ABSTRACT Anidulafungin is an echinocandin with activity against Candida species and Aspergillus species. Adult dosages under study are 50 mg/day for esophageal candidiasis and 100 mg/day for invasive candidiasis and aspergillosis. Little is known, however, about the safety and pharmacokinetics of anidulafungin in children. A multicenter, ascending-dosage study of neutropenic pediatric patients was therefore conducted. Patients were divided into two age cohorts (2 to 11 years and 12 to 17 years) and were enrolled into sequential groups to receive 0.75 or 1.5 mg/kg of body weight/day. Blood samples were obtained following the first and fifth doses. Anidulafungin was assayed in plasma, and pharmacokinetic parameters were determined. Safety was assessed using National Cancer Institute (NCI) common toxicity criteria. Pharmacokinetic parameters were determined for 12 patients at each dosage (0.75 mg/kg/day or 1.5 mg/kg/day). Concentrations and drug exposures were similar for patients between age cohorts, and weight-adjusted clearance was consistent across age. No drug-related serious adverse events were observed. One patient had fever (NCI toxicity grade of 3), and one patient had facial erythema, which resolved with slowing the infusion rate. Anidulafungin in pediatric patients was well tolerated and can be dosed based on body weight. Pediatric patients receiving 0.75 mg/kg/day or 1.5 mg/kg/day have anidulafungin concentration profiles similar to those of adult patients receiving 50 or 100 mg/day, respectively.

Anidulafungin is a novel antifungal agent of the echinocandin class that is intended for the treatment of invasive fungal disease. It is likely that anidulafungin will be coadministered with cyclosporine. In vitro studies and clinical studies were performed to evaluate the effect of anidulafungin on cyclosporine metabolism and to investigate the safety and pharmacokinetics of anidulafungin when concomitantly administered with cyclosporine. The potential for anidulafungin to inhibit the metabolism of cyclosporine was evaluated by pooled human hepatic microsomal protein fractions in vitro, incubating 3 H‐cyclosporine with different concentrations of anidulafungin. The safety of coadministration and the effects of cyclosporine on the pharmacokinetics of anidulafungin were assessed in a multiple‐dose, open‐label clinical study of 12 healthy volunteers. Subjects received a 200‐mg intravenous loading dose of anidulafungin, followed by a daily 100‐mg intravenous maintenance dose on days 2 through 8. An oral solution of cyclosporine (Neoral oral solution; 100 mg/mL) 1.25 mg/kg was also administered to subjects twice daily on days 5 through 8. In the in vitro study, the addition of anidulafungin had no effect on cyclosporine metabolism by human hepatic microsomal protein fractions. In the clinical study, no dose‐limiting toxicities or serious adverse events occurred. A small increase in anidulafungin concentrations and drug exposure (22%) was observed after 4 days of dosing with cyclosporine and was not considered to be clinically relevant. The results support the concomitant use of anidulafungin and cyclosporine without the need for dosage adjustments of either drug.

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.

Gemtuzumab ozogamicin is currently approved to treat CD33‐positive acute myeloid leukemia (AML) in first relapse in patients older than age 60 years. The objective of this study was to characterize the pharmacokinetics of gemtuzumab ozogamicin in pediatric patients with relapsed or refractory AML. The study population comprised 29 subjects younger than age 18 with AML in first relapse. Dosages of 6, 7.5, and 9 mg/m2 were administered during the study. Pharmacokinetic parameters were determined following each dose for hP67.6, total calicheamicin derivatives, and unconjugated calicheamicin derivatives. hP67.6 pharmacokinetic parameters had a consistent and statistically significant change between the first and second doses. Increases in AUC and decreases in both CL and Vss from the first dose to the second dose were consistent with those of the adult population. Changes between dose periods for total calicheamicin derivatives and unconjugated calicheamicin derivatives were consistent with those of hP67.6. Changes in pharmacokinetic parameters between dose periods are attributed to saturation of CD33 binding sites and diminished clearance resulting from a lower peripheral blast burden and antigen. Children receiving 9 mg/m2 had the following hP67.6 pharmacokinetic parameters: Cmax, 3.47±1.04 mg/L; AUC, 136 ±107 mg•h/L; CL, 0.12 ±0.15 L/h/m2; Vss, 6.5 ±5.5 L; and t1/2, 64±44 h after their first dose. Mean pharmacokinetic values are similar to values reported in adults. Individual children demonstrated large intersubject variability, similar to adults. The pharmacokinetics of gemtuzumab ozogamicin in pediatric patients closely follow the profile and variability of adult patients.

The objective of this analysis was to describe the pharmacokinetic characteristics of anidulafungin in patients with serious fungal disease based on pharmacokinetic data collected during four recently completed or ongoing Phase II/III clinical studies. A total of 600 anidulafungin plasma samples from 225 patients across the four studies were available for analysis. Patients received daily intravenous infusions of 50, 75, or 100 mg anidulafungin, preceded by a loading dose that was twice the daily dose. The analysis population consisted of 129 patients with esophageal candidiasis, 87 with invasive candidiasis, 7 with invasive aspergillosis, and 2 with azole refractory mucosal candidiasis. A population analysis approach was used to develop a steady‐state pharmacokinetic model for anidulafungin, assess the significance of possible covariates, and determine the amount of intersubject and random residual variability. A two‐compartment model with first‐order elimination provided the best fit to the data. The clearance of anidulafungin was influenced by weight and gender, and subjects in the invasive candidiasis study had a typical clearance that was approximately 30% higher than subjects from other studies. Weight was determined to be a predictor of the central volume of distribution. The covariates on clearance accounted for less than 20% of the intersubject variability and therefore are deemed to be of little clinical relevance. There was no evidence that the presence of rifampin or metabolic substrates, inhibitors, or inducers of cytochrome P450 influenced the clearance of anidulafungin. This indicates that dosing adjustments are not necessary when anidulafungin is administered in the presence of medications falling into these classifications.

Dalbavancin, a novel glycopeptide with a long elimination half-life ( approximately 9-12 days), was compared to standard antimicrobial therapy for skin and soft-tissue infections (SSTIs). In a randomized, controlled, open-label, phase 2 proof-of-concept trial, adults received 1100 mg of dalbavancin (as a single intravenous infusion), 1000 mg of dalbavancin intravenously and then 500 mg intravenously 1 week later, or a prospectively defined standard-of-care regimen. A gram-positive pathogen was isolated from samples obtained from 41 (66%) of 62 patients at baseline; Staphylococcus aureus was the most prevalent species (83% of pathogens). Clinical success rates at a follow-up visit (test of cure) were 94.1% among patients treated with 2 doses of dalbavancin, 61.5% among patients treated with 1 dose of dalbavancin, and 76.2% among patients treated with a standard-of-care regimen. All treatment regimens were well tolerated; drug-related adverse reaction rates were similar across the 3 groups. These findings suggest that a regimen of 2 doses of dalbavancin administered 1 week apart is effective in the treatment of complicated, gram-positive bacterial SSTIs and warrants further study.

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·h/L;t1/2, 72.4 ± 42.0 hours; and clearance, 0.265 ± 0.229 L/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.

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.

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 studySetting. 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/m(2). 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.

An effective methodology to determine the amount of cisplatin or carboplatin at the solid tumor site in a noninvasive manner may enable clinicians to design drug regimens based on an individual’s in situ pharmacokinetics. Such noninvasive methods may allow optimization of an individual’s drug exposure at the target site, as well as provide a screening measure to determine individual efficacy based on exposure to these platinated drugs. 195mPt appears to be the radionuclide of platinum most suitable for radiolabeling cisplatin or carboplatin, and an analysis is presented of the methods available for preparing such radiolabeled drugs. The use of this methodology is illustrated in detail in studies in animals, as well as some preliminary studies in humans. The animals used were Sprague Dawley rats bearing the Walker 256 carcinoma, and drug biodistribution was studied following administration of cisplatin or carboplatin radiolabeled with 195mPt. This radionuclide permitted noninvasive imaging of the drug and its metabolites at the tumor site and at selected organs. The results obtained show an ability to estimate the amount of platinated drug species in the tumor environment using a noninvasive methodology. Various compartmental models were tested, some of which could be validated experimentally. This noninvasive method is able to provide individual estimates of the active component of the drug at the target site, and is therefore a method that can be implemented in human studies.