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Three open-label studies assessed the safety, tolerability, and pharmacokinetics of intravenous dalbavancin in patients with hepatic or renal impairment, including patients with end-stage renal disease (ESRD) receiving dialysis. In each study, 4 to 10 patients with mild, moderate, or severe impairment and age-, sex-, and weight-matched controls were administered either a single dose (500 or 1000 mg) or 2 doses (1000 mg followed by 500 mg 1 week apart) of dalbavancin. Dalbavancin exposures were not increased due to mild renal impairment. The mean area under the concentration-time curve from time 0 to infinity (AUC0-infinity) values were approximately 50% higher in patients with moderate renal impairment or ESRD and 100% higher in patients with severe renal impairment. Dose adjustment is not considered necessary in patients with mild or moderate renal impairment or for patients with ESRD receiving hemodialysis; however, a lower dose of dalbavancin (750 mg followed 1 week later by 375 mg) may be considered for patients with severe renal impairment (creatinine clearance<30 mL/min). AUC0-infinity values were similar in patients with mild hepatic impairment and were about 27% to 36% lower in patients with moderate to severe hepatic impairment compared with controls. No dosage adjustment is recommended in patients with any degree of hepatic impairment. Dalbavancin was well tolerated in all impairment groups.

Dalbavancin is a novel glycopeptide with a 2-dose, once-weekly dosing regimen that is being developed for the treatment of complicated skin and skin structure infections caused by gram-positive bacteria. Monte Carlo simulations were performed for dalbavancin using population pharmacokinetic data and minimum inhibitory concentrations (MICs) for clinical trial isolates. The time-dependent target was the maintenance of free drug concentrations above the MIC for 14 days (t>MIC). The concentration-dependent target was an area under the concentration-time curve (AUC)/MIC ratio of approximately 1000 for Staphylococcus aureus and 100 for Streptococcus sp. These targets were used to estimate susceptibility breakpoints for dalbavancin. For S aureus, the estimated susceptibility breakpoint was MIC. For Streptococcus sp, the estimated susceptibility breakpoint was at least 2 mug/mL. Because dalbavancin MIC(90)s for these species are well below these values, the analysis supports the use of once-weekly dosing regimens of dalbavancin in the treatment of complicated skin and skin structure infections.

Objectives: Dalbavancin is a novel lipoglycopeptide antibiotic in development for the treatment of complicated skin and skin structure infections (cSSSIs) caused by Gram-positive bacteria. The aim of the present study was to assess the penetration of dalbavancin into skin blister fluid., Methods: Nine healthy subjects (five males; ranging in age from 26 to 57 years) were administered a single 30 min intravenous infusion of dalbavancin at a dose of 1000 mg. Skin blisters were induced by application of cantharidin ointment. Plasma and blister fluid samples were collected over 7 days post-dose, and concentrations of dalbavancin were assessed by a validated LC/MS/MS assay. Pharmacokinetics were determined by non-compartmental methods, and drug penetration was assessed based on the ratio of area under the curve (AUC) in the blister fluid versus plasma for each subject., Results: The mean (SD) peak concentration of dalbavancin in plasma and blister fluid was 285 (31.1) and 67.3 (18.2) mg/L, respectively; the corresponding AUC(Day 7) values were 10 806 (1926) and 6438 (1238) mg . h/L, respectively. The mean (SD) penetration of dalbavancin into blister fluid was 59.6% (6.3%). By Day 7, the mean concentration of dalbavancin in plasma and blister fluid was 46.5 and 30.3 mg/L, respectively., Conclusions: Dalbavancin concentrations in blister fluid remained well above the MIC90 values for pathogens commonly implicated in cSSSIs such as Staphylococcus aureus, including methicillin-resistant S. aureus (MIC90 = 0.06 mg/L) and beta-haemolytic streptococci (MIC90 = 0.03 mg/L) through Day 7. These pharmacokinetic data support the use of dalbavancin in the treatment of cSSSIs caused by susceptible Gram-positive pathogens.

Penetration of dalbavancin into noninfected bone and joint tissues was assessed after an intravenous dose of 20 mg/kg (of body weight) [(14)C]dalbavancin given to rabbits. Drug-derived radioactivity, determined over 14 days by either liquid scintillation counting or autoradiography, remained above the MIC for common gram-positive pathogens that cause bone and joint infections.

Dalbavancin is a lipoglycopeptide antibiotic in clinical development as a once-weekly treatment for serious infections. A total of 532 patients, consisting of 502 patients with skin and soft tissue infections requiring parenteral therapy and 30 patients with catheter-related bloodstream infections, was available for population pharmacokinetic analysis. The majority of patients (78.4%) received dalbavancin intravenously as a 1000-mg dose on day 1 and a single 500-mg dose on day 8. A 2-compartment model with first-order elimination provided the best fit to the data. The clearance of dalbavancin was influenced by body surface area and creatinine clearance, but together they described less than 25% of the interpatient variability. Body surface area was determined to be a predictor of the central volume of distribution. There was no evidence that the presence of metabolic substrates, inhibitors, or inducers of cytochrome P450 or selected concomitant medications influenced the clearance of dalbavancin.

This paper discusses background information and the body of clinical data that has been accumulated to demonstrate the efficacy and safety of gemtuzumab ozogamicin (Mylotarg, Wyeth Pharmaceuticals, Philadelphia, PA). Based on these data, gemtuzumab ozogamicin was approved by the United States Food and Drug Administration for the treatment of patients with CD33-positive acute myeloid leukemia in first relapse who are 60 years of age or older and who are not considered candidates for other cytotoxic chemotherapy. The recommended dosage of gemtuzumab ozogamicin is 9 mg/m2, administered as a 2-hour intravenous infusion for a total of 2 doses with 14 days between doses.

The purpose of this study was to characterize the pharmacokinetics of gemtuzumab ozogamicin (Mylotarg; Wyeth-Ayerst Laboratories, St. Davids, PA) in patients with acute myeloid leukemia (AML) in first relapse. Gemtuzumab ozogamicin is an antibody-chemotherapeutic conjugate characterized as antibody-targeted chemotherapy, consisting of an engineered human anti-CD33 antibody (hP67.6) linked to a potent cytotoxic agent, N-acetyl-gamma calicheamicin DMH. The pharmacokinetics of gemtuzumab ozogamicin was evaluated in 59 adult AML patients in first relapse, enrolled in a phase II study. Plasma was collected following each dose at specified times, and the pharmacokinetics was characterized by measures of hP67.6, total calicheamicin derivatives, and unconjugated calicheamicin derivatives. After administration of the first 9 mg/m2 dose of gemtuzumab ozogamicin, the pharmacokinetic parameters (mean +/- SD) of hP67.6 following the first dose were as follows: peak plasma concentration, 2.86 +/- 1.35 mg/L; AUC, 123 +/- 105 mg x h/L; t 1/2, 72.4 +/- 42.0 hours; and clearance, 0.265 +/- 0.229L/h. Increased concentrations were observed after the second dose and are believed to be due to a decrease in clearance by CD33-positive blast cells, a result of the reduced tumor burden following the first dose. The concentration profiles of calicheamicin followed the same time course as hP67.6, evidence that calicheamicin remained conjugated to the antibody and delivered to leukemic cells. No relationship was found between plasma concentration and response at the recommended dose. The pharmacokinetics of gemtuzumab ozogamicin has been characterized in AML patients receiving doses at the proposed therapeutic level.

Study Objective: To determine the pharmacokinetic parameters of the components of gemtuzumab ozogamicin and to assess the possible influence of age and gender on the values., Design: Phase II, multicenter, open-label, nonrandomized, parallel study, Setting: Hospitals and outpatient oncology clinics., Patients: Fifty-eight patients with acute myeloid leukemia in first relapse participated. Demographic data included 29 men and 29 women; 34 were younger than 60 years of age (mean age 53+/-16 yrs)., Intervention: Patients received gemtuzumab ozogamicin as a single 2-hour infusion of 9 mg/m2. Serial plasma samples were collected over 10 days after the beginning of the infusion., Measurements and Main Results: Plasma concentrations of components of gemtuzumab ozogamicin (hP67.6 antibody, total and unconjugated calicheamicin derivatives) were measured by validated enzyme-linked immunosorbent assays. Pharmacokinetic parameters were determined by noncompartmental methods and comparisons between groups were made by analysis of variance. No significant differences were seen between men and women or between those over 60 and those less than 60 years of age in maximum concentration, time to maximum concentration, area under the curve, clearance, or volume of distribution for components of gemtuzumab ozogamicin., Conclusion: No differences occur in the pharmacokinetics of the components of gemtuzumab ozogamicin (hP67.6 or calicheamicin) based on gender or age.

A study was performed to further investigate the apparent instability of tobramycin when coadministered with piperacillin/tazobactam in subjects with renal impairment. Twenty-six otherwise healthy volunteers between 23 and 74 years of age were studied. Eight subjects had moderate renal impairment, 10 had mild renal impairment, and 8 had normal renal function. Each subject received single doses of piperacillin/tazobactam and tobramycin alone as well as combined doses in a randomized, three-way crossover design. The subjects with normal renal function also received combined doses of piperacillin and tobramycin. Considerable care was taken to protect against in vitro inactivation of plasma and urine samples after collection. No systematic changes in pharmacokinetic parameters were observed. It is concluded that piperacillin, either alone or with tazobactam, did not change the pharmacokinetics of tobramycin in subjects with renal impairment. The apparent in vivo inactivation of tobramycin in the presence of piperacillin or piperacillin/tazobactam reported by others may be an artifact of ex vivo inactivation.