Population Modeling Integrating Pharmacokinetics, Pharmacodynamics, Pharmacogenetics, and Clinical Outcome in Patients With Sunitinib-Treated Cancer.

The tyrosine kinase inhibitor sunitinib is used as first-line therapy in patients with metastasized renal cell carcinoma (mRCC), given in fixed-dose regimens despite its high variability in pharmacokinetics (PKs). Interindividual variability of drug exposure may be responsible for differences in response. Therefore, dosing strategies based on pharmacokinetic/pharmacodynamic (PK/PD) models may be useful to optimize treatment. Plasma concentrations of sunitinib, its active metabolite SU12662, and the soluble vascular endothelial growth factor receptors sVEGFR-2 and sVEGFR-3, were measured in 26 patients with mRCC within the EuroTARGET project and 21 patients with metastasized colorectal cancer (mCRC) from the C-II-005 study. Based on these observations, PK/PD models with potential influence of genetic predictors were developed and linked to time-to-event (TTE) models. Baseline sVEGFR-2 levels were associated with clinical outcome in patients with mRCC, whereas active drug PKs seemed to be more predictive in patients with mCRC. The models provide the basis of PK/PD-guided strategies for the individualization of anti-angiogenic therapies.

[Pharmacokinetics and pharmacodynamics of antibiotics in intensive care]. / Pharmakokinetik und Pharmakodynamik von Antibiotika in der Intensivmedizin.

Optimized dosage regimens of antibiotics have remained obscure since their introduction. During the last two decades pharmacokinetic(PK)-pharmacodynamic(PD) relationships, originally established in animal experiments, have been increasingly used in patients. The action of betalactams is believed to be governed by the time the plasma concentration is above the minimum inhibitory concentration (MIC). Aminoglycosides act as planned when the peak concentration is a multiple of the MIC and vancomycin seems to work best when the area under the plasma vs. time curve (AUC) to MIC has a certain ratio. Clinicians should be aware that these relationships can only be an indication in which direction dosing should go. Larger studies with sufficiently high numbers of patients and particularly severely sick patients are needed to prove the concepts. In times where all antibiotics can be measured with new technologies, the introduction of therapeutic drug monitoring (TDM) is suggested for ICUs (Intensive Care Unit). The idea of a central lab for TDM of antibiotics such as PEAK (Paul Ehrlich Antibiotika Konzentrationsmessung) is supported.

Blood, tissue, and intracellular concentrations of azithromycin during and after end of therapy.

Although azithromycin is extensively used in the treatment of respiratory tract infections as well as skin and skin-related infections, pharmacokinetics of azithromycin in extracellular space fluid of soft tissues, i.e., one of its therapeutic target sites, are not yet fully elucidated. In this study, azithromycin concentration-time profiles in extracellular space of muscle and subcutaneous adipose tissue, but also in plasma and white blood cells, were determined at days 1 and 3 of treatment as well as 2 and 7 days after the end of treatment. Of all compartments, azithromycin concentrations were highest in white blood cells, attesting for intracellular accumulation. However, azithromycin concentrations in both soft tissues were markedly lower than in plasma both during and after treatment. Calculation of the area under the concentration-time curve from 0 to 24 h (AUC(0-24))/MIC(90) ratios for selected pathogens suggests that azithromycin concentrations measured in the present study are subinhibitory at all time points in both soft tissues and at the large majority of observed time points in plasma. Hence, it might be speculated that azithromycin's clinical efficacy relies not only on elevated intracellular concentrations but possibly also on its known pleotropic effects, including immunomodulation and influence on bacterial virulence factors. However, prolonged subinhibitory azithromycin concentrations at the target site, as observed in the present study, might favor the emergence of bacterial resistance and should therefore be considered with concern. In conclusion, this study has added important information to the pharmacokinetic profile of the widely used antibiotic drug azithromycin and evidentiates the need for further research on its potential for induction of bacterial resistance.

Blood, tissue, and intracellular concentrations of erythromycin and its metabolite anhydroerythromycin during and after therapy.

For macrolides, clinical activity but also the development of bacterial resistance has been attributed to prolonged therapeutic and subtherapeutic concentrations. Although erythromycin is a long-established antimicrobial, concomitant determination of the pharmacokinetics of erythromycin and its metabolites in different compartments is limited. To better characterize the pharmacokinetics of erythromycin and its anhydrometabolite (anhydroerythromycin [AHE]) in different compartments during and after the end of treatment with 500 mg of erythromycin four times daily, concentration-time profiles were determined in plasma, interstitial space of muscle and subcutaneous adipose tissue, and white blood cells (WBCs) at days 1 and 3 of treatment and 2 and 7 days after end of therapy. In WBCs, concentrations of erythromycin exceeded those in plasma approximately 40-fold, while free concentrations in plasma and tissue were comparable. The observed delay of peak concentrations in tissue might be caused by fast initial cellular uptake. Two days after the end of treatment, subinhibitory concentrations were observed in plasma and interstitial space of both soft tissues, while 7 days after the end of treatment, erythromycin was not detectable in any compartment. This relatively short period of subinhibitory concentrations may be advantageous compared to other macrolides. The ratio of erythromycin over AHE on day 1 was highest in plasma (2.81 ± 3.45) and lowest in WBCs (0.27 ± 0.22). While the ratio remained constant between single dose and steady state, after the end of treatment the concentration of AHE declined more slowly than that of the parent compound, indicating the importance of the metabolite for the prolonged drug interaction of erythromycin.

Comparable population pharmacokinetics and pharmacodynamic breakpoints of cefpirome in cystic fibrosis patients and healthy volunteers.

Cystic fibrosis (CF) patients are often reported to have higher clearances and larger volumes of distribution per kilogram of total body weight (WT) for beta-lactams than healthy volunteers. As pharmacokinetic (PK) data on cefpirome from studies of CF patients are lacking, we systematically compared its population PK and pharmacodynamic breakpoints for CF patients and healthy volunteers of similar body size. Twelve adult CF patients (median lean body mass [LBM] = 45.7 kg) and 12 healthy volunteers (LBM = 50.0 kg) received a single 10-min intravenous infusion of 2 g cefpirome. Plasma and urine concentrations were determined by high-performance liquid chromatography (HPLC). Population PK and Monte Carlo simulations were performed using NONMEM and S-ADAPT and a duration of an unbound plasma concentration above the MIC ≥ 65% of the dosing interval as a pharmacodynamic target. Unscaled clearances for CF patients were similar to those seen with healthy volunteers, and the volume of distribution was 6% lower for CF patients. Linear scaling of total clearance by WT resulted in clearance that was 20% higher (P ≤ 0.001 [nonparametric bootstrap]) in CF patients. Allometric scaling by LBM explained the differences between the two subject groups with respect to average clearance and volume of distribution and reduced the unexplained between-subject variability of renal and nonrenal clearance by 10 to 14%. For the CF patients, robust (>90%) probabilities of target attainment (PTA) were achieved by the administration of a standard dose of 2 g/70 kg WT every 12 h (Q12h) given as 30-min infusions for MICs ≤ 1.5 mg/liter. As alternative dosage regimens, a 5-h infusion of 1.33 g/70 kg WT Q8h achieved robust PTAs for MICs ≤ 8 to 12 mg/liter and a continuous infusion of 4 g/day for MICs ≤ 12 mg/liter. Prolonged infusion of cefpirome is expected to be superior to short-term infusions for MICs between 2 and 12 mg/liter.

Penetration of meropenem into epithelial lining fluid of patients with ventilator-associated pneumonia.

Antibiotic penetration to the infection site is critical for obtaining a good clinical outcome in patients with ventilator-associated pneumonia (VAP). Surprisingly few studies have quantified the penetration of ß-lactam agents into the lung, as measured by the ratio of area under the concentration-time curve (AUC) in epithelial lining fluid (ELF) to AUC in plasma (AUC(ELF)/AUC(plasma) ratio). These have typically involved noninfected patients. This study examines the penetration and pharmacodynamics of meropenem in the ELF among patients with VAP. Meropenem plasma and ELF concentration-time data were obtained from patients in a multicenter clinical trial. Concentration-time profiles in plasma and ELF were simultaneously modeled using a three-compartment model with zero-order infusion and first-order elimination and transfer (big nonparametric adaptive grid [BigNPAG]). A Monte Carlo simulation was performed to estimate the range of ELF/plasma penetration ratios one would expect to observe in patients with VAP, as measured by the AUC(ELF)/AUC(plasma) ratio. The range of AUC(ELF)/AUC(plasma) penetration ratios predicted by the Monte Carlo simulation was large. The 10th percentile of lung penetration was 3.7%, while the 90th percentile of penetration was 178%. The variability of ELF penetration is such that if relatively high ELF exposure targets are required to attain multilog kill or resistance suppression for bacteria like Pseudomonas aeruginosa, then even receiving the largest licensed dose of meropenem with an optimal prolonged infusion may not result in target attainment for a substantial fraction of the population.

Use of an in vitro pharmacodynamic model to derive a moxifloxacin regimen that optimizes kill of Yersinia pestis and prevents emergence of resistance.

Yersinia pestis, the causative agent of bubonic, septicemic, and pneumonic plague, is classified as a CDC category A bioterrorism pathogen. Streptomycin and doxycycline are the "gold standards" for the treatment of plague. However, streptomycin is not available in many countries, and Y. pestis isolates resistant to streptomycin and doxycycline occur naturally and have been generated in laboratories. Moxifloxacin is a fluoroquinolone antibiotic that demonstrates potent activity against Y. pestis in in vitro and animal infection models. However, the dose and frequency of administration of moxifloxacin that would be predicted to optimize treatment efficacy in humans while preventing the emergence of resistance are unknown. Therefore, dose range and dose fractionation studies for moxifloxacin were conducted for Y. pestis in an in vitro pharmacodynamic model in which the half-lives of moxifloxacin in human serum were simulated so as to identify the lowest drug exposure and the schedule of administration that are linked with killing of Y. pestis and with the suppression of resistance. In the dose range studies, simulated moxifloxacin regimens of ≥175 mg/day killed drug-susceptible bacteria without resistance amplification. Dose fractionation studies demonstrated that the AUC (area under the concentration-time curve)/MIC ratio predicted kill of drug-susceptible Y. pestis, while the C(max) (maximum concentration of the drug in serum)/MIC ratio was linked to resistance prevention. Monte Carlo simulations predicted that moxifloxacin at 400 mg/day would successfully treat human infection due to Y. pestis in 99.8% of subjects and would prevent resistance amplification. We conclude that in an in vitro pharmacodynamic model, the clinically prescribed moxifloxacin regimen of 400 mg/day is predicted to be highly effective for the treatment of Y. pestis infections in humans. Studies of moxifloxacin in animal models of plague are warranted.

Pharmacokinetic/pharmacodynamic modeling of biomarker response to sunitinib in healthy volunteers.

A pharmacokinetic/pharmacodynamic (PK/PD) study of the tyrosine kinase inhibitor sunitinib was conducted in 12 healthy volunteers using blood pressure and circulating biomarker levels as PD markers. Blood pressure was measured, and plasma concentration-time courses of sunitinib, its major metabolite SU12662, vascular endothelial growth factors VEGF-A and VEGF-C, and soluble VEGF receptor-2 (sVEGFR-2) were studied in healthy subjects receiving 50 mg of sunitinib orally for 3-5 consecutive days. Using NONMEM, PK/PD models were established that predicted changes (expressed as multiples relative to baseline values) in systolic blood pressure, diastolic blood pressure, VEGF-A level, and sVEGFR-2 level, of 1.10, 1.18, 2.24, and 0.76, respectively, for a typical subject after 4 weeks of treatment with 50 mg/day. Simulated blood pressure-time courses compare excellently with published data in patients, whereas changes in circulating biomarkers were greater in patients than simulations suggest for healthy subjects. In conclusion, the tumor-independent pharmacological response to sunitinib could be described by PK/PD models, thereby facilitating model-based investigations with antiangiogenic drugs, using blood pressure and circulating proteins as biomarkers.

Population pharmacokinetic comparison and pharmacodynamic breakpoints of ceftazidime in cystic fibrosis patients and healthy volunteers.

Despite the promising activity of ceftazidime against Pseudomonas aeruginosa and Burkholderia cepacia, there has not yet been a study that directly compared the pharmacokinetics (PK) of ceftazidime in cystic fibrosis (CF) patients and healthy volunteers by population PK methodology. We assessed the population PK and PK/pharmacodynamic (PD) breakpoints of ceftazidime in CF patients and healthy volunteers. Eight CF patients (total body weight [WT] [average +/- standard deviation] = 42.9 +/- 18.4 kg) and seven healthy volunteers (WT = 66.2 +/- 4.9 kg) received 2 g ceftazidime as a 5-min intravenous infusion. High-performance liquid chromatography (HPLC) was used for drug analysis, and NONMEM (results reported), S-ADAPT, and NPAG were used for parametric and nonparametric population PK modeling. We considered linear and allometric body size models to scale clearance and volume of distribution. Monte Carlo simulations were based on a target time of non-protein-bound plasma concentration of ceftazidime above MIC of > or =65%, which represents near-maximal killing. Unscaled total clearance was 19% lower in CF patients, and volume of distribution was 36% lower. Total clearance was 7.82 liters/h for CF patients and 6.68 liters/h for healthy volunteers with 53 kg fat-free mass. Allometric scaling by fat-free mass reduced the between-subject variability by 32% for clearance and by 18 to 26% for volume of both peripheral compartments compared to linear scaling by WT. A 30-min ceftazidime infusion of 2 g/70 kg WT every 8 h (q8h) achieved robust (> or =90%) probabilities of target attainment (PTAs) for MICs of < or =1 mg/liter in CF patients and < or =3 mg/liter in healthy volunteers. Alternative modes of administration achieved robust PTAs up to markedly higher MICs of < or =8 to 12 mg/liter in CF patients for 5-h infusions of 2 g/70 kg WT q8h and < or =12 mg/liter for continuous infusion of 6 g/70 kg WT daily.

Development of a new G-CSF product based on biosimilarity assessment.

BACKGROUND: Zarzio, a new recombinant human granulocyte colony-stimulating factor (filgrastim), was evaluated in healthy volunteers and neutropenic patients in phase I and III studies. PATIENTS AND METHODS: Healthy volunteers in randomized, two-period crossover studies received single- and multiple-dose s.c. injections of 1 microg/kg (n = 24), 2.5 microg/kg (n = 28), 5 microg/kg (n = 28), or 10 microg/kg (n = 40), as well as single-dose i.v. infusions of 5 microg/kg (n = 26), of Zarzio or the reference product (Neupogen). Filgrastim serum levels were monitored; pharmacodynamic parameters were absolute neutrophil count (all studies) and CD34(+) cells (multiple-dose studies). Supportive efficacy and safety data were obtained from an open phase III study in 170 breast cancer patients undergoing four cycles of doxorubicin and docetaxel (Taxotere) chemotherapy, receiving Zarzio (300 or 480 microg) as primary prophylaxis of severe neutropenia. RESULTS: The results of the studies in healthy volunteers confirm the comparability of the test and reference products with respect to their pharmacodynamics and pharmacokinetics. Confidence intervals were within the predefined equivalence boundaries. In the phase III study in breast cancer patients, the administration of Zarzio was efficacious and safe, triggering no immunogenicity. CONCLUSION: The results of these studies demonstrate the biosimilarity of Zarzio with its reference product Neupogen.

Impact of spore biology on the rate of kill and suppression of resistance in Bacillus anthracis.

Bacillus anthracis is complex because of its spore form. The spore is invulnerable to antibiotic action. It also has an impact on the emergence of resistance. We employed the hollow-fiber infection model to study the impacts of different doses and schedules of moxifloxacin on the total-organism population, the spore population, and the subpopulations of vegetative- and spore-phase organisms that were resistant to moxifloxacin. We then generated a mathematical model of the impact of moxifloxacin, administered by continuous infusion or once daily, on vegetative- and spore-phase organisms. The ratio of the rate constant for vegetative-phase cells going to spore phase (K(vs)) to the rate constant for spore-phase cells going to vegetative phase (K(sv)) determines the rate of organism clearance. The continuous-infusion drug profile is more easily sensed as a threat; the K(vs)/K(sv) ratio increases at lower drug exposures (possibly related to quorum sensing). This movement to spore phase protects the organism but makes the emergence of resistance less likely. Suppression of resistance requires a higher level of drug exposure with once-daily administration than with a continuous infusion, a difference that is related to vegetative-to-spore (and back) transitioning. Spore biology has a major impact on drug therapy and resistance suppression. These findings explain why all drugs of different classes have approximately the same rate of organism clearance for Bacillus anthracis.

New semiphysiological absorption model to assess the pharmacodynamic profile of cefuroxime axetil using nonparametric and parametric population pharmacokinetics.

Cefuroxime axetil is widely used to treat respiratory tract infections. We are not aware of a population pharmacokinetic (PK) model for cefuroxime axetil. Our objectives were to develop a semiphysiological population PK model and evaluate the pharmacodynamic profile for cefuroxime axetil. Twenty-four healthy volunteers received 250 mg oral cefuroxime as a suspension after a standardized breakfast. Liquid chromatography-tandem mass spectrometry was used for drug analysis, NONMEM and S-ADAPT (results reported) were used for parametric population PK modeling, and NPAG was used for nonparametric population PK modeling. Monte Carlo simulations were used to predict the duration for which the non-protein-bound-plasma concentration was above the MIC (fT(>MIC)). A model with one disposition compartment, a saturable and time-dependent drug release from the stomach, and fast drug absorption from the intestine yielded precise (r > 0.992) and unbiased curve fits and an excellent predictive performance. The apparent clearance was 21.7 liters/h (19.8% coefficient of variation [CV]) and the volume of distribution 38.7 liters (18.3% CV). Robust (>or=90%) probabilities of target attainment (PTAs) were achieved by 250 mg cefuroxime given every 12 h (q12h) or q8h for MICs of MIC) of >or=40% and for MICs of MIC) of >or=65%. For the >or=40% fT(>MIC) target, the PTAs for 250 mg cefuroxime q12h were >or=97.8% for Streptococcus pyogenes and penicillin-susceptible Streptococcus pneumoniae. Cefuroxime at 250 mg q12h or q8h achieved PTAs below 73% or 92%, respectively, for Haemophilus influenzae, Moraxella catarrhalis, and penicillin-intermediate S. pneumoniae for susceptibility data from various countries. Depending on the MIC distribution, 250 mg oral cefuroxime q8h instead of q12h should be considered, especially for more-severe infections that require near-maximal killing by cefuroxime.

Biosimilarity of HX575 (human recombinant epoetin alfa) and epoetin beta after multiple subcutaneous administration.

OBJECTIVE: To compare the steady-state pharmacokinetics and pharmacodynamics following multiple subcutaneous administration of a new erythropoiesis stimulating agent (HX575, Binocrit, Sandoz GmbH, Holzkirchen, Germany) with that of epoetin beta (NeoRecormon, Roche Ltd., Welwyn Garden City, UK). METHODS: An open, randomized, parallel group study was conducted in 80 healthy adult males. Subjects were randomized to multiple subcutaneous doses of 100 IU/kg body weight of HX575 or epoetin beta three-times-weekly for 4 weeks. Serum epoetin concentrations were measured using an enzyme-linked immunosorbent assay (ELISA) and pharmacokinetic parameters for the two treatments were compared. The time course and area under the effect curve ratios of hematological characteristics were used as surrogate parameters for efficacy evaluation. RESULTS: The pharmacokinetic profiles after multiple doses were similar for both treatments. HX575 was bioequivalent to epoetin beta with respect to the rate and extent of exposure of exogenous epoetin, as indicated by the ratios (90% confidence intervals) of AUC(tau) (96.1 (86.4 - 106.9)) and C(max,ss) (98.5 (85.2 - 113.9)). The hematological profiles of both treatments were similar as determined from the population mean curves and the AUEC(Hb) ratio (90% confidence interval] (99.2 (97.7 - 100.7)), the primary endpoint of this study. Study medication was well tolerated with no clinically relevant differences between safety profiles of the treatments. Anti-epoetin antibodies were not detected at any time. CONCLUSIONS: HX575 and epoetin beta were bioequivalent with respect to their steady-state pharmacokinetic profile and pharmacodynamic action. These results support the conclusion that HX575 and epoetin beta will be equally efficacious and may be interchangeable as therapy.

Ertapenem clearance during modeled continuous renal replacement therapy.

PURPOSE: To determine ertapenem transmembrane clearance (CLtm) during continuous renal replacement therapy (CRRT) using a validated in vitro model. METHODS: Ertapenem clearance during continuous hemofiltration and hemodialysis was assessed with AN69 and polysulfone hemodiafilters at 4 dialysate (Qd) and ultrafiltration rates (Quf): 1, 2, 3, and 6 l/hour. Blood and dialysate samples were collected at each flow rate and assayed for urea (control solute) and ertapenem concentrations. The experiment was repeated 5 times for each hemodiafilter type. Ertapenem and urea sieving coefficient (SC) and saturation coefficient (SA) were assessed, and CLtm calculated. RESULTS: In continuous hemofiltration mode, urea and ertapenem SC ranged from 1.00 to 1.19 at all Quf and did not differ between hemodiafilter types. Consequently, convective CLtm also did not differ between hemodiafilters. In continuous dialysis mode, urea Cltm did not differ between hemodiafilter types at any Qd. However, ertapenem SA and CLtm were significantly different between hemodiafilter types at Qd 6l/hour (p<0.001). As Qd increased, mean +/- SD AN69 SA declined significantly from 0.87 +/- 0.12 at Qd 1 l/hour to 0.45 +/- 0.02 at Qd 6 l/hour (p<0.001). Ertapenem SA did not differ at any Qd with the polysulfone hemodiafilter (range 0.71-0.80). CONCLUSION: Ertapenem was cleared substantially in these in vitro CRRT models. However, our findings illustrate discordance between our observed SC and SA and the published unbound fraction of ertapenem. This finding has been reported with many other drugs, including carbapenem antibiotics. If in vivo studies corroborate our SA and SC findings, dosage adjustment for patients receiving CRRT will be required.

Bioavailability of amoxicillin and clavulanic acid from extended release tablets depends on intragastric tablet deposition and gastric emptying.

The rate and extent of amoxicillin and clavulanic acid absorption from pharmacokinetically enhanced extended release (ER) tablets is strongly influenced by the intake conditions. In order to investigate the cause of the food effects, a pharmacokinetic study with simultaneous imaging of the in vivo behaviour of the ER tablets by magnetic marker monitoring (MMM) was performed. Under fasting conditions the amoxicillin AUC (1854+/-280microg min ml(-1)) was significantly lower than after intake at the beginning of the breakfast (2452+/-354microg min ml(-1)) or after the breakfast (2605+/-446microg min ml(-1)). In contrast, clavulanic acid AUC was well comparable after tablet intake under fasting conditions and intake at the beginning of a breakfast (191+/-46 and 189+/-44microg min ml(-1), respectively) but significantly lower following a breakfast (126+/-71microg min ml(-1)). The localization data showed that the reduced bioavailability of amoxicillin under fasting conditions is due to early gastric emptying in combination with poor absorption from deeper parts of the small intestine. Prolonged gastric residence of clavulanic acid caused by intragastric tablet deposition in the proximal stomach was identified as the reason for the decreased bioavailability of clavulanic acid after tablet intake following the meal.

Use of an in vitro pharmacodynamic model to derive a linezolid regimen that optimizes bacterial kill and prevents emergence of resistance in Bacillus anthracis.

Simulating the average non-protein-bound (free) human serum drug concentration-time profiles for linezolid in an in vitro pharmacodynamic model, we characterized the pharmacodynamic parameter(s) of linezolid predictive of kill and for prevention of resistance in Bacillus anthracis. In 10-day dose-ranging studies, the average exposure for > or =700 mg of linezolid given once daily (QD) resulted in >3-log CFU/ml declines in B. anthracis without resistance selection. Linezolid at < or =600 mg QD amplified for resistance. With twice-daily (q12h) dosing, linezolid at > or =500 mg q12 h was required for resistance prevention. In dose fractionation studies, killing of B. anthracis was predicted by the area under the time-concentration curve (AUC)/MIC ratio. However, resistance prevention was linked to the maximum serum drug concentration (C(max))/MIC ratio. Monte Carlo simulations predicted that linezolid at 1,100 mg QD would produce in 96.7% of human subjects a free 24-h AUC that would match or exceed the average 24-h AUC of 78.5 mg x h/liter generated by linezolid at 700 mg QD while reproducing the shape of the concentration-time profile for this pharmacodynamically optimized regimen. However, linezolid at 700 mg q12h (cumulative daily dose of 1,400 mg) would produce an exposure that would equal or exceed the average free 24-h AUC of 90 mg x h/liter generated by linezolid at 500 mg q12h in 93.8% of human subjects. In conclusion, in our in vitro studies, the QD-administered, pharmacodynamically optimized regimen for linezolid killed drug-susceptible B. anthracis and prevented resistance emergence at lower dosages than q12h regimens. The lower dosage for the pharmacodynamically optimized regimen may decrease drug toxicity. Also, the QD administration schedule may improve patient compliance.

Pharmacodynamics of ceftazidime and meropenem in cerebrospinal fluid: results of population pharmacokinetic modelling and Monte Carlo simulation.

BACKGROUND: Ceftazidime and meropenem are frequently used in the empirical treatment of hospital-acquired cerebrospinal fluid (CSF) infections. Although their dispositions in CSF have been described, the ability of these agents to achieve critical pharmacodynamic targets against the array of nosocomial CSF Gram-negative bacteria encountered in practice has not been reported. METHODS: Serum and CSF pharmacokinetic data were obtained from hospital patients with external ventricular drains and who received ceftazidime or meropenem. Concentration-time profiles in serum and CSF were modelled using a three-compartment model with zero-order infusion and first-order elimination and transfer. The model parameters were identified using population pharmacokinetic analysis [Big Non-Parametric Adaptive Grid (BigNPAG)]. A Monte Carlo simulation (9999 subjects) estimated the probability of target attainment (PTA) for total drug CSF concentrations at 50% and 100% T(>MIC) for ceftazidime 2 g intravenously every 8 h and meropenem 2 g intravenously every 8 h. The Gram-negative infection isolates of the seven most prevalent Gram-negative bacilli from the Meropenem Yearly Susceptibility Test Information Collection Program were used as a measure of contemporary MIC distribution. RESULTS: Post-Bayesian measures of bias and precision, observed-predicted plots and R(2) values were highly acceptable for both drugs. Although the PTA in CSF was approximately one dilution higher for ceftazidime compared with meropenem at a given MIC value, the cumulative fraction of response (CFR) in CSF against all Gram-negatives was markedly higher for meropenem when compared with ceftazidime secondary to the higher occurrence of lower MIC values for meropenem. Both agents had a low CFR against Pseudomonas aeruginosa. CONCLUSIONS: The pharmacodynamics of meropenem was superior to that of ceftazidime against Gram-negative pathogens in the CSF.

Systematic comparison of the population pharmacokinetics and pharmacodynamics of piperacillin in cystic fibrosis patients and healthy volunteers.

Respiratory tract infections cause 90% of premature mortality in patients with cystic fibrosis (CF). Treatment of Pseudomonas aeruginosa infection is often very problematic. Piperacillin-tazobactam has good activity against P. aeruginosa, but its pharmacokinetics (PK) in CF patients has not been compared to the PK in healthy volunteers in a controlled clinical study. Therefore, we compared the population PK and pharmacodynamics (PD) of piperacillin between CF patients and healthy volunteers. We studied 8 adult (median age, 20 years) CF patients (average total body weight [WT], 43.1 +/- 7.8 kg) and 26 healthy volunteers (WT, 71.1 +/- 11.8 kg) who each received 4 g piperacillin as a 5-min intravenous infusion. We determined piperacillin levels by high-performance liquid chromatography, and we used NONMEM for population PK and Monte Carlo simulation. We used a target time of nonprotein-bound concentration above the MIC of 50%, which represents near-maximal bacterial killing. Unscaled total clearance was 25% lower, and the volume of distribution was 31% lower in CF patients. Allometric scaling by lean body mass reduced the unexplained (random) between-subject variability in clearance by 26% compared to the variability of linear scaling by WT. A standard dosage regimen of 3 g/70 kg body WT every 4 h as a 30-min infusion (daily dose, 18 g) achieved a robust (> or =90%) probability-of-target attainment (PTA) for MICs of < or =12 mg/liter in CF patients and < or =16 mg/liter in healthy volunteers. Alternative modes of administration allowed a marked dose reduction to 9 g daily. Prolonged (4-h) infusions of 3 g/70 kg WT every 8 h and continuous infusion (daily dose, 9 g), achieved a robust PTA for MICs of < or =16 mg/liter in both groups. Piperacillin achieved PTA expectation values of 64% and 89% against P. aeruginosa infection in CF patients, based on susceptibility data from two German CF clinics.