 to 16.29; P = 0.006) and was a better predictor of nephrotoxicity than vancomycin trough concentrations. Overall, AKI is associated with higher vancomycin exposure as measured by AUC0–24. These results suggest that individualized patient dosing may be possible with dose modifications directed toward established pharmacodynamic targets while balancing AKI risks.

scholarly journals Identification of Vancomycin Exposure-Toxicity Thresholds in Hospitalized Patients Receiving Intravenous Vancomycin

2017 ◽  
Vol 62 (1) ◽  
Author(s):  
Evan J. Zasowski ◽  
Kyle P. Murray ◽  
Trang D. Trinh ◽  
Natalie A. Finch ◽  
Jason M. Pogue ◽  
...  
Keyword(s):  
Poisson Regression ◽  
Regression Tree ◽  
Predictive Performance ◽  
Classification And Regression Tree ◽  
Therapeutic Drug ◽  
Time Curve ◽  
Minimum Concentration ◽  
Content Type ◽  
Cart Analysis ◽  
Increased Risk

ABSTRACTEvidence supports vancomycin therapeutic-drug monitoring by area under the concentration-time curve (AUC), but data to establish an AUC upper limit are limited and published nephrotoxicity thresholds range widely. The objective of this analysis was to examine the association between initial vancomycin AUC and nephrotoxicity. This was a multicenter, retrospective cohort study of adult patients receiving intravenous vancomycin from 2014 to 2015. Nephrotoxicity was defined as a serum creatinine increase of 0.5 mg/liter and 50% from baseline on consecutive measurements. Vancomycin exposure profile during the initial 48 h of therapy was estimated using maximuma posterioriprobability Bayesian estimation. Vancomycin AUC and minimum-concentration (Cmin) thresholds most strongly associated with nephrotoxicity were identified via classification and regression tree (CART) analysis. Predictive performances of CART-derived and other candidate AUC thresholds was assessed through positive and negative predictive value and receiver operating characteristic curves. Poisson regression was used to quantify the association between exposure thresholds and nephrotoxicity while adjusting for confounders. Among 323 patients included, nephrotoxicity was significantly higher in patients with AUCs from 0 to 48 h (AUC0–48) of ≥1,218 mg · h/liter, AUC0–24of ≥677 mg · h/liter, AUC24–48of ≥683 mg · h/liter, and day 1Cmin(Cmin24) of ≥18.8 mg/liter. Vancomycin exposure in excess of these thresholds was associated with a 3- to 4-fold-increased risk of nephrotoxicity in Poisson regression. The predictive performance of AUC for nephrotoxicity was maximized at daily AUC values between 600 and 800 mg · h/liter. Although these data support an AUC range for vancomycin-associated nephrotoxity rather than a single threshold, available evidence suggests that a daily AUC limit of 700 mg · h/liter is reasonable.

scholarly journals Population Pharmacokinetics and Pharmacodynamics of Levofloxacin in Acutely Hospitalized Older Patients with Various Degrees of Renal Function

2016 ◽  
Vol 61 (3) ◽  
Author(s):  
Pier Giorgio Cojutti ◽  
Virginia Ramos-Martin ◽  
Isabella Schiavon ◽  
Paolo Rossi ◽  
Massimo Baraldo ◽  
...  
Keyword(s):  
Renal Function ◽  
Clinical Outcome ◽  
Creatinine Clearance ◽  
Population Pharmacokinetics ◽  
Older Patients ◽  
Classification And Regression Tree ◽  
Therapeutic Drug ◽  
Time Curve ◽  
Content Type ◽  
Cart Analysis

ABSTRACT A retrospective study was conducted in a large sample of acutely hospitalized older patients who underwent therapeutic drug monitoring during levofloxacin treatment. The aim was to assess the population pharmacokinetics (popPK) and pharmacodynamics of levofloxacin among older patients. PopPK and Monte Carlo simulation were performed to define the permissible doses in older patients according to various degrees of renal function. Classification and regression tree (CART) analysis was used to detect the cutoff 24-hour area under the concentration-time curve (AUC24)/MIC ratio that best correlated with the clinical outcome. The probability of target attainment (PTA) of this value was calculated against different pathogens. A total of 168 patients were included, and 330 trough and 239 peak concentrations were used for the popPK analysis. Creatinine clearance (CrCL) was the only covariate that improved the model fit (levofloxacin CL = 0.399 + 0.051 × CrCLCKD-EPI [creatinine clearance estimated by means of the chronic kidney disease epidemiology]). Drug doses ranged between 500 mg every 48 h and 500 mg every 12 h in relation to different renal functions. The identified cutoff AUC24/MIC ratio (≥95.7) was the only covariate that correlated with a favorable clinical outcome in multivariate regression analysis (odds ratio [OR], 20.85; 95% confidence interval [CI], 1.56 to 186.73). PTAs were optimal (>80%) against Escherichia coli and Haemophilus influenzae, borderline against Staphylococcus aureus, and suboptimal against Pseudomonas aeruginosa. The levofloxacin doses defined in our study may be effective for the treatment of infections due to bacterial pathogens, with an MIC of ≤0.5 mg/liter in older patients with various degrees of renal function, while minimizing the toxicity risk. Conversely, the addition of another active antimicrobial should be considered whenever treating infections caused by less susceptible pathogens.

scholarly journals Exposure-Response Analyses of Tigecycline Efficacy in Patients with Complicated Skin and Skin-Structure Infections

2007 ◽  
Vol 51 (6) ◽  
pp. 1939-1945 ◽  
Author(s):  
A. K. Meagher ◽  
J. A. Passarell ◽  
B. B. Cirincione ◽  
S. A. Van Wart ◽  
K. Liolios ◽  
...  
Keyword(s):  
Sample Size ◽  
Regression Tree ◽  
Classification And Regression Tree ◽  
Loading Dose ◽  
Time Curve ◽  
Skin Structure ◽  
Exposure Response ◽  
Concentration Time ◽  
Complicated Skin ◽  
Clinical Responses

ABSTRACT Exposure-response analyses were performed for the microbiological and clinical efficacy of tigecycline in the treatment of complicated skin and skin-structure infections, where Staphylococcus aureus and streptococci are the predominant pathogens. A prospective method was developed to create homogeneous patient populations for PK-PD analyses. Evaluable patients from three clinical trials were pooled for analysis. Patients received a tigecycline 100-mg loading dose/50 mg every 12 h or a 50-mg loading dose/25 mg every 12 h. At the test-of-cure visit, microbiologic and clinical responses were evaluated. Patients were prospectively evaluated and classified into cohorts based on baseline pathogens: S. aureus only (cohort 1), monomicrobial S. aureus or streptococci (cohort 2), two gram-positive pathogens (cohort 3), polymicrobial (cohort 4), or other monomicrobial infections (cohort 5). A prospective procedure for combining cohorts was used to increase the sample size. Logistic regression evaluated steady-state 24-h area under the concentration-time curve (AUC24)/MIC ratio as a predictor of response, and classification and regression tree (CART) analyses were utilized to determine AUC/MIC breakpoints. Analysis began with pooled cohorts 2 and 3, the focus of these analyses, and included 35 patients with 40 S. aureus and/or streptococcal pathogens. CART analyses identified a significant AUC/MIC breakpoint of 17.9 (P = 0.0001 for microbiological response and P = 0.0376 for clinical response). The continuous AUC/MIC ratio was predictive of microbiological response based on sample size (P = 0.0563). Analysis of all pathogens combined decreased the ability to detect exposure-response relationships. The prospective approach of creating homogeneous populations based on S. aureus and streptococci pathogens was critical for identifying exposure-response relationships.

scholarly journals Association between Vancomycin Day 1 Exposure Profile and Outcomes among Patients with Methicillin-Resistant Staphylococcus aureus Infective Endocarditis

2015 ◽  
Vol 59 (6) ◽  
pp. 2978-2985 ◽  
Author(s):  
Anthony M. Casapao ◽  
Thomas P. Lodise ◽  
Susan L. Davis ◽  
Kimberly C. Claeys ◽  
Ravina Kullar ◽  
...  
Keyword(s):  
Infective Endocarditis ◽  
Medical Center ◽  
Regression Tree ◽  
Classification And Regression Tree ◽  
Attributable Mortality ◽  
Time Curve ◽  
Minimum Concentration ◽  
Cart Analysis ◽  
Increased Risk ◽  
Exposure Profile

ABSTRACTGiven the critical importance of early appropriate therapy, a retrospective cohort (2002 to 2013) was performed at the Detroit Medical Center to evaluate the association between the day 1 vancomycin exposure profile and outcomes among patients with MRSA infective endocarditis (IE). The day 1 vancomycin area under the concentration-time curve (AUC0–24) and the minimum concentration at 24 h (Cmin 24) was estimated for each patient using the Bayesian procedure in ADAPT 5, an approach shown to accurately predict the vancomycin exposure with low bias and high precision with limited pharmacokinetic sampling. Initial MRSA isolates were collected and vancomycin MIC was determined by broth microdilution (BMD) and Etest. The primary outcome was failure, defined as persistent bacteremia (≥7 days) or 30-day attributable mortality. Classification and regression tree analysis (CART) was used to determine the vancomycin exposure variables associated with an increased probability of failure. In total, 139 patients met study criteria; 76.3% had right-sided IE, 16.5% had left-sided IE, and 7.2% had both left and right-sided IE. A total of 89/139 (64%) experienced failure by composite definition. In the CART analysis, failure was more pronounced in patients with an AUC0–24/MIC as determined by BMD of ≤600 relative to those with AUC0–24/MIC as determined by BMD of >600 (69.8% versus 54.7%, respectively,P= 0.073). In the logistic regression analysis, an AUC/MIC as determined by BMD of ≤600 (adjusted odds ratio, 2.3; 95% confidence interval, 1.01 to 5.37;P= 0.047) was independently associated with failure. Given the retrospective nature of the present study, further prospective studies are required but these data suggest that patients with an AUC0–24/MIC as determined by BMD of ≤600 present an increased risk of failure.

scholarly journals Validation and verification of predictive salivary biomarkers for oral health

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Nagihan Bostanci ◽  
Konstantinos Mitsakakis ◽  
Beral Afacan ◽  
Kai Bao ◽  
Benita Johannsen ◽  
...  
Keyword(s):  
Oral Health ◽  
Predictive Accuracy ◽  
Statistical Tests ◽  
Area Under The Curve ◽  
Regression Tree ◽  
High Sensitivity ◽  
Oral Health Status ◽  
Classification And Regression Tree ◽  
Cart Analysis ◽  
Salivary Biomarkers

AbstractOral health is important not only due to the diseases emerging in the oral cavity but also due to the direct relation to systemic health. Thus, early and accurate characterization of the oral health status is of utmost importance. There are several salivary biomarkers as candidates for gingivitis and periodontitis, which are major oral health threats, affecting the gums. These need to be verified and validated for their potential use as differentiators of health, gingivitis and periodontitis status, before they are translated to chair-side for diagnostics and personalized monitoring. We aimed to measure 10 candidates using high sensitivity ELISAs in a well-controlled cohort of 127 individuals from three groups: periodontitis (60), gingivitis (31) and healthy (36). The statistical approaches included univariate statistical tests, receiver operating characteristic curves (ROC) with the corresponding Area Under the Curve (AUC) and Classification and Regression Tree (CART) analysis. The main outcomes were that the combination of multiple biomarker assays, rather than the use of single ones, can offer a predictive accuracy of > 90% for gingivitis versus health groups; and 100% for periodontitis versus health and periodontitis versus gingivitis groups. Furthermore, ratios of biomarkers MMP-8, MMP-9 and TIMP-1 were also proven to be powerful differentiating values compared to the single biomarkers.

scholarly journals Cognitive and Behavioral Domains That Reliably Differentiate Normal Aging and Dementia in Down Syndrome

2021 ◽  
Vol 11 (9) ◽  
pp. 1128
Author(s):  
Jordan P. Harp ◽  
Lisa M. Koehl ◽  
Kathryn L. Van Pelt ◽  
Christy L. Hom ◽  
Eric Doran ◽  
...  
Keyword(s):  
Primary Care ◽  
Down Syndrome ◽  
Area Under The Curve ◽  
Regression Tree ◽  
Classification And Regression Tree ◽  
Vineland Adaptive Behavior Scales ◽  
Cart Analysis ◽  
Dementia Screening ◽  
Significant Difference ◽  
Unit Increase

Primary care integration of Down syndrome (DS)-specific dementia screening is strongly advised. The current study employed principal components analysis (PCA) and classification and regression tree (CART) analyses to identify an abbreviated battery for dementia classification. Scale- and subscale-level scores from 141 participants (no dementia n = 68; probable Alzheimer’s disease n = 73), for the Severe Impairment Battery (SIB), Dementia Scale for People with Learning Disabilities (DLD), and Vineland Adaptive Behavior Scales—Second Edition (Vineland-II) were analyzed. Two principle components (PC1, PC2) were identified with the odds of a probable dementia diagnosis increasing 2.54 times per PC1 unit increase and by 3.73 times per PC2 unit increase. CART analysis identified that the DLD sum of cognitive scores (SCS < 35 raw) and Vineland-II community subdomain (<36 raw) scores best classified dementia. No significant difference in the PCA versus CART area under the curve (AUC) was noted (D(65.196) = −0.57683; p = 0.57; PCA AUC = 0.87; CART AUC = 0.91). The PCA sensitivity was 80% and specificity was 70%; CART was 100% and specificity was 81%. These results support an abbreviated dementia screening battery to identify at-risk individuals with DS in primary care settings to guide specialized diagnostic referral.

scholarly journals Pharmacodynamic Analysis of Daptomycin-treated Enterococcal Bacteremia: It Is Time to Change the Breakpoint

2018 ◽  
Vol 68 (10) ◽  
pp. 1650-1657 ◽  
Author(s):  
Lindsay M Avery ◽  
Joseph L Kuti ◽  
Maja Weisser ◽  
Adrian Egli ◽  
Michael J Rybak ◽  
...  
Keyword(s):  
Regression Tree ◽  
Classification And Regression Tree ◽  
Population Pharmacokinetic ◽  
Time Curve ◽  
Regression Tree Analysis ◽  
Lactam Antibiotic ◽  
Infection Source ◽  
High Doses ◽  
Susceptibility Breakpoint ◽  
Enterococcal Bacteremia

Abstract Background Currently, there is debate over whether the daptomycin susceptibility breakpoint for enterococci (ie, minimum inhibitory concentration [MIC] ≤4 mg/L) is appropriate. In bacteremia, observational data support prescription of high doses (&gt;8 mg/kg). However, pharmacodynamic targets associated with positive patient outcomes are undefined. Methods Data were pooled from observational studies that assessed outcomes in daptomycin-treated enterococcal bacteremia. Patients who received an additional antienterococcal antibiotic and/or a β-lactam antibiotic at any time during treatment were excluded. Daptomycin exposures were calculated using a published population pharmacokinetic model. The free drug area under the concentration-time curve to MIC ratio (fAUC/MIC) threshold predictive of survival at 30 days was identified by classification and regression tree analysis and confirmed with multivariable logistic regression. Monte Carlo simulations determined the probability of target attainment (PTA) at clinically relevant MICs. Results Of 114 patients who received daptomycin monotherapy, 67 (58.8%) were alive at 30 days. A fAUC/MIC &gt;27.43 was associated with survival in low-acuity (n = 77) patients (68.9 vs 37.5%, P = .006), which remained significant after adjusting for infection source and immunosuppression (P = .026). The PTA for a 6-mg/kg/day (every 24 hours) dose was 1.5%–5.5% when the MIC was 4 mg/L (ie, daptomycin-susceptible) and 91.0%–97.9% when the MIC was 1 mg/L. Conclusions For enterococcal bacteremia, a daptomycin fAUC/MIC &gt;27.43 was associated with 30-day survival among low-acuity patients. As pharmacodynamics for the approved dose are optimized only when MIC ≤1 mg/L, these data continue to stress the importance of reevaluation of the susceptibility breakpoint.

scholarly journals Artificial liver support system therapy in acute-on-chronic hepatitis B liver failure: Classification and regression tree analysis

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Kaizhou Huang ◽  
Feiyang Ji ◽  
Zhongyang Xie ◽  
Daxian Wu ◽  
Xiaowei Xu ◽  
...  
Keyword(s):  
High Risk ◽  
Hepatitis B ◽  
Regression Tree ◽  
Classification And Regression Tree ◽  
Artificial Liver ◽  
Liver Support ◽  
Artificial Liver Support ◽  
Cart Analysis ◽  
Classification And Regression ◽  
Cart Model

Abstract Artificial liver support systems (ALSS) are widely used to treat patients with hepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF). The aims of the present study were to investigate the subgroups of patients with HBV-ACLF who may benefit from ALSS therapy, and the relevant patient-specific factors. 489 ALSS-treated HBV-ACLF patients were enrolled, and served as derivation and validation cohorts for classification and regression tree (CART) analysis. CART analysis identified three factors prognostic of survival: hepatic encephalopathy (HE), prothrombin time (PT), and total bilirubin (TBil) level; and two distinct risk groups: low (28-day mortality 10.2–39.5%) and high risk (63.8–91.1%). The CART model showed that patients lacking HE and with a PT ≤ 27.8 s and a TBil level ≤455 μmol/L experienced less 28-day mortality after ALSS therapy. For HBV-ACLF patients with HE and a PT > 27.8 s, mortality remained high after such therapy. Patients lacking HE with a PT ≤ 27.8 s and TBil level ≤ 455 μmol/L may benefit markedly from ALSS therapy. For HBV-ACLF patients at high risk, unnecessary ALSS therapy should be avoided. The CART model is a novel user-friendly tool for screening HBV-ACLF patient eligibility for ALSS therapy, and will aid clinicians via ACLF risk stratification and therapeutic guidance.

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