CLcr Values Research Articles

611. Meropenem Dosage Optimization in Critically Ill Patients Based on a Population Pharmacokinetic Approach.

Abstract Background Meropenem (MRP) is commonly used to treat serious infections and displays wide variability in plasma concentrations after administration of the same dose in critically ill patients due to factors that affect MRP volume of distribution (V) and clearance (CL) (e.g. edema, sepsis, kidney failure). These alterations could lead to not achieve the pharmacokinetic/pharmacodinamic (PK/PD) target with the consequent failure of antibacterial therapy. The aim of this study was to describe MRP pharmacokinetic parameters in critically ill patients in order to establish safe and effective initial dosing regimens adapted to patients characteristics. Methods This prospective observational study enrolled 78 critically ill patients receiving MRP based on the clinical, biochemical and microbiological findings. Blood sampling occurred at pre-dose, 1, 3 and 6h post-dose. MRP plasma concentrations were determined by high-performance liquid chromatography. Population pharmacokinetic modelling and Monte Carlo simulations were executed with NONMEM. Several regimen dosages of MRP under different scenarios were simulated in order to achieve high probability of target attainment (PTA > 90%) for PK/PD targets of %t > CMI 50% and 100%. Results In critically-ill Mexican patients, MRP PK were best described by a one compartment model. The final population model was: CL (L/h) = 11.9 ∗ (CLCr/102.23) and V (L) = 25.2. Final model was internally validated proving that it was stable and showed an adequate estimation of variability. Precision and bias fit were assessed through external validation comparing the predictive performance of the base and final models. Different initial dosage regimens were found for CLCr values in which the clinician can choose between a lower dose, a longer dosage interval or a shorter infusion time. However, for patients with augmented renal clearance or PK/PD target 100%t > MIC it was observed that no regimen complied PTA > 90%, suggesting a continuous infusion would be more appropriate. Conclusion This study demonstrates the wide variability in MRP pharmacokinetics and enhances the need to include therapeutic drug monitoring as part of stewardships interventions in critically ill patients to maximize bacteriological and clinical responses. Disclosures All Authors: No reported disclosures.

Pharmacokinetic-Pharmacodynamic Target Attainment Analyses To Support Dose Selection for ME1100, an Arbekacin Inhalation Solution.

ME1100 (arbekacin inhalation solution) is an inhaled aminoglycoside that is being developed to treat patients with hospital-acquired and ventilator-associated bacterial pneumonia (HABP and VABP, respectively). Pharmacokinetic-pharmacodynamic (PK-PD) target attainment analyses were undertaken to evaluate ME1100 regimens for the treatment of patients with HABP/VABP. The data used included a population pharmacokinetic (PPK) 4-compartment model with 1st-order elimination, nonclinical PK-PD targets from one-compartment in vitro and/or in vivo infection models, and in vitro surveillance data. Using the PPK model, total-drug epithelial lining fluid (ELF) concentration-time profiles were generated for simulated patients with varying creatinine clearance (CLcr) (ml/min/1.73 m2) values. Percent probabilities of PK-PD target attainment by MIC were determined based on the ratio of total-drug ELF area under the concentration-time curve (AUC) to MIC (AUC/MIC ratio) targets associated with 1- and 2-log10 CFU reductions from baseline for Klebsiella pneumoniae, Pseudomonas aeruginosa, and Staphylococcus aureus Percent probabilities of PK-PD target attainment based on PK-PD targets for a 1-log10 CFU reduction from baseline at MIC values above the MIC90 value for K. pneumoniae (8 μg/ml), P. aeruginosa (4 μg/ml), and S. aureus (0.5 μg/ml) were ≥99.8% for ME1100 600 mg twice daily (BID) in simulated patients with CLcr values >80 to ≤120 ml/min/1.73 m2 ME1100 600 mg BID, 450 mg BID, and 600 mg once daily in simulated patients with CLcr values >50 to ≤80, >30 to ≤50, and 0 to ≤30 ml/min/1.73 m2, respectively, provided arbekacin exposures that best matched those for 600 mg BID in simulated patients with normal renal function. These data provide support for ME1100 as a treatment for patients with HABP/VABP.

Renal changes and estimation of glomerular filtration rate using different equations in morbidly obese Egyptian patients

Background and aimsObesity is a worldwide pandemic with multiple consequences including kidney affection. This study aimed to assess the effects of obesity on renal functions and to detect the most reliable formula of estimated glomerular filtration rate (eGFR) in morbidly obese patients. MethodsA cross-sectional, observational study was conducted on 82 morbidly obese patients. Anthropometric measurements were done for all patients and body adiposity (BAI) and visceral adiposity (VAI) indices were calculated after assessment of abdominal fat tissue analysis by computerized tomography (CT). Serum creatinine was incorporated into six different formulae of eGFR, then eGFR was compared with the 24-h measured creatinine clearance (CLcr) values. ResultsThe mean body mass index was 55.8 ± 9.5 kg/m2. Proteinuria and glomerular hyperfiltration (CLcr > 130 ml/min/1.73 m2) were detected in 68.3% and 91.5% of the patients, respectively. Cockcroft–Gault formula using total (CCG-TBW-eGFR) and adjusted body water (CCG-AjBW-eGFR) had the nearest values to measured CLCr. These two formulae had a moderate reliability and the lowest percentage of error (30% and 23%, respectively). Visceral and total abdominal fat tissue surface area and volume assessed by CT were directly correlated to the 24-h urinary protein excretion (r = 0.32, 0.24, 0.37 and 0.34, respectively; p = 0.02, 0.03, 0.004 and 0.002, respectively). ConclusionsGlomerular hyperfiltration and proteinuria are highly prevalent in morbidly obese patients. There is no ideal formula for GFR estimation in morbidly obese patients, however, TBW and AjBW incorporated into the Cockcroft–Gault can be helpful in those patients.

Augmented renal clearance in critically ill trauma patients: A pathophysiologic approach using renal vascular index

BackgroundThe aim of the present study was to explore the relationship between creatinine clearance (ClCr), cardiac index (CI) and renal vascular index (RVI) in order to assess the potential mechanisms driving ARC in critically ill trauma patient. The secondary objective was to assess the performance of RVI for prediction of ARC. MethodsEvery trauma patient who underwent cardiac and renal ultrasound measurements during their initial ICU management was retrospectively reviewed over a 3-month period. ARC was defined by a 24-hr measured ClCr ≥ 130 mL/min/1.73m2. A mixed effect model was constructed to explore covariates associated with ClCr over time. The performance of RVI for prediction of ARC was assessed by receiver operating characteristic (ROC) curve and compared to the ARCTIC (ARC in trauma intensive care) predictive scoring model. ResultsThirty patients, contributing for 121 coupled physiologic data, were retrospectively analysed. There was a significant correlation between ClCr values and RVI (r = −0.495; P = 0.005) but not between ClCr and CI values (r = 0.023; P = 0.967) at day 1. Using a mixed effect model, only age remained associated with ClCr variations over time. The area under the ROC curve of RVI for predicting ARC was 0.742 (95% CI: 0.649–0.834; P < 0.0001), with statistical difference when compared to the ROC curve of ARCTIC [0.842 (0.771–0.913); P < 0.0001]. ConclusionUltrasonic evaluation of CI and RVI did not allow approaching the haemodynamic mechanisms responsible for ARC in patients. RVI was inaccurate and not better than clinical score for predicting ARC.

Association between augmented renal clearance, antibiotic exposure and clinical outcome in critically ill septic patients receiving high doses of β-lactams administered by continuous infusion: a prospective observational study

This study assessed whether augmented renal clearance (ARC) impacts negatively on antibiotic concentrations and clinical outcomes in patients treated by high-dose β-lactams administered continuously. Over a 9-month period, all critically ill patients without renal impairment treated by one of the monitored β-lactams for a documented infection were eligible. During the first 3 days of antibiotic therapy, every patient underwent 24-h CLCr measurements and therapeutic drug monitoring. The main outcome was the rate of β-lactam underdosing, defined as a free drug concentration <4 × MIC of the known pathogen. Secondary outcomes were rates of subexposure for β-lactams and therapeutic failure. The performance of CLCr in predicting underdosing was assessed by a ROC curve, and multivariable logistic regression was performed to determine risk factors for subexposure and therapeutic failure. A total of 79 patients were included and 235 samples were analysed. The rate of underdosing<4×MIC was 12%, with a significant association with CLCr (P < 0.0001). A threshold of CLCr ≥ 170 mL/min had a sensitivity and specificity of 0.93 (95% CI 0.77–0.99) and 0.65 (95% CI 0.58–0.71) for predicting β-lactam underdosing<4×MIC. Mean CLCr values ≥170 mL/min were significantly associated with subexposure<4xMIC [OR = 10.1 (2.4–41.6); P = 0.001]. Patients with subexposure<4×MIC presented higher rates of therapeutic failure [OR = 6.3 (1.2–33.2); P = 0.03]. Mean CLCr values ≥170 mL/min remain a risk factor for subexposure to β-lactams despite high doses of β-lactams administered continuously. β-Lactam subexposure was associated with higher rates of therapeutic failure in septic critically ill patients.

Influences of renal function descriptors on population pharmacokinetic modeling of vancomycin in Chinese adult patients.

Vancomycin, a glycopeptide antibiotic for the treatment of grampositive infections, is mainly eliminated via glomerular filtration. Thus, its therapeutic effects are affected predominantly by renal function. The aim of this study was to develop a population pharmacokinetic model of vancomycin for Chinese adult patients and to investigate the influence of different renal function descriptors on the predictability of the model. A retrospective analysis was performed based on the blood concentrations of vancomycin in 218 Chinese adult patients. Among these patients, the data from 160 were used to establish the population pharmacokinetic model, and the data from the remaining 58 patients were used for external model validation. A simulation was employed to determine the appropriate initial vancomycin dosage regimens in adult Chinese patients for reaching the target steady-state trough concentrations of 10-15 mg/L and 15-20 mg/L. We developed a one-compartment model with first-order absorption to characterize the concentration-time profile of vancomycin. There was a positive correlation between the body clearance of vancomycin and renal function; both creatinine clearance (CLCr) and age were the covariates that influenced the PK of vancomycin, and the excretion of vancomycin decreased as renal function diminishing with age. The typical clearance (CL) value was 2.829 L/h for 75-year-old patients with CLCr values of 80 mL/min, and the rate constant of CL with the CLCr changing at 1 mL/min was 0.00842. The influence coefficient of age on CL was 0.08143. The external validation results revealed that the current different descriptors of renal function behaved similarly to the predicted performance of the models. In conclusion, the developed model is appropriate for Bayesian dose predictions of vancomycin concentrations in the population of Chinese adult patients. Furthermore, the simulation provides a reference for clinical optimized antibacterial therapy with vancomycin.

Applicability of the Schwartz Equation and the Chronic Kidney Disease in Children Bedside Equation for Estimating Glomerular Filtration Rate in Overweight Children.

To determine if significant correlations exist between glomerular filtration rate (GFR) prediction equation values, derived by using the original Schwartz equation and the Chronic Kidney Disease in Children (CKiD) bedside equation with a 24-hour urine creatinine clearance (Clcr ) value normalized to a body surface area of 1.73 m(2) in overweight and obese children. Prospective analysis (20 patients) and retrospective analysis (43 patients). Pediatric inpatient ward and pediatric nephrology clinic at a comprehensive academic medical center. Sixty-three pediatric patients (aged 5-17 years), of whom 27 were overweight (body mass index [BMI] at the 85th percentile or higher) and 36 were not overweight (BMI lower than the 85th percentile [controls]) between 2007 and 2012. Data from the overweight patients were compared with nonoverweight controls. GFR values were calculated by using the original Schwartz equation and the CKiD bedside equation. Each patient's 24-hour urine Clcr value normalized to a body surface area of 1.73 m(2) served as the index value. A Pearson correlation coefficient model was used to determine association between the 24-hour urine Clcr value (index value) with the Schwartz and CKiD GFR estimations. Significant correlation was found to exist between the Schwartz and CKiD bedside GFR estimations relative to the 24-hour urine Clcr in the control subjects (r = 0.85, p<0.0001, and r = 0.85, p<0.0001, respectively). Significant correlation was also found to exist between the Schwartz and CKiD bedside GFR values with the 24-hour urine Clcr value in overweight subjects (r = 0.86, p<0.0001, and r = 0.86, p<0.0001, respectively). The Schwartz equation estimated average GFR 21.75 ml/minute/1.73 m(2) higher than 24-hour urine Clcr (p<0.0001) in overweight children with a kidney disorder. The CKiD bedside GFR estimations were not significantly different compared with 24-hour urine Clcr values for the overweight group with kidney disorder (p=0.85). The Schwartz and CKiD bedside estimations of GFR correlated with 24-hour urine Clcr values in both overweight and nonoverweight children. Compared with the Schwartz equation, which tended to overestimate renal function, the CKiD bedside equation appeared to approximate 24-hour urine Clcr more closely in overweight children with kidney disorder.

Are standard doses of piperacillin sufficient for critically ill patients with augmented creatinine clearance?

IntroductionThe aim of this study was to explore the impact of augmented creatinine clearance and differing minimum inhibitory concentrations (MIC) on piperacillin pharmacokinetic/pharmacodynamic (PK/PD) target attainment (time above MIC (fT>MIC)) in critically ill patients with sepsis receiving intermittent dosing.MethodsTo be eligible for enrolment, critically ill patients with sepsis had to be receiving piperacillin-tazobactam 4.5 g intravenously (IV) by intermittent infusion every 6 hours for presumed or confirmed nosocomial infection without significant renal impairment (defined by a plasma creatinine concentration greater than 171 μmol/L or the need for renal replacement therapy). Over a single dosing interval, blood samples were drawn to determine unbound plasma piperacillin concentrations. Renal function was assessed by measuring creatinine clearance (CLCR). A population PK model was constructed, and the probability of target attainment (PTA) for 50% and 100% fT>MIC was calculated for varying MIC and CLCR values.ResultsIn total, 48 patients provided data. Increasing CLCR values were associated with lower trough plasma piperacillin concentrations (P < 0.01), such that with an MIC of 16 mg/L, 100% fT>MIC would be achieved in only one-third (n = 16) of patients. Mean piperacillin clearance was approximately 1.5-fold higher than in healthy volunteers and correlated with CLCR (r = 0.58, P < 0.01). A reduced PTA for all MIC values, when targeting either 50% or 100% fT>MIC, was noted with increasing CLCR measures.ConclusionsStandard intermittent piperacillin-tazobactam dosing is unlikely to achieve optimal piperacillin exposures in a significant proportion of critically ill patients with sepsis, owing to elevated drug clearance. These data suggest that CLCR can be employed as a useful tool to determine whether piperacillin PK/PD target attainment is likely with a range of MIC values.

Population pharmacokinetics of deferiprone in healthy subjects.

To characterize the pharmacokinetics of deferiprone in healthy subjects using a model-based approach and to assess the effect of demographic and physiological factors on drug exposure. Data from 55 adult healthy subjects receiving deferiprone (solution 100 mg ml(-1)) were used for model building purposes. A population pharmacokinetic analysis was performed using nonmem v.7.2. The contribution of gender, age, weight and creatinine clearance (CLcr) on drug disposition was evaluated according to standard forward inclusion, backward deletion procedures. Model selection criteria were based on graphical and statistical summaries. A one compartment model with first order oral absorption was found to describe best the pharmacokinetics of deferiprone. Simulated exposure values were comparable with previously published data. Mean AUC estimates were 45.8 and 137.4 mg l(-1) h, whereas Cmax increased from 17.6 to 26.5 mg l(-1) after administration of 25 and 75 mg kg(-1) doses, respectively. Gender differences in the apparent volume of distribution (20%) have been identified, which are unlikely to be of clinical relevance. Furthermore, simulation scenarios reveal that dose adjustment is required for patients with reduced CLcr . Doses of 60, 40 and 25 mg kg(-1) for patients showing mild, moderate and severe renal impairment are proposed based on CLcr values of 60-89, 30-59 and 15-29 ml min(-1), respectively. Our analysis has enabled the assessment of the impact of gender and CLcr on the pharmacokinetics of deferiprone. Moreover, it provides the basis for dosing recommendations in renal impairment. The implication of these covariates on systemic exposure is currently not available in the prescribing information of deferiprone.

Tobramycin exposure from active calcium sulfate bone graft substitute

BackgroundBone graft substitute such as calcium sulfate are frequently used as carrier material for local antimicrobial therapy in orthopedic surgery. This study aimed to assess the systemic absorption and disposition of tobramycin in patients treated with a tobramycin-laden bone graft substitute (Osteoset® T).MethodsNine blood samples were taken from 12 patients over 10 days after Osteoset® T surgical implantation. Tobramycin concentration was measured by fluorescence polarization. Population pharmacokinetic analysis was performed using NONMEM to assess the average value and variability (CV) of pharmacokinetic parameters. Bioavailability (F) was assessed by equating clearance (CL) with creatinine clearance (Cockcroft CLCr). Based on the final model, simulations with various doses and renal function levels were performed. (ClinicalTrials.gov number, NCT01938417).ResultsThe patients were 52 +/− 20 years old, their mean body weight was 73 +/− 17 kg and their mean CLCr was 119 +/− 55 mL/min. Either 10 g or 20 g Osteoset® T with 4% tobramycin sulfate was implanted in various sites. Concentration profiles remained low and consistent with absorption rate-limited first-order release, while showing important variability. With CL equated to CLCr, mean absorption rate constant (ka) was 0.06 h-1, F was 63% or 32% (CV 74%) for 10 and 20 g Osteoset® T respectively, and volume of distribution (V) was 16.6 L (CV 89%). Simulations predicted sustained high, potentially toxic concentrations with 10 g, 30 g and 50 g Osteoset® T for CLCr values below 10, 20 and 30 mL/min, respectively.ConclusionsOsteoset® T does not raise toxicity concerns in subjects without significant renal failure. The risk/benefit ratio might turn unfavorable in case of severe renal failure, even after standard dose implantation.

How to manage intravenous vinflunine in cancer patients with renal impairment: results of a pharmacokinetic and tolerability phase I study

Vinflunine (VFL) ditartrate, a novel tubulin-targeted inhibitor, is registered for the treatment of patients with advanced or metastatic urothelial transitional cell carcinoma. This phase I study assessed the effect of renal impairment on the pharmacokinetics and tolerability of VFL. VFL was infused in patients with advanced/metastatic solid tumours once every 3 weeks with anticipated dose reduction on the first cycle stratified according to the creatinine clearance (CLcr ) values. Pharmacokinetic data were collected on the first two cycles in renally impaired patients (CLcr ≤ 60 ml min(-1) ) and were compared with a control cohort of patients (CLcr > 60 ml min(-1) ). Thirty-three patients (46-86 years) were treated, 13 in group 1 (40 ml min(-1) ≤ CLcr ≤ 60 ml min(-1) ) and 20 in group 2 (20 ml min(-1) ≤ CLcr < 40 ml min(-1) ). The renal dysfunction induced a mean decrease in VFL clearance of 12% in group 1 and 28% in group 2, compared with the control group. The anticipated dose reduction given in renally impaired patients (i.e. 280 mg m(-2) and 250 mg m(-2) in groups 1 and 2, respectively) yielded similar drug exposure to control patients. The tolerance profile of VFL in patients with renal dysfunction was similar to that observed in patients with CLcr > 60 ml min(-1) . In conclusion, the recommended doses of intravenous VFL administered once every 3 weeks in cancer patients with renal impairment are 280 mg m(-2) when CLcr is between 40 and 60 ml min(-1) and 250 mg m(-2) when CLcr is between 20 and <40 ml min(-1) .

Subtherapeutic Initial β-Lactam Concentrations in Select Critically Ill Patients

β-Lactams are routinely used as empirical therapy in critical illness, with extended concentrations above the minimum inhibitory concentration (MIC) of the infecting organism required for effective treatment. Changes in renal function in this setting can significantly impact the probability of achieving such targets.Analysis was made of trough plasma drug concentrations obtained via therapeutic drug monitoring, compared with renal function, in critically ill patients receiving empirical β-lactam therapy. Drug concentrations were measured by means of high-performance liquid chromatography and corrected for protein binding. Therapeutic levels were defined as greater than or equal to MIC and greater than or equal to four times MIC (maximum bacterial eradication), respectively. Renal function was assessed by means of an 8-h creatinine clearance (CLCR).Fifty-two concurrent trough concentrations and CLCR measures were used in analysis. Piperacillin was the most frequent β-lactam prescribed (48%), whereas empirical cover and Staphylococcus species were the most common indications for therapy (62%). Most patients were mechanically ventilated on the day of study (85%), although only 25% were receiving vasopressors. In only 58% (n = 30) was the trough drug concentration greater than or equal to MIC, falling to 31% (n = 16) when using four times MIC as the target. CLCR values ≥ 130 mL/min/1.73 m2 were associated with trough concentrations less than MIC in 82% (P < .001) and less than four times MIC in 72% (P < .001). CLCR remained a significant predictor of subtherapeutic concentrations in multivariate analysis.Elevated CLCR appears to be an important predictor of subtherapeutic β-lactam concentrations and suggests an important role in identifying such patients in the ICU.

Zoledronic dose adjustment in cancer patients

BackgroundZoledronic acid (ZA) is used in the prevention of skeletal related events in patients with advanced malignancies involving bone as well as in the treatment of tumour-induced hypercalcaemia. Due to...

Correlation of Bivalirudin Dose with Creatinine Clearance During Treatment of Heparin‐Induced Thrombocytopenia

To evaluate steady-state bivalirudin dosing requirements in patients with a wide range of kidney function who were being treated for heparin-induced thrombocytopenia (HIT)-related disorders. Retrospective medical record review. Academic medical center. Sixty-four adults with varying degrees of renal function who were receiving bivalirudin for at least 48 hours for HIT-related disorders between March 2007 and May 2010. Steady-state conditions were defined as a constant bivalirudin infusion dose for at least 12 hours, with serum creatinine concentration varying less than 20% for 48 hours (for patients not receiving renal replacement therapy) and at least two therapeutic activated partial thromboplastin time (aPTT) values (60-80 sec). Patients were assigned to five groups based on Cockcroft-Gault-estimated creatinine clearance (Clcr) of less than 30, 30-60, or greater than 60 ml/minute, or by type of renal replacement therapy-intermittent hemodialysis or continuous venovenous hemofiltration (CVVH). For Clcr greater than 60 ml/minute, the median bivalirudin dose was 0.15 mg/kg/hour (interquartile range [IQR] 0.11-0.15 mg/kg/hr), which was greater than median doses for Clcr 30-60 ml/minute (0.10 mg/kg/hr, IQR 0.06-0.13 mg/kg/hr, p=0.004), Clcr less than 30 ml/minute (0.08 mg/kg/hr, IQR 0.04-0.1 mg/kg/hr, p=0.001), CVVH (0.06 mg/kg/hr, IQR 0.03-0.10 mg/kg/hr, p=0.046), and hemodialysis (0.04 mg/kg/hr, IQR 0.03-0.05 mg/kg/hr, p=0.0001). Bivalirudin doses correlated with Clcr (Spearman r = 0.58, p<0.01). The median aPTT value of 70 seconds (IQR 63-74 sec) was similar in all groups. Thrombosis was present before bivalirudin therapy in 18 (28%) of 64 patients, and two patients (3%) developed thromboemboli during bivalirudin therapy. Clinically significant bleeding related to bivalirudin and leading to discontinuation of bivalirudin occurred in four patients (6%). The median international normalized ratio increased from 1.5 (IQR 1.3-1.7) before bivalirudin therapy to 1.9 (IQR 1.8-2.1) during bivalirudin therapy (p=0.002) in 11 patients who were not receiving warfarin. Bivalirudin dosing requirements increased with increasing Clcr values. The high degree of variability suggests that dosing in individual patients will require careful titration to achieve adequate anticoagulation.

Population pharmacokinetics of fluconazole after administration of fosfluconazole and fluconazole in critically ill patients

Fluconazole is an antifungal agent that is commonly used to treat patients with serious systemic fungal infections in intensive care units. Fosfluconazole is a phosphate prodrug of fluconazole, which was developed to reduce the volume of fluid required to administer fluconazole by intravenous injection. The objective of this study was to characterize the pharmacokinetics of the antifungal fluconazole after the intravenous administration of the prodrug fosfluconazole or fluconazole in critically ill patients with serious systemic fungal infections, by population pharmacokinetic analysis using the nonmem software package. Clinical biochemical data including serum fluconazole levels were obtained from 57 patients treated in the intensive care unit along with two naïve pooled patients gleaned from previous reports. The pharmacokinetic model of fluconazole was estimated using a one-compartment model. The probability that the area under the concentration-time curve is higher than 800 μg h/mL was determined by simulation. It was assumed that all the administered fosfluconazole was converted to fluconazole with an estimated fosfluconazole-fluconazole conversion rate constant of 2·05/h. The significant covariates for clearance for fluconazole (CL) and volume of distribution for fluconazole (Vd) were resulted in creatinine clearance (CLcr) and body weight (BW), respectively, in the final pharmacokinetic model equations: CL (L/h) = 0·799 × [CLcr (mL/min)/92·7](0·685) and Vd (L) = 48·1 × [BW (kg)/65](1·40) , where the interpatient variabilities in CL and Vd and the intrapatient variability were 44·8%, 79·7% and 19·8%, respectively. On the basis of the results of the Monte Carlo simulation, the probabilities of target attainment were 60%, 26% and 11% for 400 mg/day administration as fluconazole equivalent at CLcr values of 40, 70 and 100 mL/min, respectively. The present population pharmacokinetic analysis strongly indicates that fosfluconazole (and fluconazole) dosage should be optimized in terms of CLcr in critically ill patients.

Comparison of methods for determination of glomerular filtration rate in hypertensive subjects with normal serum creatinine

Background. Glomerular filtration rate (GFR) measured through technetium-99m diethyl triamine penta-acetic acid (Tc99mDTPA) renal scintigraphy (rsGFR) was compared with that estimated (eGFR) from 24-h creatinine clearance (CrCl) and, using both the Cockcroft–Gault (CG) and Modification of Diet in Renal Disease (MDRD) formulas, in a population of hypertensive subjects (HTs) with normal serum creatinine (SCr) levels. Patients and methods. In 200 normoalbuminuric (<30 mg/24 h) HTs 55–75 years old, without diabetes and history of coronary and cerebrovascular diseases, Pearson's correlation assess the relationship between rsGFR and eGFR. The Bland–Altman method was used to assess the agreement between rsGFR and eGFR, separately in subjects with low (<60 ml/min/1.73 m2) and normal (≥60 ml/min/1.73 m2) rsGFR. The span between −1.96 and +1.96 standard deviations of mean difference (bias) was calculated and used for this purpose. Results. In 76 subjects, an unknown low renal function was found by Tc99mDTPA renal scintigraphy. In subjects with normal rsGFR the Bland–Altman analysis showed that the smallest span between rsGFR and eGFR was evident for ClCr values (26.0 ml/min/1.73 m2), whereas higher values were detected with the CG and MDRD formulas (41.0 and 40.4 ml/min/1.73 m2, respectively). The same results were observed for low rsGFR, where a smaller span was found for ClCr (21.2 ml/min/1.73 m2), whereas CG and MDRD methods gave greater results (30.4 and 31.8 ml/min/1.73 m2 respectively); no differences were found between genders. The degree of agreement for eGFR estimated with the CG and MDRD formulas was wider than that derived from ClCr, reflecting a greater between-methods variability and a considerable discrepancy of rsGFR values in the former than in the latter. Conclusions. In HTs with normal SCr values, Tc99mDTPA renal scintigraphy discovered un known renal organ damage in 38% of cases. If this methodology is not available, ClCr measurement should be preferred to estimate GFR whereas CG and MDRD formulas are of limited efficacy.

Estimation of creatinine clearance in morbidly obese patients

Estimates of creatinine clearance (CL(cr)) based on equations and various body-size descriptors were compared with 24-hour measured CL(cr) values in morbidly obese patients. Patients age 18-75 years with a body mass index (BMI) of >/=40 kg/m(2) with stable serum creatinine values were enrolled. Covariates known to contribute to alteration in CL(cr) were used to exclude patients. Twenty-four-hour urine collection was performed to measure CL(cr). Bioelectric impedance analysis was used to estimate fat-free weight (FFW). Glomerular filtration rate was estimated using the four-variable Modification of Diet in Renal Disease (MDRD4) equation. CL(cr) was estimated using the Cockcroft-Gault and Salazar-Corcoran methods using total body weight (TBW). Body-size descriptors, such as ideal body weight (IBW), adjusted body weight (ABW), and lean body weight (LBW), and FFW were substituted in the Cockcroft-Gault equation to generate additional estimates of CL(cr). Fifty-four patients (mean +/- S.D. age, 48.4 +/- 12.9 years; TBW, 142.3 +/- 41.7 kg; BMI, 50.5 +/- 12.6 kg/m(2)) completed the study. All three equations were biased in their estimation of CL(cr). Use of MDRD4 and IBW in the Cockcroft-Gault equation underestimated CL(cr), while the Salazar-Corcoran equation and use of TBW or ABW in the Cockcroft-Gault equation overestimated this value. Substitution of fat-free weight or LBW in the Cockcroft-Gault equation provided unbiased estimates of CL(cr). An LBW estimate, based on TBW and BMI, incorporated into the Cockcroft-Gault equation provided an unbiased, relatively precise, accurate, and clinically practical estimate of 24-hour measured CL(cr) in morbidly obese patients.

Population pharmacokinetic and pharmacodynamic modeling of norvancomycin

In this paper, population pharmacokinetics (PPK) and pharmacodynamics of norvancomycin in patients were investigated. The studied dataset was derived from 146 patients with confirmed or suspected gram-positive bacterial infections, as well as 20 healthy volunteers. A PPK model was developed and validated by the nonlinear mixed effect model (NONMEM) software. The norvancomycin minimum inhibitory concentrations (MICs) for the isolates from patients were determined by the agar dilution method. The best model was a two-compartment pharmacokinetic model with exponential inter-individual error and an additive residual error statistic model. The findings of the present study indicated that the change in CLcr values had different effects on drug clearance (CL). In patients with renal dysfunction (CLcr< or =85 ml/min), CL (L/h)=2.54.(CLcr /50)1.20, while in patients with normal renal function (CLcr>85 ml/min), CL=6.0.(WT/60)0.52. An increased volume of peripheral distribution (V2) was observed when norvancomycin was co-administered with diuretics. Inter-individual variability in CL, V1, Q, and V2 was 35.92%, 11.40%, 0, and 79.75%, respectively. Residual variability was 3.05 mg/L. The logistic stepwise analyses revealed that only the ratio of AUC24 /MIC was a major factor which could significantly predict the clinical outcome and bacterial eradication in patients. As the AUC24/MIC ratio was >579.90 for staphylococcal infection and >637.67 for enterococcal infections, approximately 95% of patients would be predicted to achieve a cured clinical outcome. In conclusion, AUC24/MIC should be a major pharmacokinetics/pharmacodynamics (PK/PD) parameter to predict the clinical efficacy of norvancomycin. An optimized regimen of norvancomycin can be simulated and developed for different subgroups of patients who have special physiologic and pathologic conditions.

入院患者へのヒスタミンＨ２受容体きっ抗薬の適正使用：クレアチニンクリアランス予測値に基づく補正用量と処方用量との比較

The major elimination route for histamine H2-receptor antagonists (H2-antagonists), such as famotidine, ranitidine, and cimetidine, is urinary excretion. Therefore, if the dosage adjustments for renally impaired patients or elderly patients are improper, such patients will likely have adverse effects such as mental confusion andseizures due to these drugs. In the package inserts of these H2-antagonists, methods for adjusting the dosage according to the creatinine clearance (CLcr) are provided. In this study we investigated the prescription profiles of famotidine, ranitidine, and cimetidine for inpatients during a three month period at the Kansai Rosai Hospital. The CLcr values were estimated based on the serum creatinine concentration, age, and body weight of each patient according to the equation of Cockcroft and Gault, in order to consider the appropriate usage of H2-antagonists from the relationship between the patient's renal function and dosage. More than 70% of all patients who were prescribed the H2-antagonists were elderly patients (more than 60years old), and 37% were found to have their estimated CLcr to be less than 60mL/min. The dosage for 22% of patients was calculated to be excessive according to the estimated CLcr. These results indicated that prescription monitoring by hospital pharmacists according to the patient's CLcr may contribute to the appropriate dosage management of H2-antagonists for inpatients.

Clinical efficacy of therapeutic drug monitoring in patients receiving vancomycin.

Efficacy of therapeutic drug monitoring (TDM) of vancomycin (VCM) was retrospectively investigated in 184 patients with methicillin-resistant Staphylococcus aureus (MRSA) infection. The incidence of nephrotoxicity was compared between the patients who received TDM practice (TDM group, n=73) and did not (non-TDM group, n=111). Creatinine clearance (CLcr) values decreased significantly after the VCM therapy in the non-TDM group (p<0.05). The patients with MRSA bacteremia or pneumonia were classified into two groups according to peak concentrations of VCM: above 25 microg/ml (Group A: n=29) and below (Group B: n=24). Mean duration of VCM therapy (14.1 d) in Group A was significantly shorter than that (27.0 d) in Group B. Mean cumulative total VCM doses (13.3 g) in Group A was significantly less than that (25.0 g) in Group B. These results indicate that monitoring peak concentration is essential to obtain better clinical effects for VCM therapy, and that the peak concentration above 25 microg/ml is more effective.