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1.  Relevance of Soft-Tissue Penetration by Levofloxacin for Target Site Bacterial Killing in Patients with Sepsis 
Antimicrobial Agents and Chemotherapy  2003;47(11):3548-3553.
Antimicrobial therapy of soft tissue infections in patients with sepsis sometimes lacks efficiency, despite the documented susceptibility of the causative pathogen to the administered antibiotic. In this context, impaired equilibration between the antibiotic concentrations in plasma and those in tissues in critically ill patients has been discussed. To characterize the impact of tissue penetration of anti-infective agents on antimicrobial killing, we used microdialysis to measure the concentration-versus-time profiles of levofloxacin in the interstitial space fluid of skeletal muscle in patients with sepsis. Subsequently, we applied an established dynamic in vivo pharmacokinetic-in vitro pharmacodynamic approach to simulate bacterial killing at the site of infection. The population mean areas under the concentration-time curves (AUCs) for levofloxacin showed that levofloxacin excellently penetrates soft tissues, as indicated by the ratio of the AUC from time zero to 8 h (AUC0-8) for muscle tissue (AUC0-8 muscle) to the AUC0-8 for free drug in plasma (AUC0-8 plasma free) (AUC0-8 muscle/AUC0-8 plasma free ratio) of 0.85. The individual values of tissue penetration and maximum concentration (Cmax) in muscle tissue were highly variable. No difference in bacterial killing of a select Staphylococcus aureus strain for which the MIC was 0.5 μg/ml was found between individuals after exposure to dynamically changing concentrations of levofloxacin in plasma and tissue in vitro. In contrast, the decrease in the bacterial counts of Pseudomonas aeruginosa (MIC = 2 μg/ml) varied extensively when the bacteria were exposed to levofloxacin at the concentrations determined from the individual concentration-versus-time profiles obtained in skeletal muscle. The extent of bacterial killing could be predicted by calculating individual Cmax/MIC and AUC0-8 muscle/AUC0-8 plasma free ratios (R = 0.96 and 0.93, respectively). We have therefore shown in the present study that individual differences in the tissue penetration of levofloxacin may markedly affect target site killing of bacteria for which MICs are close to 2 μg/ml.
doi:10.1128/AAC.47.11.3548-3553.2003
PMCID: PMC253769  PMID: 14576116
2.  The Relationship Between Fluticasone Furoate Systemic Exposure and Cortisol Suppression 
Clinical Pharmacokinetics  2013;52(10):885-896.
Introduction
The inhaled corticosteroid (ICS) fluticasone furoate is in development, in combination with the long-acting beta2-agonist vilanterol for the once-daily treatment of asthma and chronic obstructive pulmonary disease and as a monotherapy treatment for asthma. Corticosteroids, including ICSs, have the potential to induce dose-dependent systemic effects on the hypothalamic–pituitary–adrenal (HPA) axis. Cortisol suppression has been observed in asthma patients with normal HPA axis function at baseline on receiving high doses of ICSs, and is associated with adverse effects on a number of physiological processes. The measurement of 24-h serum cortisol and 24-h urinary cortisol excretion are sensitive methods for assessing adrenocortical activity, and can evaluate cortisol suppression in a dose-dependent manner.
Objective
The purpose of the meta-analysis presented here was to characterize the population pharmacokinetic/pharmacodynamic relationship between fluticasone furoate systemic exposure [as measured by area under the concentration–time curve over 24 h postdose (AUC24)] and both 24-h weighted mean serum cortisol (WM24) and 24-h urine cortisol excretion in healthy subjects and subjects with asthma.
Methods
The serum cortisol meta-analysis integrated eight studies; five Phase I studies in healthy subjects, two Phase IIa studies, and one Phase III study in subjects with asthma. Each study included serial blood sampling for estimation of WM24. The urine cortisol meta-analysis integrated three studies: one Phase I study in healthy subjects, and one Phase IIb and one Phase III study in subjects with asthma. Each study included complete 0–24 h urine collection for estimation of urine cortisol excretion. All studies included blood sampling for estimation of fluticasone furoate AUC24. A sigmoid maximum effect (Emax) model was fitted to fluticasone furoate AUC24 and serum cortisol and urine cortisol data using nonlinear mixed-effect modeling with the computer program NONMEM®.
Results
Over a wide range of systemic fluticasone furoate exposure representing the therapeutic and supratherapeutic range, the relationship between fluticasone furoate AUC24 and WM24 and 24-h urine cortisol excretion was well described by an Emax model. The average estimate of AUC producing 50 % of maximum effect (AUC50) was similar for the serum cortisol and urine cortisol models with values of 1,556 and 1,686 pg·h/mL, respectively. Although formulation/inhaler was shown to be a significant covariate on the estimates of both WM24 at zero concentration (C0) and AUC50 in the serum cortisol model, the differences were small and believed to be due to study variability. Age was shown to be a significant covariate on the estimates of both C0 and AUC50 in the urine cortisol model, and was considered to be a reflection of lower urine cortisol excretion in adolescents.
Conclusion
A pharmacokinetic/pharmacodynamic model has been established over a wide range of systemic fluticasone furoate exposure representing the therapeutic and supratherapeutic range to both WM24 and 24-h urine cortisol excretion. The values of AUC50 of 1,556 and 1,686 pg·h/mL, respectively, are several times higher than average fluticasone furoate AUC24 values observed at clinical doses of fluticasone furoate (≤200 μg). The models predict a fluticasone furoate AUC24 of 1,000 pg·h/mL would be required to reduce 24-h serum cortisol or 24-h urine cortisol excretion by 20 and 17 %, respectively.
doi:10.1007/s40262-013-0078-1
PMCID: PMC3779313  PMID: 23719680
3.  Twenty-four-hour area under the concentration-time curve/MIC ratio as a generic predictor of fluoroquinolone antimicrobial effect by using three strains of Pseudomonas aeruginosa and an in vitro pharmacodynamic model. 
Several investigators have suggested that the 24-h area under the concentration-time curve (AUC)/MIC ratio (AUC/MIC24 or AUIC24) can be used to make comparisons of antimicrobial activity between fluoroquinolone antibiotics. Limited data exist regarding the generic predictive ability of AUC/MIC24 for the antimicrobial effects of fluoroquinolones. The purposes of the present investigation were to determine if the AUC/MIC24 can be used as a generic outcome predictor of fluoroquinolone antibacterial activity and to determine if a similar AUC/MIC24 breakpoint can be established for different fluoroquinolones. Using an in vitro pharmacodynamic model, 29 duplicate concentration time-kill curve experiments simulated AUC/MIC24s ranging from 52 to 508 SIT-1.h (inverse serum inhibitory titer integrated over time) with ciprofloxacin or ofloxacin against three strains of Pseudomonas aeruginosa. Each 24-h experiment was performed in cation-supplemented Mueller-Hinton broth with a starting inoculum of 10(6) CFU/ml. At timed intervals cation-supplemented Mueller-Hinton broth samples were collected for CFU and fluoroquinolone concentration determinations. Transformation of bacterial counts into the cumulative bacterial effect parameter of the 24-h area under the effect curve (AUEC24) was performed for each concentration time-kill curve. Multivariate regression analysis was used to compare pharmacodynamic predictors (AUC/MIC24, 24-h AUC, peak concentration [Cmax] to MIC ratios [Cmax:MIC], etc.) with ln AUEC24. To identify threshold breakpoint AUC/MIC24s, AUEC24s were stratified by the magnitude of AUC/MIC24 into subgroups, which were analyzed for differences in antibacterial effect. The Kruskal-Wallis test and subsequent Tukey's multiple comparison test were used to determine which AUC/MIC subgroups were significantly different. Multiple regression analysis revealed that only AUC/MIC24 (r2 = 0.65) and MIC (r2 = 0.03) were significantly correlated with antibacterial effect. At similar AUC/MIC24s, yet different MICs, Cmaxs, or elimination half-lives, the AUEC24s were similar for both fluoroquinolones. The relationship between AUC/MIC24 and ln AUEC24 was best described by a sigmoidal maximal antimicrobial effect (Emax) model (r2 = 0.72; Emax = 9.1; AUC/MIC50 = 119 SIT-1.h; S = 2.01 [S is an exponent that reflects the degree of sigmoidicity]). Ciprofloxacin-bacteria AUC/MIC24 values of < 100 SIT-1.h were significantly different (P < 0.05) from the AUC/MIC24 values of > 100 SIT-1.h. An ofloxacin AUC/MIC24 of > 100 SIT-1.h and an AUC/MIC24 of < 100 SIT-1.h exhibited a trend toward a significant difference (P > 0.05 but < 0.1). The inverse relationship between drug exposure and MIC increase postexposure was described by a sigmoidal fixed Emax model (AUC/MIC24, r2 = 0.40; AUC/MIC50 = 95 SIT-1.h; S = 1.97; Cmax:MIC, r2 = 0.41; Cmax:MIC50 = 7.3; S = 2.01). These data suggest that AUC/MIC24 may be the most descriptive measurement of fluoroquinolone antimicrobial activity against P. aeruginosa, that ofloxacin and ciprofloxacin have similar AUC/MIC24 threshold breakpoints at approximately 100 SIT-1.h, that the concentration-dependent selection of resistant organisms may parallel the threshold breakpoint of the antimicrobial effect, and that AUC/MIC24 generically describes the antibacterial effects of different fluoroquinolones.
PMCID: PMC163170  PMID: 8851583
4.  Pharmacodynamics of the New Fluoroquinolone Gatifloxacin in Murine Thigh and Lung Infection Models 
Gatifloxacin is a new 8-methoxy fluoroquinolone with enhanced activity against gram-positive cocci. We used the neutropenic murine thigh infection model to characterize the time course of antimicrobial activity of gatifloxacin and determine which pharmacokinetic (PK)-pharmacodynamic (PD) parameter best correlated with efficacy. The thighs of mice were infected with 106.5 to 107.4 CFU of strains of Staphylococcus aureus, Streptococcus pneumoniae, or Escherichia coli, and the mice were then treated for 24 h with 0.29 to 600 mg of gatifloxacin per kg of body weight per day, with the dose fractionated for dosing every 3, 6, 12, and 24 h. Levels in serum were measured by microbiologic assay. In vivo postantibiotic effects (PAEs) were calculated from serial values of the log10 numbers of CFU per thigh 2 to 4 h after the administration of doses of 8 and 32 mg/kg. Nonlinear regression analysis was used to determine which PK-PD parameter best correlated with the numbers of CFU per thigh at 24 h. Pharmacokinetic studies revealed peak/dose values of 0.23 to 0.32, area under the concentration-time curve (AUC)/dose values of 0.47 to 0.62, and half-lives of 0.6 to 1.1 h. Gatifloxacin produced in vivo PAEs of 0.2 to 3.1 h for S. pneumoniae and 0.4 to 2.3 h for S. aureus. The 24-h AUC/MIC was the PK-PD parameter that best correlated with efficacy (R2 = 90 to 94% for the three organisms, whereas R2 = 70 to 81% for peak level/MIC and R2 = 48 to 73% for the time that the concentration in serum was greater than the MIC). There was some reduced activity when dosing every 24 h was used due to the short half-life of gatifloxacin in mice. In subsequent studies we used the neutropenic and nonneutropenic murine thigh and lung infection models to determine if the magnitude of the AUC/MIC needed for the efficacy of gatifloxacin varied among pathogens (including resistant strains) and infection sites. The mice were infected with 106.5 to 107.4 CFU of four isolates of S. aureus (one methicillin resistant) per thigh, nine isolates of S. pneumoniae (two penicillin intermediate, four penicillin resistant, and two ciprofloxacin resistant) per thigh, four isolates of the family Enterobacteriaceae per thigh, a single isolate of Pseudomonas aeruginosa per thigh, and 108.3 CFU of Klebsiella pneumoniae per lung. The mice were then treated for 24 h with 0.29 to 600 mg of gatifloxacin per kg every 6 or 12 h. A sigmoid dose-response model was used to estimate the dose (in milligrams per kilogram per 24 h) required to achieve a net bacteriostatic effect over 24 h. MICs ranged from 0.015 to 8 μg/ml. The 24-h AUC/MICs for each static dose (1.7 to 592) varied from 16 to 72. Mean ± standard deviation 24-h AUC/MICs for isolates of the family Enterobacteriaceae, S. pneumoniae, and S. aureus were 41 ± 21, 52 ± 20, and 36 ± 9, respectively. Methicillin, penicillin, or ciprofloxacin resistance did not alter the magnitude of the AUC/MIC required for efficacy. The 24-h AUC/MICs required to achieve bacteriostatic effects against K. pneumoniae were quite similar in the thigh and lung (70 versus 56 in neutropenic mice and 32 versus 43 in nonneutropenic mice, respectively). The magnitude of the 24-h AUC/MIC of gatifloxacin required for efficacy against multiple pathogens varied only fourfold and was not significantly altered by drug resistance or site of infection.
doi:10.1128/AAC.46.6.1665-1670.2002
PMCID: PMC127205  PMID: 12019073
5.  Population Pharmacokinetics and Pharmacodynamic Modeling of Abacavir (1592U89) from a Dose-Ranging, Double-Blind, Randomized Monotherapy Trial with Human Immunodeficiency Virus-Infected Subjects 
Abacavir (formerly 1592U89) is a carbocyclic nucleoside analog with potent anti-human immunodeficiency virus (anti-HIV) activity when administered alone or in combination with other antiretroviral agents. The population pharmacokinetics and pharmacodynamics of abacavir were investigated in 41 HIV type 1 (HIV-1)-infected, antiretroviral naive adults with baseline CD4+ cell counts of ≥100/mm3 and plasma HIV-1 RNA levels of >30,000 copies/ml. Data for analysis were obtained from patients who received randomized, blinded monotherapy with abacavir at 100, 300, or 600 mg twice-daily (BID) for up to 12 weeks. Plasma abacavir concentrations from sparse sampling were analyzed by standard population pharmacokinetic methods, and the effects of dose, combination therapy, gender, weight, and age on parameter estimates were investigated. Bayesian pharmacokinetic parameter estimates were calculated to determine the peak concentration of abacavir in plasma (Cmax) and the area under the concentration-time curve from time zero to infinity (AUC0–∞) for individual subjects. The pharmacokinetics of abacavir were dose proportional over the 100- to 600-mg dose range and were unaffected by any covariates. No significant correlations were observed between the incidence of the five most common adverse events (headache, nausea, diarrhea, vomiting, and malaise or fatigue) and AUC0–∞. A significant correlation was observed between Cmax and nausea by categorical analysis (P = 0.019), but this was of borderline significance by logistic regression (odds ratio, 1.45; 95% confidence interval, 0.95 to 2.32). The log10 time-averaged AUC0–∞ minus baseline (AAUCMB) values for HIV-1 RNA and CD4+ cell count correlated significantly with Cmax and AUC0–∞, but with better model fits for AUC0–∞. The increase in AAUCMB values for CD4+ cell count plateaued early for drug exposures that were associated with little change in AAUCMB values for plasma HIV-1 RNA. There was less than a 0.4 log10 difference over 12 weeks in the HIV-1 RNA levels with the doubling of the abacavir AUC0–∞ from 300 to 600 mg BID dosing. In conclusion, pharmacodynamic modeling supports the selection of abacavir 300 mg twice-daily dosing.
PMCID: PMC90013  PMID: 10898675
6.  Underestimation of the Calculated Area Under the Concentration-Time Curve Based on Serum Creatinine for Vancomycin Dosing 
Infection & Chemotherapy  2014;46(1):21-29.
Background
The ratio of the steady-state 24-hour area under the concentration-time curve (ssAUC24) to the MIC (AUC24/MIC) for vancomycin has been recommended as the preferred pharmacodynamic index. The aim of this study was to assess whether the calculated AUC24 (cAUC24) using the creatinine clearance (CLcr) differs from the ssAUC24 based on the individual pharmacokinetic data estimated by a commercial software.
Materials and Methods
The cAUC24 was compared with the ssAUC24 with respect to age, body mass index, and trough concentration of vancomycin and the results were expressed as median and interquartile ranges. A correlation between the cAUC24 and ssAUC24 and the trough concentration of vancomycin was evaluated. The probability of reaching an AUC24/MIC of 400 or higher was compared between the cAUC24 and ssAUC24 for different MICs of vancomycin and different daily doses by simulation in a subgroup with a trough concentration of 10 mg/L and higher.
Results
The cAUC24 was significantly lower than the ssAUC24 (392.38 vs. 418.32 mg·hr/L, P < 0.0001) and correlated weakly with the trough concentration (r = 0.649 vs. r = 0.964). Assuming a MIC of 1.0 mg/L, the probability of reaching the value of 400 or higher was 77.5% for the cAUC24/MIC and 100% for the ssAUC24/MIC in patients with a trough concentration of 10 mg/L and higher. If the MIC increased to 2.0 mg/L, the probability was 57.7% for the cAUC24/MIC and 71.8% for the ssAUC24/MIC at a daily vancomycin dose of 4,000 mg.
Conclusions
The cAUC24 using the calculated CLcr is usually underestimated compared with the ssAUC24 based on individual pharmacokinetic data. Therefore, to obtain a more accurate AUC24, therapeutic monitoring of vancomycin rather than a simple calculation based on the CLcr should be performed, and a more accurate biomarker for renal function is needed.
doi:10.3947/ic.2014.46.1.21
PMCID: PMC3970305  PMID: 24693466
Vancomycin; Pharmacodynamics; Area under curve; Drug monitoring, Therapeutic
7.  Safety, Pharmacokinetics, and Pharmacodynamics of Cyclodextrin Itraconazole in Pediatric Patients with Oropharyngeal Candidiasis 
The safety, pharmacokinetics, and pharmacodynamics of cyclodextrin itraconazole (CD-ITRA) oral suspension were investigated in an open sequential dose escalation study with 26 human immunodeficiency virus (HIV)-infected children and adolescents (5 to 18 years old; mean CD4+-cell count, 128/μl) with oropharyngeal candidiasis (OPC). Patients received CD-ITRA at either 2.5 mg/kg of body weight once a day (QD) or 2.5 mg/kg twice a day (BID) for a total of 15 days. Pharmacokinetic sampling was performed after the first dose and for up to 120 h after the last dose, and antifungal efficacy was evaluated by standardized scoring of the oropharynx. Apart from mild to moderate gastrointestinal disturbances in three patients (11.5%), CD-ITRA was well tolerated. Two patients (7.6%) discontinued treatment prematurely due to study drug-related adverse events. After 15 days of treatment, the peak concentration of drug in plasma (Cmax), the area under the plasma concentration-time curve (AUC) from 0 to 24 h (AUC0-24), the concentration in plasma at the end of the dosing interval (predose) (Cmin), and the terminal half-life of itraconazole (ITRA) were (means and standard deviations) 0.604 ± 0.53 μg/ml, 6.80 ± 7.4 μg · h/ml, 0.192 ± 0.06 μg/ml, and 56.48 ± 44 h, respectively, for the QD regimen and 1.340 ± 0.75 μg/ml, 23.04 ± 14.5 μg · h/ml, 0.782 ± 0.19 μg/ml, and 104.22 ± 94 h, respectively, for the BID regimen. The mean AUC-based accumulation factors for ITRA on day 15 were 4.14 ± 0.9 and 3.53 ± 0.6, respectively. A comparison of the dose-normalized median AUC of the two dosage regimens revealed a trend toward nonlinear drug disposition (P = 0.05). The mean metabolic ratios (AUC of hydroxyitraconazole/AUC of ITRA) at day 15 were 1.96 ± 0.1 for the QD regimen and 1.29 ± 0.2 for the BID regimen, respectively (P < 0.05). The OPC score (range, 0 to 13) for all 26 patients decreased from a mean of 7.46 ± 0.8 at baseline to 2.8 ± 0.7 at the end of therapy (P < 0.001), demonstrating antifungal efficacy in this setting. The relationships among Cmax, Cmin, AUC0-12, Cmax/MIC, Cmin/MIC, AUC0-12/MIC, time during the dosing interval when the plasma drug concentrations were above the MIC for the infecting isolate, and the residual OPC score at day 15 for the entire study population fit inhibitory effect pharmacodynamic models (r, 0.595 to 0.421; P, <0.01 to <0.05). All patients with fluconazole-resistant isolates responded to treatment with CD-ITRA; however, there was no clear correlation between the MIC of ITRA and response to therapy. In conclusion, CD-ITRA was well tolerated and efficacious for the treatment of OPC in HIV-infected pediatric patients. Pharmacodynamic modeling revealed significant correlations between plasma drug concentrations and antifungal efficacy. Based on this documented safety and efficacy, a dosage of 2.5 mg/kg BID can be recommended for the treatment of OPC in pediatric patients ≥5 years old.
doi:10.1128/AAC.46.8.2554-2563.2002
PMCID: PMC127364  PMID: 12121932
8.  Pharmacokinetics and pharmacodynamics of two multiple-dose piperacillin-tazobactam regimens. 
Antimicrobial Agents and Chemotherapy  1997;41(11):2511-2517.
The pharmacokinetics and pharmacodynamics of two multiple-dose regimens of piperacillin-tazobactam (3.375 g every 6 h and 4.5 g every 8 h) were evaluated at steady state for 12 healthy adult volunteers. Inhibitory and bactericidal activities for the two regimens were determined with five American Type Culture Collection (ATCC) organisms (Escherichia coli, Staphylococcus aureus, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Bacteroides fragilis). The percentage of time that plasma concentrations remained above the MIC (T > MIC) for each organism and dosage regimen was calculated. Areas under the inhibitory (AUIC0-24) and bactericidal activity (AUBC0-24) curves were calculated with the trapezoidal rule by using the reciprocal of the inhibitory and bactericidal titers determined for each dosage regimen. In order to assess the validity of predicted measures of bactericidal (AUC0-24/MBC) and inhibitory (AUC0-24/MIC) activity to determine bacteriological response to beta-lactam antimicrobial agents, AUC0-24/MBC and AUC0-24/MIC values were compared with measured AUBC0-24 and AUIC0-24 values. Total body clearance values were equivalent for piperacillin (183.96 +/- 22.66 versus 181.72 +/- 19.54 ml/min/1.73 m2, P > 0.05) and tazobactam (184.71 +/- 19.89 versus 184.87 +/- 18.35 ml/min/1.73 m2, P > 0.05) following the administration of the 3.375-g-every-6-h and 4.5-g-every-8-h dosages, respectively. Comparison of area under the plasma concentration-time curve (AUC0-24) for piperacillin (967.74 +/- 135.56 microg x h/ml versus 978.88 +/- 140.96 microg x h/ml) and tazobactam (120.14 +/- 15.78 microg x h/ml versus 120.01 +/- 16.22 microg x h/ml) revealed no significant differences (P > 0.05) between the 3.375-g-every-6-h and 4.5-g-every-8-h regimens, respectively. Both regimens provided T > MIC values of > 60% for all organisms tested. Measured values of bactericidal (AUBC) and inhibitory (AUIC) activity were significantly different (P < 0.05) from predicted values (AUC0-24/MBC and AUC0-24/MIC) for all organisms studied with the exception of the bactericidal activity for P. aeruginosa and S. aureus. Additionally, ATCC organisms possessing the same MICs and MBCs exhibited great differences in measured AUBC0-24 and AUIC0-24 values. Reasons for this difference may be inherent differences in organism specific susceptibility.
PMCID: PMC164153  PMID: 9371358
9.  On the analysis of glycomics mass spectrometry data via the regularized area under the ROC curve 
BMC Bioinformatics  2007;8:477.
Background
Novel molecular and statistical methods are in rising demand for disease diagnosis and prognosis with the help of recent advanced biotechnology. High-resolution mass spectrometry (MS) is one of those biotechnologies that are highly promising to improve health outcome. Previous literatures have identified some proteomics biomarkers that can distinguish healthy patients from cancer patients using MS data. In this paper, an MS study is demonstrated which uses glycomics to identify ovarian cancer. Glycomics is the study of glycans and glycoproteins. The glycans on the proteins may deviate between a cancer cell and a normal cell and may be visible in the blood. High-resolution MS has been applied to measure relative abundances of potential glycan biomarkers in human serum. Multiple potential glycan biomarkers are measured in MS spectra. With the objection of maximizing the empirical area under the ROC curve (AUC), an analysis method was considered which combines potential glycan biomarkers for the diagnosis of cancer.
Results
Maximizing the empirical AUC of glycomics MS data is a large-dimensional optimization problem. The technical difficulty is that the empirical AUC function is not continuous. Instead, it is in fact an empirical 0–1 loss function with a large number of linear predictors. An approach was investigated that regularizes the area under the ROC curve while replacing the 0–1 loss function with a smooth surrogate function. The constrained threshold gradient descent regularization algorithm was applied, where the regularization parameters were chosen by the cross-validation method, and the confidence intervals of the regression parameters were estimated by the bootstrap method. The method is called TGDR-AUC algorithm. The properties of the approach were studied through a numerical simulation study, which incorporates the positive values of mass spectrometry data with the correlations between measurements within person. The simulation proved asymptotic properties that estimated AUC approaches the true AUC. Finally, mass spectrometry data of serum glycan for ovarian cancer diagnosis was analyzed. The optimal combination based on TGDR-AUC algorithm yields plausible result and the detected biomarkers are confirmed based on biological evidence.
Conclusion
The TGDR-AUC algorithm relaxes the normality and independence assumptions from previous literatures. In addition to its flexibility and easy interpretability, the algorithm yields good performance in combining potential biomarkers and is computationally feasible. Thus, the approach of TGDR-AUC is a plausible algorithm to classify disease status on the basis of multiple biomarkers.
doi:10.1186/1471-2105-8-477
PMCID: PMC2211327  PMID: 18076765
10.  A boosting method for maximizing the partial area under the ROC curve 
BMC Bioinformatics  2010;11:314.
Background
The receiver operating characteristic (ROC) curve is a fundamental tool to assess the discriminant performance for not only a single marker but also a score function combining multiple markers. The area under the ROC curve (AUC) for a score function measures the intrinsic ability for the score function to discriminate between the controls and cases. Recently, the partial AUC (pAUC) has been paid more attention than the AUC, because a suitable range of the false positive rate can be focused according to various clinical situations. However, existing pAUC-based methods only handle a few markers and do not take nonlinear combination of markers into consideration.
Results
We have developed a new statistical method that focuses on the pAUC based on a boosting technique. The markers are combined componentially for maximizing the pAUC in the boosting algorithm using natural cubic splines or decision stumps (single-level decision trees), according to the values of markers (continuous or discrete). We show that the resulting score plots are useful for understanding how each marker is associated with the outcome variable. We compare the performance of the proposed boosting method with those of other existing methods, and demonstrate the utility using real data sets. As a result, we have much better discrimination performances in the sense of the pAUC in both simulation studies and real data analysis.
Conclusions
The proposed method addresses how to combine the markers after a pAUC-based filtering procedure in high dimensional setting. Hence, it provides a consistent way of analyzing data based on the pAUC from maker selection to marker combination for discrimination problems. The method can capture not only linear but also nonlinear association between the outcome variable and the markers, about which the nonlinearity is known to be necessary in general for the maximization of the pAUC. The method also puts importance on the accuracy of classification performance as well as interpretability of the association, by offering simple and smooth resultant score plots for each marker.
doi:10.1186/1471-2105-11-314
PMCID: PMC2898798  PMID: 20537139
11.  Parameters of bacterial killing and regrowth kinetics and antimicrobial effect examined in terms of area under the concentration-time curve relationships: action of ciprofloxacin against Escherichia coli in an in vitro dynamic model. 
Although many parameters have been described to quantitate the killing and regrowth of bacteria, substantial shortcomings are inherent in most of them, such as low sensitivity to pharmacokinetic determinants of the antimicrobial effect, an inability to predict a total effect, insufficient robustness, and uncertain interrelations between the parameters that prevent an ultimate determination of the effect. To examine different parameters, the kinetics of killing and regrowth of Escherichia coli (MIC, 0.013 microg/ml) were studied in vitro by simulating a series of ciprofloxacin monoexponential pharmacokinetic profiles. Initial ciprofloxacin concentrations varied from 0.02 to 19.2 microg/ml, whereas the half-life of 4 h was the same in all experiments. The following parameters were calculated and estimated: the time to reduce the initial inoculum (N0) 10-, 100-, and 1,000-fold (T90%, T99%, and T99.9%, respectively), the rate constant of bacterial elimination (k(elb)), the nadir level (Nmin) in the viable count (N)-versus-time (t) curve, the time to reach Nmin (t(min)), the numbers of bacteria that survived (Ntau) by the end of the observation period (tau), the area under the bacterial killing and regrowth curve (log N(A)-t curve) from the zero point (time zero) to tau (AUBC), the area above this curve (AAC), the area between the control growth curve (log N(C)-t curve) and the bacterial killing and regrowth curve (log N(A)-t curve) from the zero point to tau (ABBC) or to the time point when log N(A) reaches the maximal values observed in the log N(C)-t curve (I(E); intensity of the effect), and the time shift between the control growth and regrowth curves (T(E); duration of the effect). Being highly sensitive to the AUC, I(E), and T(E) showed the most regular AUC relationships: the effect expressed by I(E) or T(E) increased systematically when the AUC or initial concentration of ciprofloxacin rose. Other parameters, especially T90%, T99%, T99.9%, t(min), and log N0 - log Nmin = delta log Nmin, related to the AUC less regularly and were poorly sensitive to the AUC. T(E) proved to be the best predictor and t(min) proved to be the worst predictor of the total antimicrobial effect reflected by I(E). Distinct feedback relationships between the effect determination and the experimental design were demonstrated. It was shown that unjustified shortening of the observation period, i.e., cutting off the log N(A)-t curves, may lead to the degeneration of the AUC-response relationships, as expressed by log N0 - log Ntau = delta log Ntau, AUBC, AAC, or ABBC, to a point where it gives rise to the false idea of an AUC- or concentration-independent effect. Thus, use of I(E) and T(E) provides the most unbiased, robust, and comprehensive means of determining the antimicrobial effect.
PMCID: PMC163900  PMID: 9174184
12.  Pharmacodynamics of a Novel Des-F(6)-Quinolone, BMS-284756, against Streptococcus pneumoniae in the Thigh Infection Model 
BMS-284756 is a novel quinolone that lacks the six-position fluorine typical of existing compounds. Despite this structural change, BMS-284756 maintains potent antibacterial activity against gram-negative and gram-positive aerobic and anaerobic pathogens. The objective of this study was to define the pharmacodynamic profile of BMS-284756 against Streptococcus pneumoniae. Protein binding in mice was assessed by the ultrafiltration method. For pharmacodynamic studies, neutropenic ICR mice were used, as well as an immunocompetent mouse species, CBA/J, in order to evaluate the impact of white blood cells on infection outcome. Mice were infected with 105 to 106 CFU per thigh, and therapy was initiated after 2 h. Animals received BMS-284756 orally over a range of 1.25 to 100 mg/kg/day divided into one to four doses. At 0 and 24 h postinfection, thighs were harvested for bacterial density measurement. Survival was assessed during 96 h of therapy and again at 3 days after therapy. Pharmacokinetic studies were also conducted with infected mice. Protein binding was determined to be 80%. The MICs for clinical isolates (n = 8) ranged from 0.03 to 2 μg/ml. The change in bacterial density and survival was correlated with the pharmacodynamic parameters percentage of time that the drug concentration in serum remains above the MIC, AUC (area under the concentration-time curve)/MIC ratio, and peak/MIC ratio, and the best predictor of response was the AUC/MIC ratio for both outcome measures. Total AUC/MIC ratios of 100 to 200 appear to result in maximal bactericidal effects. While a total AUC/MIC ratio exposure value of 100 (free AUC/MIC ratio, ∼20) resulted in nearly 100% survival at the conclusion of therapy, a total AUC/MIC ratio of 200 (free AUC/MIC ratio, ∼40) was required to ensure survival at 3 days posttherapy. These data demonstrate (i) the in vivo bactericidal activity of BMS-284756 against S. pneumoniae, (ii) that protein binding has a profound impact on the in vivo pharmacodynamic assessment of BMS-284756, and (iii) that an AUC/MIC ratio of 200 (free AUC/MIC ratio, ∼40) appears to best characterize the required dynamic exposure for optimization of bactericidal activity and maximal survival.
doi:10.1128/AAC.47.5.1630-1635.2003
PMCID: PMC153298  PMID: 12709332
13.  AKT1 G205T Genotype Influences Obesity-Related Metabolic Phenotypes and Their Responses to Aerobic Exercise Training in Older Caucasians 
Experimental physiology  2010;96(3):338-347.
As part of the insulin signaling pathway, AKT influences growth and metabolism. The AKT1 gene G205T (rs1130214) polymorphism has potential functional effects. Thus, we determined whether the G205T polymorphism influences metabolic variables and their responses to aerobic exercise training. Following dietary stabilization, healthy, sedentary, 50-75 yr old Caucasian men (n = 51) and women (n = 58) underwent 6 months of aerobic exercise training. Before and after completing the intervention, dual-energy x-ray absorptiometry measured percent body fat, computed tomography measured visceral and subcutaneous fat, and oral glucose tolerance testing measured glucose total area under the curve (AUC), insulin AUC, and insulin sensitivity. Taqman assay determined AKT1 G205T genotypes. At baseline, men with the GG genotype (n = 29) had lower VO2max values (p = 0.026), and higher percent body fat (p = 0.046), subcutaneous fat (p = 0.021), and insulin AUC (p = 0.003) values than T allele carriers (n = 22). Despite their rather disadvantageous starting values, men with the GG genotype seemed to respond to exercise training more robustly than men with the T allele, highlighted by significantly greater fold change improvements in insulin AUC (p = 0.012) and glucose AUC (p = 0.035). Although the GG group also significantly improved VO2max with training, the change in VO2max was not as great as that of the T allele carriers (p = 0.037). In contrast, after accounting for hormone replacement therapy use, none of the variables differed in the women at baseline. As a result of exercise training, women with the T allele (n = 20) had greater fold change improvements in fasting glucose (p = 0.011), glucose AUC (p = 0.017), and insulin sensitivity (p = 0.044) than GG genotype women (n = 38). Our results suggest that the AKT1 G205T polymorphism influences metabolic variables and their responses to aerobic exercise training in older previously sedentary individuals.
doi:10.1113/expphysiol.2010.055400
PMCID: PMC3075436  PMID: 21097644
polymorphism; exercise; glucose
14.  Evaluation of Glycemic Variability in Well-Controlled Type 2 Diabetes Mellitus 
Abstract
Aims
It is necessary to evaluate glucose variability and postprandial hyperglycemia in patients with well-controlled type 2 diabetes mellitus because of the limitations associated with hemoglobin A1c (HbA1c) measurements. We evaluated parameters reflecting postprandial hyperglycemia and glycemic variability in patients with optimal HbA1c.
Patients and Methods
Thirty-nine patients with HbA1c levels below 7% were recruited to the study. A continuous glucose monitoring system (CGMS) was applied for two 72-h periods. 1,5-Anhydroglucitol (1,5-AG) and fructosamine (FA) were measured as parameters for postprandial hyperglycemia and glucose variability. Using CGMS data, the following postprandial hyperglycemia parameters were calculated: mean postprandial maximum glucose (MPMG) and area under the curve for glucose above 180 mg/dL (AUC-180). To measure glycemic variability, we calculated mean amplitude of glucose excursion (MAGE) using a classical (MAGEc) and new method (MAGE group of sign [MAGEgos]).
Results
The baseline HbA1c level was 6.3±0.3%. The mean MPMG was 10.34±1.84 mmol/L, and the mean AUC-180 was 0.17±0.23 mmol/L/day. The mean MAGEgos was 3.27±1.29 mmol/L, and MAGEc was 4.30±1.43 mmol/L, indicating glycemic variability in our patients. The mean levels of 1,5-AG and FA were 16.7±7.4 μg/mL and 273.0±22.5 μmol/L, respectively. In a correlation analysis, FA was significantly correlated with MPMG, AUC-180, MAGEgos, and MAGEc. In contrast, 1,5-AG was only correlated with AUC-180.
Conclusions
This study demonstrated postprandial hyperglycemia and glycemic variability in subjects with well-controlled diabetes. FA may reflect postprandial hyperglycemia and glycemic variability, but 1,5-AG may be of limited value for assessing glucose variability in patients with well-controlled type 2 diabetes mellitus.
doi:10.1089/dia.2012.0315
PMCID: PMC3671661  PMID: 23617251
15.  Risk Models for Progression to Advanced Age-Related Macular Degeneration Using Demographic, Environmental, Genetic, and Ocular Factors 
Ophthalmology  2011;118(11):2203-2211.
Purpose
To expand our predictive models for progression to advanced stages of age-related macular degeneration (AMD) based on demographic, environmental, genetic, and ocular factors, using longer follow-up, time varying analyses, calculation of absolute risks, adjustment for competing risks, and detailed baseline AMD and drusen status.
Design
Prospective, longitudinal study.
Participants
We included 2937 individuals in the Age-Related Eye Disease Study, of which 819 subjects progressed to advanced AMD during 12 years of follow-up.
Methods
Cox proportional hazards regression analyses were performed to calculate hazard ratios for progression. Covariates included demographic and environmental factors, 6 variants in 5 genes, baseline macular drusen size, and presence and type of advanced AMD in 1 eye at baseline. To assess the ability of risk scores based on all covariates to discriminate between progressors and nonprogressors, an algorithm was developed and the area under the receiver operating characteristic curve (AUC) was calculated. To validate the overall model, the total sample was randomly subdivided into derivation and test samples. Another model was built based on the derivation sample and assessed for calibration and discrimination in the test sample. Sample sizes needed for testing new treatments in clinical trials were estimated based on models with and without genetic variables.
Main Outcome Measures
Progression to advanced AMD, including geographic atrophy and neovascular disease.
Results
In multivariate models, age, smoking, body mass index, single nucleotide polymorphisms in the CFH, ARMS2/HTRA1, C3, C2, and CFB genes, as well as presence of advanced AMD in 1 eye and drusen size in both eyes were all independently associated with progression. The AUC for progression at 10 years in the model with genetic factors, drusen size, and environmental covariates was 0.915 in the total sample. In the test sample, based on a model estimated from the derivation sample, the AUC was 0.908. The sample sizes needed for clinical trials were estimated to be lower when genetic susceptibility was considered.
Conclusions
Factors reflective of nature and nurture were incorporated into an expanded algorithm for risk prediction, which performed very well in both derivation and test samples. Risk scores and predicted progression rates will be useful for AMD surveillance and for designing clinical trials.
Financial Disclosure(s)
Proprietary or commercial disclosure may be found after the references.
doi:10.1016/j.ophtha.2011.04.029
PMCID: PMC4097877  PMID: 21959373
16.  Evaluation of a cumulative SUV-volume histogram method for parameterizing heterogeneous intratumoural FDG uptake in non-small cell lung cancer PET studies 
Purpose
Standardized uptake values (SUV) are commonly used for quantification of whole-body [18F]fluoro-2-deoxy-D-glucose (FDG) positron emission tomography (PET) studies. Changes in SUV following therapy, however, only provide a proper measure of response in case of homogeneous FDG uptake in the tumour. The purpose of this study was therefore to implement and characterize a method that enables quantification of heterogeneity in tumour FDG uptake.
Methods
Cumulative SUV-volume histograms (CSH), describing % of total tumour volume above % threshold of maximum SUV (SUVmax), were calculated. The area under a CSH curve (AUC) is a quantitative index of tumour uptake heterogeneity, with lower AUC corresponding to higher degrees of heterogeneity. Simulations of homogeneous and heterogeneous responses were performed to assess the value of AUC-CSH for measuring uptake and/or response heterogeneity. In addition, partial volume correction and image denoising was applied prior to calculating AUC-CSH. Finally, the method was applied to a number of human FDG scans.
Results
Partial volume correction and noise reduction improved CSH curves. Both simulations and clinical examples showed that AUC-CSH values corresponded with level of tumour heterogeneity and/or heterogeneity in response. In contrast, this correspondence was not seen with SUVmax alone. The results indicate that the main advantage of AUC-CSH above other measures, such as 1/COV (coefficient of variation), is the possibility to measure or normalize AUC-CSH in different ways.
Conclusion
AUC-CSH might be used as a quantitative index of heterogeneity in tracer uptake. In response monitoring studies it can be used to address heterogeneity in response.
doi:10.1007/s00259-011-1845-6
PMCID: PMC3151405  PMID: 21617975
Positron emission tomography (PET); Standardized uptake value (SUV); Intratumoural heterogeneity; Cumulative SUV-volume histogram (CSH); Intensity-volume histograms (IVH)
17.  Comparison of Stress-Hemoconcentration Correction Techniques for Stress-Induced Coagulation 
BioMed Research International  2013;2013:480648.
When examining stress effects on coagulation, arithmetic correction is typically used to adjust for concomitant hemoconcentration but may be inappropriate for coagulation activity assays. We examined a new physiologically relevant method of correcting for stress-hemoconcentration. Blood was drawn from healthy men (N = 40) during baseline, mental stress, and recovery, and factor VII activity (FVII:C), factor VIII activity (FVIII:C), activated partial thromboplastin time (APTT), prothrombin time (PT%), fibrinogen, D-dimer, and plasma volume were determined. Three hemoconcentration correction techniques were assessed: arithmetic correction and two reconstitution techniques using baseline plasma or physiological saline. Area-under-the-curve (AUC) was computed for each technique. For FVII:C, uncorrected AUC was significantly greater than AUC corrected arithmetically. For PT%, uncorrected AUC was significantly greater than AUC corrected with saline or arithmetically. For APTT, uncorrected AUC was significantly less than AUC corrected with saline and greater than AUC corrected arithmetically. For fibrinogen, uncorrected AUC was significantly greater than AUC corrected with saline or arithmetically. For D-dimer, uncorrected AUC was significantly greater than AUC corrected arithmetically. No differences in AUC were observed for FVIII:C. Saline reconstitution seems most appropriate when adjusting for hemoconcentration effects on clotting time and activity. Stress-hemoconcentration accounted for the majority of coagulation changes.
doi:10.1155/2013/480648
PMCID: PMC3814105  PMID: 24222908
18.  Effects of Reusing Baseline Volumes of Interest by Applying (Non-)Rigid Image Registration on Positron Emission Tomography Response Assessments 
PLoS ONE  2014;9(1):e87167.
Objectives
Reusing baseline volumes of interest (VOI) by applying non-rigid and to some extent (local) rigid image registration showed good test-retest variability similar to delineating VOI on both scans individually. The aim of the present study was to compare response assessments and classifications based on various types of image registration with those based on (semi)-automatic tumour delineation.
Methods
Baseline (n = 13), early (n = 12) and late (n = 9) response (after one and three cycles of treatment, respectively) whole body [18F]fluoro-2-deoxy-D-glucose positron emission tomography/computed tomography (PET/CT) scans were acquired in subjects with advanced gastrointestinal malignancies. Lesions were identified for early and late response scans. VOI were drawn independently on all scans using an adaptive 50% threshold method (A50). In addition, various types of (non-)rigid image registration were applied to PET and/or CT images, after which baseline VOI were projected onto response scans. Response was classified using PET Response Criteria in Solid Tumors for maximum standardized uptake value (SUVmax), average SUV (SUVmean), peak SUV (SUVpeak), metabolically active tumour volume (MATV), total lesion glycolysis (TLG) and the area under a cumulative SUV-volume histogram curve (AUC).
Results
Non-rigid PET-based registration and non-rigid CT-based registration followed by non-rigid PET-based registration (CTPET) did not show differences in response classifications compared to A50 for SUVmax and SUVpeak,, however, differences were observed for MATV, SUVmean, TLG and AUC. For the latter, these registrations demonstrated a poorer performance for small lung lesions (<2.8 ml), whereas A50 showed a poorer performance when another area with high uptake was close to the target lesion. All methods were affected by lesions with very heterogeneous tracer uptake.
Conclusions
Non-rigid PET- and CTPET-based image registrations may be used to classify response based on SUVmax and SUVpeak. For other quantitative measures future studies should assess which method is valid for response evaluations by correlating with survival data.
doi:10.1371/journal.pone.0087167
PMCID: PMC3904976  PMID: 24489860
19.  Pharmacodynamics of the New Des-F(6)-Quinolone Garenoxacin in a Murine Thigh Infection Model 
Antimicrobial Agents and Chemotherapy  2003;47(12):3935-3941.
Garenoxacin is a new des-F(6)-quinolone with broad-spectrum activity against both gram-positive cocci and gram-negative bacilli. We used the neutropenic murine thigh infection model to characterize the time course of antimicrobial activity of garenoxacin and determine which pharmacokinetic-pharmacodynamic (PK-PD) parameter best correlated with efficacy. Serum drug levels following three fourfold-escalating single-dose levels of garenoxacin were measured by microbiologic assay. In vivo postantibiotic effects (PAEs) were determined after doses of 16 and 64 mg/kg of body weight. Mice had 106.5 to 106.7 CFU of Streptococcus pneumoniae strain ATCC 10813 or Staphylococcus aureus strain ATCC 33591 per thigh when they were treated for 24 h with garenoxacin at a dose of 4 to 128 mg/kg/day fractionated for 3-, 6-, 12-, and 24-hour dosing regimens. Nonlinear regression analysis was used to determine which PK-PD parameter best correlated with the measurement of CFU/thigh at 24 h. Pharmacokinetic studies yielded peak/dose values of 0.2 to 0.3, area under the concentration-time curve (AUC)/dose values of 0.1 to 0.5, and half-lives of 0.7 to 1.6 h. Garenoxacin produced in vivo PAEs of 1.4 to 8.2 h with S. pneumoniae ATCC 10813, 7.6 to >12.4 h with S. aureus ATCC 25923, and 0 to 1.5 h with Klebsiella pneumoniae ATCC 43816. The 24-h AUC/MIC ratio was the PK-PD parameter that best correlated with efficacy (R2 = 71 to 90% for the two organisms compared with 43 to 56% for the peak/MIC ratio and 47 to 75% for percent time above the MIC [% T>MIC]).In subsequent studies we used the neutropenic murine thigh infection model to determine if the magnitude of the AUC/MIC ratio needed for efficacy of garenoxacin varied among pathogens (including resistant strains). Mice had 105.9 to 107.2 CFU of 6 strains of S. aureus (2 methicillin resistant), 11 strains of S. pneumoniae (5 penicillin susceptible, 1 penicillin intermediate, and 5 penicillin resistant, and of the resistant strains, 3 were also ciprofloxacin resistant), and 4 gram-negative strains per thigh when treated for 24 h with 1 to 64 mg of garenoxacin per kg every 12 h. A sigmoid dose-response model was used to estimate the doses (mg/kg/24 h) required to achieve a net bacteriostatic effect over 24 h. MICs ranged from 0.008 to 4 μg/ml. The free drug 24-h AUC/MIC ratios for each static dose (2.8 to 128 mg/kg/day) varied from 8.2 to 145. The mean 24-h AUC/MIC ratios ± standard deviations for S. pneumoniae, S. aureus, and gram-negative strains were 33 ± 18, 81 ± 37, and 33 ± 30, respectively. Methicillin, penicillin, or ciprofloxacin resistance did not alter the magnitude of the AUC/MIC ratio required for efficacy.
doi:10.1128/AAC.47.12.3935-3941.2003
PMCID: PMC296207  PMID: 14638504
20.  Bioequivalence and Pharmacokinetic Evaluation of Two Formulations of Risperidone 2 mg 
Drugs in R&d  2012;13(1):29-36.
Background
Risperidone is a benzisoxazole derivate and is effective in the treatment of schizophrenia and other psychiatric illnesses in adults and children. Although there are a few reports in the literature regarding the pharmacokinetic characteristics of risperidone, insufficient data on its pharmacokinetic properties in a Chinese population are available.
Objective
To meet the requirements for marketing a new generic product, this study was designed to compare the pharmacokinetic properties and bioequivalence of two 2 mg tablet formulations of risperidone: a newly developed generic formulation (test) and a branded formulation (reference) in healthy adult male Chinese volunteers.
Methods
A single-dose, open-label, randomized-sequence, 2 × 2 crossover study was conducted in fasted healthy male Chinese volunteers. Eligible participants were randomly assigned in a 1:1 ratio to receive 1 tablet (2 mg each) of the test formulation (Risperidone tablet; Dr. Reddy’s Laboratories Ltd., Hyderabad, India) or the reference formulation (Risperdal® tablet; Xian-Janssen Pharmaceutical Ltd., Xi-an, China), followed by a 2-week washout period and subsequent administration of the alternate formulation. The study drugs were administered after a 10-hour overnight fast. Plasma samples were collected over 96 hours. Plasma concentrations of the parent drug, risperidone, and its active metabolite, 9-hydroxy-risperidone, were analyzed by a liquid chromatography–tandem mass spectrometry method. The formulations would be considered bioequivalent if the 90% confidence intervals (CIs) of the natural log-transformed values were within the predetermined 80–125% equivalence range for the maximum plasma drug concentration (Cmax) and the area under the plasma concentration–time curve (AUC), in accordance with guidelines issued by the US Food and Drug Administration. Assessment of tolerability was based on recording of adverse events (AEs), monitoring of vital signs, electrocardiograms, and laboratory tests at baseline and at completion of the study.
Results
A total of 24 healthy male Chinese volunteers (mean age 22.9 years [standard deviation (SD) 2.7, range 19.2–27.1]; weight 63.2 kg [SD 7.0, range 52.0–78.0]; and height 171.3 cm [SD 6.1, range 162.0–187.0]) were enrolled, and all completed the study. For the parent drug, risperidone, the 90% CIs of the relative values (test vs. reference) of the Cmax, AUC from time zero to time t (AUCt), and AUC from time zero to infinity (AUC∞) were 97.0–124.0%, 92.7–115.1%, and 92.8–114.2%, respectively. For the active metabolite, 9-hydroxy-risperidone, the values were 104.4–117.7%, 101.0–113.7%, and 100.4–113.4%, respectively. The two formulations met the predetermined criteria for bioequivalence. A total of 73 AEs were observed in 24 subjects during the study. The most common AE was sedation (48 events), followed by nasal reactions (14 events), postural hypotension (3 events), hypertriglyceridemia (2 events), dizziness (4 events), nausea (1 event), and anorexia (1 event). Their severity was as follows: 16 were mild, 57 were moderate, and none were severe. The majority of the AEs were considered to be related (48 events) or probably related (23 events) to the study medication. No clinically significant abnormalities on physical examination, vital sign measurements, or electrocardiographic recordings were reported. No serious AEs were reported.
Conclusions
The data from this study in healthy adult male Chinese subjects suggest that the test formulation met the regulatory criteria for bioequivalence to the reference formulation, on the basis of the rate and extent of absorption. Both formulations were well tolerated.
doi:10.1007/s40268-012-0002-4
PMCID: PMC3627046  PMID: 23322527
21.  Bioequivalence and Pharmacokinetic Evaluation of Two Formulations of Risperidone 2 mg 
Drugs in R&D  2012;13(1):29-36.
Background
Risperidone is a benzisoxazole derivate and is effective in the treatment of schizophrenia and other psychiatric illnesses in adults and children. Although there are a few reports in the literature regarding the pharmacokinetic characteristics of risperidone, insufficient data on its pharmacokinetic properties in a Chinese population are available.
Objective
To meet the requirements for marketing a new generic product, this study was designed to compare the pharmacokinetic properties and bioequivalence of two 2 mg tablet formulations of risperidone: a newly developed generic formulation (test) and a branded formulation (reference) in healthy adult male Chinese volunteers.
Methods
A single-dose, open-label, randomized-sequence, 2 × 2 crossover study was conducted in fasted healthy male Chinese volunteers. Eligible participants were randomly assigned in a 1:1 ratio to receive 1 tablet (2 mg each) of the test formulation (Risperidone tablet; Dr. Reddy’s Laboratories Ltd., Hyderabad, India) or the reference formulation (Risperdal® tablet; Xian-Janssen Pharmaceutical Ltd., Xi-an, China), followed by a 2-week washout period and subsequent administration of the alternate formulation. The study drugs were administered after a 10-hour overnight fast. Plasma samples were collected over 96 hours. Plasma concentrations of the parent drug, risperidone, and its active metabolite, 9-hydroxy-risperidone, were analyzed by a liquid chromatography–tandem mass spectrometry method. The formulations would be considered bioequivalent if the 90% confidence intervals (CIs) of the natural log-transformed values were within the predetermined 80–125% equivalence range for the maximum plasma drug concentration (Cmax) and the area under the plasma concentration–time curve (AUC), in accordance with guidelines issued by the US Food and Drug Administration. Assessment of tolerability was based on recording of adverse events (AEs), monitoring of vital signs, electrocardiograms, and laboratory tests at baseline and at completion of the study.
Results
A total of 24 healthy male Chinese volunteers (mean age 22.9 years [standard deviation (SD) 2.7, range 19.2–27.1]; weight 63.2 kg [SD 7.0, range 52.0–78.0]; and height 171.3 cm [SD 6.1, range 162.0–187.0]) were enrolled, and all completed the study. For the parent drug, risperidone, the 90% CIs of the relative values (test vs. reference) of the Cmax, AUC from time zero to time t (AUCt), and AUC from time zero to infinity (AUC∞) were 97.0–124.0%, 92.7–115.1%, and 92.8–114.2%, respectively. For the active metabolite, 9-hydroxy-risperidone, the values were 104.4–117.7%, 101.0–113.7%, and 100.4–113.4%, respectively. The two formulations met the predetermined criteria for bioequivalence. A total of 73 AEs were observed in 24 subjects during the study. The most common AE was sedation (48 events), followed by nasal reactions (14 events), postural hypotension (3 events), hypertriglyceridemia (2 events), dizziness (4 events), nausea (1 event), and anorexia (1 event). Their severity was as follows: 16 were mild, 57 were moderate, and none were severe. The majority of the AEs were considered to be related (48 events) or probably related (23 events) to the study medication. No clinically significant abnormalities on physical examination, vital sign measurements, or electrocardiographic recordings were reported. No serious AEs were reported.
Conclusions
The data from this study in healthy adult male Chinese subjects suggest that the test formulation met the regulatory criteria for bioequivalence to the reference formulation, on the basis of the rate and extent of absorption. Both formulations were well tolerated.
doi:10.1007/s40268-012-0002-4
PMCID: PMC3627046  PMID: 23322527
22.  Limited-Sampling Strategy Models for Itraconazole and Hydroxy-Itraconazole Based on Data from a Bioequivalence Study 
The extensive interindividual variability in oral bioavailability of itraconazole prompted an assessment of the bioequivalence of two formulations marketed in Brazil, namely, Sporanox (reference) and Traconal (test). Eighteen healthy volunteers received single 200-mg oral doses of each formulation at 2-week intervals in a randomized, crossover protocol. The concentrations of itraconazole and hydroxy-itraconazole in plasma were measured by high-performance liquid chromatography, and the datum points (n = 396) were subsequently used to develop limited-sampling strategy models for estimation of the areas under the curve (AUCs) for both compounds. The 90% confidence intervals for individual percent ratios (test/reference formulations) of the maximum concentration of drug in serum, the AUC from 0 to 48 h and the AUC from time zero to infinity (AUC0–∞) for itraconazole and hydoxy-itraconazole were below the range of 80 to 125%, suggesting that these formulations are not bioequivalent. Linear regression analysis of the AUC0–∞ against time and a “jackknife” validation procedure revealed that models based on three sampling times accurately predict (R2, >0.98; bias, <3%; precision, 3 to 7%) the AUC0–∞ for each of the four formulation-compound pairs tested. Increasing the number of sampling points to more than three adds little to the accuracy of the estimates of AUC0–∞. The three-point models developed for the reference formulation were validated retrospectively and were found to predict within 2% the AUC0–∞ reported in previous studies performed under similar protocols. In conclusion, the data in this study indicate (i) that the tested formulations are not bioequivalent when single doses are compared and (ii) that limited-sampling strategy models based on three points predict accurately the AUC0–∞s for itraconazole and hydroxy-itraconazole and could be a valuable tool in pharmacokinetic and bioequivalence studies of single oral doses of itraconazole.
PMCID: PMC89033  PMID: 9869578
23.  Value of DCE-MRI and FDG-PET/CT in the prediction of response to preoperative chemotherapy with bevacizumab for colorectal liver metastases 
British Journal of Cancer  2012;106(12):1926-1933.
Background:
The purpose of this study was to assess the role of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and 18F-fluorodeoxyglucose positron emission tomography computed tomography (FDG-PET/CT) for evaluation of response to chemotherapy and bevacizumab and for prediction of progression-free survival (PFS) in patients with metastatic colorectal cancer (mCRC) with potentially resectable liver lesions.
Methods:
A total of 19 mCRC patients were treated with FOLFOX/FOLFIRI and bevacizumab followed by surgery. Dynamic contrast-enhanced magnetic resonance imaging and FDG-PET/CT were performed before treatment and after cycle 5. PET results were quantified by calculating maximum standardised uptake value (SUVmax) whereas area under the enhancement curve (AUC), initial AUC (iAUC) and the endothelial transfer constant (Ktrans) were used to quantify DCE-MRI. Pathological analysis of the resection specimen was performed, including measurement of microvessel density (MVD) and proliferation index.
Results:
Both AUC and iAUC were significantly decreased following bevacizumab therapy (median change of 22% (P=0.002) and 40% (P=0.001) for AUC and iAUC, respectively). Progression-free survival benefit was shown for patients with >40% reduction in Ktrans (P=0.019). In the group of radiological responders, the median baseline SUVmax was 3.77 (IQR: 2.88–5.60) compared with 7.20 (IQR: 4.67–8.73) in nonresponders (P=0.021). A higher follow-up SUVmax was correlated with worse PFS (P=0.012). Median MVD was 10.9. Progression-free survival was significantly shorter in patients with an MVD greater than 10, compared with patients with lower MVD (10 months compared with 16 months, P=0.016).
Conclusion:
High relative decrease in Ktrans, low follow-up SUVmax and low MVD are favourable prognostic factors for mCRC patients treated with bevacizumab before surgery.
doi:10.1038/bjc.2012.184
PMCID: PMC3388560  PMID: 22596235
bevacizumab; colorectal cancer; DCE-MRI; FDG-PET/CT; immunohistochemistry; liver metastases
24.  Filtering data from the collaborative initial glaucoma treatment study for improved identification of glaucoma progression 
Background
Open-angle glaucoma (OAG) is a prevalent, degenerate ocular disease which can lead to blindness without proper clinical management. The tests used to assess disease progression are susceptible to process and measurement noise. The aim of this study was to develop a methodology which accounts for the inherent noise in the data and improve significant disease progression identification.
Methods
Longitudinal observations from the Collaborative Initial Glaucoma Treatment Study (CIGTS) were used to parameterize and validate a Kalman filter model and logistic regression function. The Kalman filter estimates the true value of biomarkers associated with OAG and forecasts future values of these variables. We develop two logistic regression models via generalized estimating equations (GEE) for calculating the probability of experiencing significant OAG progression: one model based on the raw measurements from CIGTS and another model based on the Kalman filter estimates of the CIGTS data. Receiver operating characteristic (ROC) curves and associated area under the ROC curve (AUC) estimates are calculated using cross-fold validation.
Results
The logistic regression model developed using Kalman filter estimates as data input achieves higher sensitivity and specificity than the model developed using raw measurements. The mean AUC for the Kalman filter-based model is 0.961 while the mean AUC for the raw measurements model is 0.889. Hence, using the probability function generated via Kalman filter estimates and GEE for logistic regression, we are able to more accurately classify patients and instances as experiencing significant OAG progression.
Conclusion
A Kalman filter approach for estimating the true value of OAG biomarkers resulted in data input which improved the accuracy of a logistic regression classification model compared to a model using raw measurements as input. This methodology accounts for process and measurement noise to enable improved discrimination between progression and nonprogression in chronic diseases.
doi:10.1186/1472-6947-13-137
PMCID: PMC3878032  PMID: 24359562
25.  Pharmacodynamics of Gemifloxacin against Streptococcus pneumoniae in an In Vitro Pharmacokinetic Model of Infection 
Antimicrobial Agents and Chemotherapy  2001;45(10):2916-2921.
The pharmacodynamics of gemifloxacin against Streptococcus pneumoniae were investigated in a dilutional pharmacodynamic model of infection. Dose fractionation was used to simulate concentrations of gemifloxacin in human serum associated with 640 mg every 48 h (one dose), 320 mg every 24 h (two doses), and 160 mg every 12 h (four doses). Five strains of S. pneumoniae for which MICs were 0.016, 0.06, 0.1, 0.16, and 0.24 mg/liter were used to assess the antibacterial effect of gemifloxacin. An inoculum of 107 to 108 CFU/ml was used, and each experiment was performed at least in triplicate. The pharmacodynamic parameters (area under the concentration-time curve [AUC]/MIC, maximum concentration of drug in serum [Cmax]/MIC, and the time that the serum drug concentration remains higher than the MIC [T > MIC]) were related to antibacterial effect as measured by the area under the bacterial-kill curve from 0 to 48 h (AUBKC48) using an inhibitory sigmoid Emax model. Weighted least-squares regression was used to predict the effect of the pharmacodynamic parameters on AUBKC48, and Cox proportional-hazards regression was used to predict the effect of the three pharmacodynamic parameters on the time needed to kill 99.9% of the starting inoculum (T99.9). There was a clear relationship between strain susceptibility and clearance from the model. The simulations (160 mg every 12 h) were associated with slower initial clearance than were the other simulations; in contrast, bacterial regrowth occurred with the 640-mg simulation when MICs were ≥0.1 mg/liter. The percentage coefficient of variance was 19% for AUBKC48, and the inhibitory sigmoid Emax model best fit the relationship between AUBKC48 and AUC/MIC. Cmax/MIC and T > MIC fit less well. The maximum response occurred at an AUC/MIC of >300 to 400. In weighted least-squares regression analysis, there was no evidence that Cmax/MIC was predictive of AUBKC48, but both AUC/MIC and T > MIC were. A repeat analysis using only data for which the T > MIC was >75% and for which hence regrowth was minimized indicated that AUC/MIC alone was predictive of AUBKC48. Initial univariate analysis indicated that all three pharmacodynamic parameters were predictive of T99.9, but in the multivariate model only Cmax/MIC reached significance. These data indicate that gemifloxacin is an effective antipneumococcal agent and that AUC/MIC is the best predictor of antibacterial effect as measured by AUBKC48. However, Cmax/MIC is the best predictor of speed of kill, as measured by T99.9. T > MIC also has a role in determining AUBKC48, especially when the dose spacing is considerable. Once-daily dosing seems most suitable for gemifloxacin.
doi:10.1128/AAC.45.10.2916-2921.2001
PMCID: PMC90752  PMID: 11557490

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