Publications by authors named "Mark N Kirstein"

33 Publications

polymorphism and voriconazole-associated hepatotoxicity in children undergoing hematopoietic cell transplant.

Int J Clin Pharmacol Ther 2021 Feb 9. Epub 2021 Feb 9.

Fungal (14α-sterol demethylase) is the target of an azole antifungal, voriconazole (VCZ), which also partially inhibits human . Hepatotoxicity is a common adverse effect of azoles, which is reported to be caused by altered gene expressions secondary to cholesterol synthesis inhibition by azoles. This is a post-hoc analysis of a previously conducted phase 1 dose-finding study of prophylactic VCZ in 56 pediatric hematopoietic cell transplant recipients. We explored an association between variants in human (rs2282976 and rs6465348) and VCZ-induced hepatotoxicity. Genotype A/G or G/G in rs6465348 showed lower odds of hepatotoxicity after adjusting for VCZ area-under-the-curve (OR: 0.10, 95% CI: 0.01 - 0.79, vs. A/A).
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http://dx.doi.org/10.5414/CP203920DOI Listing
February 2021

Impact of Obesity on Voriconazole Pharmacokinetics among Pediatric Hematopoietic Cell Transplant Recipients.

Antimicrob Agents Chemother 2020 11 17;64(12). Epub 2020 Nov 17.

Department of Experimental and Clinical Pharmacology, University of Minnesota, Minneapolis, Minnesota, USA

Voriconazole (VCZ) is an antifungal agent with wide inter- and intrapatient pharmacokinetic (PK) variability and narrow therapeutic index. Although obesity was associated with higher VCZ trough concentrations in adults, the impact of obesity had yet to be studied in children. We characterized the PK of VCZ in obese patients by accounting for age and CYP2C19 phenotype. We conducted intensive PK studies of VCZ and VCZ -oxide metabolite in 44 hematopoietic stem cell transplantation (HSCT) recipients aged 2 to 21 years who received prophylactic intravenous VCZ every 12 hours (q12h). Blood samples were collected at 5 and 30 minutes; at 1, 3, 6, and 9 hours after infusion completion; and immediately before the next infusion start. We estimated PK parameters with noncompartmental analysis and evaluated for an association with obesity by multiple linear regression analysis. The 44 participants included 9 (20%) with obesity. CYP2C19 metabolism phenotypes were identified as normal in 22 (50%), poor/intermediate in 13 (30%), and rapid/ultrarapid in 9 patients (21%). Obesity status significantly affects the VCZ minimum concentration of drug in serum () (higher by 1.4 mg/liter; 95% confidence interval [CI], 0.0 to 2.8;  = 0.047) and VCZ metabolism ratio (VCZ) (higher by 0.4; 95% CI, 0.0 to 0.7;  = 0.03), while no association was observed with VCZ area under the curve (AUC) ( = 0.09) after adjusting for clinical factors. A younger age and a CYP2C19 phenotype were associated with lower VCZ AUC. Obesity was associated with decreased metabolism of VCZ to its inactive -oxide metabolite and, concurrently, increased VCZ , which is deemed clinically meaningful. Future research should aim to further characterize its effects and determine a proper dosing regimen for the obese.
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http://dx.doi.org/10.1128/AAC.00653-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7674053PMC
November 2020

A phase I dose finding study of intravenous voriconazole in pediatric patients undergoing hematopoietic cell transplantation.

Bone Marrow Transplant 2020 05 25;55(5):955-964. Epub 2019 Nov 25.

Department of Pediatrics, Division of Blood and Marrow Transplant, University of Minnesota School of Medicine, Minneapolis, MN, USA.

To optimize voriconazole dosing in pediatric hematopoietic cell transplantation (HCT), we conducted a phase I study with a modified 3 + 3 dose-escalation followed by an expansion cohort at the maximum tolerated, minimum efficacious dose (MTD/MED). Patients ≤21 years who required voriconazole for prevention or treatment of an invasive fungal infection were assigned to three age groups. Of the 59 evaluable patients, 13 were <2 years, 23 were 2-11, and 23 were 12-21. Therapeutic serum voriconazole troughs (1.5-5 µg/mL) drawn at 7 days after initiation determined efficacy. The MTD/MED was 12 mg/kg/dose q12 h × 2 loading doses, then 10 mg/kg/dose q12 h in patients <2, and was 10 mg/kg/dose q12 h in patients 2-11. The 12-21 age group had no dose-limiting toxicity at 8 mg/kg/dose q12 h; however, the MED was not reached. Drug-related AEs ≥grade 3 included increased bilirubin, transaminases, and creatinine, all occurring in <10%. There was no significant association between supra-therapeutic troughs and AEs. Five of 17 patients who had supra-therapeutic troughs (29%) had an AE, compared to 8 of 42 who did not (19%, p = 0.38). Observational population pharmacokinetic analysis demonstrated that inter-individual variability on voriconazole clearance was >100% CV, and clearance increased with age.
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http://dx.doi.org/10.1038/s41409-019-0757-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7643732PMC
May 2020

Gemcitabine and metabolite pharmacokinetics in advanced NSCLC patients after bronchial artery infusion and intravenous infusion.

Cancer Chemother Pharmacol 2019 02 12;83(2):387-391. Epub 2018 Dec 12.

Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, MN, 55455, USA.

Purpose: We investigated the safety, pharmacokinetics, and efficacy of gemcitabine administered via bronchial artery infusion (BAI) and IV infusion in advanced NSCLC patients.

Methods: Patients were eligible if they had received at least two prior cytotoxic chemotherapy regimens. Gemcitabine was administered via BAI as 600 mg/m on day one of cycle one, followed by IV as 1000 mg/m on day eight of cycle one, and IV on days one and eight of all subsequent cycles. Pharmacokinetics for gemcitabine and dFdU metabolite in plasma, and dFdCTP active metabolite in peripheral blood mononuclear cells (PBMC) were evaluated. Intensive pharmacokinetic sampling was performed after BAI and IV infusions during cycle one.

Results: Three male patients (age range 59-68 years) were evaluated. All patients responded with stable disease or better. One PR was observed after cycle three, and the remaining had SD. C (mean ± SD) following BAI for gemcitabine, dFdCTP, and dFdU were 7.71 ± 0.13, 66.5 ± 40.6, and 38 ± 6.27 µM and following IV infusion, 17 ± 2.36, 50.8 ± 3.61, and 83.2 ± 12.3 µM, respectively. The AUCinf (mean ± SD) following BAI for gemcitabine, dFdCTP, and dFdU were 6.89 ± 1.2, 791.1 ± 551.2, and 829.9 ± 217.8 µM h and following IV infusion, 12.5 ± 3.13, 584 ± 86.6, and 1394.64 ± 682.2 µM h, respectively. The AUC and Cmax of dFdCTP after BAI were higher than IV. The median OS was 6.27 months. No grade 3 or 4 toxicity was observed. The most common side effects were all grade ≤ 2 involving nausea, vomiting, rigor, thrombocytopenia, and anemia.

Conclusions: Systemic exposure to dFdCTP was higher after BAI than IV in two out of three patients.
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http://dx.doi.org/10.1007/s00280-018-3757-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6859936PMC
February 2019

Genetically engineered minipigs model the major clinical features of human neurofibromatosis type 1.

Commun Biol 2018 2;1:158. Epub 2018 Oct 2.

Recombinetics Inc., 1246 University Avenue W., Suite 301, St. Paul, MN, 55104, USA.

Neurofibromatosis Type 1 (NF1) is a genetic disease caused by mutations in (). NF1 patients present with a variety of clinical manifestations and are predisposed to cancer development. Many NF1 animal models have been developed, yet none display the spectrum of disease seen in patients and the translational impact of these models has been limited. We describe a minipig model that exhibits clinical hallmarks of NF1, including café au lait macules, neurofibromas, and optic pathway glioma. Spontaneous loss of heterozygosity is observed in this model, a phenomenon also described in NF1 patients. Oral administration of a mitogen-activated protein kinase/extracellular signal-regulated kinase inhibitor suppresses Ras signaling. To our knowledge, this model provides an unprecedented opportunity to study the complex biology and natural history of NF1 and could prove indispensable for development of imaging methods, biomarkers, and evaluation of safety and efficacy of NF1-targeted therapies.
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http://dx.doi.org/10.1038/s42003-018-0163-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6168575PMC
October 2018

Pharmacokinetic-pharmacodynamic modelling of acute N-terminal pro B-type natriuretic peptide after doxorubicin infusion in breast cancer.

Br J Clin Pharmacol 2016 09 3;82(3):773-83. Epub 2016 Jun 3.

Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, MN, 55455, USA.

Aims: The aim of the present study was to develop a pharmacokinetic-pharmacodynamic (PK-PD) model to characterize the relationship between plasma doxorubicin and N-terminal pro B-type natriuretic peptide (NT-proBNP) concentrations within 48 h of doxorubicin treatment.

Methods: The study enrolled 17 female patients with stages 1-3 breast cancer and receiving adjuvant doxorubicin (60 mg m(-2) ) and cyclophosphamide (600 mg m(-2) ) every 14 days for four cycles. In two consecutive cycles, plasma concentrations of doxorubicin, doxorubicinol, troponin and NT-proBNP were collected before infusion, and up to 48 h after the end of doxorubicin infusion. Nonlinear mixed-effects modelling was used to describe the PK-PD relationship of doxorubicin and NT-proBNP.

Results: A three-compartment parent drug with a one-compartment metabolite model best described the PK of doxorubicin and doxorubicinol. Troponin concentrations remained similar to baseline. An indirect PD model with transit compartments best described the relationship of doxorubicin exposure and acute NT-proBNP response. Estimated PD parameters were associated with large between-subject variability (total assay variability 38.8-73.9%). Patient clinical factors, including the use of enalapril, were not observed to be significantly associated with doxorubicin PK or NT-proBNP PD variability.

Conclusion: The relationship between doxorubicin concentration and the acute NT-proBNP response was successfully described with a population PK-PD model. This model will serve as a valuable framework for future studies to identify clinical factors associated with the acute response to doxorubicin. Future studies are warranted to examine the relationship between this acute response and subsequent heart failure. Should such a relationship be established, this model could provide useful information on patients' susceptibility to doxorubicin-induced long-term cardiotoxicity.
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http://dx.doi.org/10.1111/bcp.12989DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5338127PMC
September 2016

Personalized fludarabine dosing to reduce nonrelapse mortality in hematopoietic stem-cell transplant recipients receiving reduced intensity conditioning.

Transl Res 2016 09 31;175:103-115.e4. Epub 2016 Mar 31.

Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, Minn. Electronic address:

Patients undergoing hematopoietic cell transplantation (HCT) with reduced intensity conditioning (RIC) commonly receive fludarabine. Higher exposure of F-ara-A, the active component of fludarabine, has been associated with a greater risk of nonrelapse mortality (NRM). We sought to develop a model for fludarabine dosing in adult HCT recipients that would allow for precise dose targeting and predict adverse clinical outcomes. We developed a pharmacokinetic model from 87 adults undergoing allogeneic RIC HCT that predicts F-ara-A population clearance (Clpop) accounting for ideal body weight and renal function. We then applied the developed model to an independent cohort of 240 patients to identify whether model predictions were associated with NRM and acute graft versus host disease (GVHD). Renal mechanisms accounted for 35.6% of total F-ara-A Clpop. In the independent cohort, the hazard ratio of NRM at day 100 was significantly higher in patients with predicted F-ara-A clearance (Clpred) <8.50 L/h (P < 0.01) and area under the curve (AUCpred) >6.00 μg × h/mL (P = 0.01). A lower Clpred was also associated with more NRM at month 6 (P = 0.01) and trended toward significance at 12 months (P = 0.05). In multivariate analysis, low fludarabine clearance trended toward higher risk of acute GVHD (P = 0.05). We developed a model that predicts an individual's systemic F-ara-A exposure accounting for kidney function and weight. This model may provide guidance in dosing especially in overweight individuals and those with altered kidney function.
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http://dx.doi.org/10.1016/j.trsl.2016.03.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5003687PMC
September 2016

Randomized, blinded trial of vitamin D3 for treating aromatase inhibitor-associated musculoskeletal symptoms (AIMSS).

Breast Cancer Res Treat 2016 Feb 11;155(3):501-12. Epub 2016 Feb 11.

Park Nicollet Frauenshuh Cancer Center, Minneapolis, MN, USA.

The purpose of the study was to evaluate the efficacy and safety of vitamin D3 at 4000 IU/day as a treatment option for aromatase inhibitor-associated musculoskeletal symptoms (AIMSS) when compared with the usual care dose of 600 IU D3. We conducted a single site randomized, double-blind, phase 3 clinical trial in women with AIMSS comparing change in symptoms, reproductive hormones and AI pharmacokinetics. Postmenopausal women ≥18 years with stages I-IIIA breast cancer, taking AI and experiencing AIMSS [breast cancer prevention trial symptom scale-musculoskeletal (BCPT-MS) subscale ≥1.5] were admitted. Following randomization, 116 patients had a run-in period of 1 month on 600 IU D3, then began the randomized assignment to either 600 IU D3 (n = 56) or 4000 IU D3 (n = 57) daily for 6 months. The primary endpoint was a change in AIMSS from baseline (after 1 month run-in) on the BCPT-MS (general MS pain, joint pain, muscle stiffness, range for each question: 0 = not at all to 4 = extremely). Groups had no statistically significant differences demographically or clinically. There were no discernable differences between the randomly allocated treatment groups at 6 months in measures of AIMSS, pharmacokinetics of anastrozole and letrozole, serum levels of reproductive hormones, or adverse events. We found no significant changes in AIMSS measures between women who took 4000 IU D3 daily compared with 600 IU D3. The 4000 IU D3 did not adversely affect reproductive hormone levels or the steady state pharmacokinetics of anastrozole or letrozole. In both groups, serum 25(OH)D remained in the recommended range for bone health (≥30 ng/mL) and safety (<50 ng/mL).
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http://dx.doi.org/10.1007/s10549-016-3710-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5260816PMC
February 2016

Pathway-based pharmacogenomics of gemcitabine pharmacokinetics in patients with solid tumors.

Pharmacogenomics 2012 Jul;13(9):1009-21

Department of Experimental & Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, MN, USA.

Aim: The aim of this study was to evaluate the association of gemcitabine pathway SNPs with detailed pharmacokinetic measures obtained from solid tumor patients receiving gemcitabine-based therapy.

Materials & Methods: SNPs within nine gemcitabine pathway genes, namely CDA, CMPK, DCK, DCTD, NT5C2, NT5C3, SLC28A1, SLC28A3 and SLC29A1 were analyzed for association with gemcitabine pharmacokinetics.

Results: Significant association of gemcitabine clearance with SNPs in NT5C2 was identified. Clearance of 2´,2´-difluorodeoxyuridine, a gemcitabine metabolite was significantly predicted by CDA, SLC29A1 and NT5C2 SNPs. This study reports an association of formation clearance of 2´,2´-difluoro-2´-deoxycytidine triphosphate, an active form of gemcitabine with SNPs within uptake transporters SLC28A1, SLC28A3 and SLC29A1.

Conclusion: Genetic variation in gemcitabine pathway genes is associated with its pharmacokinetics and hence could influence gemcitabine response. Our study identified pharmacogenetic markers that could be further tested in larger patient cohorts and could open up opportunities to individualize therapy in solid tumor patients.
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http://dx.doi.org/10.2217/pgs.12.81DOI Listing
July 2012

Cytotoxic purine nucleoside analogues bind to A1, A2A, and A3 adenosine receptors.

Naunyn Schmiedebergs Arch Pharmacol 2012 May 17;385(5):519-25. Epub 2012 Jan 17.

College of Pharmacy, Department of Experimental and Clinical Pharmacology, University of Minnesota, 308 Harvard ST SE, Minneapolis, MN, USA.

Fludarabine, clofarabine, and cladribine are anticancer agents which are analogues of the purine nucleoside adenosine. These agents have been associated with cardiac and neurological toxicities. Because these agents are analogues of adenosine, they may act through adenosine receptors to elicit their toxic effects. The objective of this study was to evaluate the ability of cytotoxic nucleoside analogues to bind and activate adenosine receptor subtypes (A(1), A(2A), A(2B), and A(3)). Radioligand binding studies utilizing Chinese hamster ovary cells, stably transfected with adenosine A(1), A(2A), or A(3) receptor subtype, were used to assess the binding affinities of these compounds, whereas adenylyl cyclase activity was used to assess the binding to A(2B) receptors. Clofarabine and cladribine both bound to the A(2A) receptor with a K (i) of 17 and 15 μM, respectively. Clofarabine was the only adenosine analogue to bind to the A(3) receptor with a K (i) of 10 μM, and none of these compounds bound to the A(2B) receptor. Results show that clofarabine, cladribine, and fludarabine bind to the A(1) receptor. In addition, clofarabine, cladribine, and fludarabine were A(1) agonists (IC(50) 3.1, 30, and 30 μM, respectively). Neither pyrimidine nucleoside analogues gemcitabine nor cytarabine associated with any of the adenosine receptor subtypes (K (i) > 100μM). This is the first report of an interaction between all adenosine receptor subtypes and chemotherapeutic nucleoside analogues commonly used in the treatment of cancer. Therefore, activation of these receptors may be at least one mechanism through which fludarabine-associated toxicity occurs.
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http://dx.doi.org/10.1007/s00210-011-0719-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3831620PMC
May 2012

Pharmacodynamic modeling of sequence-dependent antitumor activity of insulin-like growth factor blockade and gemcitabine.

AAPS J 2012 Mar 19;14(1):1-9. Epub 2011 Nov 19.

Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, 55455, USA.

Agents that block insulin-like growth factor (IGF) signaling are under investigation in clinical trials. Antitumor effects are likely to be enhanced when combined with other agents, but administration sequence effects on activity are not well-described. Three breast cancer cell lines (MCF-7, MDA-MB-231, and Hs-578T) were treated with Gemcitabine and small molecule receptor tyrosine kinase inhibitor cis-3-[3-(4-methyl-piperazin-l-yl)-cyclobutyl]1-(2-phenyl-quinolin-7-yl)-imidazo [1,5-a]pyrazin-8-ylamine (PQIP) as single agents and then in combination in the forward (Gemcitabine followed by PQIP) and reverse (PQIP followed by Gemcitabine) sequences. Antitumor effects were assessed longitudinally by Bayesian analysis using WinBUGS. The pharmacodynamic model adequately predicted the observed data. The differences in the cell-kill rate constants for the forward vs. reverse sequence ranged from 0.11 to 0.64 (day(-1)), and statistical significance was generally dependent on cell line and PQIP concentration. These data indicate that treatment with Gemcitabine first, followed by PQIP is superior to the reverse sequence in vitro.
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http://dx.doi.org/10.1208/s12248-011-9308-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3291184PMC
March 2012

Combinatorial pharmacologic effects of gemcitabine and its metabolite dFdU.

ChemMedChem 2011 Mar 30;6(3):457-64. Epub 2011 Jan 30.

Department of Medicine, Medical School, University of Minnesota, Minneapolis, Minnesota 55414, USA.

Recent evidence has shown that the gemcitabine metabolite, dFdU, is pharmacologically active. Though less potent, dFdU has a longer half-life and could potentiate or antagonize the activity of gemcitabine. Hence, studies were undertaken to evaluate the combined effects. Following chemical synthesis, an improved purification procedure for dFdU was developed (80 % yield; >99 % purity). Zebrafish phenotype-based embryo screens revealed no acute toxicity after gemcitabine or dFdU treatment. Only gemcitabine affected zebrafish development in a dose-dependent manner. Synergy or antagonism for the combination was not observed. Antitumor effects for dFdU were dose dependent. Antagonism was tumor cell-line dependent and did not depend on formation of the intracellular active metabolite of gemcitabine, suggesting that the drug-metabolite interaction occurs later. These studies highlight a platform for testing the pharmacologic activity for anticancer agent and metabolite combinations. Such analyses are expected to provide insight into the beneficial or harmful effect(s) of metabolites towards parent drug activity.
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http://dx.doi.org/10.1002/cmdc.201000447DOI Listing
March 2011

Effect of radiation on the penetration of irinotecan in rat cerebrospinal fluid.

Cancer Chemother Pharmacol 2011 Sep 16;68(3):721-31. Epub 2010 Dec 16.

Department of Experimental and Clinical Pharmacology, University of Minnesota, Minneapolis, MN, USA.

Purpose: Anticancer agents are useful for treating brain tumors, but sub therapeutic concentrations due to decreased blood-brain barrier (BBB) penetration limit their effectiveness. This study evaluated the effect of cranial radiation on the pharmacokinetics of irinotecan in plasma and cerebrospinal fluid (CSF).

Methods: Rats (n = 48) were treated with irinotecan (10 mg/kg), and then administered 10 or 20 Gy or sham irradiation as control after drug. The pharmacokinetics for irinotecan, SN-38, and APC were measured in plasma and CSF over 6 h. Up to 7 plasma samples per animal were collected, and one CSF sample was collected per animal (serial sacrifice design). Population pharmacokinetic analysis was performed with NONMEM, and radiation tested as a covariate for the fraction of irinotecan (f(CSF)) entering the CSF.

Results: The estimate of f(CSF) (% and RSE) was 0.165 (73.5) for the control group and 0.265 (66.5) for radiation-treated groups, respectively (P < 0.05). Predictive check plots showed that the model adequately described the overall trend and variability in the observed data. The median values of bootstrap parameters were similar to the NONMEM estimates based on the original data set.

Conclusions: These results indicate that cranially administered radiation can increase the penetration of anticancer agents such as irinotecan into the CSF. Studies that evaluate radiation-fractionation, radiation-time course effect relationships, blood-brain barrier and blood-tumor barrier effects for irinotecan and other anticancer agents are warranted.
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http://dx.doi.org/10.1007/s00280-010-1542-3DOI Listing
September 2011

Phase 1 trial of gemcitabine with bortezomib in elderly patients with advanced solid tumors.

Am J Clin Oncol 2011 Dec;34(6):597-602

Department of Medicine, Division of Hematology, Oncology and Transplantation, Comprehensive Cancer Center, University of Minnesota, Minneapolis, USA.

Introduction: Bortezomib, a proteasome inhibitor, has synergistic antitumor activity with gemcitabine, an antimetabolite, in preclinical and clinical studies. The safety of this combination has not yet been established in elderly patients; therefore, this dose-escalation study was designed to assess the maximum-tolerated dose of bortezomib and gemcitabine in patients aged 70 years or older with advanced-stage solid tumors.

Patients And Methods: Gemcitabine was administered intravenously (800 to 1000 mg/m) over 30 minutes on days 1 and 8, followed 60 minutes later by bortezomib administered as an intravenous push over 3 to 5 seconds (1.0 to 1.8 mg/m) on a 21-day cycle. This study used a standard phase 1 dose-escalation design with 3 or 6 patients per dose level.

Results: Seventeen patients with stage IV solid tumors were treated. Median age was 73 years (range: 70 to 87 y). All patients had an Eastern Cooperative Oncology Group (ECOG) performance status less than 2. Median number of earlier chemotherapy regimens was 2 (range: 0 to 6). Dose-limiting toxicities were seen in 2 of 8 patients enrolled at the second dose level of gemcitabine (1000 mg/m) and bortezomib (1.0 mg/m), which consisted of grade ≥3 lower extremity edema, thrombocytopenia, fatigue, and dehydration. The most common grade ≥3 toxicities included thrombocytopenia (n=9), neutropenia (n=6), and anemia (n=5). Partial response (n=3) or disease stabilization (n=3) was seen in 6 of 14 evaluable patients.

Conclusions: Concurrent weekly gemcitabine (800 mg/m) and bortezomib (1 mg/m) is the recommended schedule for future phase 2 trials in elderly patients with stage IV solid tumors.
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http://dx.doi.org/10.1097/COC.0b013e3181f9441fDOI Listing
December 2011

Severe electrolyte disturbances after hyperthermic intraperitoneal chemotherapy: oxaliplatin versus mitomycin C.

Ann Surg Oncol 2011 Jan 8;18(1):174-80. Epub 2010 Jul 8.

Division of Surgical Oncology, Department of Surgery, University of Minnesota, Minneapolis, MN, USA.

Background: Oxaliplatin (OX) is increasingly used for hyperthermic intraperitoneal chemotherapy (HIPC) for patients with peritoneal metastases. Our aim was to review electrolyte disturbances and complications after HIPC with oxaliplatin (OX) versus mitomycin C (MMC).

Materials And Methods: We included patients enrolled in single-institution prospective clinical trials who underwent cytoreductive surgery and HIPC with MMC or OX. We reviewed patient demographics, pathology, perioperative course, HIPC administration, and postoperative electrolyte disturbances. Measured postoperative sodium values were corrected for systemic hyperglycemia using the formula: (measured Na(+)) × [(glucose - 100/100) × 1.6].

Results: From January 2002 to April 2009 we performed 80 HIPC procedures. A total of 60 patients (75%) received MMC (dose range 12.5-50 mg/m(2)) carried in lactated ringers solution. There were 20 patients (25%) who received OX (dose range 300 × 400 mg/m(2)) carried in 5% dextrose solution. For patients receiving HIPC with OX, electrolyte disturbances were the most common complication. Compared with MMC, patients receiving OX had significant 24-h postoperative uncorrected hyponatremia (P < 0.001), corrected hyponatremia (P < 0.001), hyperglycemia (P < 0.001), and metabolic acidosis (P < 0.001). In the OX group, corrected (mean 130.5) and uncorrected (mean 127.4) sodium levels were significantly lower than preoperatively (mean 139.9, P < 0.001). The overall nonelectrolyte complication rate was 56.2%. (MMC n = 33, 55.0%; OX n = 12, 60%); the 30-day mortality rate was 0% in both groups.

Conclusions: Compared with MMC, HIPC with OX was associated with significant but predictable electrolyte disturbances; however, these electrolyte disturbances were not associated with higher overall complication rates. Close monitoring with early correction is imperative to maximize perioperative care. Further studies are needed to provide mechanistic insight.
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http://dx.doi.org/10.1245/s10434-010-1210-1DOI Listing
January 2011

Cytotoxic effect of zoledronic acid-loaded bone cement on giant cell tumor, multiple myeloma, and renal cell carcinoma cell lines.

J Bone Joint Surg Am 2010 Jan;92(1):162-8

Department of Orthopaedic Surgery, University of Minnesota Medical School and Masonic Cancer Center, 2450 Riverside Avenue, R200, Minneapolis, MN 55454, USA.

Background: Local recurrence with subsequent osteolysis is a problem after intralesional curettage of giant cell tumor of bone, myeloma, and metastatic carcinoma. The bisphosphonate zoledronic acid (zoledronate) has been shown to reduce osteoclast activity, and its local administration is a potentially attractive therapy, especially for the osteoclast-rich giant cell tumor. The aim of this study was to analyze the elution dynamics of zoledronic acid release from acrylic bone cement and its in vitro antitumor efficacy.

Methods: Various concentrations of zoledronic acid were mixed with bone cement and placed in distilled water. The concentration in the water was measured daily for fourteen days. The cytotoxic effects of the dissolved zoledronic acid on cultures of multiple myeloma, giant cell tumor, and renal cell carcinoma cells were tested with use of the MTT assay (tetrazolium [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] dye) and analyzed according to the zoledronic acid concentration and the elapsed time.

Results: The release of zoledronic acid was greatest during the first twenty-four hours for all concentrations and decreased rapidly during the next forty-eight hours to reach a plateau after four days. The proliferation assay (MTT) showed zoledronic acid to have significant cytotoxicity in cultures of stromal giant cell tumor, multiple myeloma, and renal cell carcinoma cells. In addition, zoledronic acid decreased the number of viable tumor cells in a dose-dependent manner. Renal cell carcinoma from bone (RBM1-IT4) and stromal giant cell tumor of bone were more susceptible to zoledronic acid than was multiple myeloma.

Conclusions: The method presented in our study is a reproducible technique for evaluating zoledronic acid elution from bone cement and determining its impact on tumor growth. Zoledronic acid is released from bone cement, remains biologically active despite the polymerization of cement, and inhibits the in vitro growth of cell lines from giant cell tumor of bone, myeloma, and renal cell carcinoma.
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http://dx.doi.org/10.2106/JBJS.H.01679DOI Listing
January 2010

Cap-dependent translation blockade and fixed dose-rate gemcitabine: interaction in an in vitro bioreactor system.

Cancer Lett 2009 Oct 12;284(1):37-46. Epub 2009 May 12.

Department of Experimental and Clinical Pharmacology, College of Pharmacy and Comprehensive Cancer Center, University of Minnesota, 717 Delaware St. SE, Minneapolis, MN 55414, USA.

Translation initiation commences with the binding of eIF-4F to the mRNA 5'-end cap. eIF-4F binds the cap structure via its eIF-4E subunit, which is the rate-limiting step for the initiation of translation. This pathway can be inhibited by 4E-binding proteins (4E-BPs). The present study investigated prolonged gemcitabine infusion in combination with reduced eIF-4E function on NSCLC cell viability in an in vitro bioreactor system. To assess attachment to the hollow fibers, cells with dominant active 4E-BP1 were first analyzed by scanning electron microscopy. Cells were treated with 0.5- or 2.5h (fixed dose rate) infusion (same total dose), simulating human plasma gemcitabine concentration-time profiles. An interaction was observed between fixed dose rate infusion gemcitabine and presence of dominant active 4E-BP1. We conclude that cap-dependent translation blockade and fixed dose rate infusion gemcitabine treatment results in a significant interaction affecting cell viability in vitro.
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http://dx.doi.org/10.1016/j.canlet.2009.04.006DOI Listing
October 2009

Review of selected patents for cancer therapy targeting tumor angiogenesis.

Recent Pat Anticancer Drug Discov 2006 Jun;1(2):153-61

Department of Experimental and Clinical Pharmacology, College of Pharmacy and Comprehensive Cancer Center, University of Minnesota, Minneapolis, Minnesota 55455, USA.

Targeting tumor angiogenesis to treat cancer has been the focus of intense research in recent decades. The resulting increase in our knowledge of cancer biology has lead to the development of several new classes of investigational agents that inhibit the angiogenic process. While many clinical trials on antiangiogenic compounds have had disappointing results, the recent approval of the first effective drug targeting tumor vessels has revived interest in further drug development for angiogenesis inhibitors. Of the plethora of new patents for antiangiogenic compounds, only a few describe compounds that will become effective and non-toxic therapies for patients with cancer. This review examines representative patents related to cancer angiogenesis in the context of our current knowledge of the biological processes leading to tumor vascularization and explores the future of multi-targeted therapy and nanoformulation technology in the field of angiogenic therapy.
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http://dx.doi.org/10.2174/157489206777442269DOI Listing
June 2006

Exposure-response relationships for oxaliplatin-treated colon cancer cells.

Anticancer Drugs 2008 Jan;19(1):37-44

Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis 55455, USA.

Data are lacking for an optimal infusion length for oxaliplatin administered intraperitoneally. Our objectives were to establish the roles of hyperthermia and an effective length of oxaliplatin treatment in maximizing antitumor activity. SW620 cells were treated for 0.5 vs. 2 h and at 37 vs. 42 degrees C. Cytotoxicity, cell cycle analysis, subG1 and survival were assessed with the MTT assay, flow cytometry and the clonogenic assay. The IC50 for cells treated at 37 degrees C was 2.90+/-0.83 microg/ml and at 42 degrees C, 1.99+/-0.66 microg/ml (P=0.14). The Emax for 37 degrees C was 93.9+/-2.57% and for 42 degrees C, 97.8+/-1.59% (P=0.05). The subG1 fraction did not differ between cells treated at 37 and 42 degrees C (P=0.12). The IC50 for the cells treated for 0.5 h was 10.6+/-0.60 microg/ml and for 2 h, 2.80+/-1.70 microg/ml (P=0.02). The Emax for 0.5 h was 87.9+/-5.13% and for 2 h, 96.6+/-3.35% (P=0.09). SubG1 for 0.5 h was 8.24+/-1.33% and for 2 h, 15.8+/-2.45% (P=0.02). Clonogenic assays demonstrated diminished survival when treated with low concentrations (10 microg/ml) of oxaliplatin combined with heat treatment (P=0.017) for 2 h, but not 0.5 h. Similar clonogenic assay experiments were performed with the oxaliplatin-resistant WiDr cell line, and differences in survival following oxaliplatin and heat treatment were again observed for 2 h, but not for 0.5 h (P=0.002). Drug treatment for 2 h of both SW620 and WiDr cell lines is superior to treatment for 0.5 h. Cell kill effects are reliant on treatment length; hence, the choice of time exposure must be made with a view to maintaining a balance between the cell kill effects and the clinical feasibility of treating the patient.
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http://dx.doi.org/10.1097/CAD.0b013e3282f07791DOI Listing
January 2008

Short versus continuous gemcitabine treatment of non-small cell lung cancer in an in vitro cell culture bioreactor system.

Lung Cancer 2007 Nov 25;58(2):196-204. Epub 2007 Jul 25.

Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, MN 55455, USA.

Five-year survival for non-small cell lung cancer is 15%. Gemcitabine is a nucleoside analogue that inhibits ribonucleotide reductase and interferes with DNA replication. In this study, we sought to compare short versus continuous infusion gemcitabine in an in vitro bioreactor system using pharmacokinetic-guided dosing. Gemcitabine was infused over either 0.5 or 2.5h to produce concentration-time profiles that mimic those measured in biological samples (i.e., patient plasma). The effects of gemcitabine on the growth and survival of H2009 cells were examined using trypan blue staining, cell cycle analysis, TUNEL assay, and clonogenic assay. Data were analyzed with two ways analysis of variance. Maximum gemcitabine (Cmax) concentrations during the short infusion were 51.2+/-10.4 microM and for the continuous, 14.8+/-2.93 microM. Steady-state concentrations during the continuous infusions were 14.9+/-2.90 microM. Gemcitabine treatment resulted in a decrease for G1 fraction relative to controls. G2/M, subG1 and TUNEL were higher following gemcitabine relative to controls. Survival was approximately 20-fold higher following the short infusion compared with the continuous infusion (p = 0.0085). In conclusion, gemcitabine infused by this novel method induced apoptosis after both the short and continuous infusions, and long-term survival was significantly diminished following continuous compared with the short infusion.
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http://dx.doi.org/10.1016/j.lungcan.2007.06.005DOI Listing
November 2007

Pharmacodynamic characterization of gemcitabine cytotoxicity in an in vitro cell culture bioreactor system.

Cancer Chemother Pharmacol 2008 Feb 12;61(2):291-9. Epub 2007 Apr 12.

Department of Experimental and Clinical Pharmacology, College of Pharmacy and Comprehensive Cancer Center, University of Minnesota, 308 Harvard St SE, Minneapolis, MN 55455, USA.

Purpose: Gemcitabine, a pyrimidine nucleoside, is approved for the treatment of non-small cell lung cancer, pancreatic carcinoma, and breast cancer. Chemotherapy regimens are determined experimentally with static tissue culture systems, animal models, and in Phase I clinical trials. The aim of this study was to assess for gemcitabine-induced cell death following infusion of drug under clinically-relevant conditions of infusion rate and drug exposure in an in vitro bioreactor system.

Methods: To estimate an appropriate harvest time for cells from the bioreactor after drug treatment, we estimated the temporal relationship between gemcitabine treatment for 1 h and cell death at a later time point with monolayer growth assays (i.e., static culture). Afterward, 5.3 mg gemcitabine was infused over 0.5 h in the bioreactor, followed by mono-exponential decay, simulating patient concentration-time profiles (n = 4). Controls were run with drug-free media (n = 4). Cells were harvested from the bioreactor at a later time point and assessed for cell death by flow cytometry.

Results: According to monolayer growth assay results, cytotoxicity became more apparent with increasing time. The E Max for cells 48 h after treatment was 50% and after 144 h, 93% (P = 0.022; t test), while flow cytometry showed complete DNA degradation by 120 h. Gemcitabine was infused in the bioreactor. The gemcitabine area under the concentration-time curve (AUC) was 56.4 microM h and the maximum concentration was 87.5 +/- 2.65 microM. Flow cytometry results were as follows: the G1 fraction decreased from 65.1 +/- 4.91 to 28.6 +/- 12% (P = 0.005) and subG1 increased from 14.1 +/- 5.28 to 42.6 +/- 9.78% (P = 0.004) relative to control. An increase in apoptotic cells was observed by TUNEL assay.

Conclusions: The in vitro bioreactor system will be expanded to test additional cell lines, and will serve as a useful model system for assessing the role of drug pharmacokinetics in delivery of optimized anticancer treatment.
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http://dx.doi.org/10.1007/s00280-007-0474-zDOI Listing
February 2008

High-performance liquid chromatographic method for the determination of gemcitabine and 2',2'-difluorodeoxyuridine in plasma and tissue culture media.

J Chromatogr B Analyt Technol Biomed Life Sci 2006 May 11;835(1-2):136-42. Epub 2006 Apr 11.

Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, 308 Harvard St SE, Minneapolis, 55455, USA.

Gemcitabine, a pyrimidine antimetabolite undergoes metabolism by plasma and liver cytidine deaminase to form the inactive compound, 2',2'-difluorodeoxyuridine (dFdU). The parent molecule is activated by intracellular phosphorylation. To evaluate the population pharmacokinetics in patients receiving gemcitabine, and to test the relation between gemcitabine infusion rate and antitumor activity in an in vitro bioreactor cell culture system, we developed and validated a sensitive and specific HPLC-UV method for gemcitabine and dFdU. Deproteinized plasma is vortexed, centrifuged, and 25 microL of the acidified extract sample is injected onto a Waters Spherisorb 4.6 mm x 250 mm, 5 microm C18 column at 40 degrees C. The mobile phase (flow rate, 1.0 mL/min) consists of 10:90 (v/v) acetonitrile-aqueous buffer (50 mM sodium phosphate and 3.0 mM octyl sulfonic acid, pH 2.9). Gemcitabine, dFdU, and the internal standard, 2'-deoxycytidine (2'dC) were detected with UV wavelength set at 267 nm. The standard curves for gemcitabine in both matrices ranged from 2 to 200 microM, and for dFdU in plasma, from 2 to 100 microM. Within-run and between-run component precision (CV%) was
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http://dx.doi.org/10.1016/j.jchromb.2006.03.023DOI Listing
May 2006

Characterization of an in vitro cell culture bioreactor system to evaluate anti-neoplastic drug regimens.

Breast Cancer Res Treat 2006 Apr;96(3):217-25

Department of Experimental and Clinical Pharmacology, College of Pharmacy and Comprehensive Cancer Center, University of Minnesota, Minneapolis 55455, USA.

A dynamic 3-dimensional tissue culture system has been developed that will allow for control of gemcitabine exposure to mimic concentration-time profiles measured from biologic samples. Gemcitabine was infused into a central reservoir. Media is mixed and delivered through hollow fiber capillaries, where it diffuses into the extracapillary space containing anchorage-dependent MDA-231 cells. To test for control of gemcitabine concentration-time profiles, drug was first infused through bioreactors without cells, and gemcitabine concentrations were measured with HPLC. Concentrations could be controlled to simulate 30-min and 2.5 h infusions, and were similar in both the lumen and extracapillary space. MDA-231 cells were then seeded into control (n = 4) and gemcitabine treatment (n = 4) groups, and maintained in culture for 2 weeks. Gemcitabine (5.3 mg) was infused over 30 min to the treatment group, and blank media to the control group. Accuracy of measured gemcitabine maximum concentration (Cmax) was 83.4%, and area under the curve (AUC), 106.2%, relative to pre-experimental theoretical values. With cells present, gemcitabine AUC in the extracapillary space was 32% of the value in the lumen. For the control group, 21.2 million cells (94.3% viable) were recovered, and for the gemcitabine-treated group, 16.8 million cells (87.1 % viable). Flow cytometry showed that 13.3 % of cells in the control group were in S-phase and 34.3 % in the gemcitabine-treated group were in S-phase (p = 0.003). In conclusion, gemcitabine concentration-time profiles could be accurately controlled through dosage, infusion rate, and pump flow rate, and cells could be recovered afterward to evaluate drug treatment.
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http://dx.doi.org/10.1007/s10549-005-9004-zDOI Listing
April 2006

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.

Cancer Invest 2005 ;23(6):511-9

The Multidisciplinary Thoracic Oncology Program, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina, USA.

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.
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http://dx.doi.org/10.1080/07357900500201400DOI Listing
November 2005

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

Cancer Chemother Pharmacol 2005 May 26;55(5):433-8. Epub 2005 Jan 26.

Department of Pharmaceutical Sciences, St Jude Children's Research Hospital, 332 N. Lauderdale, Memphis, TN 38105, USA.

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.
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http://dx.doi.org/10.1007/s00280-004-0896-9DOI Listing
May 2005

A mechanistic mathematical model of temozolomide myelosuppression in children with high-grade gliomas.

Math Biosci 2003 Nov;186(1):29-41

Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, 332 North Lauderdale St., Memphis, TN 38105-2794, USA.

Temozolomide (TMZ) is currently being evaluated for the treatment of high-grade gliomas in children. Myelosuppression (the suppression of bone marrow activity) is the dose-limiting toxicity for TMZ in adults and children. Empirical methods (i.e. relations between the percent change in absolute neutrophil count (ANC) and the area under the plasma concentration curve (AUC) of TMZ or its active metabolite MTIC) showed poor results when attempting to describe myelosuppression from serial data derived during TMZ therapy in a Phase II study of children with high-grade glioma. Therefore, to improve our understanding of the myelosuppressive effects of TMZ and MTIC in children we developed a mechanistic mathematical model. The model describes the progression of neutrophils from their production in the bone marrow to their release in the plasma. Included in the model are the feedback effects of granulocyte colony stimulating factor (G-CSF), which stimulates neutrophil production when there is a decrease in circulating neutrophils. The model is fit to serial ANC measurements obtained after TMZ dosing and it is able to explain, among other things, the lag in ANC reduction following a dose of TMZ, the ANC nadir, and the 'rebound effect' observed where the ANC recovers to levels greater than that observed pre-TMZ dose. This model will be useful for the prospective design of clinical trials of TMZ in children with cancer.
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http://dx.doi.org/10.1016/j.mbs.2003.07.002DOI Listing
November 2003

Population pharmacokinetics of temozolomide and metabolites in infants and children with primary central nervous system tumors.

Cancer Chemother Pharmacol 2003 Dec 16;52(6):435-41. Epub 2003 Sep 16.

Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, 332 N. Lauderdale, Memphis, TN 38105, USA.

Purpose: To construct a population pharmacokinetic model for temozolomide (TMZ), a novel imidazo-tetrazine methylating agent and its metabolites MTIC and AIC in infants and children with primary central nervous system tumors.

Methods: We evaluated the pharmacokinetics of TMZ and MTIC in 39 children (20 boys and 19 girls) with 132 pharmacokinetic studies (109 in the training set and 23 in the validation set). The median age was 7.1 years (range 0.7 to 21.9 years). Children received oral TMZ dosages ranging from 145 to 200 mg/m(2) per day for 5 days in each course of therapy. Serial plasma samples were collected after the first and fifth doses of the first and third courses. Approximately eight plasma samples were collected up to 8 h after each dose, and assayed for TMZ, MTIC, and AIC by HPLC with UV detection. A one-compartment model was fitted to the TMZ and metabolite plasma concentrations using maximum likelihood estimation. Covariates, including demographics and biochemical data were tested for their effects on TMZ clearance (CL/F) and MTIC AUC utilizing a two-stage approach via linear mixed-effects modeling.

Results: The population mean (inter- and intrapatient variability expressed as %CV) for the pharmacokinetic parameters (based on the training set) were as follows: TMZ CL/F 5.4 l/h (53.4, 17.5), Vc/F 14.0 l (48.5, 39.2), C(max) 9.1 mg/l (20.8, 29.1), and MTIC AUC 1.0 microg/ml.h (13.9, 30.0). Covariate analysis showed that increasing age and body surface area (BSA) were associated with a significant increases in TMZ CL, Vc, and C(max) ( P<0.05), and that increasing age was associated with significant decreases in TMZ and MTIC AUC. Indicators of liver and renal function were not significantly associated with TMZ pharmacokinetics or MTIC AUC. The final model with the significant covariates was validated using the remaining 23 pharmacokinetic studies.

Conclusions: This study extends previous work done in adults, and identified BSA and age as covariates that account for variability in TMZ disposition in infants and children with primary CNS malignancies.
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http://dx.doi.org/10.1007/s00280-003-0670-4DOI Listing
December 2003

Molecular targets in the inhibition of angiogenesis.

Expert Opin Ther Targets 2003 Aug;7(4):527-41

Division of Hematology, Oncology and Transplantation, Department of Medicine and Comprehensive Cancer Center, 420 Delaware Street, MMC 480, University of Minnesota, Minneapolis, MN 55455, USA.

Angiogenesis, the process of blood vessel formation, is crucial for malignant tumour growth and metastases; therefore, it has become an attractive target for anticancer therapy. Theoretically applicable to most solid tumours, this therapy may be advantageous over existing cytotoxic therapy, since it is directed at genetically stable endothelium growing within tumours rather than at malignant cells, which acquire resistance to treatment. Many promising angiogenesis inhibitors have been developed, although their activity has yet to be demonstrated in human clinical trials. To improve therapeutic benefit, this may require further insight into tumour angiogenesis, development of appropriate surrogate markers of activity, treatment of early stage neoplastic disease and probably a combination of different classes of antiangiogenesis agents to overcome redundant mechanisms of angiogenesis control.
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http://dx.doi.org/10.1517/14728222.7.4.527DOI Listing
August 2003

Topoisomerase I interactive agents.

Cancer Chemother Biol Response Modif 2002 ;20:99-123

Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, 332 N. Lauderdale, Memphis, TN 38105, USA.

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.
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May 2003