Imipenem pharmacokinetics in patients with burns

The pharmacokinetics of imipenem were studied in 11 adult patients with severe burns who were receiving a therapeutic regimen of imipenem-cilastatin 500 mg intravenously every 6 hours. Serial blood samples for measuring imipenem and 24-hour urine collections for creatinine clearance (CrCl) were obtained after the initial dose and after multiple dosing. Plasma was assayed for imipenem by use of HPLC. A two-compartment model provided a superior fit to the data compared with a one-compartment model in 9 of the 11 patients. There was no significant difference in any pharmacokinetic parameter between the initial dose and after multiple dosing (p greater than 0.05). Combined mean (+/- SD) parameter estimates for the two dosing periods were as follows: VC, 0.11 +/- 0.06 L/kg; Vss, 0.22 +/- 0.06 L/kg; CL, 12.5 +/- 3.6 L/hr/1.73 m2; t1/2 alpha, 0.18 +/- 0.13 hr; t1/2 beta, 1.12 +/- 0.44 hr. Mean clearance in two patients with creatinine clearance values greater than 150 ml/min/1.73 m2 was 17.7 L/hr/1.73 m2. Mean clearance in two patients with creatinine clearance values less than 50 ml/min/1.73 m2 was 8.5 L/hr/1.73 m2. No pharmacokinetic parameter was significantly different from previously reported parameters in normal volunteers (p greater than 0.05). Creatinine clearance ranged from 17 to 218 ml/min/1.73 m2. Imipenem clearance was significantly related to creatinine clearance (CL = 63 + 0.059 CLCR; r2 = 0.60, p = 0.001). No significant association was found between total body surface area burns and imipenem clearance (p greater than 0.05). Our data suggest imipenem pharmacokinetics in patients with burns are comparable to those in normal volunteers although substantial intersubject variability exists.(ABSTRACT TRUNCATED AT 250 WORDS)     

Pharmacokinetics and pharmacodynamics of cefepime in patients with various degrees of renal function

This study evaluated the pharmacokinetics of cefepime in 36 patients with different levels of renal function. Pharmacokinetic and pharmacodynamic parameters were calculated using samples obtained at steady state. Patients with creatinine clearance (CL(CR)) of >100 ml/min had more rapid clearance (CL) and a lower minimum concentration in serum (C(min)). C(min) in this group was found to be 3.3 +/- 3.6 mg/liter (mean and standard deviation), compared to 19.5 +/- 21.5 mg/liter in patients with a CL(CR) of between 60 and 100 ml/min (P = 0.025) and 14.0 +/- 11.5 mg/liter in patients with a CL(CR) of <60 ml/min (P = 0.009). Patient data were also analyzed by the nonparametric expectation maximization method and Bayesian forecasting. The median volume of distribution in the central compartment was 27.08 liters. CL and CL(CR) were highly correlated (P = 0.00033) according to the equation CL= 0.324 liters/h + (0.0551 x CL(CR)). The median rate constants from the central compartment to the peripheral compartment and from the peripheral compartment to the central compartment were 12.58 and 41.09 h(-1), respectively. The time-concentration profiles for 1,000 patients (CL(CR)s, 120, 60, and 30 ml/min) each receiving various dosing regimens were simulated by using Monte Carlo simulations. Standard dosing resulted in a C(min) that was greater than or equal to the MIC in more than 80% of the simulated profiles with MICs < or = 2 mg/liter. Current dosing recommendations may be suboptimal for monotherapy of infections due to less susceptible pathogens (e.g., those for which MICs are > or = 4 mg/liter), particularly when CL(CR) exceeds 120 ml/min.     

Determination of the production rate and non-renal clearance of cystatin C and estimation of the glomerular filtration rate from the serum concentration of cystatin C in humans

Cystatin C has been proposed as an endogenous marker for measuring glomerular filtration rate (GFR) and is regarded as being equivalent to or better than creatinine. However, there are no published data on the production rate (Cys(pr)) or on the non-renal clearance of cystatin C (CL(nr)) in humans, which are essential parameters for GFR calculation. GFR was determined by measuring the plasma clearance of iohexol. Cystatin C, creatinine, urea and albumin were determined on the same serum samples as iohexol; 381 patients with a GFR range of 12-151 ml/min/1.73 m2, and 70 patients on haemodialysis were evaluated. Renal clearance of cystatin C (CLr) equals GFR * S (the sieving coefficient). Plasma clearance (CL) = CLr + CLnr. The relationship between Cys(pr) and the elimination rate (CL * serum-cystatin C) can be expressed as Cys(pr) = (S * GFR+CLnr) * serum-cystatin C. Assuming that the unknown values of Cys(pr) and CLnr are independent of GFR, the equation can be solved from GFR (iohexol clearance) and serum cystatin C (s-Cys) patient data. For S=1, we found Cys(pr) = 0.124 +/- 0.023 mg/min/1.73 m2 and Cl(nr)=22.3 ml/min/1.73 m2. For S = 0.94, found in rats, the values will be Cys(pr) = 0.117 mg/min/1.73 m2 and Cl(nr) = 21 ml/min/1.73 m2 and S-Cys in 70 patients on chronic haemodialysis was found to be 5.74 +/- 1.15 mg/l, in agreement with a calculated value of 5.56 mg/l (s-Cys=124/22.3) for GFR=zero. The mean value of the calculated Cl(nr) for the 70 patients was 22.7 +/- 6.6 ml/min/1.73 m2, which confirms the calculated level and indicates its biological variation. We thus propose the following formula for calculating GFR using the values found for CLnr and Cys(pr) in this study: GFR=124/s - Cys - 22.3 ml/min/1.73 m2, where serum cystatin C concentration is given as mg/l.     

Pharmacokinetics of single-dose oral stavudine in subjects with renal impairment and in subjects requiring hemodialysis

Two open-label studies assessed the pharmacokinetics of single orally administered doses of 40 mg of stavudine in subjects with renal impairment. In one study (study I), 15 subjects with selected degrees of renal impairment, but not requiring hemodialysis, were stratified into three groups of five subjects each according to creatinine clearance (CL(CR)) normalized by body surface area (ml/min/1.73 m(2)): mild (CL(CR), 60 to 80), moderate (30 to 50), and severe (/= 90) were also enrolled. The stavudine area under the curve from 0 h to infinity (AUC(0-infinity)) increased nonlinearly with declining renal function: 1,864, 2,215, 3,609, and 5,928 ng. h/ml for normal renal function and for mild, moderate, and severe renal impairment, respectively (P = 0.0001 between renal impairment groups). The following stavudine dosage recommendations for renal impairment were proposed for subjects weighing >/=60 kg: CL(CR) of >50 ml/min/1.73 m(2), 40 mg every 12 h; CL(CR) of 21 to 50 ml/min/1. 73 m(2), 20 mg every 12 h; and CL(CR) of 10 to 20 ml/min/1.73 m(2), 20 mg every 24 h. For subjects weighing <60 kg, the proposed doses were 30, 15, and 15 mg, respectively, with the same dosing intervals specified above. In a second study (study II), 12 subjects with end-stage renal disease requiring hemodialysis three times a week were enrolled in a randomized, open-label crossover study (dialysis 2 h after dosing and lasting 4 h or dosing without dialysis). There were no statistically significant differences for AUC(0-infinity), AUC(2-6), time to maximum concentration of drug in serum, half-life, or apparent oral clearance when the two treatment dosage regimens were compared. As a result of study II, the recommended dosing rate for subjects requiring hemodialysis was the same as that proposed for those with severe renal impairment not requiring hemodialysis; however, dosing was recommended to follow hemodialysis and to occur at the same time each day.     

Modeling of transfer kinetics at the serum-cerebrospinal fluid barrier in rabbits with experimental meningitis: application to grepafloxacin

The goals of the present study were to model the population kinetics of in vivo influx and efflux processes of grepafloxacin at the serum-cerebrospinal fluid (CSF) barrier and to propose a simulation-based approach to optimize the design of dose-finding trials in the meningitis rabbit model. Twenty-nine rabbits with pneumococcal meningitis receiving grepafloxacin at 15 mg/kg of body weight (intravenous administration at 0 h), 30 mg/kg (at 0 h), or 50 mg/kg twice (at 0 and 4 h) were studied. A three-compartment population pharmacokinetic model was fit to the data with the program NONMEM (Nonlinear Mixed Effects Modeling). Passive diffusion clearance (CL(diff)) and active efflux clearance (CL(active)) are transfer kinetic modeling parameters. Influx clearance is assumed to be equal to CL(diff), and efflux clearance is the sum of CL(diff), CL(active), and bulk flow clearance (CL(bulk)). The average influx clearance for the population was 0.0055 ml/min (interindividual variability, 17%). Passive diffusion clearance was greater in rabbits receiving grepafloxacin at 15 mg/kg than in those treated with higher doses (0.0088 versus 0.0034 ml/min). Assuming a CL(bulk) of 0.01 ml/min, CL(active) was estimated to be 0.017 ml/min (11%), and clearance by total efflux was estimated to be 0.032 ml/min. The population kinetic model allows not only to quantify in vivo efflux and influx mechanisms at the serum-CSF barrier but also to analyze the effects of different dose regimens on transfer kinetic parameters in the rabbit meningitis model. The modeling-based approach also provides a tool for the simulation and prediction of various outcomes in which researchers might be interested, which is of great potential in designing dose-finding trials.     

Pharmacokinetics, pharmacodynamics, allometry, and dose selection of rPSGL-Ig for phase I trial

rPSGL-Ig is a recombinant, soluble, and chimeric form of P-selectin glycoprotein ligand-1, which is developed as an antagonist to P-selectin. Allometric and pharmacokinetic/pharmacodynamic modeling was used to select doses for human clinical trials. Pharmacokinetic parameters of rPSGL-Ig such as clearance (CL), volume of distribution (Vc), and t(1/2) across animal species are well described by power functions with body weight as an independent variable. The power functions for CL, Vc, and t(1/2) were CL = 0.37. W(0.93) ml/h (r(2) = 0.94), Vc = 45.0.W(1.064) ml (r(2) = 0.988), and t(1/2) = 190.W(0.159) h (r(2) = 0.75), respectively. These functions provide a means to predict pharmacokinetics of rPSGL-Ig in humans. For a 70-kg human, the values of CL, Vc, and t(1/2) are predicted to be 19.9 ml/h, 4138 ml, and 15.5 days, respectively. The predicted pharmacokinetics in humans is used in conjunction with pharmacological data to estimate appropriate doses for clinical trials. The doses that may provide potential effects in humans range from 0.13 to 4.7 mg/kg. The predicted doses produce concentrations above those that are associated with efficacy in animal disease models and, maintain concentrations above the EC(50) of in vitro binding between rPSGL-Ig and stimulated human platelets. Hence, rPSGL-Ig in clinical trials may provide therapeutic activities for P-selectin-mediated diseases.     

Pharmacokinetics of lomefloxacin in renally compromised patients

The single-dose pharmacokinetics of orally administered lomefloxacin (400 mg) were studied in normal subjects and in patients with various degrees of renal function. The subjects were classified by creatinine clearance (CLCR) normalized for body surface area: group 1, CLCR of greater than 80 ml/min/1.73 m2; group 2, CLCR of 80 to greater than 40 ml/min/1.73 m2; group 3, CLCR of 40 to greater than 10 ml/min/1.73 m2; and group 4, CLCR of less than or equal to 10 ml/min/1.73 m2. Each group consisted of eight subjects. The pharmacokinetics of lomefloxacin were significantly influenced by renal function. There were significant differences in the elimination rate constant, half-life, area under the concentration-time curve from 0 h to infinity, apparent total drug clearance, renal clearance, and apparent nonrenal drug clearance between the four renal function groups. Mean half-lives for groups 1, 2, 3, and 4 were 8.09, 9.11, 20.90, and 44.25 h, respectively. There were no significant differences between the renal groups for maximum concentration of the drug in serum and apparent volume of distribution. Age had no apparent effect on lomefloxacin disposition. There was a significant relationship between CLCR and lomefloxacin total body clearance (r = 0.92, P = 0.001) and renal clearance (r = 0.94, P = 0.001). Despite a predominate renal route of elimination, nonrenal lomefloxacin clearance significantly decreased with decreasing renal function (r = 0.72, P = 0.001). Mean lomefloxacin excretion rates over 48 h were 60.7, 56.0, 29.1, and 1.0% of the administered dose for groups 1, 2, 3, and 4, respectively. Mean glucuronide excretion rates over 48 h were 7.8, 6.3, 10.0, and 0.6% of the administered dose for groups 1, 2, 3, and 4, respectively. Hemodialysis had no effect on lomefloxacin concentrations in plasma. In patients with normal to moderate renal function, 400 mg of lomefloxacin per day should provide therapeutic concentrations in blood. The lomefloxacin dose should be reduced to 200 mg/day as the CL(CR) falls below 30 ml/min/1.73 m2. No additional dosage adjustments appear to be necessary for hemodialysis patients.     

Application of two-point assay of digoxin serum concentration in studying population pharmacokinetics in Egyptian pediatric patients with heart failure: does it make sense?

Digoxin pharmacokinetics (PK) was studied among a selected group of Egyptian pediatric patients (n = 40) with an age range of 0.33 to 15 years. All the patients had heart failure and were maintained on i.v. digoxin (10 microg/kg/d in 2 equal doses). For population PK analysis, 2 serum samples of digoxin were taken per patient. From 30 patients' trough (before the next dose) and 4 hours postdose samples were obtained, while in the other 10 patients, 0.5- and 6-hour postdose samples were taken. Serum concentrations were measured by fluorescence polarization immunoassay. PK modeling was performed using NONMEM software on log-transformed serum digoxin data. The best structural covariate-free model was a linear 2-compartment model with an exponential error model for intersubject variability and an additive model for intrasubject variability. Serum creatinine (SCR) was a significant covariate for clearance. The final population PK parameters were CL (L/h) = 0.388 - [0.78 x (SCR-0.6)], V1 (L/kg) = 1.38, Q (L/h/kg) = 0.48, V2 (L/kg) = 9.11, where CL is the total body clearance, V1 and V2 are the apparent volumes of distribution in the central and peripheral compartments, and Q is intercompartment clearance. A bootstrap resampling for internal validation achieved excellent agreement with the original data sets for PK parameters. In conclusion, 2 points of digoxin concentration allow good regression analysis for clearance-covariate relationship. The inclusion of SCR into the final model might allow better selection of initial maintenance dose of the drug. A prospective study on larger sample size of pediatric patients is recommended for clinical validation of the final model.     

Clinical pharmacology of trimetrexate

The clinical pharmacokinetics of trimetrexate were determined in 11 patients during the phase I trial. The plasma drug disappearance curve was triphasic, with a t1/2 alpha of 8 +/- 5 minutes, t1/2 beta of 102 +/- 48 minutes, and t1/2 gamma of 15.2 +/- 5.7 hours. The AUC was 373 +/- 336 (micrograms/ml) hr (normalized to a dose of 200 mg/m2), volume of distribution by the area method (Varea) was 25.2 +/- 16.1 L/m2, total clearance (CL) was 14 +/- 8 ml/min/m2, and renal clearance (CLR) was 8 +/- 6 ml/min/m2. Four patients who received 190 to 200 mg/m2 did not develop severe toxicity. However, three patients who received 120 to 210 mg/m2 developed severe myelosuppression, skin rash, and stomatitis. This latter group had significantly longer terminal half-lives, greater AUCs, smaller Vareas, and lower rates of CL and CLR. One of these patients received an unusually large total amount of trimetrexate (470 mg) because of his obesity. The remaining two patients had renal problems. One developed toxicity despite having received a reduced dose (120 mg/m2) because of impaired renal function. The other patient, with normal renal function, had ascites and had undergone a unilateral nephrectomy for renal carcinoma. These data suggest that prolonged exposure to high trimetrexate levels may lead to increased toxicity. Dosage adjustment may have to be considered for patients who have renal dysfunction.     

Age-related differences in hepatic drug clearance in children: studies with lorazepam and antipyrine

The disposition of intravenous antipyrine and lorazepam, administered as model substrates for hepatic oxidative metabolism and conjugation, was evaluated in 50 children (mean age, 7.8 years; range, 2.3 to 17.8 years) with acute lymphocytic leukemia in complete remission and compared with a group of ten healthy adults. Antipyrine clearance normalized to body weight was significantly greater in children than in adults (0.91 versus 0.59 ml/min/kg; p = 0.012), but was not different when normalized to body surface area. In contrast, lorazepam total clearance (CL) and unbound clearance (CLu) normalized to body weight were not significantly different between children and adults but were smaller in children when normalized to body surface area (CL = 31.9 versus 40.6 ml/min/m2, p = 0.036; CLu = 352 versus 485 ml/min/m2, p = 0.010). The mean lorazepam fraction unbound in children was 0.087, which was not different from adult volunteers (0.084). This study has identified significant differences between children and adults in the disposition of these two compounds, with higher milliliter per minute per kilogram clearance for antipyrine but not lorazepam.     

Pharmacokinetics of the novel cephalosporin cefepime (BMY-28142) in rats and monkeys.

The disposition of the novel cephalosporin cefepime (BMY-28142) was characterized for intravenous administration of single doses to rats and cynomolgus monkeys, the species used most extensively for safety evaluation of the compound. Serial blood samples were collected from individual animals, and plasma was analyzed for intact cefepime by a high-pressure liquid chromatography-UV method. Assay results were evaluated by compartmental and noncompartmental methods to characterize pharmacokinetics for each species and dosage regimen. For intravenous (i.v.) bolus administration of 28 to 386 mg/kg (body weight) to rats, total body clearance (CL; 11.0 ml/min per kg) was essentially invariant with the dose; however, the terminal half-life (t1/2) and the steady-state distribution volume (Vss) increased with increasing dose level. After administration of 87 to 1,502 mg/kg by i.v. infusion, CL (12.5 ml/min per kg) was again similar for all dose groups. Mean t1/2 values (1.3 to 4.6 h) appeared unusually long for a cephalosporin in rats, and inordinately variable. No consistent differences among dose group mean Vss values were found. The maximal concentration of drug in plasma at the end of infusion was not a linear function of dose. For the cynomolgus monkey, kinetic parameters for 5-min i.v. infusions were linearly related to dose over the range of 10 to 600 mg/kg. Mean parameter values were t1/2 = 1.7 h, CL = 1.6 ml/min per kg, and Vss = 0.21 liters/kg. The pharmacokinetic results indicate substantive differences between the two species with respect to their response to toxicologic doses of cefepime.     

Pharmacokinetic disposition of 14C-glyburide in patients with varying renal function

The pharmacokinetics of 14C-labeled glyburide were studied in 13 men with varying degrees of renal impairment. Patients received a single, 5 mg oral dose of glyburide as a solution (10 microCi/ml/mg) after a high-carbohydrate breakfast. Serial plasma and breath samples were collected for 48 hours and urine and feces were collected for 5 to 7 days. Patients with normal to moderately impaired renal function (creatinine clearance [CLCR] of 29 to 131 ml/min/1.7 m2) had glyburide plasma t1/2 values of 2.0 to 5.0 hours, with no relationship between CLCR and glyburide clearance. One subject with severe renal impairment (CLCR = 5 ml/min/1.7 m2) had decreased glyburide clearance that resulted in a t1/2 of 11 hours. The elimination of metabolites was more dependent on renal status but was only significantly affected in the patient with severe renal impairment.     

Development and evaluation of a Bayesian pharmacokinetic estimator and optimal, sparse sampling strategies for ceftazidime.

Data were gathered during an activity-controlled trial in which seriously ill, elderly patients were randomized to receive intravenous ceftazidime or ciprofloxacin and for which adaptive feedback control of drug concentrations in plasma and activity profiles was prospectively performed. The adaptive feedback control algorithm for ceftazidime used an initial population model, a maximum a posteriori (MAP)-Bayesian pharmacokinetic parameter value estimator, and an optimal, sparse sampling strategy for ceftazidime that had been derived from data in the literature obtained from volunteers. Iterative two-stage population pharmacokinetic analysis was performed to develop an unbiased MAP-Bayesian estimator and updated optimal, sparse sampling strategies. The final median values of the population parameters were follows: the volume of distribution of the central compartment was equal to 0.249 liter/kg, the volume of distribution of the peripheral compartment was equal to 0.173 liter/kg, the distributional clearance between the central and peripheral compartments was equal to 0.2251 liter/h/kg, the slope of the total clearance (CL) versus the creatinine clearance (CLCR) was equal to 0.000736 liter/h/kg of CL/1 ml/min/1.73 m2 of CLCR, and nonrenal clearance was equal to + 0.00527 liter/h/kg. Optimal sampling times were dependent on CLCR; for CLCR of > or = 30 ml/min/1.73 m2, the optimal sampling times were 0.583, 3.0, 7.0, and 16.0 h and, for CLCR of < 30 ml/min/1.73 m2, optimal sampling times were 0.583, 4.15, 11.5, and 24.0 h. The study demonstrates that because pharmacokinetic information from volunteers may often not be reflective of specialty populations such as critically ill elderly individuals, iterative two-stage population pharmacokinetic analysis, MAP-Bayesian parameter estimation, and optimal, sparse sampling strategy can be important tools in characterizing their pharmacokinetics.     

Pharmacokinetics of colistin in cerebrospinal fluid after intraventricular administration of colistin methanesulfonate

Intraventricular colistin, administered as colistin methanesulfonate (CMS), is the last resource for the treatment of central nervous system infections caused by panresistant Gram-negative bacteria. The doses and daily regimens vary considerably and are empirically chosen; the cerebrospinal fluid (CSF) pharmacokinetics of colistin after intraventricular administration of CMS has never been characterized. Nine patients (aged 18 to 73 years) were treated with intraventricular CMS (daily doses of 2.61 to 10.44 mg). Colistin concentrations were measured using a selective high-performance liquid chromatography (HPLC) assay. The population pharmacokinetics analysis was performed with the P-Pharm program. The pharmacokinetics of colistin could be best described by the one-compartment model. The estimated values (means ± standard deviations) of apparent CSF total clearance (CL/Fm, where Fm is the unknown fraction of CMS converted to colistin) and terminal half-life (t(1/2λ)) were 0.033 ± 0.014 liter/h and 7.8 ± 3.2 h, respectively, and the average time to the peak concentration was 3.7 ± 0.9 h. A positive correlation between CL/Fm and the amount of CSF drained (range 40 to 300 ml) was observed. When CMS was administered at doses of ≥5.22 mg/day, measured CSF concentrations of colistin were continuously above the MIC of 2 μg/ml, and measured values of trough concentration (C(trough)) ranged between 2.0 and 9.7 μg/ml. Microbiological cure was observed in 8/9 patients. Intraventricular administration of CMS at doses of ≥5.22 mg per day was appropriate in our patients, but since external CSF efflux is variable and can influence the clearance of colistin and its concentrations in CSF, the daily dose of 10 mg suggested by the Infectious Diseases Society of America may be more prudent.     

Single-dose pharmacokinetics of ceftibuten (SCH 39720) in infants and children.

Ceftibuten (CFB), a new broad-spectrum cephalosporin for oral administration, possesses potent activity in vitro against a wide range of gram-negative and certain gram-positive pathogens frequently encountered in pediatric patients. Its antimicrobial spectrum and dosage formulation suggest a use for CFB in the treatment of otitis media and upper and lower respiratory and urinary tract infections in infants and children. To assess the pharmacokinetic characteristics of CFB in pediatric patients, we completed a multicenter investigation of 49 children (26 females) between the ages of 6 months and 17 years who had normal hepatic and renal functions and no evidence of chronic disease. Pharmacokinetic parameters were determined from repeated blood samples (n = 12) and, when possible, quantitative urine collections (n = 7) obtained over a 12- to 24-h period following a single oral CFB dose of either 4.5 or 9.0 mg/kg of body weight. CFB was quantitated from plasma and urine samples by using a sensitive, microanalytical high-pressure liquid chromatography method. The drug was rapidly absorbed (mean time to maximum concentration in serum = 140 min) and produced apparent peak concentrations in plasma (Cmax) ranging from 5.0 to 19.0 mg/liter. Average CFB pharmacokinetic parameters (+/- standard deviations) were as follows: apparent elimination half-life, 2.0 +/- 0.5 h; mean residence time, 3.9 +/- 1.1 h; apparent steady-state volume of distribution, 0.4 +/- 0.2 liter/kg; and apparent total plasma clearance (CL/F), 2.5 +/- 0.9 ml/min/kg. No significant differences in any of the pharmacokinetic parameters were observed between the two dosing groups. Significant (P < 0.05) negative correlations were found between patient age and CFB elimination half-life and CL/F and between the estimated creatinine clearance and renal clearance and CL/F. Apparent age dependence of CFB disposition was also reflected by a greater CL/F in children from 0.5 to less than or equal 5 years of age (3.1 +/- 1.1 ml/min/kg) than in children > 10 years of age (2.0 +/- 0.6 ml/min/kg; P < 0.005). The increased CL/f for CFB (3.0 +/- 0.5 ml/min/kg) was corroborated by a validation study performed with 11 infants (1.0 +/- 0.5 ml/min/kg) with CL/F for 19 subjects suggested that appreciable nonrenal clearance (1.3 +/- 0.6 ml/min/kg) of CFB occurred in children, a finding different from preliminary data for adults.     

Determination of 51Cr-EDTA clearance between 15 and 40 ml/min/1.73 m2 by a single plasma sample

A single-sample method for calculation of 51Cr-EDTA clearance (Cl) between 15 and 40 ml/min/1.73 m2 (ClB) is introduced. It was tested in 109 consecutive patients and compared with a previously published single-sample method for calculation of Cl for Cl greater than or equal to 30 ml/min/1.73 m2 (ClA). When Cl less than 40 ml/min/1.73 m2 the results were more precise when calculated as ClB than when calculated as ClA (p greater than or equal to 0.05). The ClA values were more precise than the ClB values when Cl was greater than or equal to 40 ml/min/1.73 m2 (p less than 0.01). Used in combination (ClA/B) there was a close correlation with Cl (r = 0.98) for the whole range of tested clearance values. It is concluded that Cl can be precisely determined by combined use of the two methods, provided Cl greater than 15 ml/min/1.73 m2 and the single blood-sample is drawn between 240 and 300 min after the injection. If ClA/B less than or equal to 15 ml/min/1.73 m2 it is recommended that a second blood-sample be drawn after 24 h and that Cl is calculated by a conventional slope method.     

Interpatient and intrapatient variability in vinblastine pharmacokinetics

We analyzed interpatient and intrapatient differences in vinblastine pharmacokinetics in 24 patients treated with a bolus dose of vinblastine followed by prolonged (2 to 36 weeks) continuous infusion via an implantable pump. The bolus vinblastine serum clearance was 552 +/- 182 ml/min/m2, with a terminal half-life of 29.2 +/- 11.2 hours. After steady state was achieved (2 weeks), the infusion clearance was 646 +/- 221 ml/min/m2. Interpatient differences in serum albumin levels were correlated with both the bolus clearance (r = 0.49) and the initial (first month) infusion clearance (r = 0.39). The infusion clearance decreased over the duration of the infusion (726 vs. 489 ml/min/m2; P = 0.001;months 1 vs. 4). Analysis of intrapatient changes in vinblastine clearance demonstrated a positive correlation with albumin (P less than 0.01) and negative correlation with dose (P less than 0.05). These results are consistent with a nonlinear pharmacokinetic model. We conclude that interpatient and intrapatient differences in vinblastine pharmacokinetics can be attributed partially to changes in hepatic function and nonlinear elimination at higher doses.     

Population pharmacokinetics of amphotericin B lipid complex in neonates

The pharmacokinetics of amphotericin B lipid complex (ABLC) were investigated in neonates with invasive candidiasis enrolled in a phase II multicenter trial. Sparse blood (153 samples; 1 to 9 per patient, 1 to 254 h after the dose) and random urine and cerebrospinal fluid (CSF) samples of 28 neonates (median weight [WT], 1.06 kg; range, 0.48 to 4.9 kg; median gestational age, 27 weeks; range, 24 to 41 weeks) were analyzed. Patients received intravenous ABLC at 2.5 (n = 15) or 5 (n = 13) mg/kg of body weight once a day over 1 or 2 h, respectively, for a median of 21 days (range, 4 to 47 days). Concentrations of amphotericin B were quantified as total drug by high-performance liquid chromatography. Blood data for time after dose (TAD) of <24 h fitted best to a one-compartment model with an additive-error model for residual variability, WT0.75 (where 0.75 is an exponent) as a covariate of clearance (CL), and WT as a covariate of volume of distribution (V). Prior amphotericin B, postnatal age, and gestational age did not further improve the model. The final model equations were CL (liters/h) = 0.399 x WT(0.75) (interindividual variability, 35%) and V (liters) = 10.5 x WT (interindividual variability, 43%). Noncompartmental analysis of pooled data with a TAD of >24 h revealed a terminal half-life of 395 h. Mean concentrations in the urine after 1, 2, and 3 weeks ranged from 0.082 to 0.430 microg/ml, and those in CSF ranged from undetectable to 0.074 microg/ml. The disposition of ABLC in neonates was similar to that observed in other age groups: weight was the only factor that influenced clearance. Based on these results and previously published safety and efficacy data, we recommend a daily dosage between 2.5 and 5.0 mg/kg for treatment of invasive Candida infections in neonates.     

Plasma and renal clearance of iohexol--a study on the reproducibility of a method for the glomerular filtration rate

The reproducibility of iohexol clearance as a determination of the glomerular filtration rate was assessed in 12 healthy subjects during triplicate constant-rate infusions. Renal and plasma clearance of iohexol demonstrated a total within-subject variation (CV) ranging between 0% and 16%. The inter-individual variation in renal clearance was about 10%, the clearance values being (mean +/- SD) 116 +/- 10, 117 +/- 9 and 110 +/- 12 ml/min 1.73 m2 in the three experiments and corresponding figures for the plasma clearance were 120 +/- 17, 118 +/- 12 and 112 +/- 14 ml/min 1.73 m2. The renal clearance (CLR) and the plasma clearance (CL) showed good correlation (regression equation CL = 11.80 + 0.93 CLR, rs = 0.67). The method is simple and reproducible; thus, it is suitable for both clinical examinations and research.     

Pharmacokinetics and pharmacodynamics of imipenem during continuous renal replacement therapy in critically ill patients

The pharmacokinetics of imipenem were studied in adult intensive care unit (ICU) patients during continuous venovenous hemofiltration (CVVH; n=6 patients) or hemodiafiltration (CVVHDF; n=6 patients). Patients (mean+/-standard deviation age, 50.9+/-15.9 years; weight, 98.5+/-15.9 kg) received imipenem at 0.5 g every 8 to 12 h (total daily doses of 1 to 1.5 g/day) by intravenous infusion over 30 min. Pre- and postmembrane blood (plasma) and corresponding ultrafiltrate or dialysate samples were collected 1, 2, 4, and 8 or 12 h (depending on dosing interval) after completion of the drug infusion. Drug concentrations were measured using validated high-performance liquid chromatography methods. Mean systemic clearance (CL(S)) and elimination half-life (t1/2) of imipenem were 145+/-18 ml/min and 2.7+/-1.3 h during CVVH versus 178+/-18 ml/min and 2.6+/-1.6 h during CVVHDF, respectively. Imipenem clearance was substantially increased during both CVVH and CVVHDF, with membrane clearance representing 25% and 32% of CL(S), respectively. The results of this study indicate that CVVH and CVVHDF contribute to imipenem clearance to a greater degree than previously reported. Imipenem doses of 1.0 g/day appear to achieve concentrations adequate to treat most common gram-negative pathogens (MIC up to 2 microg/ml) during CVVH or CVVHDF, but doses of 2.0 g/day or more may be required to adequately treat and prevent resistance in pathogens with higher MICs (MIC=4 to 8 microg/ml). Higher doses should only be used after consideration of potential central nervous system toxicities or other risks of therapy in these severely ill patients.