Biomedical subjects

P Kellie Turner

Publications and source records attributed to P Kellie Turner.

5 recordsLinked to original sources

PubMed2005

Development and validation of limited sampling models for topotecan lactone pharmacokinetic studies in children.

PURPOSE: To develop and validate a pharmacokinetic limited sampling model (LSM) for intravenous and oral topotecan pharmacokinetic studies in children. METHODS: Topotecan lactone concentration-time data from five trials were used to develop and validate LSM for intravenous and oral topotecan. Based on full sampling from one intravenous study (30 patients; 195 studies), a LSM for intravenous topotecan was determined using a modification of the D-optimality algorithm. For oral topotecan we used full sampling data from one oral topotecan study (27 patients; 47 studies) to develop an LSM. Accuracy and bias of each LSM were determined relative to the full sampling method. Predictive performance of the LSM was validated using additional data and Monte-Carlo simulations based on these data. RESULTS: LSM for intravenous topotecan includes: 5 min, 1.5, and 2.5 h after the end of the 30 min infusion. The median accuracy (absolute predicted error) and bias (predicted error) are < or =8% and < or =6.1%, respectively. For oral topotecan, the optimal LSM includes: 15 min, 1.5, and 6 h. The median accuracy and bias are 6% and 4%, respectively. CONCLUSIONS: Our results indicate that the optimal sampling times for the intravenous LSM for topotecan in children consist of: predose, and 5 min, 1.5, and 2.5 h after the end of infusion. For oral topotecan the sample times are predose, 15 min, 1.5, and 6 h after dose administration. These LSM are invaluable to children receiving topotecan because it minimizes inconvenience and blood collection.

Administration, Oral↗

PubMed2003

Interferon-gamma pharmacokinetics and pharmacodynamics in patients with colorectal cancer.

PURPOSE: The study objectives were to define subcutaneous (s.c.) interferon gamma (IFN-gamma) disposition in patients with gastrointestinal malignancies receiving 5-fluorouracil (5-FU) and leucovorin (LV) and to examine the relationship between IFN-gamma exposures and Fas upregulation in vivo and in vitro. METHODS: Patients received IFN-gamma (10, 25, 50, 75, and 100 microg/m(2)) with LV and 5-FU, and serial samples were collected after the first dose. IFN-gamma concentrations were measured by ELISA. A linear one-compartment model with a lag was fitted to the IFN-gamma plasma concentration-time data. To examine the relationship between IFN-gamma systemic exposure and biological activity in vivo, cell surface Fas upregulation was assessed in peripheral blood mononuclear cell (PBMC) subcompartments. RESULTS: The median (range) apparent IFN-gamma clearance was 46 l/m(2) per hour (2.6-92 l/m(2) per hour). With increasing IFN-gamma dosages, the area under the concentration-time curve (AUC(0--> infinity )) and C(max) increased; however, significant interpatient variability was observed. IFN-gamma AUC(0--> infinity ) and time above 33.3 pg/ml significantly correlated with Fas upregulation in several PBMC compartments, but dosage was significantly correlated with this pharmacodynamic marker only in CD4(+) and CD56(+) cells. In vitro studies in HT29 cells demonstrated that clinically relevant IFN-gamma concentrations (1 to 10 U/ml for 6.5 h) with 5-FU/LV upregulated Fas expression 3.5-fold, similar to that in PBMC in vivo. CONCLUSIONS: We characterized IFN-gamma disposition and developed a limited sampling model for use in future pharmacokinetic studies. Our results showed that IFN-gamma upregulates Fas in PBMC in vivo and in HT29 cells in vitro at tolerable, clinically relevant exposures and that monitoring IFN-gamma pharmacokinetics/pharmacodynamics may be warranted in IFN-gamma clinical use.

Adult↗

PubMed2003

Topoisomerase I interactive agents.

Increased insight into the mechanism of interaction of topoisomerase I interactive agents will maximize the therapeutic index and enhance the development of additional agents. Preclinical studies designed to elucidate mechanisms by which the topoisomerase I interactive agents induce cell death will be essential. The role of ABC transporters in resistance to topoisomerase I interactive agents has been recently appreciated and future studies should be directed at circumventing this resistance. The results of preclinical studies must be translated into the design of clinical trials so that these agents can be used rationally. In this regard results of preclinical studies have clearly pointed to the enhanced antitumor activity from protracted dosing of topoisomerase I interactive agents and results of clinical trials are now supporting these preclinical findings. Finally, investigators are trying to understand better the mechanism(s) of the dose-limiting toxicities observed with the currently available topoisomerase I interactive agents in an effort to enable the optimal dosing of these agents. Even though the first priority must be to determine the therapeutic potential of the currently available agents, it is reassuring to know that other topoisomerase I interactive agents are currently under development.

Adult↗

PubMed2002

Modulation of the Fas signaling pathway by IFN-gamma in therapy of colon cancer: phase I trial and correlative studies of IFN-gamma, 5-fluorouracil, and leucovorin.

Potentiation of 5-fluorouracil/leucovorin (FUra/LV) cytotoxicity by IFN-gamma in colon carcinoma cells is dependent on FUra-induced DNA damage, the Fas death receptor, and independent of p53 and RNA-mediated FUra toxicity, which occurs in normal gastrointestinal tissues. This provides a rationale for enhancing the selective action of FUra/LV by IFN-gamma in the treatment of colorectal carcinoma. Based on results from our preclinical studies we designed a Phase I trial combining FUra (370 mg/m2) and LV (200 mg/m2), i.v. bolus daily x 5 days, with escalating doses of IFN-gamma (10-100 micro g/m2) s.c. on days 1, 3, and 5, every 28 days. Twenty-five patients with carcinomas were enrolled; 6 patients received IFN-gamma on days 1 and 3 only. The dose-limiting toxicity, stomatitis, occurred most frequently at 100 micro g/m2 IFN-gamma. Minor response or SD was observed in 2 of 9 patients and in 4 of 12 patients at dose levels of < or =50 micro g/m2 and > or =75 micro g/m2 IFN-gamma, respectively. Three evaluable chemonaive patients demonstrated partial response (2) or complete response (1). Serial plasma samples revealed peak FUra concentrations of >100 micro M; at 100 micro g/m2 IFN-gamma plasma concentrations >5 units/ml persisted for 6.5 h and >1 unit/ml for 28.5 h. The pharmacokinetic parameters of IFN-gamma correlated with a 2-3-fold up-regulation of Fas expression at 24 h in CD15+ cells in peripheral blood samples. Furthermore, clinically relevant IFN-gamma concentrations up-regulated Fas expression and sensitized HT29 colon carcinoma cells in vitro to FUra/LV cytotoxicity. On the basis of the modulation of Fas signaling, FUra/LV combined with IFN-gamma has shown activity in a Phase I trial in colorectal carcinoma and warrants additional evaluation in Phase II.

Adult↗

PubMed2002

Topoisomerase I interactive agents.

Elucidation of the crystal structure of topoisomerase I will enhance the rational development of topoisomerase I interactive agents. Although the first topoisomerase I interactive agents were camptothecin derivatives, future drugs may be designed to take advantage of the knowledge of the mechanism of interaction with topoisomerase I to increase the therapeutic index. Preclinical studies designed to determine the precise mechanism by which the topoisomerase I interactive agents lead to cell death will be essential. Future clinical trials must rationally utilize the results of preclinical studies in the design of combination regimens, both with other cytotoxics and with the newer cytostatics. Moreover, the optimum schedule of administration for irinotecan and topotecan are not known, although results of preclinical studies clearly point to protracted dosing of these S-phase-specific agents. Future clinical trials should evaluate these schedules in an effort to optimize the currently available agents, prior to introducing new analogs, which may not provide any therapeutic benefit over the current agents properly dosed. Finally, many investigators are trying to better understand the mechanism(s) of the dose-limiting toxicities observed with the currently available topoisomerase I interactive agents (e.g., glucuronidation for irinotecan diarrhea). The results of these studies may also enable the maximal dosing of the currently available agents. Even though the first priority must be to determine the therapeutic potential of the currently available agents, it is reassuring to know that many topoisomerase I interactive agents are currently under development. However, it is essential that these agents have the proper preclinical studies performed and that they be rationally developed.

Animals↗