Enoxaparin dosage adjustment in patients with severe renal failure: antifactor xa concentrations and safety

STUDY OBJECTIVE: To evaluate the safety and efficacy, by measuring antifactor Xa levels, of enoxaparin 1 mg/kg subcutaneously once every 24 hours in patients with severe renal failure. DESIGN: Prospective study. SETTING: Emergency, internal medicine, geriatrics, and cardiology departments of a medical center in Israel. PATIENTS: Nineteen patients with stage 4 or 5 chronic kidney disease who required full anticoagulation. INTERVENTION: Patients received enoxaparin 1 mg/kg subcutaneously every 24 hours for 2 or more days, as determined by a treating physician. MEASUREMENTS AND MAIN RESULTS: Data on patients' demographic and clinical characteristics were collected. Blood samples for peak and trough antifactor Xa levels were obtained during the enoxaparin treatment period. Of the 19 study patients, 14 (74%) had peak antifactor Xa levels within the recommended range for full anticoagulation of 0.5-1.0 U/ml after their first enoxaparin dose; no concentration exceeded 1.0 U/ml. The mean peak antifactor Xa level was not significantly different after the first enoxaparin dose compared with the second and third doses. The mean +/- SD trough antifactor Xa level, thought to be an indicator of drug accumulation, was 0.12 +/- 0.12 U/ml; its clinical significance and target range are still unknown. No major bleeding events were noted. CONCLUSION: Enoxaparin 1 mg/kg once every 24 hours in patients with stage 4 or 5 chronic kidney disease who required full anticoagulation was safe, and this dose did not exceed recommended concentrations. The significance of enoxaparin trough levels remains unclear and should be investigated in future studies. Other dosing regimens of enoxaparin for specific patient populations should also be assessed for safety and efficacy.     

Enoxaparin use in the neonatal intensive care unit: experience over 8 years

STUDY OBJECTIVE: To evaluate the effectiveness and safety of enoxaparin therapy in a neonatal intensive care unit (NICU). DESIGN: Retrospective chart review. SETTING: Level III NICU in a Canadian academic center. PATIENTS: All neonates treated with enoxaparin while in the NICU between January 1, 1998, and June 1, 2006. MEASUREMENTS AND MAIN RESULTS: Data abstracted included patient demographics, diagnosis of thrombosis and its progression, enoxaparin dosages with corresponding antifactor Xa levels, and adverse events. Sixteen neonates (four term, 12 preterm) were treated with enoxaparin at a mean +/- SD initial subcutaneous dose of 1.41 +/- 0.15 mg/kg every 12 hours. The target therapeutic range (antifactor Xa level 0.5-1.0 U/ml) was achieved by 12 infants at a mean +/- SD dose of 1.92 +/- 0.43 mg/kg every 12 hours, after a mean of 5.6 days (range 1-15 days). Preterm infants required a higher dose (per kilogram) compared with term infants to maintain therapeutic antifactor Xa levels (mean +/- SD 1.94 +/- 0.39 vs 1.65 +/- 0.14 mg/kg every 12 hrs, p<0.001). Enoxaparin doses were more strongly correlated to antifactor Xa levels in term infants (r(2)=0.51, p<0.001) compared with preterm infants (r(2)=0.20, p<0.001). Ten (71%) of 14 thromboembolic events resolved, either partially or completely, at a mean of 39 days (range 8-61 days) of enoxaparin therapy. Nine infants (56%) experienced minor local adverse effects at the site of the indwelling subcutaneous catheter (induration, bruises, hematomas, or leakage). Systemic adverse events that were possibly related to enoxaparin therapy included osteopenia (one infant), scleral hemorrhage (one), and minor gastrointestinal tract bleeding (three) found in gastric feeding tubes. No adverse effects were associated with antifactor Xa levels greater than 1.0 U/ml. CONCLUSION: Enoxaparin may be effective in the treatment of neonatal thrombosis. An initial dosage of 1.5 mg/kg every 12 hours is likely inadequate to obtain therapeutic antifactor Xa levels rapidly and differs for term and preterm neonates. Therapeutic levels in preterm infants may be more variable, and the pharmacokinetics of this drug in preterm infants requires further evaluation. Future studies in neonates should prospectively evaluate a higher starting dose of enoxaparin to document effectiveness, acceptance, compliance with treatment guidelines, and adverse effects.     

Use of low-molecular-weight heparin to bridge therapy in obese patients and in patients with renal dysfunction

OBJECTIVE: To recommend strategies to bridge therapy with low-molecular-weight heparin (LMWH) in obese patients and in patients with renal dysfunction. METHODS: A MEDLINE search was performed of the literature from January 1966-November 2005. Published material dealing with bridging of anticoagulation therapy or short-term use of LMWH therapy in patients with renal dysfunction or obesity was reviewed. The manufacturers of enoxaparin, dalteparin, and tinzaparin were contacted for the references used to determine dosing recommendations. RESULTS: Although LMWH has been commonly used to bridge therapy, our search revealed no trials that specifically examined LMWH bridge therapy in obese patients or in patients with renal dysfunction. However, nine trials using LMWH in obese patients and 14 trials using LMWH in patients with renal dysfunction were identified. When compared with normal-weight individuals, obese patients receiving enoxaparin and dalteparin based on total body weight did not demonstrate higher hemorrhage rates or antifactor Xa levels. Subtherapeutic antifactor Xa levels were more common with once-daily dosing of enoxaparin than with dosing every 12 hours. Enoxaparin accumulates in patients with a creatinine clearance of 30 ml/minute or less; in this population, enoxaparin dosage adjustments have been attempted. Tinzaparin does not accumulate in patients with a creatinine clearance of 20 ml/minute or greater after at least 10 days of dosing. CONCLUSION: Obese patients, weighing 90-150 kg, receiving LMWH for bridge therapy should receive dosages based on total body weight. Unfractionated heparin is recommended in patients weighing more than 150 kg; however, if LMWH is used, antifactor Xa levels should be monitored. Bridging with enoxaparin should be limited to patients with a creatinine clearance greater than 30 ml/minute. The use of enoxaparin 1 mg/kg once/day for patients with a creatinine clearance of 30 ml/minute or less is not recommended for anticoagulation bridge therapy. Tinzaparin may be considered for cross-coverage of high-risk patients with recent or recurrent venous thromboembolism who have a creatinine clearance of at least 20 ml/minute.     

Development of an efficient sampling strategy to predict enoxaparin pharmacokinetics in stage 5 chronic kidney disease

Patients with renal dysfunction are at greater risk for hemorrhagic events than patients with normal renal function. The objective of this study was to develop an efficient sampling strategy that optimally predicts anti-Xa activity exposure after enoxaparin administration in patients with chronic kidney disease to optimize enoxaparin therapy. The antifactor Xa activity data of 8 anuric patients who were administered 1 mg/kg enoxaparin immediately after hemodialysis were used for the development of the optimal sampling strategies. Maximum A Posteriori Bayesian (MAPB) priors were developed by pharmacokinetic analysis. The 2, 3, and 4 D-optimal sampling designs were determined and Monte Carlo simulations using the MAPB estimator were performed. The original model with the estimator was used to determine the predictive power of the sampling schemes. The most efficient sampling scheme (OSS-2) was accurate and precise in predicting apparent enoxaparin clearance (-3.2% bias, 6.5% precision). The addition of a third sampling time at 30 minutes (OSS-3) was more accurate (P < 0.01) and precise (P < 0.01) than OSS-2 at predicting the rate of absorption (ka) but did not improve the accuracy (P > 0.05) or precision (P = 0.20) of the CLs/F estimate. The determination of antifactor Xa activity at 5 and 24 hours, along with the Bayesian estimators generated from this study, accurately and precisely predict the apparent clearance of antifactor Xa activity. This sampling strategy may be used for therapeutic drug monitoring of enoxaparin and for future clinical trials in patients with chronic kidney disease.     

Antifactor Xa levels in four patients with burn injuries who received enoxaparin to prevent venous thromboembolism

Four patients with severe burn injuries received enoxaparin 40 mg twice/day subcutaneously for the prophylaxis of venous thromboembolism (VTE). Peak antifactor Xa levels were measured 4 hours after administration of a dose, and trough antifactor Xa levels were measured 30 minutes before the next scheduled dose. Ultrasonography was performed once/week to assess the presence of VTE. Any occurrence of major bleeding was documented in the patients' charts. All patients had trough antifactor Xa levels below 0.1 U/ml. Enoxaparin dosages were subsequently adjusted to achieve trough antifactor Xa levels of 0.1-0.2 U/ml. This required dosages higher than those typically recommended for VTE prophylaxis (40 mg every 24 hrs or 30 mg every 12 hrs). One patient needed more than 60 mg every 12 hours. No patient had a venous thromboembolic event or major bleeding. The low antifactor Xa levels that were observed suggest that a reduced dose-response relationship may exist between subcutaneously administered enoxaparin and antifactor Xa activity in patients with severe burn injuries. Prospective studies should be performed to further investigate this relationship.     

The pharmacokinetics of enoxaparin do not correlate with its pharmacodynamic effect in patients receiving dialysis therapies

The pharmacokinetics and pharmacodynamics of enoxaparin were studied in healthy volunteers and hemodialysis and peritoneal dialysis subjects. Antifactor Xa activity estimated the pharmacokinetics, whereas thrombin generation time (TGT) estimated the pharmacodynamics. Enoxaparin 1 mg/kg was given subcutaneously to all subjects. Antifactor Xa Amax and AUC(0-12) were similar between groups, but the TGTmax was significantly greater in the dialysis groups (P = .001). The thrombin generation time remained significantly more prolonged throughout the 12-hour study period, and there was a trend toward greater TGT AUEC(0-12) for both dialysis groups (P = .07). Patients receiving hemodialysis had greater sensitivity to enoxaparin compared to the other groups. These results suggest that in dialysis patients, there may be accumulation of active heparin metabolites that are undetected by the antifactor Xa assay. Therefore, these subjects exhibit greater thrombin generation time prolongation despite similar antifactor Xa exposure. Further large-scale studies are needed to corroborate the results of this exploratory pilot study.     

Peak antifactor xa activity produced by dalteparin treatment in patients with renal impairment compared with controls

STUDY OBJECTIVE: To evaluate the relationship between impaired renal function and antifactor Xa activity in patients receiving dalteparin. DESIGN: Open-label prospective study. SETTING: Inpatient and outpatient units of a large teaching hospital. SUBJECTS: Eleven patients with renal impairment and 11 control subjects with normal renal function. INTERVENTION: Subjects were administered dalteparin at a dosage of approximately 100 U/kg subcutaneously every 12 hours. MEASUREMENTS AND MAIN RESULTS: Peak steady-state antifactor Xa levels were compared between the groups. Mean +/- SD levels were similar for patients with and without renal impairment: 0.47 +/- 0.25 and 0.55 +/- 0.20 U/ml, respectively. A test of equivalency showed statistical significance (p=0.0001). CONCLUSION: No meaningful difference in peak antifactor Xa activity was found between patients with renal impairment and control subjects. To the extent that peak antifactor Xa levels can be used as markers for adjusting doses of dalteparin, these data suggest that such adjustments are not necessary for patients with renal impairment who are not receiving dialysis.     

Correlation of antifactor Xa concentrations with renal function in patients on enoxaparin

Enoxaparin is a low molecular weight heparin (LMWH) that has been shown to be effective in deep vein thrombosis, pulmonary embolism, and unstable angina. Because renal function plays an important role in the clearance of LMWH, the authors sought to investigate the effect of renal function on enoxaparin. This prospective multiple-dose study evaluated 18 patients with varying degrees of renal function initiated on enoxaparin 1 mg/kg subcutaneously every 12 hours. Peak blood levels of anti-Xa concentrations were obtained 4 +/- 0.5 hours postdose after receiving at least three doses of enoxaparin. The median antifactor Xa levels were higher in patients with creatinine clearance (CLCr) < or = 30 mL/min compared to CLCr > or = 31 mL/min (1.34 IU/mL vs. 0.91 IU/mL, respectively, p < 0.05). A linear correlation was established between creatinine clearance and anti-Xa concentrations (p < 0.0005). On the basis of the data, the authors believe that a dose adjustment is necessary in patients receiving repeated doses of enoxaparin with CLCr < or = 30 mL/min.     

Pharmacokinetic and pharmacodynamic perspectives on the clinical drug development of panitumumab

Panitumumab is a recombinant, fully human IgG2 monoclonal antibody directed against the epidermal growth factor receptor (EGFR). It is indicated for use as monotherapy in the treatment of patients with EGFR-expressing metastatic colorectal cancer after disease progression with standard chemotherapy. The currently indicated dose is 6 mg/kg given every 2 weeks. Panitumumab is mainly distributed into the vascular space and exhibits nonlinear pharmacokinetics that are consistent with target-mediated drug disposition, involving saturable binding to EGFR and subsequent internalization and degradation inside the cells. Panitumumab is also cleared in a linear fashion by the reticuloendothelial system, similarly to other endogenous immunoglobulins. After single-dose administration of panitumumab as a 1-hour intravenous infusion, the area under the serum concentration-time curve increases in a greater-than-dose-proportional manner as the dose increases from 0.75 to 5 mg/kg; however, at doses above 2 mg/kg, the exposure to panitumumab increases in a dose-proportional manner. Panitumumab pharmacokinetics are not meaningfully affected by the tumour type, EGFR membrane expression, tumour KRAS mutation, sex, age, race or renal or hepatic dysfunction. In addition, irinotecan-containing and paclitaxel/carboplatin-containing chemotherapeutic regimens do not appear to affect panitumumab pharmacokinetics. The results of population pharmacokinetic analyses have shown that bodyweight is the most influential covariate on panitumumab exposure, supporting the current use of bodyweight-adjusted doses (mg/kg). The relationship between the weekly dose of panitumumab and skin rash, an on-target pharmacodynamic effect of EGFR inhibition, reaches a plateau at 2.5 mg/kg, indicating that this is the optimal weekly dose. Two less-frequent dosing regimens (6 mg/kg given every 2 weeks and 9 mg/kg given every 3 weeks) achieve steady-state serum trough concentrations similar to those achieved by 2.5 mg/kg given every week, ensuring maximal EGFR coverage. Anti-panitumumab antibody production is uncommon and does not appear to have an impact on the pharmacokinetics of panitumumab.     

The pharmacokinetics of nelfinavir in HIV-1-infected children

The authors investigated the steady-state plasma pharmacokinetics of nelfinavir in HIV-1-infected children in a dosage of 30 mg/kg every 8 hours and 45 mg/kg every 12 hours in 12 HIV-1-infected children (aged 2.1 to 10.8 years) participating in an open-label study of nelfinavir in combination with stavudine and lamivudine.Median values of the primary pharmacokinetic parameters of nelfinavir 30 mg/kg every-8-hours (n = 8) and 45 mg/kg every 12 hours (n = 10) were, respectively, for the area under the plasma concentration-time curve over 24 hours, 90.5 and 71.9 h x microg/mL, for the trough concentration 1.9 and 1.0 microg/mL, and for the maximal concentration 6.3 and 5.2 microg/mL. Overall, a 7-fold interpatient variability was observed for the exposure to nelfinavir. Nelfinavir 30 mg/kg every-8-hours or 45 mg/kg every 12 hours in HIV-1-infected children generally resulted in plasma concentrations higher than those obtained in adults. However, due to a large interpatient variability in the exposure, individual dosage adjustments based on plasma concentrations may be necessary for both dosing regimens to ensure optimal treatment.     

Clinical Application and Pharmacodynamic Monitoring of Apixaban in a Patient with End‐Stage Renal Disease Requiring Chronic Hemodialysis

Despite prescribing guidance, limited data exist to describe the use of apixaban in patients with end‐stage renal disease (ESRD) requiring hemodialysis (HD). Current apixaban dosing recommendations for this patient population are based largely on a single‐dose pharmacokinetic study of eight patients. We describe the clinical application and pharmacodynamic monitoring of apixaban in a 62‐year‐old 156‐kg African‐American woman with nonvalvular atrial fibrillation and ESRD requiring hemodialysis who developed calciphylaxis while receiving warfarin therapy. Based on a multidisciplinary clinical judgment decision due to concern for drug accumulation after multiple doses in patients with ESRD receiving HD, she was anticoagulated with apixaban 2.5 mg twice/day, as opposed to 5 mg twice/day as recommended by the package insert. Antifactor Xa monitoring was used, and resultant peak and trough apixaban concentrations were above the upper limit of detection for our clinical laboratory (more than 2.00 IU/ml). On day 7 of her hospitalization, the patient developed gastrointestinal bleeding, and apixaban was discontinued; no further clinical signs of bleeding occurred during her subsequent hospitalization course. Use of the Naranjo Adverse Drug Reaction Probability Scale indicated a probable relationship (score of 6) between apixaban exposure and the manifestation of gastrointestinal bleeding. The patient ultimately died 44 days after the acute bleeding event; however, coagulation concerns were not implicated in the patient's death. To our knowledge, this is the first case report that describes apixaban use and associated antifactor Xa monitoring in a patient with ESRD receiving HD, and it provides concern for current apixaban dosing recommendations in this patient population. Further pharmacokinetic and clinical data are likely necessary to better characterize apixaban use in these patients to optimize safety and efficacy.     

Lack of unique ciprofloxacin pharmacokinetic characteristics in patients with cystic fibrosis

The single-dose pharmacokinetics of oral ciprofloxacin 750 mg were evaluated in six subjects with cystic fibrosis (CF subjects) and six age, sex and approximate weight-matched control subjects (controls). In addition, the effect of concurrently administered oral pancreatic enzyme replacement on the pharmacokinetics of ciprofloxacin was studied in 12 CF subjects. Ciprofloxacin t1/2, VSSF, CLF, and CLR in the matched CF subjects averaged 4.5 hours, 2.8 L/kg, 2.73 mL/min/kg and 5.7 mL/min/kg, respectively. Forty-two percent of the ciprofloxacin dose was excreted in the urine (0-48 hours) as the parent compound. No statistically significant differences in these ciprofloxacin pharmacokinetic parameter estimates were observed between CF and control subjects. In three CF subjects and two controls, the urinary excretion of ciprofloxacin and four of its metabolities were similar. In contrast, CF subjects demonstrated a prolonged tmax (2.3 versus 1.3 hours P less than .05) though ciprofloxacin Cmax was similar (4.7 versus 3.8 mg/L, NS). The concurrent administration of oral pancreatic enzyme replacement had no effect on the pharmacokinetics of ciprofloxacin. Apparent ciprofloxacin pharmacokinetic parameters in sputum were similar to those observed in serum. Sputum ciprofloxacin concentrations lagged behind serum concentrations but, on average, exceeded serum concentrations for 20 hours of the 24-hour sampling period. These sputum ciprofloxacin concentrations exceeded the reported MIC90 for Pseudomonas aeruginosa for approximately 15 hours. These data suggest an oral ciprofloxacin dose of 750 mg administered q8h to promote accumulation and maintenance of sputum drug concentrations well above pathogen MICs for the majority of a dosing interval in patients with CF.     

Pharmacokinetics and Safety of Ebastine in Healthy Subjects and Patients with Renal Impairment

OBJECTIVE: To assess the differences in the pharmacokinetics and cardiac safety of ebastine and its active metabolite, carebastine, in patients with normal and impaired renal function. METHODS: Twenty-four patients with varying degrees of renal impairment (mild, moderate or severe: n = 8 per group) and 12 healthy subjects participated in an open-label, parallel-group, multicentre study. Ebastine 20mg was administered orally once daily for 5 days. Plasma concentrations of ebastine and carebastine were determined for 24 hours on day 1 and for 72 hours on day 5 by using a validated sensitive liquid chromatography-tandem mass spectrometry assay with a minimum quantifiable limit of 0.05 ng/mL for ebastine and 1.00 ng/mL for carebastine. Renal function was assessed by measuring 24-hour creatinine clearance (CL(CR)) at baseline. Cardiac and general safety parameters were also monitored. RESULTS: The pharmacokinetics of ebastine were not modified by renal impairment. No correlation between ebastine pharmacokinetics and renal function, as expressed by CL(CR) assessed 2 days prior to dosing, was observed. Comparison of the plasma exposure and the elimination half-life of ebastine and carebastine between groups showed no significant differences. Therefore, no apparent accumulation of ebastine and carebastine occurred, and steady-state concentrations of ebastine and carebastine were predictable from single-dose pharmacokinetics for both healthy subjects and patients with renal impairment, even though the variability between the groups was large. In addition, no differences were observed in the safety of ebastine between patients with renal impairment and healthy subjects when assessing adverse events, vital signs, laboratory parameters or ECGs. CONCLUSION: Ebastine was generally well tolerated in subjects with impaired renal function. No clinically important pharmacokinetic or safety differences were observed between patients with renal impairment and healthy subjects with normal renal function.     

Nizatidine suppression of basal gastric acid output: a comparison of two intravenous dosage regimens

To study the pharmacokinetics and pharmacodynamics of two intravenous nizatidine dosing regimens, serial plasma concentrations and continuous intragastric pH were monitored simultaneously in 10 subjects with a documented history of duodenal or gastric ulcers. A 24-hour gastric pH profile was characterized for a 300 mg daily dose of nizatidine randomly administered both as 100 mg every 8 hours and 150 mg every 12 hours. No significant differences were observed in the mean pharmacokinetic parameters between the two dosing regimens. Pharmacodynamic parameters for the 100 mg every 8 hours versus the 150 mg every 12 hours regimen were not significantly different except for percent of time during the 24-hour study period that the pH was maintained greater than 4 (43.6 +/- 20.7 versus 34.7 +/- 18.3, P less than .05). A significant relationship was demonstrated for both regimens (P less than .05) between the percent time pH greater than 4 and area under the plasma curve for the 24 hour study period. The lack of a significant difference in nizatidine pharmacokinetics between the two dosage regimens suggests a pharmacodynamic cause for the greater cumulative pH effect of the every 8 hour regimen.     

Steady-state pharmacokinetics and pharmacodynamics of meropenem in hospitalized patients

STUDY OBJECTIVE: To evaluate the steady-state pharmacokinetics and pharmacodynamics of meropenem 500 mg every 6, 8, and 12 hours, based on renal function, in hospitalized patients. DESIGN: Prospective, open-label, steady-state pharmacokinetic study. SETTING: One tertiary care medical center and one community hospital. PATIENTS: Twenty adult patients (12 men, 8 women) with suspected or documented bacterial infections requiring antimicrobial therapy. INTERVENTION: Patients received 30-minute infusions of meropenem 500 mg every 6 hours (group 1), every 8 hours (group 2), or every 12 hours (group 3) based on estimated creatinine clearances greater than 60, 40-60, or 10-39 ml/minute, respectively. MEASUREMENTS AND MAIN RESULTS: Serial blood samples were collected after 2 or more days of therapy. Meropenem concentrations were determined by high-performance liquid chromatography, and pharmacokinetic data were analyzed by noncompartmental methods. Monte Carlo simulations (10,000 patients) were performed to calculate the cumulative fraction of response (CFR) for a percentage of the dosing interval that free drug concentrations remain above the minimum inhibitory concentration (fT>MIC) of 40% by using pharmacokinetic data for each group and MIC data for seven gram-negative pathogens from the Meropenem Yearly Susceptibility Test Information Collection (MYSTIC, 2004-2005) database. Maximum and minimum serum concentrations (mean +/- SD) were 29.2+/-9.8 and 2.4+/-1.1 microg/ml, 33.2+/-8.5 and 3.8+/-2.7 microg/ml, and 33.5+/-4.7 and 4.9+/-1.6 microg/ml for groups 1, 2, and 3, respectively. The half-life values were 2.5+/-0.9, 3.4+/-1.3, and 6.1+/-1.4 hours, and the values for volume of distribution at steady state were 29.3+/-8.7, 23.8+/-8.1, and 28.7+/-8.6 L for groups 1, 2, and 3, respectively. For all three groups, the CFR was greater than 90% for the enteric pathogens and Pseudomonas aeruginosa and 82.4-85.2% for Acinetobacter species. CONCLUSION: Pharmacodynamic analyses suggest that regimens of meropenem 500 mg every 6, 8, or 12 hours, adjusted for renal function, are acceptable for treatment of infections caused by enteric gram-negative pathogens and P. aeruginosa. However, more aggressive dosing or alternative dosing strategies may be necessary for Acinetobacter species.     

Limiting cefotaxime pediatric dosing to adult standards: a pharmacokinetic simulation study.

OBJECTIVE: The recommended cefotaxime dose of 50 mg/kg every six to eight hours for pediatric patients with a body weight greater than 20 kg exceeds the standard 1-gram dose recommended for adult patients. This study estimated whether limiting the cefotaxime dose recommended for children with mild to moderate infections to a standard 1-gram dose would achieve serum concentrations and time above the MIC90 comparable to those in adults. METHODS: Serum concentration profiles were simulated from mean cefotaxime pharmacokinetic parameters that have been published for children and for adults using widely available spreadsheet software. The simulations employed an open, one-compartment, multiple-dose model and were calculated using a common commercial spreadsheet. The model was used to predict serum concentrations using dosage regimens of 1 g or 50 mg/kg administered every six or eight hours in pediatric patients of various weights with pediatric pharmacokinetic parameters and 1 g every six or eight hours for adult patients with adult pharmacokinetic parameters. The time that cefotaxime concentrations exceeded the MIC90 for pediatric pathogens was also calculated. RESULTS: The 50 mg/kg pediatric dosing regimens administered every 8 hours (q8h) or every 6 hours (q6h) consistently produced peak serum concentrations and area under the concentration versus time curve (AUC) values higher than those in adults. Serum concentrations and AUCs generated for the 1-gram regimens for various pediatric weight categories were also above those predicted in adults. The time above the MIC90 for pediatric patients was equivalent to or exceeded those of the adult simulations for all pathogens. CONCLUSIONS: The results support the concept of limiting cefotaxime dosage regimens to 1 g administered every 6 or 8 hours for mild to moderate infections in children weighing more than 20 kg. This dosage regimen could lead to dose standardization procedures, which could produce reductions in drug costs associated with individualized dosage preparation.     

Effects of chronic renal failure on the pharmacokinetics of ruboxistaurin and its active metabolite 338522

BACKGROUND: Ruboxistaurin, a specific inhibitor of the beta(1) and beta(2) isoforms of protein kinase C, is currently in clinical development for the treatment of several diabetic microvascular complications. The major metabolite, N-desmethyl ruboxistaurin (metabolite 338522), is equipotent in its inhibitory activity. The elimination of ruboxistaurin and its metabolites is primarily through bile and the faecal route, with urinary excretion constituting only a minor route. OBJECTIVE: To assess the effects of chronic renal insufficiency on the pharmacokinetics of ruboxistaurin and metabolite 338522. METHODS: Six healthy subjects (creatinine clearance >80 mL/min/1.73 m(2)) and six end-stage renal disease (ESRD) subjects requiring long-term haemodialysis were studied. All subjects received a single oral dose of ruboxistaurin 32 mg followed by serial blood sampling up to 72 hours. ESRD subjects underwent haemodialysis approximately 58 hours after dosing, with blood samples obtained immediately before and after dialysis. RESULTS: No differences were observed in the pharmacokinetic parameters (area under the plasma concentration-time curve from time zero to infinity [AUC(infinity)], maximum plasma concentration [C(max)] and elimination half-life [t(1/2)]) of ruboxistaurin and metabolite 338522 between healthy and ESRD subjects Plasma concentrations of ruboxistaurin were below the lower limit of quantification by the time of haemodialysis. The predicted post-dialysis plasma concentrations of metabolite 338522 were not statistically different from the observed values (p=0.163). Ruboxistaurin was well tolerated in both groups of subjects. CONCLUSION: These results indicate that the kidney is not an important route of metabolism or excretion for ruboxistaurin and metabolite 338522. Based on the pharmacokinetic and tolerability findings, no formal dosage adjustment of ruboxistaurin should be required for patients with any degree of renal impairment who are undergoing haemodialysis.     

Distribution and elimination kinetics of carbamazepine in man

Summary Carbamazepine (2.7–3 mg/kg) was administered orally as an alcoholic solution (50% v/v) to eight healthy volunteers. Two of the subjects were also given 50 mg and 100 mg of carbamazepine in alcoholic solution and 200 mg as a tablet. Plasma concentrations, which were analysed by mass fragmentography, reached a maximum 1 – 7 hours after dosing, and then declined monoexponentially with half-lives ranging from 24 to 46 hours. The half-lives were independent of dose. The apparent distribution volume ranged from 0.79 to 1.40 l/kg. It was found that 72% of carbamazepine was bound to plasma proteins with little interindividual variation, and this was not influenced by the presence of diphenylhydantoin or phenobarbital in therapeutic concentrations. The pharmacokinetic parameters calculated from single oral doses were used to predict the steady-state plasma concentration expected after treatment with multiple doses of 200 mg three times daily. The predicted steady-state concentration was 2 – 3 times higher than that reported in patients undergoing chronic treatment with carbamazepine at this dose level, i.e. the pharmacokinetics of carbamazepine apparently change during multiple dosing.Dedicated to the memory of Balzar Alexandersson, MD.Medical Research Council (U.K.) Travelling Fellow     

Comparison of Bactericidal Activities of Intermittent and Continuous Infusion Dosing of Vancomycin against Methicillin-Resistant Staphylococcus aureus and Enterococcus faecalis

Study Objective . To describe the pharmacokinetic profiles of vancomycin administered by continuous infusion and intermittent dosing and compare the duration of activity of the regimens. Design . Randomized, open-label, cross-over study. Setting . Clinical research center at an academic medical center. Subjects . Twelve healthy, nonpregnant volunteers age 27.6 ± 2.3 years. Intervention . Subjects received the following intravenous vancomycin regimens: 1 g every 12 hours; 2 g continuous infusion over 24 hours; and 1 g continuous infusion over 24 hours. Dosages were administered with and without gentamicin 2 mg/kg. Measurements and Main Results . Serum samples were collected, drug concentrations determined, and bactericidal activity measured against two isolates each of methicillin-resistant Staphylococcus aureus and Enterococcus faecalis. Subjects had poor tolerability for continuous infusions. Trough concentration for the intermittent regimen was 5.5 ± 1.9 mg/ml, and steady-state concentrations were 8.8 ± 1.6 and 16.9 ± 1.9 mg/ml for 1 and 2 g continuous infusions, respectively. In general, all regimens provided bactericidal activity throughout the study interval. Against one isolate of E. faecalis, 2 g continuous infusion plus gentamicin provided cidal activity for a significantly greater percentage of the dosing interval (p<0.001). Conclusion . Continuous infusion does not greatly improve the activity of vancomycin and should not be routinely administered. However, it may prove useful against isolates with reduced susceptibility to the agent.