Pharmacokinetics of gemtuzumab ozogamicin, an antibody-targeted chemotherapy agent for the treatment of patients with acute myeloid leukemia in first relapse.

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.

Impact of age and gender on the pharmacokinetics of gemtuzumab ozogamicin.

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.

Evaluating possible pharmacokinetic interactions between tobramycin, piperacillin, and a combination of piperacillin and tazobactam in patients with various degrees of renal impairment.

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.

Noninvasive measurements for studying the tumoral pharmacokinetics of platinum anticancer drugs in solid tumors.

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.

Artificial neural networks applied to the in vitro-in vivo correlation of an extended-release formulation: initial trials and experience.

Artificial neural networks applied to in vitro-in vivo correlations (ANN-IVIVC) have the potential to be a reliable predictive tool that overcomes some of the difficulties associated with classical regression methods, principally, that of providing an a priori specification of the regression equation structure. A number of unique ANN configurations are presented, that have been evaluated for their ability to determine an IVIVC from different formulations of the same product. Configuration variables included a combination of architectural structures, learning algorithms, and input-output association structures. The initial training set consisted of two formulations and included the dissolution from each of the six cells in the dissolution bath as inputs, with associated outputs consisting of 1512 pharmacokinetic time points from nine patients enrolled in a crossover study. A third formulation IVIVC data set was used for predictive validation. Using these data, a total of 29 ANN configurations were evaluated. The ANN structures included the traditional feed forward, recurrent, jump connections, and general regression neural networks, with input-output association types consisting of the direct mapping of the dissolution profiles to the pharmacokinetic observations, mapping the individual dissolution points to the individual observations, and using a "memorative" input-output association. The ANNs were evaluated on the basis of their predictive performance, which was excellent for some of these ANN models. This work provides a basic foundation for ANN-IVIVC modeling and is the basis for continued modeling with other desirable inputs, such as formulation variables and subject demographics.

The effects of anesthesia on the biodistribution of drugs in rats: a carboplatin study.

PURPOSE: Anesthetics can alter the biodistribution profile of drugs and, consequently, the regional pharmacokinetics of antineoplastic drugs at the tumor site. The effect of coadministered anesthetics on the biodistribution profile of carboplatin was studied in rats. METHODS: Female Wistar rats were used to compare the effects of ketamine/xylazine, thiopental and pentobarbital on the biodistribution of 30 mg/kg radiolabelled 195mPt-carboplatin administered intravenously, with conscious rats as the control group. Blood and urine samples were collected between 5 and 120 min. RESULTS: The percentage values of the injected dose of platinum per ml (%ID/ml) in plasma at the final time-point were respectively, 0.557%, 0.156%, 0.115% and 0.086%, in pentobarbital-, ketamine/xylazine- and thiopental-injected rats, and in conscious animals. Following the same sequence of groups, the %ID/ml values of platinum in the cumulative urine were 0.001%, 0.619%, 0.184% and 0.118%, respectively. Urine output varied from very little in the pentobarbital group, to several milliliters in the other groups. CONCLUSIONS: There was an increase of almost 100-fold in total platinum uptake in the kidneys, cerebrum and cerebellum of rats receiving pentobarbital over the uptake in the control rats, whereas the biodistribution profile of the thiopental group had the least variance. These results demonstrate the importance of anesthetic selection in animal pharmacokinetic studies, as it influences the biodistribution and pharmacokinetic profile of the drug being studied.