Real-world utilization of ceftazidime/avibactam among inpatients in the national Veterans Affairs Healthcare System.

PURPOSE: Multidrug-resistant (MDR) infections are challenging to treat due to underlying patient conditions, pathogen characteristics, and high antibiotic resistance rates. As newer antibiotic therapies come to market, limited data exist about their real-world utilization. METHODS: This was a national retrospective cohort study of ceftazidime/avibactam (approved in 2015) utilization among inpatients from the Veterans Affairs (VA) Healthcare System, from 2015 through 2021. Joinpoint regression was used to estimate time trends in utilization. RESULTS: Ceftazidime/avibactam use increased by 52.3% each year (days of therapy per 1,000 bed days; 95% confidence interval, 12.4%-106.4%). We identified 1,048 unique predominantly male (98.3%) and white (66.2%; Black, 27.7%) patients treated with ceftazidime/avibactam, with a mean (SD) age of 71.5 (11.9) years. The most commonly isolated organisms were Pseudomonas aeruginosa (36.3%; carbapenem resistant, 80.6%; MDR, 65.0%) and Klebsiella species (34.1%; carbapenem resistant, 78.4%; extended-spectrum cephalosporin resistant, 90.7%). Common comorbid conditions included hypertension (74.8%), nervous system disorders (60.2%), diabetes mellitus (48.7%), and cancer (45.1%). Median time to ceftazidime/avibactam initiation from admission was 6 days, with a median of 3 changes in therapy before ceftazidime/avibactam initiation and a subsequent median length of inpatient stay of 14 days (median of 8 days of ceftazidime/avibactam therapy). Treatment heterogeneity was high, both before ceftazidime/avibactam initiation (89.6%) and during ceftazidime/avibactam treatment (85.6%), and common concomitant antibiotics included vancomycin (41.4%), meropenem (24.1%), cefepime (15.2%), and piperacillin/tazobactam (15.2%). The inpatient mortality rate was 23.6%, and 20.8% of patients had a subsequent admission with ceftazidime/avibactam treatment. CONCLUSION: Utilization of ceftazidime/avibactam increased from 2015 to 2021 in the national VA Healthcare System. Ceftazidime/avibactam was utilized in complex, difficult-to-treat patients, with substantial treatment heterogeneity and variation in the causative organism and culture sites.

Population Pharmacokinetic and Pharmacokinetic/Pharmacodynamic Target Attainment Analyses for Dalbavancin in Pediatric Patients.

BACKGROUND: Dalbavancin, approved for the treatment of pediatric and adult patients with acute bacterial skin and skin structure infections, has a terminal half-life of >14 days allowing administration as a single-dose regimen. METHODS: We developed a population pharmacokinetic (PK) model using 1124 dalbavancin concentrations from 211 pediatric patients, with allometric scaling of clearance and volume parameter exponents fixed at 0.75 and 1, respectively. Serum albumin was included as a covariate on all PK parameters; creatinine clearance or estimated glomerular filtration rate was a covariate on clearance. The final model, qualified by visual predictive checks and bootstrapping, was used to simulate 1000 PK profiles for a range of pediatric age groups. PK/pharmacodynamic target attainment (PTA) was calculated for targets associated with stasis, 1-log kill, and 2-log kill of Staphylococcus aureus (neutropenic murine thigh infection model). RESULTS: Dalbavancin PK was well characterized by a three-compartment model. No additional significant covariates were identified. Simulations showed that single-dose (30-minute intravenous infusion) regimens of 22.5 mg/kg (patients <6 years) and 18 mg/kg (patients 6 years to <18 years) resulted in PTA ≥94% for minimal inhibitory concentrations ≤2 mg/L and ≤0.5 mg/L for the stasis and 2-log kill targets, respectively. PTA for pediatric patients was similar to adults with exposures within the range for adults administered 1500 mg dalbavancin. CONCLUSION: Dalbavancin PK in pediatric patients was well characterized by a three-compartment model. Simulations with the final model demonstrated adequate PTA across the entire age range for the approved pediatric dalbavancin doses.

The Safety and Efficacy of Dalbavancin and Active Comparator in Pediatric Patients With Acute Bacterial Skin and Skin Structure Infections.

BACKGROUND: Acute bacterial skin and skin structure infections (ABSSSIs) are a significant source of morbidity in children. Dalbavancin, approved for the treatment of adults and children with ABSSSI, has a well-established safety profile in adults. We report safety and descriptive efficacy data for the treatment of ABSSSI in children. METHODS: Children with ABSSSI (birth-<18 years old) or sepsis (<3 months old) known/suspected to be caused by susceptible Gram-positive organisms were enrolled in this phase 3, multicenter, open-label, comparator-controlled study (NCT02814916). Children ≥3 months old were randomized 3:3:1 to receive single-dose dalbavancin, 2-dose dalbavancin, or a comparator antibiotic in 4 age cohorts; those <3 months old received single-dose dalbavancin. Clinical response and microbiologic efficacy were evaluated 48-72 hours and 14, 28 and 54 days posttreatment. Bowel flora testing and audiology were collected in a subset of patients at baseline and day 28. Adverse events (AEs) were collected throughout the study. RESULTS: Treatment-emergent AEs occurred in 7.2%, 9.0% and 3.3% of patients in dalbavancin single-dose, dalbavancin 2-dose and comparator arms, respectively. Three serious AEs occurred in the dalbavancin single-dose arm; no treatment-related AEs, serious AEs, or AEs leading to study discontinuation were reported. Favorable clinical response at 48-72 hours was documented in 97.4%, 98.6% and 89.7% of patients. Safety and efficacy were comparable across age cohorts. The microbiologic intent-to-treat population had comparable clinical response for all baseline pathogens, including methicillin-resistant Staphylococcus aureus . CONCLUSION: The safety profile of dalbavancin was consistent in children and adults with ABSSSI. No new safety signals were identified.

Pharmacokinetic and Pharmacodynamic Target Attainment in Adult and Pediatric Patients Following Administration of Ceftaroline Fosamil as a 5-Minute Infusion.

The key pharmacokinetic/pharmacodynamic (PK/PD) efficacy index for ß-lactam antibiotics is the percentage of time that free drug concentrations exceed the minimum inhibitory concentration (MIC) of bacteria during each dosing interval (fT>MIC). Ceftaroline fosamil, the prodrug of the ß-lactam ceftaroline, was initially approved for administration as 60-minute intravenous (IV) infusions. Population PK analyses comparing exposure and PK/PD target attainment for 5-minute and 60-minute IV infusions, described here, have supported ceftaroline fosamil labeling updates to include variable infusion durations of 5 to 60 minutes in adults and children aged ≥2 months. A 2-compartment disposition PK model for ceftaroline fosamil and ceftaroline was used to predict steady-state ceftaroline exposures (maximum plasma concentrations [Cmax,ss ] and area under the plasma concentration-time curve over 24 hours [AUCss,0-24 ]) and probability of target attainment in simulated adult and pediatric patients with various degrees of renal function receiving standard doses of ceftaroline fosamil as 5-minute or 60-minute IV infusions. Across age groups and renal function categories, median ceftaroline AUCss,0-24 values were similar for 5-minute and 60-minute infusions, whereas Cmax,ss was up to 42% higher for 5-minute infusions. Both infusion durations achieved >99% probability of target attainment based on PK/PD targets for Staphylococcus aureus (35% fT>MIC) and Streptococcus pneumoniae (44% fT>MIC) at European Committee on Antimicrobial Susceptibility Testing/Clinical and Laboratory Standards Institute MIC breakpoints (1 mg/L and 0.25/0.5 mg/L, respectively). These findings support administration of standard ceftaroline fosamil doses over 5 to 60 minutes for adults and children aged ≥2 months, providing added flexibility to clinicians and patients.

Population PK Modeling and Target Attainment Simulations to Support Dosing of Ceftaroline Fosamil in Pediatric Patients With Acute Bacterial Skin and Skin Structure Infections and Community-Acquired Bacterial Pneumonia.

Ceftaroline, the active form of the prodrug ceftaroline fosamil, is approved for use in adults with community-acquired bacterial pneumonia (CABP) or acute bacterial skin and skin structure infections (ABSSSI) in the United States and for similar indications in Europe. Pharmacokinetic (PK) data from 5 pediatric (birth to <18 years) studies of ceftaroline fosamil were combined with PK data from adults to update a population PK model for ceftaroline and ceftaroline fosamil. This model, based on a data set including 305 children, was used to conduct simulations to estimate ceftaroline exposures and percentage of time that free drug concentrations were above the minimum inhibitory concentration (%fT>MIC) for pediatric dose regimens. With dose regimens of 8 mg/kg every 8 hours (q8h) in children aged 2 months to <2 years and 12 mg/kg (up to a maximum of 400 mg) q8h in children aged 2 years to <18 years or 600 mg q12h in children aged 12 to <18 years, >90% of children were predicted to achieve a target of 36% fT>MIC at an MIC of 2 mg/L, and >97% were predicted to achieve 44% fT>MIC at an MIC of 1 mg/L. Thus, high PK/pharmacodynamic target attainment would be maintained in children for targets associated with 1-log kill of Staphylococcus aureus and Streptococcus pneumoniae. The predicted ceftaroline exposures for these dose regimens were similar to those in adults given 600 mg q12h ceftaroline fosamil. This work contributed to the approval of dose regimens for children aged 2 months to <18 years by the FDA and EMA, which are presented.

Penetration of Ceftaroline into the Epithelial Lining Fluid of Healthy Adult Subjects.

Ceftaroline, the active metabolite of the prodrug ceftaroline fosamil, is a cephalosporin with bactericidal activity against Gram-positive organisms, including methicillin-resistant Staphylococcus aureus (MRSA). This study aimed to (i) evaluate ceftaroline concentrations in human plasma and epithelial lining fluid (ELF) and (ii) develop a population pharmacokinetic (PK) model for plasma and ELF to be used in PK/pharmacodynamic (PD) target attainment simulations. Ceftaroline concentrations in ELF and plasma at steady state (day 4) were measured in healthy adult subjects for two dosages: 600 mg every 12 h (q12h) and 600 mg every 8 h (q8h). Both were well tolerated with no serious adverse events. The penetration of free ceftaroline into ELF, assuming 20% protein binding in plasma and no protein binding in ELF, was ≈23%. The population PK model utilized a two-compartment model for both ceftaroline fosamil and ceftaroline. Goodness-of-fit criteria revealed the model was consistent with observed data and no systematic bias remained. At 600 mg q12h and a MIC of 1 mg/liter, 98.1% of simulated patients would be expected to achieve a target free drug concentration above the MIC (fT>MIC) in plasma of 42%, and in ELF 81.7% would be expected to achieve a target fT>MIC of 17%; at 600 mg q8h, 100% were predicted to achieve an fT>MIC in plasma of 42% and 94.7% to achieve an fT>MIC of 17% in ELF. The literature and data suggest the 600 mg q12h dose is adequate for MICs of ≤1 mg/liter. There is a need for clinical data in patients with MRSA pneumonia and data to correlate PK/PD relationships in ELF with clinical outcomes.

Ceftazidime-avibactam for the treatment of complicated urinary tract infections and complicated intra-abdominal infections.

Treatment of complicated urinary tract infections and complicated intra-abdominal infections is increasingly difficult due to the rising prevalence of multidrug-resistant Gram-negative bacteria. Ceftazidime-avibactam is a combination of the established third-generation cephalosporin ceftazidime with avibactam, a novel non-ß-lactam ß-lactamase inhibitor, which restores the activity of ceftazidime against many ß-lactamase-producing Gram-negative bacteria, including extended-spectrum ß-lactamases and Klebsiella pneumoniae carbapenemases. Clinical and nonclinical studies supporting the safety and efficacy of ceftazidime-avibactam include microbiological surveillance studies of clinically relevant pathogens, in vivo animal models of infection, pharmacokinetic/pharmacodynamic target attainment analyses, Phase I clinical pharmacology studies, and Phase II/III studies in the treatment of complicated intra-abdominal infections and complicated urinary tract infections, including patients with ceftazidime-nonsusceptible Gram-negative infections.

Pharmacokinetic-pharmacodynamic analysis for efficacy of ceftaroline fosamil in patients with acute bacterial skin and skin structure infections.

Ceftaroline is a cephalosporin with broad-spectrum in vitro activity against pathogens commonly associated with acute bacterial skin and skin structure infections (ABSSSI), including methicillin-resistant Staphylococcus aureus. Ceftaroline fosamil, the prodrug of ceftaroline, is approved for the treatment of patients with ABSSSI. Using data from the microbiologically evaluable population from two phase 2 and two phase 3 randomized, multicenter, double-blind studies of patients with ABSSSI, an analysis examining the relationship between drug exposure, as measured by the percentage of time during the dosing interval that free-drug steady-state concentrations remain above the MIC (f%T>MIC), and clinical and microbiological responses was undertaken. The analysis population included 526 patients, of whom 423 had infections associated with S. aureus. Clinical and microbiological success percentages were 94.7 and 94.5%, respectively, among all of the patients and 95.3 and 95.7%, respectively, among those with S. aureus infections. Univariable analysis based on data from all of the patients and those with S. aureus infections demonstrated significant relationships between f%T>MIC and microbiological response (P < 0.001 and P = 0.026, respectively). Multivariable logistic regression analyses demonstrated other patient factors in addition to f%T>MIC to be significant predictors of microbiological response, including age and infection type for all of the patients evaluated and age, infection type, and the presence of diabetes mellitus for patients with S. aureus infections. Results of these analyses confirm that a ceftaroline fosamil dosing regimen of 600 mg every 12 h provides exposures associated with the upper plateau of the pharmacokinetic-pharmacodynamic relationship for efficacy.

Pharmacokinetic-pharmacodynamic target attainment analyses to evaluate in vitro susceptibility test interpretive criteria for ceftaroline against Staphylococcus aureus and Streptococcus pneumoniae.

To provide support for in vitro susceptibility test interpretive criteria decisions for ceftaroline against Staphylococcus aureus and Streptococcus pneumoniae, as well as dose adjustment recommendations for renal impairment, pharmacokinetic-pharmacodynamic (PK-PD) target attainment was evaluated for simulated patients administered intravenous (i.v.) ceftaroline fosamil at 600 mg twice daily (q12h) and simulated patients with renal impairment administered various dosing regimens. Using a previously developed population PK model, Monte Carlo simulation was used to generate ceftaroline plasma concentration profiles for simulated patients with normal renal function or mild, moderate, or severe renal impairment. Using these profiles, the percentage of time during the dosing interval that free-drug concentrations remained above the MIC (f%T>MIC) for ceftaroline at steady state was calculated. Percentages of simulated patients achieving f %T>MIC targets for S. aureus and S. pneumoniae based on murine infection models were calculated by MIC. At MICs of 2 mg/liter for S. aureus and 1 mg/liter for S. pneumoniae, the percentages of simulated patients with normal renal function and mild renal impairment following administration of ceftaroline fosamil at 600 mg q12h, moderate renal impairment following administration of ceftaroline fosamil at 400 mg q12h, and severe renal impairment following administration of ceftaroline fosamil at 300 mg q12h achieving f %T>MIC targets (≥26 for S. aureus and ≥44 for S. pneumoniae) exceeded 90%. The results of these analyses, which suggested that in vitro susceptibility test interpretive criteria defining susceptible could be as high as MICs of ≤2 and ≤1 mg/liter for ceftaroline against S. aureus and S. pneumoniae, respectively, provide support for current FDA and CLSI criteria, which define susceptible as MICs of 1 and 0.5 mg/liter, respectively. Recommendations for dose adjustments for patients with renal impairment were also supported by the results of these analyses.

Pharmacokinetic-pharmacodynamic analyses for efficacy of ceftaroline fosamil in patients with community-acquired bacterial pneumonia.

Pharmacokinetic-pharmacodynamic (PK-PD) analyses for efficacy using phase III trial data from patients treated with a ceftaroline fosamil dosing regimen of 600 mg intravenously (i.v.) every 12 h (q12h) for 5 to 7 days for community-acquired bacterial pneumonia (CABP) were conducted. High clinical and microbiological success rates (84.7 and 86.3%, respectively) and percentages of time during the dosing interval that free-drug steady-state concentrations remained above the MIC (f%T>MIC) (98.4% had f%T>MIC values of ≥63.3) were observed among 124 microbiologically evaluable patients. As a result, significant PK-PD relationships could not be identified. These data provide support for the use of a ceftaroline fosamil dosing regimen of 600 mg i.v. q12h to treat patients with CABP.

Evaluation of the effect of a supratherapeutic dose of intravenous ceftaroline fosamil on the corrected QT interval.

A randomized, double-blind, placebo-controlled, 3-period crossover study was conducted in 54 healthy adults to assess the effect of ceftaroline fosamil on the corrected QT (QTc) interval. The QT interval, corrected for heart rate using an individual correction formula (QTcIb), was determined predose and at 1, 1.25, 1.5, 2, 4, 8, 12, and 24.5 h after intravenous dosing with a supratherapeutic dose (1,500 mg) of ceftaroline fosamil, 400 mg moxifloxacin (positive control), and placebo. The pharmacokinetic profile of ceftaroline was also evaluated. At each time point following ceftaroline fosamil administration, the upper limit of the 90% confidence interval (CI) for the placebo-corrected change from predose baseline in QTcIb (ΔΔQTcIb) was below 10 ms (maximum, 3.4 ms at 1.5 h after dosing), indicating an absence of clinically meaningful QTc increase. The lower limit of the 90% CI of ΔΔQTcIb for moxifloxacin versus placebo was greater than 5 ms at 5 time points (maximum, 12.8 ms at 1 h after dosing), demonstrating assay sensitivity. There was no apparent correlation between ceftaroline plasma concentrations and ΔΔQTcIb. The supratherapeutic dose of ceftaroline fosamil (1,500 mg) resulted in substantially greater systemic exposure to ceftaroline than previously observed with standard therapeutic doses. Ceftaroline fosamil was well tolerated after a single 1,500-mg intravenous dose, and no clinically meaningful abnormalities in laboratory values or vital signs were observed.

Single- and multiple-dose study to determine the safety, tolerability, and pharmacokinetics of ceftaroline fosamil in combination with avibactam in healthy subjects.

This study was conducted to determine the safety, tolerability, and pharmacokinetics of intravenous doses of ceftaroline fosamil administered in combination with the novel non-ß-lactam ß-lactamase inhibitor avibactam in healthy adults. In the single-dose, open-label arm, 12 subjects received single 1-h intravenous infusions of ceftaroline fosamil alone (600 mg), avibactam alone (600 mg), and ceftaroline fosamil in combination with avibactam (600/600 mg) separated by 5-day washout periods. In the multiple-dose, placebo-controlled, double-blind arm, 48 subjects received intravenous infusions of ceftaroline fosamil/avibactam at 600/600 mg every 12 h (q12h), 400/400 mg q8h, 900/900 mg q12h, 600/600 mg q8h, or placebo for 10 days. Ceftaroline and avibactam levels in plasma and urine were measured by liquid chromatography coupled with tandem mass spectrometry. No significant differences in systemic exposure of ceftaroline or avibactam were observed when the drugs were administered alone versus concomitantly, indicating that there was no apparent pharmacokinetic interaction between ceftaroline fosamil and avibactam administered as a single dose. No appreciable accumulation of either drug occurred with multiple intravenous doses of ceftaroline fosamil/avibactam, and pharmacokinetic parameters for ceftaroline and avibactam were similar on days 1 and 10. Infusions of ceftaroline fosamil/avibactam were well tolerated at total daily doses of up to 1,800 mg of each compound, and all adverse events (AEs) were mild to moderate in severity. Infusion-site reactions were the most common AEs reported with multiple dosing. The pharmacokinetic and safety profiles of ceftaroline fosamil/avibactam demonstrate that the 2 drugs can be administered concomitantly to provide an important broad-spectrum antimicrobial treatment option.

Ceftaroline fosamil: a novel broad-spectrum cephalosporin with expanded anti-Gram-positive activity.

Ceftaroline fosamil is a novel cephalosporin with broad-spectrum activity against Gram-positive pathogens, including methicillin-resistant Staphylococcus aureus (MRSA) and multidrug-resistant Streptococcus pneumoniae, and common Gram-negative organisms. The activity of ceftaroline against MRSA is attributed to its ability to bind to penicillin-binding protein (PBP) 2a with high affinity and inhibit the biochemical activity of PBP 2a more efficiently than other presently available ß-lactams. The activity of ceftaroline against MRSA and the ß-haemolytic streptococci makes it an attractive monotherapy agent for the treatment of complicated skin and skin structure infections (cSSSIs). Recent profiling and surveillance studies have shown that ceftaroline is active against contemporary skin pathogens collected from US and European medical centres in 2008. The mean free drug %T  >  MIC (percentage of time the drug concentration remains above the MIC) needed for stasis ranged from 26% for S. aureus to 39% for S. pneumoniae in the murine thigh infection model. Pharmacokinetic and pharmacodynamic target attainment predictions for 600 mg of ceftaroline fosamil every 12 h showed that the mean %T  >  MICs for which plasma free-drug concentrations exceeded an MIC of 1 and 2 mg/L were 71% and 51% of the dosing interval, respectively. For a 40% T  >  MIC target, the predicted attainments for infections due to pathogens for which ceftaroline MICs were 1 or 2 mg/L were 100% and 90%, respectively. Clinical and microbiological successes of ceftaroline fosamil in treating cSSSIs were demonstrated in two Phase III clinical studies, in which 96.8% of all baseline cSSSI isolates from the microbiologically evaluable population were inhibited by ceftaroline at ≤ 2 mg/L. Ceftaroline fosamil is a promising broad-spectrum agent for the treatment of cSSSIs.

Rapid and specific targeting of 125I-labeled B lymphocyte stimulator to lymphoid tissues and B cell tumors in mice.

UNLABELLED: B lymphocyte stimulator (BLyS) protein is a member of the tumor necrosis factor (TNF) superfamily of cytokines that binds to B lineage cells, but not T cells, monocytes, natural killer cells, or granulocytes. BLyS protein binding to B cells is restricted to immunoglobulin-positive cells and is not evident on pro- or pre-B cell populations. This unique binding profile suggests that a radiolabeled form of BLyS protein may be a useful treatment for B cell neoplasias such as B cell lymphoma and multiple myeloma. Here, we report the biodistribution of radiolabeled recombinant human BLyS after intravenous injection into normal mice and mice bearing BCL1 tumor in the spleen or J558 tumor in the subcutaneous space. We also report the use of these data to estimate human dosimetry. METHODS: (125)I-Labeled BLyS protein (50 micro g/kg, 0.185-0.37 MBq per mouse) was injected intravenously into BALB/c mice, and biodistribution was measured by direct counting of radioactivity in dissected tissues and by quantitative whole-body autoradiography (QWBA). RESULTS: The half-life of radiolabeled BLyS protein in blood was approximately 2.7 h in both normal and tumor-bearing mice. The spleen showed the highest uptake of BLyS protein in both normal and tumor-bearing mice, with a maximum concentration (C(max)) of 35-45 percentage injected dose per gram (%ID/g) occurring between 1 and 3 h after injection. In lymph nodes, C(max) was approximately 20 %ID/g in normal and J558 tumor-bearing mice and 8-15 %ID/g in BCL1 tumor-bearing mice. Limited biodistribution data from the J558 tumors showed a C(max) of approximately 15 %ID/g. By contrast, C(max) was only approximately 5 %ID/g for both kidney and liver. QWBA confirmed high radioactivity in spleen, lymph nodes, and stomach contents and low radioactivity in kidney and liver. After 24 h, spleen and lymph nodes were still positive in QWBA images, whereas liver and kidney no longer had observable levels. CONCLUSION: Radiolabeled BLyS showed specific and rapid targeting to lymphoid tissues and B cell tumors in mice. Unlike monoclonal antibodies, which have long plasma half-lives and considerable liver uptake, BLyS has distinct pharmacokinetic and biodistribution properties that may offer advantages compared with antibody-based radioimmunotherapy.

Albugranin, a recombinant human granulocyte colony stimulating factor (G-CSF) genetically fused to recombinant human albumin induces prolonged myelopoietic effects in mice and monkeys.

PURPOSE: Albugranin fusion protein is recombinant granulocyte colony stimulating factor (rG-CSF) genetically fused at its N-terminus to the C-terminus of recombinant serum human albumin and is expected to have a relatively long half-life compared with rG-CSF alone. In this study, the pharmacodynamics and pharmacokinetics of Albugranin were evaluated in BDF1 mice and cynomolgus monkeys. METHODS: Single doses of Albugranin (0.25-5 mg/kg) or Filgrastim (methionyl rG-CSF, 0.25, or 1.25 mg/kg) were administered subcutaneously (SC) to mice and multiple doses of Albugranin (25-100 microg/kg every 4 or 7 days) or Filgrastim (5 microg/kg daily) were administered SC for 14 days to monkeys for hematologic evaluation. For pharmacokinetics studies, mice were injected intravenously (IV) or SC with single doses of Albugranin (0.25-1.25 mg/kg) or Filgrastim (0.25 mg/ kg) and monkeys were injected SC with multiple doses of Albugranin (100-1,000 microg/kg once weekly for 5 weeks). Plasma levels of Albugranin and Filgrastim were measured by enzyme-linked immunosorbent assay. RESULTS: In mice, administration of Albugranin effectively increased the number of peripheral granulocytes and mobilized hematopoietic progenitor cells for up to 5 days. The magnitude and duration of this effect were dose-dependent. In contrast, administration of Filgrastim resulted in a small increase in both cell types on day 1 only. Albugranin administered to cynomolgus monkeys caused an increase in peripheral neutrophils, with a less prominent increase in peripheral monocytes. Albugranin-induced neutrophilia peaked 24 h following each dose administration. Administration of Filgrastim daily in monkeys resulted in moderate increases in neutrophils that were maximal on days 8-12 during the course of treatment. Compared with Filgrastim, Albugranin had a longer terminal half-life (t(1/2,term)) and mean residence time (MRT), and slower clearance (CL/F) in mice. The t(1/2,term), MRT, and CL/F of Albugranin following SC administration to BDF1 mice were 5.6-5.7 h, 16.7-20.7 h, and 6.37-12.2 mL/h/kg, respectively, compared with 2.54 h, 4.9 h, and 164 mL/h/kg, respectively for Filgrastim. In cynomolgus monkeys, the corresponding values of t(1/2,term), MRT, and CL/F for Albugranin were 7.73-133 h, 19.4-27.3 h, and 7.90-27.5 mL/h/kg, respectively, for doses of 100-1000 microg/kg. An exposure-response relationship that could be empirically described with a simple Emax model with baseline was found between day 15 absolute neutrophil count and area under the curve following the first dose in cynomolgus monkeys. CONCLUSION: The sustained activity of Albugranin in mice and monkeys demonstrated in these studies suggests that this agent could be given less frequently than Filgrastim to achieve similar therapeutic effects in patients.

Pharmacologic and pharmacokinetic profile of repifermin (KGF-2) in monkeys and comparative pharmacokinetics in humans.

Repifermin (truncated, recombinant human keratinocyte growth factor-2, KGF-2) was evaluated in cynomolgus monkeys and healthy humans during a phase 1 trial. Monkeys received vehicle or repifermin at 20, 75, or 200 microg/kg IV or 750 microg/kg subcutaneous (SC) daily for 29 days. Clinical observations were made during the entire dosing period. Gross and microscopic changes were assessed at necropsy. Pharmacokinetic parameters and immunogenicity were evaluated in these monkeys and in humans, following a single or 7 daily IV bolus injections of 1, 5, 25, or 50 microg/kg repifermin. In monkeys, repifermin was well tolerated, and histologic evaluation demonstrated dose-dependent, reversible thickening of the mucosa throughout the alimentary tract, except for the stomach. In the alimentary tract tissues, nonepithelial tissues were not affected, indicating a specificity of repifermin for epithelial cells. Pharmacokinetics in both monkeys and humans were dose proportional, showed lack of drug accumulation with repeated daily dosing, and were characterized by high volumes of distribution and clearance rates, indicating substantial tissue binding and metabolism. Repifermin was not markedly immunogenic following multiple daily IV injections in either species. Serum repifermin concentrations in humans were comparable to those attained in monkeys that produced significant pharmacological effects on epithelial cells in the alimentary tract. These findings provide additional support for the ongoing clinical development of repifermin for diseases involving epithelial injury.