Biomedical subjects

Clinton F Stewart

Publications and source records attributed to Clinton F Stewart.

At least 37 records · Page 2Linked 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↗

PubMed2005

Improved response in high-risk neuroblastoma with protracted topotecan administration using a pharmacokinetically guided dosing approach.

PURPOSE: To estimate the response rate and toxicity associated with intravenous topotecan when it is administered on a protracted schedule according to a pharmacokinetically guided dosing approach to treat childhood high-risk neuroblastoma. PATIENTS AND METHODS: In this prospective phase II trial, topotecan was administered intravenously daily for 5 days for each of 2 consecutive weeks for two cycles. On the basis of topotecan systemic clearance, doses were individualized to attain a single-day topotecan lactone area under the plasma concentration-time curve (AUC) of 80 to 120 ng/mL . h. Patients subsequently received standard treatment. RESULTS: Both cycles were administered to 28 (93%) of the 30 enrolled patients (median age, 3.1 years). Target topotecan AUCs were achieved in 92 (72%) of the 127 measurements conducted after pharmacokinetically guided adjustment; the median dosage required to achieve target AUCs was 2.7 mg/m(2) (range, 0.95 to 3.8 mg/m(2)). The response rate was 60% (95% CI, 41% to 77%); there were one complete and 17 partial responses. No patient experienced disease progression during initial topotecan therapy. Primary tumor volumes decreased (median decrease, -58.2%; range, -95.1% to -4.9%) in the 26 patients with available size data. Homovanillic acid levels in 16 (89%) of 18 patients and vanillylmandelic acid levels in 14 (78%) of 18 patients were lower (P = .002 and P = .018, respectively) after topotecan therapy. Reversible grade 4 myelosuppression occurred in all patients, but no deaths occurred as a result of infection or toxicity. CONCLUSION: Topotecan is active against neuroblastoma when it is administered on a protracted schedule and targeted systemic exposure is achieved.

Adolescent↗

PubMed2005

Activation and antitumor activity of CPT-11 in plasma esterase-deficient mice.

PURPOSE: To examine the antitumor activity and the pharmacokinetics of CPT-11 (irinotecan, 7-ethyl-10-[4-(1-piperidino)-1-piperidino] carbonyloxycamptothecin) in a plasma esterase-deficient scid mouse model, bearing human tumor xenografts. EXPERIMENTAL DESIGN: Plasma carboxylesterase (CE)-deficient mice were bred with scid animals to develop a strain that would allow growth of human tumor xenografts. Following xenotransplantation, the effect of the plasma esterase on antitumor activity following CPT-11 administration was assessed. In addition, detailed pharmacokinetic studies examining plasma and biliary disposition of CPT-11 and its metabolites were performed. RESULTS: In mice lacking plasma carboxylesterase, the mean SN-38 systemic exposures were approximately fourfold less than that observed in control animals. Consistent with the pharmacokinetic data, four to fivefold more CPT-11 was required to induce regressions in human Rh30 xenografts grown in esterase-deficient scid mice, as opposed to those grown in scid animals. Additionally, the route of elimination of CPT-11, SN-38, and SN-38 glucuronide (SN-38G) was principally in the bile. CONCLUSIONS: The pharmacokinetic profile for CPT-11 and its metabolites in the esterase-deficient mice more closely reflects that seen in humans. Hence, these mice may represent a more accurate model for antitumor studies with this drug and other agents metabolized by CEs.

Animals↗

PubMed2005

Development of a pharmacokinetic limited sampling model for temozolomide and its active metabolite MTIC.

PURPOSE: To develop a pharmacokinetic limited sampling model (LSM) for temozolomide and its metabolite MTIC in infants and children. METHODS: LSMs consisting of either two or four samples were determined using a modification of the D-optimality algorithm. This accounted for prior distribution of temozolomide and MTIC pharmacokinetic parameters based on full pharmacokinetic sampling from 38 patients with 120 pharmacokinetic studies (dosage range 145-200 mg/m(2) per day orally). Accuracy and bias of each LSM were determined relative to the full sampling method. We also assessed the predictive performance of the LSMs using Monte-Carlo simulations. RESULTS: The four strategies generated from the D-optimality algorithm were as follows: LSM 1=0.25, 1.25, and 3 h; LSM 2=0.25, 1.25, and 6 h; LSM 3=0.25, 0.5, 1.25, and 3 h; LSM 4=0.25, 0.5, 1.25, and 6 h. LSM 2 demonstrated the best combination of low bias [0.1% (-8.9%, 11%) and 11% (4.3%, 15%)] and high accuracy [-1.0% (-12%, 24%) and 14% (7.9%, 37%)] for temozolomide clearance and MTIC AUC, respectively. Furthermore, adding a fourth sample (e.g., LSM 4) did not substantially decrease the bias or increase the accuracy for temozolomide clearance or MTIC AUC. Results from Monte-Carlo simulations also revealed that LSM 2 had the best combination of lowest bias (0.1+/-6.1% and -0.8+/-6.5%), and the highest accuracy (4.5+/-4.1% and 5.0+/-4.3%) for temozolomide clearance and MTIC apparent clearance, respectively. CONCLUSIONS: Using data derived from our population analysis, the sampling times for a limited sample pharmacokinetic model for temozolomide and MTIC in children are prior to the temozolomide dose, and 15 min, 1.25 h and 6 h after the dose.

Antineoplastic Agents, Alkylating↗

PubMed2005

A phase I trial defining the maximum tolerated systemic exposure of topotecan in combination with Carboplatin and Etoposide in extensive stage small cell lung cancer.

PURPOSE: Topotecan is active in relapsed small cell lung cancer; thus, its addition to the standard carboplatin-etoposide regimen may improve outcomes in extensive-stage small cell lung cancer (ES-SCLC) patients. Significant interpatient variability in the topotecan systemic exposure results when it is dosed based on body surface area (mg/m2). The purpose of this Phase I trial was to determine the maximally tolerated systemic exposure (MTSE) of topotecan in combination with carboplatin and etoposide. METHODS: Thirty-four chemotherapy-naïve ES-SCLC patients received topotecan in combination with carboplatin AUC 5 mg/mL*min and oral etoposide 100 mg/m2/day. Topotecan was administered as a 30-minute infusion either on Days 1-5 or Days 1-3 and the dosage was individualized to attain a topotecan lactone AUC range (ng/mL*hr) in successive patient cohorts from 7 to 23; 24 to 36; 37 to 53; 54 to 66. RESULTS: The majority (67 percent) of the measured topotecan AUCs were within target range. Overall, 8 of 34 patients experienced Cycle 1 dose-limiting toxicity (DLT), either neutropenia or thrombocytopenia. Carboplatin administration prior to topotecan resulted in 2 of 6 patients having Cycle 1 DLT. When the administration sequence was changed (topotecan, carboplatin, etoposide), Cycle 1 hematologic toxicity decreased; however, the maximum topotecan lactone AUC of 24-36 ng/mL*hr (median dose 0.82 mg/m2) had significant cumulative hematologic toxicity. The number of topotecan doses were reduced from 5 to 3, which resulted in a maximum topotecan lactone AUC of 37 to 53 ng/mL*hr with only 1 of 6 patients having Cycle 1 DLT. Overall response rate was 71 percent with median survival of 10.8 months. CONCLUSION: It is feasible to target topotecan lactone AUC in adult ES-SCLC patients. However, this triplet regimen resulted in considerable hematologic toxicity and has a median survival comparable to carboplatin-etoposide. Alternative, less toxic regimens should be investigated for improving survival in ES-SCLC.

Adult↗

PubMed2004

Increased expression of the Abcg2 transporter during erythroid maturation plays a role in decreasing cellular protoporphyrin IX levels.

ABCG2/BCRP is a member of the adenosine triphosphate-binding cassette (ABC) transporter family and is expressed in intestine, kidney, and liver, where it modulates the absorption and excretion of xenobiotic compounds. ABCG2 is also expressed in hematopoietic stem cells and erythroid cells; however, little is known regarding its role in hematopoiesis. Abcg2 null mice have increased levels of protoporphyrin IX (PPIX) in erythroid cells, yet the mechanism for this remains uncertain. We have found that Abcg2 mRNA expression was up-regulated in differentiating erythroid cells, coinciding with increased expression of other erythroid-specific genes. This expression pattern was associated with significant amounts of ABCG2 protein on the membrane of mature peripheral blood erythrocytes. Erythroid cells engineered to express ABCG2 had significantly lower intracellular levels of PPIX, suggesting the modulation of PPIX level by ABCG2. This modulating activity was abrogated by treatment with a specific ABCG2 inhibitor, Ko143, implying that PPIX may be a direct substrate for the transporter. Taken together, our results demonstrate that ABCG2 plays a role in regulating PPIX levels during erythroid differentiation and suggest a potential role for ABCG2 as a genetic determinant in erythropoietic protoporphyria.

ATP Binding Cassette Transporter, Subfamily G, Mem↗

PubMed2004

Gefitinib enhances the antitumor activity and oral bioavailability of irinotecan in mice.

As a single agent the ERBB1 inhibitor, gefitinib (Iressa; ZD1839) showed minimal activity against a panel of 10 pediatric tumor xenografts that do not express the ERBB1 receptor. However, combined with irinotecan (CPT-11), significantly greater than additive activity was observed in four of eight models (P < 0.05), and the combination showed enhanced activity against three additional tumor lines. Breast cancer resistance protein (ABCG2), a transporter that confers resistance to SN-38 (the active metabolite of irinotecan), was readily detected in six of nine xenograft models examined by immunohistochemistry. In vitro gefitinib potently reversed resistance to SN-38 only in a cell line that overexpressed functional ABCG2. However, overexpression of ABCG2 did not decrease accumulation nor increase the rate of efflux of [(14)C]gefitinib. On the basis of these results and the distribution of Abcg2 in mouse tissues, we assessed the ability of gefitinib to modulate irinotecan pharmacokinetics. Oral gefitinib coadministration resulted in no change in clearance of intravenously administered irinotecan. However, gefitinib treatment dramatically increased the oral bioavailability of irinotecan after simultaneous oral administration. It is concluded that gefitinib may modulate SN-38 activity at the cellular level to reverse tumor resistance mediated by ABCG2 through inhibiting drug efflux and may be used potentially in humans to modulate the oral bioavailability of a poorly absorbed camptothecin such as irinotecan.

ATP Binding Cassette Transporter, Subfamily G, Mem↗

PubMed2004

Results of a phase II upfront window of pharmacokinetically guided topotecan in high-risk medulloblastoma and supratentorial primitive neuroectodermal tumor.

PURPOSE: To assess the antitumor efficacy of pharmacokinetically guided topotecan dosing in previously untreated patients with medulloblastoma and supratentorial primitive neuroectodermal tumors, and to evaluate plasma and CSF disposition of topotecan in these patients. PATIENTS AND METHODS: After maximal surgical resection, 44 children with previously untreated high-risk medulloblastoma were enrolled, of which 36 were assessable for response. The topotecan window consisted of two cycles, administered initially as a 30-minute infusion daily for 5 days, lasting 6 weeks. Pharmacokinetic studies were conducted on day 1 to attain a topotecan lactone area under the plasma concentration-time curve (AUC) of 120 to 160 ng/mL.h. After 10 patients were enrolled, the infusion was modified to 4 hours, with dosage individualization. RESULTS: Of 36 assessable patients, four patients (11.1%) had a complete response and six (16.6%) showed a partial response, and disease was stable in 17 patients (47.2%). Toxicity was mostly hematologic, with only one patient experiencing treatment delay. The target plasma AUC was achieved in 24 of 32 studies (75%) in the 30-minute infusion group, and in 58 of 93 studies (62%) in the 4-hour infusion group. The desired CSF topotecan exposure was achieved in seven of eight pharmacokinetic studies when the topotecan plasma AUC was within target range. CONCLUSION: Topotecan is an effective agent against pediatric medulloblastoma in patients who have received no therapy other than surgery. Pharmacokinetically guided dosing achieved the target plasma AUC in the majority of patients. This drug warrants testing as part of standard postradiation chemotherapeutic regimens. Furthermore, these results emphasize the importance of translational research in drug development, which in this case identified an effective drug.

Adolescent↗

PubMed2004

Imatinib mesylate is a potent inhibitor of the ABCG2 (BCRP) transporter and reverses resistance to topotecan and SN-38 in vitro.

Imatinib mesylate (Gleevec, STI571) is a kinase inhibitor selective for Bcr-Abl, activated c-Kit kinases, and platelet-derived growth factor receptor tyrosine kinase. Imatinib mesylate, similar to many other tyrosine kinase inhibitors (TKIs), such as members of the 4-anilinoquinazoline class, competes for ATP binding. Previously, 4-anilinoquinazoline TKIs have been shown to inhibit the function of the breast cancer resistance-associated drug transporter (ABCG2), reversing resistance to camptothecin derivatives topotecan and SN-38. However, the potential to inhibit ABCG2 for the 2-phenylamino-pyrimidine class of TKIs, exemplified by imatinib mesylate, has not been examined. Here, we show that imatinib mesylate potently reverses ABCG2-mediated resistance to topotecan and SN-38 and significantly increases accumulation of topotecan only in cells expressing functional ABCG2. However, overexpression of ABCG2 does not confer resistance to imatinib mesylate. Furthermore, accumulation and efflux of [(14)C]imatinib mesylate are unaltered between ABCG2-expressing and non-ABCG2-expressing cells or by ATP depletion. These results suggest that imatinib mesylate inhibits the function of ABCG2 but is not a substrate for this transporter.

ATP Binding Cassette Transporter, Subfamily G, Mem↗

PubMed2004

Phase I and pharmacokinetic study of topotecan administered orally once daily for 5 days for 2 consecutive weeks to pediatric patients with refractory solid tumors.

PURPOSE: We conducted a phase I trial of the injectable formulation of topotecan given orally once daily for 5 days for 2 consecutive weeks (qd x 5 x 2) in pediatric patients with refractory solid tumors. PATIENTS AND METHODS: Cohorts of two to six patients received oral topotecan at 0.8, 1.1, 1.4, 1.8, and 2.3 mg/m(2)/d every 28 days for a maximum of six courses. Twenty patients (median age, 10.6 years) received a total of 51 courses. Eight patients received topotecan capsules during course 2 only. RESULTS: Dose-limiting toxicity occurred at 2.3 mg/m(2)/d and consisted of prolonged grade 4 neutropenia (n = 2), grade 3 stomatitis as a result of radiation recall (n = 1), grade 3 hemorrhage (epistaxis) in the presence of grade 4 thrombocytopenia (n = 1), and grade 3 diarrhea in the presence of Clostridium difficile infection (n = 1). Dose-limiting, prolonged grade 4 neutropenia and thrombocytopenia occurred in one patient at 1.4 mg/m(2)/d. Infrequent toxicities were mild nausea, vomiting, elevated liver ALT or AST, and rash. The maximum-tolerated dosage was 1.8 mg/m(2)/d; the mean (+/- standard deviation) area under the plasma concentration-time curve for topotecan lactone at this dosage was 20.9 +/- 8.4 ng/mL. h. The population mean (+/- standard error) oral bioavailability of the injectable formulation was 0.27 +/- 0.03; that of capsules was 0.36 +/- 0.06 (P =.16). Disease stabilized in nine of 19 assessable patients for 1.5 to 6 months. CONCLUSION: Oral topotecan (1.8 mg/m(2)/d) on a qd x 5 x 2 schedule is well tolerated and warrants additional testing in pediatric patients.

Administration, Oral↗

PubMed2004

Phase I trial of temozolomide and protracted irinotecan in pediatric patients with refractory solid tumors.

PURPOSE: The purpose is to estimate the maximum-tolerated dose (MTD) of temozolomide and irinotecan given on a protracted schedule in 28-day courses to pediatric patients with refractory solid tumors. EXPERIMENTAL DESIGN: Twelve heavily pretreated patients received 56 courses of oral temozolomide at 100 mg/m(2)/day for 5 days combined with i.v. irinotecan given daily for 5 days for 2 consecutive weeks at either 10 mg/m(2)/day (n = 6) or 15 mg/m(2)/day (n = 6). We assessed toxicity, the pharmacokinetics of temozolomide and irinotecan, and the DNA repair phenotype in tumor samples. RESULTS: Two patients experienced dose-limiting toxicity (DLT) at the higher dose level; one had grade 4 diarrhea, whereas the other had bacteremia with grade 2 neutropenia. In contrast, no patient receiving temozolomide and 10 mg/m(2)/day irinotecan experienced DLT. Myelosuppression was minimal and noncumulative. No pharmacokinetic interaction was observed. Drug metabolite exposures at the MTD were similar to exposures previously associated with single-agent antitumor activity. One complete response, two partial responses, and one minor response were observed in Ewing's sarcoma and neuroblastoma patients previously treated with stem cell transplant. Responding patients had low or absent O(6)-methylguanine-DNA methyltransferase expression in tumor tissue. CONCLUSIONS: The MTD using this schedule was temozolomide (100 mg/m(2)/day) and irinotecan (10 mg/m(2)/day), with DLT being diarrhea and infection. Drug clearance was similar to single-agent values, and clinically relevant SN-38 lactone and MTIC exposures were achieved at the MTD. As predicted by xenograft models, this combination and schedule appears to be tolerable and active in pediatric solid tumors. Evaluation of a 21-day schedule is planned.

Adolescent↗

PubMed2004

Microbore HPLC method with online microdialysis for measurement of topotecan lactone and carboxylate in murine CSF.

We developed a chromatography method to measure lactone and carboxylate forms of topotecan (TPT) in mouse cerebrospinal fluid (CSF) using microdialysis sampling. The chromatography method utilized a microbore (0.8 mm) column. Analytes, which eluted in less than 5 min, were detected with a fluorescence detector. The calibration range was 0.25-100.0 ng/mL for both forms. The within-day and between-day precision was < or =16% for 0.8 ng/mL and < or =8.0% for 3, 12, and 80 ng/mL. Accuracy was +/-15% (0.8 and 3 ng/mL) and +/-10% (12 and 80 ng/mL). TPT lactone hydrolyzes to the carboxylate during sampling, so we developed an equation and parameters to describe the TPT lactone hydrolysis in artificial CSF (aCSF). After TPT administration, CSF dialysate samples (2 microL) were analyzed for lactone and carboxylate using online injection. The hydrolysis of each dialysate sample was then estimated and a correction applied. We conclude that this HPLC method coupled with online microdialysis sampling allows for the rapid measurement of both TPT forms in small volumes of murine CSF dialysate. The system allows for the determination of TPT pharmacokinetics in murine CSF and provides a tool to extend pharmacological studies in this brain compartment.

Animals↗

PubMed2004

Suppression of the Shh pathway using a small molecule inhibitor eliminates medulloblastoma in Ptc1(+/-)p53(-/-) mice.

Medulloblastoma is the most common malignant pediatric brain tumor. Current treatment is associated with major long-term side effects; therefore, new nontoxic therapies, targeting specific molecular defects in this cancer, need to be developed. We use a mouse model of medulloblastoma to show that inhibition of the Sonic Hedgehog (Shh) pathway provides a novel therapy for medulloblastoma. A small molecule inhibitor of the Shh pathway, HhAntag, blocked the function of Smoothened in mice with medulloblastoma. This resulted in suppression of several genes highly expressed in medulloblastoma, inhibition of cell proliferation, increase in cell death and, at the highest dose, complete eradication of tumors. Long-term treatment with HhAntag prolonged medulloblastoma-free survival. These findings support the development of Shh antagonists for the treatment of medulloblastoma.

Animals↗

PubMed2004

Effect of fractionated ifosfamide on the pharmacokinetics of irinotecan in pediatric patients with osteosarcoma.

The combination of irinotecan (daily for 5 days for 2 consecutive weeks) and ifosfamide (daily on days 1 through 3) was investigated in children with osteosarcoma. Irinotecan pharmacokinetic investigations were performed before ifosfamide (day 1), after 3 days of ifosfamide (day 3), and 9 days after the end of ifosfamide (day 12). On day 3, the concentrations of irinotecan's active metabolite, SN-38, were below the limit of quantitation in two patients and were decreased in a third patient. The SN-38 area under the concentration-time curve remained below the day 1 value in two patients on day 12. The reduced area under the curve to the active metabolite SN-38 during ifosfamide therapy predicts a compromised efficacy of irinotecan in this combination.

Adolescent↗

PubMed2004

Topotecan disposition in an anephric child.

Although limited data are available about topotecan disposition in patients with renal insufficiency, nothing has been reported in anephric patients. The objective of this report is to characterize topotecan disposition in an anephric child with Wilms tumor, both on and off hemodialysis. The patient received topotecan and cyclophosphamide for four cycles; topotecan was administered daily for 5 days, with hemodialysis on the second and fourth day. Therapy was well tolerated, with grade 3 thrombocytopenia and grade 2 neutropenia noted after cycle four. The median topotecan lactone clearance was 15.5 L/h/m off hemodialysis and 18.7 L/h/m on hemodialysis. Topotecan clearance was minimally affected by hemodialysis and was similar to that observed in children without renal failure.

Antineoplastic Agents↗

PubMed2004

Mrp4 confers resistance to topotecan and protects the brain from chemotherapy.

The role of the multidrug resistance protein MRP4/ABCC4 in vivo remains undefined. To explore this role, we generated Mrp4-deficient mice. Unexpectedly, these mice showed enhanced accumulation of the anticancer agent topotecan in brain tissue and cerebrospinal fluid (CSF). Further studies demonstrated that topotecan was an Mrp4 substrate and that cells overexpressing Mrp4 were resistant to its cytotoxic effects. We then used new antibodies to discover that Mrp4 is unique among the anionic ATP-dependent transporters in its dual localization at the basolateral membrane of the choroid plexus epithelium and in the apical membrane of the endothelial cells of the brain capillaries. Microdialysis sampling of ventricular CSF demonstrated that localization of Mrp4 at the choroid epithelium is integral to its function in limiting drug penetration into the CSF. The topotecan resistance of cells overexpressing Mrp4 and the polarized expression of Mrp4 in the choroid plexus and brain capillary endothelial cells indicate that Mrp4 has a dual role in protecting the brain from cytotoxins and suggest that the therapeutic efficacy of central nervous system-directed drugs that are Mrp4 substrates may be improved by developing Mrp4 inhibitors.

Animals↗

PubMed2004

Review of microdialysis in brain tumors, from concept to application: first annual Carolyn Frye-Halloran symposium.

In individuals with brain tumors, pharmacodynamic and pharmacokinetic studies of therapeutic agents have historically used analyses of drug concentrations in serum or cerebrospinal fluid, which unfortunately do not necessarily reflect concentrations within the tumor and adjacent brain. This review article introduces to neurological and medical oncologists, as well as pharmacologists, the application of microdialysis in monitoring drug metabolism and delivery within the fluid of the interstitial space of brain tumor and its surroundings. Microdialysis samples soluble molecules from the extracellular fluid via a semipermeable membrane at the tip of a probe. In the past decade, it has been used predominantly in neurointensive care in the setting of brain trauma, vasospasm, epilepsy,and intracerebral hemorrhage. At the first Carolyn Frye-Halloran Symposium held at Massachusetts General Hospital in March 2002, the concept of microdialysis was extended to specifically address its possible use in treating brain tumor patients. In doing so we provide a rationale for the use of this technology by a National Cancer Institute consortium, New Approaches to Brain Tumor Therapy, to measure levels of drugs in brain tissue as part of phase 1 trials.

Animals↗

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↗