PubMed Health⌕ Search

Biomedical subjects

Mark J Ratain

Publications and source records attributed to Mark J Ratain.

At least 19 recordsLinked to original sources
PubMed2007

The role of SN-38 exposure, UGT1A1*28 polymorphism, and baseline bilirubin level in predicting severe irinotecan toxicity.

Irinotecan, an anticancer drug, is associated with severe and potentially fatal diarrhea and neutropenia. The objective of this analysis was to evaluate the role of SN-38 exposure, the active metabolite of irinotecan, UGT1A1 genotypes, and baseline bilirubin on the maximum decrease (nadir) in absolute neutrophil counts following irinotecan. This analysis extended the work of a previous study that examined the effect of UGT1A1 genotypes on the incidence of severe neutropenia in 86 advanced cancer patients following irinotecan treatment. Regression analysis showed that the absolute neutrophil count nadir depended on SN-38 exposure (AUC) and UGT1A1*28 homozygous 7/7 genotype. An increased SN-38 AUC and the 7/7 genotype were significantly associated with a lower absolute neutrophil count nadir (R2 = .49). An alternate model suggested that higher baseline bilirubin and the 7/7 genotype were also significantly associated with a lower absolute neutrophil count nadir, although with a lower coefficient of determination (R2 = .31). Based on these findings and other reports, the irinotecan label was modified to indicate the role of UGT1A1*28 polymorphism in the metabolism of irinotecan and the associated increased risk of severe neutropenia. The label modifications also included recommendations for lower starting doses of irinotecan in patients homozygous for the UGT1A1*28 (7/7) polymorphism.

Antineoplastic Agents, Phytogenic↗
PubMed2006

Pharmacogenomics: challenges and opportunities.

The outcome of drug therapy is often unpredictable, ranging from beneficial effects to lack of efficacy to serious adverse effects. Variations in single genes are 1 well-recognized cause of such unpredictability, defining the field of pharmacogenetics (see Glossary). Such variations may involve genes controlling drug metabolism, drug transport, disease susceptibility, or drug targets. The sequencing of the human genome and the cataloguing of variants across human genomes are the enabling resources for the nascent field of pharmacogenomics (see Glossary), which tests the idea that genomic variability underlies variability in drug responses. However, there are many challenges that must be overcome to apply rapidly accumulating genomic information to understand variable drug responses, including defining candidate genes and pathways; relating disease genes to drug response genes; precisely defining drug response phenotypes; and addressing analytic, ethical, and technological issues involved in generation and management of large drug response data sets. Overcoming these challenges holds the promise of improving new drug development and ultimately individualizing the selection of appropriate drugs and dosages for individual patients.

Clinical Medicine↗
PubMed2006

Effects of green tea compounds on irinotecan metabolism.

The effects of green tea compounds on the metabolism of irinotecan have never been investigated. We aimed to study whether catechins [(-)-epigallocatechin gallate (EGCG), (-)-epicatechin gallate (ECG), (-)-epigallocatechin (EGC), (-)-epicatechin] affect the inactivation metabolism of irinotecan into 7-ethyl-10-[4-N-(1-piperidino)-1-amino]carbonyloxycamptothecin (NPC) (by CYP3A4) and 7-ethyl-10-hydroxycamptothecin (SN-38) into 7-ethyl-10-hydroxycamptothecin glucuronide (SN-38G) (by UGT1A1). Human liver microsomes, hepatocytes and Hep G2 cells were incubated with catechins and treated with irinotecan and/or SN-38. NPC and SN-38G formation was measured by high-performance liquid chromatography. UGT1A1 mRNA levels were measured by real-time polymerase chain reaction. In human liver microsomes, a concentration-dependent decrease in the formation of NPC and SN-38G was observed. In human hepatocytes, a significant increase in SN-38G production was observed in 33% (EGCG), 44% (ECG), and 44% (EGC) of the hepatocyte preparations. Phenobarbital increased the formation of SN-38G in 100% of the same hepatocyte preparations. In Hep G2 cells, no increase in SN-38G formation was observed. With the exception of ECG in one liver, catechins did not increase UGT1A1 mRNA levels. NPC production was also significantly increased in 40% of the hepatocyte preparations for each catechin. However, the production of 6beta-hydroxytestosterone remained unaffected in other hepatocyte preparations. At pharmacologically relevant concentrations, catechins are unlikely to inhibit the formation of irinotecan inactive metabolites when administered concomitantly. The induction effect of catechins on UGT1A1 seems to be modest and highly variable. Catechins do not induce CYP3A4 activity. The effect of acute and prolonged use of green tea on the pharmacokinetics of irinotecan in patients remains to be evaluated.

Antineoplastic Agents, Phytogenic↗
PubMed2006

TPMT, UGT1A1 and DPYD: genotyping to ensure safer cancer therapy?

The Food and Drug Administration (FDA) has approved label changes for two anticancer drugs, 6-mercaptopurine (6-MP) and irinotecan, to include pharmacogenetic testing as a potential means to reduce the rate of severe toxic events. Comprehensive evaluation of the clinical benefit and cost effectiveness of screening strategies with these tests has not been completed. However, the FDA decided that evidence indicates sufficient benefit to warrant informing prescribers, pharmacists and patients of the availability of pharmacogenetic tests and their possible role in the selection and dosing of these anticancer agents. Reviewing the gene-drug-phenotype relationships of 6-MP, irinotecan and 5-fluorouracil reveals properties of these relationships that lead to a clinically useful pharmacogenetic test. Research in the near future should clarify the role of pharmacogenetic testing in reducing the risk of severe toxicity and determine how these same tests might identify a subset of patients who should safely receive higher doses of treatment to derive the same benefit as the rest of the patient population.

Camptothecin↗
PubMed2006

The cancer and leukemia group B pharmacology and experimental therapeutics committee: a historical perspective.

The Chemotherapy Committee of Cancer and Leukemia Group B (CALGB) was established in the mid-1970s to assemble a group of experts in cancer chemotherapy and pharmacology who could advise the CALGB disease committees about the optimal use of drugs in the fight against cancer and to provide quality assurance for the chemotherapy section of CALGB protocols. Chaired initially by Edward Henderson and then David Van Echo, the committee was also the repository of studies in diseases for which CALGB did not have a formal committee, such as testis cancer and sarcoma. In 1990, following the appointment of Richard Schilsky as Chair, the name of the committee was changed to the Pharmacology and Experimental Therapeutics (PET) Committee to reflect a more specific focus and scientific agenda (i.e., studies of chemotherapy pharmacology and development of new agents). Three PET Committee reference pharmacology laboratories (led by Merrill Egorin, Tony Miller, and Mark Ratain) were established to measure drug concentrations in biological fluids and to perform pharmacokinetic analyses. In addition, the PET Committee embarked on a number of multi-institution phase I studies. These phase I studies included studies of special populations, including the first prospective study of an anticancer agent (paclitaxel) in patients with hepatic dysfunction. In addition, the Committee studied a number of phase I combinations destined for phase II evaluation in disease-specific committees. Following Dr. Schilsky's election as CALGB Group Chair in 1994, Mark Ratain took over as Chair of the PET Committee and continued to emphasize population pharmacology as the primary theme of the Committee's research agenda. In addition, the PET Committee began to develop novel clinical trial designs, including the first completed randomized discontinuation trial of an antineoplastic agent. Most recently, the PET Committee has launched an ambitious research program in pharmacogenetics, facilitated in large part through the recruitment of Howard McLeod as Vice Chair. This area of research is a collaborative effort with the NIH Pharmacogenetics Research Network and has the potential to definitively address the hypothesis that germ line polymorphisms are a significant determinant of the toxicity and efficacy of anticancer therapy. It is anticipated that the results of the current studies will contribute significantly to the goal of individualizing cancer treatment.

Antineoplastic Agents↗
PubMed2006

Interpreting disparate responses to cancer therapy: the role of human population genetics.

Increasingly, investigators are recognizing differences in tumor biology, drug metabolism, toxicity, and therapeutic response among different patient populations receiving anticancer agents. These observations provide exciting opportunities to identify the factors most important for predicting individual variability in pharmacologically relevant phenotypes and consequently for personalizing the delivery of cancer therapy. Although pharmacogenomic differences may explain some of these disparities, rigorous investigation of both genetic and nongenetic differences is important to identify the variables most important for optimal selection and dosing of treatment for an individual patient. For example, pharmacogenetic tests currently used in cancer therapy, such as genotyping UGT1A1 to reduce the incidence of severe toxicity of irinotecan and sequencing epidermal growth factor receptor from tumors to identify somatic mutations conferring sensitivity to tyrosine kinase inhibitors, were developed without initial identification of interpopulation differences. Although interpopulation variability in toxicity and efficacy of these agents has been observed, the basis for these population differences remains only partially explained. Here, we review concepts of human population genetics to inform interpretations of disparate drug effects of cancer therapy across patient populations. Understanding these principles will help investigators better design clinical trials to identify the variables most relevant to subsequent individualization of a cancer therapy.

Antineoplastic Agents↗
PubMed2006

Phase II placebo-controlled randomized discontinuation trial of sorafenib in patients with metastatic renal cell carcinoma.

PURPOSE: This phase II randomized discontinuation trial evaluated the effects of sorafenib (BAY 43-9006), an oral multikinase inhibitor targeting the tumor and vasculature, on tumor growth in patients with metastatic renal cell carcinoma. PATIENTS AND METHODS: Patients initially received oral sorafenib 400 mg twice daily during the initial run-in period. After 12 weeks, patients with changes in bidimensional tumor measurements that were less than 25% from baseline were randomly assigned to sorafenib or placebo for an additional 12 weeks; patients with > or = 25% tumor shrinkage continued open-label sorafenib; patients with > or = 25% tumor growth discontinued treatment. The primary end point was the percentage of randomly assigned patients remaining progression free at 24 weeks after the initiation of sorafenib. RESULTS: Of 202 patients treated during the run-in period, 73 patients had tumor shrinkage of > or = 25%. Sixty-five patients with stable disease at 12 weeks were randomly assigned to sorafenib (n = 32) or placebo (n = 33). At 24 weeks, 50% of the sorafenib-treated patients were progression free versus 18% of the placebo-treated patients (P = .0077). Median progression-free survival (PFS) from randomization was significantly longer with sorafenib (24 weeks) than placebo (6 weeks; P = .0087). Median overall PFS was 29 weeks for the entire renal cell carcinoma population (n = 202). Sorafenib was readministered in 28 patients whose disease progressed on placebo; these patients continued on sorafenib until further progression, for a median of 24 weeks. Common adverse events were skin rash/desquamation, hand-foot skin reaction, and fatigue; 9% of patients discontinued therapy, and no patients died from toxicity. CONCLUSION: Sorafenib has significant disease-stabilizing activity in metastatic renal cell carcinoma and is tolerable with chronic daily therapy.

Administration, Oral↗
PubMed2006

Prospective evaluation of the relationship of patient age and paclitaxel clinical pharmacology: Cancer and Leukemia Group B (CALGB 9762).

PURPOSE: To prospectively evaluate the pharmacokinetics and toxicity profile of paclitaxel in relation to patient age in adults > or = 55 years old. PATIENTS AND METHODS: Paclitaxel was administered at 175 mg/m2 for 3 hours to 153 patients, 46 of whom were > or = 75 years of age. Pharmacokinetic and toxicity assessments were performed. Data were analyzed by cohort (cohort 1, age 55 to 64 years; cohort 2, age 65 to 74 years; cohort 3, age > or = 75 years). RESULTS: Paclitaxel concentration versus time (AUC) and total-body clearance (CL(tb)) data were available for 122 patients (cohort 1, 46 patients; cohort 2, 44 patients; cohort 3, 32 patients). Mean paclitaxel AUC increased across cohorts (P = .01). Mean (SE) AUCs were 22.4 (2.5) micromol/L x hour, 26.2 (2.8) micromol/L x hour, and 31.7 (5.6) micromol/L x hour for cohorts 1, 2, and 3, respectively. There was a corresponding significant (P = .007) age-related decrease in mean (SE) paclitaxel CL(tb) (cohort 1, 11.0 [0.7] L/h/m2; cohort 2, 9.3 [0.6] L/h/m2; cohort 3, 8.2 [0.6] L/h/m2). Patients in cohort 3 experienced significantly lower absolute neutrophil count nadirs than did younger groups (P = .02). There was also a significant increase in percentage of patients with > or = grade 3 neutropenia across age cohorts (cohort 1, 22%; cohort 2, 35%; cohort 3, 49%; P = .006). However, the increased exposure of patients to paclitaxel and increased neutropenia were not reflected in adverse clinical sequelae such as hospitalization for toxicity (P = .82), receiving intravenous antibiotics (P = .21), or experiencing a temperature more than 38 degrees C (P = .45). CONCLUSION: Although paclitaxel CL(tb) decreases with increasing patient age, there is great interpatient variability. Cooperative group studies to evaluate the effect of aging on pharmacokinetics are feasible.

Age Factors↗
PubMed2006

Measuring response in a post-RECIST world: from black and white to shades of grey.

The unprecedented pace of therapeutic development in oncology has created a climate in which the traditional methods of evaluating agent activity might no longer be adequate. How is the field transitioning to new endpoints in early drug development and what are the difficulties in this transition? Here, we will explore the historical context for the current criteria for tumour response evaluation and some of the pitfalls in using these standards when testing newer anticancer agents for activity. We will argue that the current drug development environment dictates different outcome measurements and therefore more imaginative and rigorous early-phase trial designs.

Antineoplastic Agents↗
PubMed2006

Study of the genetic determinants of UGT1A1 inducibility by phenobarbital in cultured human hepatocytes.

UGT1A1 is induced by phenobarbital. We investigated whether three common UGT1A1 variants are associated with the variability in UGT1A1 inducibility. Human hepatocytes were incubated with 2 mM phenobarbital for 2 and 6 days followed by 5 microM SN-38 (1 h), a UGT1A1 probe. SN-38 glucuronidation in the cell media was measured by high-performance liquid chromatography. Three UGT1A1 promoter variants [-53(TA)(6>7), -3156G > A and -3279T > G] were genotyped. Significant induction of UGT1A1 catalytic activity was observed in 82% and 100% of the cultures treated with phenobarbital for 2 days (median fold-induction = 1.6, range 1.3-2.8; n = 28) and 6 days (median fold-induction = 2.8, range 1.6-6.4; n = 16), respectively. After 2 days of treatment, a negative correlation was observed between the UGT1A1 basal activities and the fold-induction (Spearman r = -0.52, P < 0.005). By contrast, the UGT1A1 activities in the basal and induced states were highly correlated (Spearman r = 0.95, P < 0.0001). Similar results were observed after 6 days of treatment. The allele frequencies were not significantly different between induced (n = 22) and non-induced preparations (n = 6) (P > 0.05). The fold-induction was not associated with any variants (P > 0.05). The basal and induced activities were correlated with -53(TA)(6>7) (and with -3156G > A due to almost complete linkage with the -53 indel) (P = 0.001). No association was found with the -3279T > G single nucleotide polymorphism (P > 0.05). The indel at -53 affects the basal phenotype and appears to limit the hepatocyte capability of maximal induction after phenobarbital. However, variants at -53, -3156 and -3279 are not associated with variability in UGT1A1 inducibility.

Adolescent↗
PubMed2006

The role of pharmacogenetics in cancer therapeutics.

The variability in treatment responses and narrow therapeutic index of anticancer drugs are some of the key challenges oncologists face. The knowledge of pharmacogenetics can potentially aid in the discovery, development and ultimately individualization of anticancer drugs. The identification of genetic variations that predict for drug response is the first step towards the translation of pharmacogenetics into clinical practice. This review provides an update on the results of studies assessing the effects of germline polymorphisms and somatic mutations on therapeutic outcomes and highlights the potential applications and future challenges in pharmacogenetic research pertaining to cancer therapeutics.

Antineoplastic Agents↗
PubMed2006

Pharmacogenetics of irinotecan: clinical perspectives on the utility of genotyping.

Depending upon the UDP glucuronosyltransferase 1A1 (UGT1A1) genotype, patients are more or less susceptible to the risk of severe toxicity of irinotecan. As the US FDA-approved label of irinotecan (CPT-11, Camptosar) has been recently revised to include UGT1A1 genotype among potential risk factors for toxicity, it is expected that UGT1A1 genotyping will be increasingly used in patients undergoing irinotecan treatment. At present, the label states that *28/*28 (7/7) genotype patients are at higher risk of neutropenia and should be treated at a lower dose of irinotecan. Although effective alternative drugs (i.e., oxaliplatin) exist for metastatic colorectal cancer (the main indication of irinotecan), recent studies have confirmed that irinotecan has an important place in the management of this disease. We feel that now is the time for addressing questions around the UGT1A1*28 testing that many oncologists might have had but remained unanswered. For example, does the test have adequate sensitivity/specificity? Can the test results be effectively utilized to guide therapy of metastatic colorectal cancer patients? Is it possible that the *1/*1 (6/6) patients are underdosed? How can the genetic prediction of irinotecan toxicity be improved? Is the UGT1A1*28 test fully predictive of the UGT1A1 deficiency in patients who are not of Caucasian origin? Clinicians and investigators interested in a discussion of each of these points could find this article a useful source.

Antineoplastic Agents, Phytogenic↗
PubMed2005

Effects of ketoconazole on glucuronidation by UDP-glucuronosyltransferase enzymes.

PURPOSE: Ketoconazole has been shown to inhibit the glucuronidation of the UGT2B7 substrates zidovudine and lorazepam. Its effect on UGT1A substrates is unclear. A recent study found that coadministration of irinotecan and ketoconazole led to a significant increase in the formation of SN-38 (7-ethyl-10-hydroxycamptothecine), an UGT1A substrate. This study investigates whether ketoconazole contributes to the increase in SN-38 formation by inhibiting SN-38 glucuronidation. EXPERIMENTAL DESIGN: SN-38 glucuronidation activities were determined by measuring the rate of SN-38 glucuronide (SN-38G) formation using pooled human liver microsomes and cDNA-expressed UGT1A isoforms (1A1, 1A7 and 1A9) in the presence of ketoconazole. Indinavir, a known UGT1A1 inhibitor, was used as a positive control. SN-38G formation was measured by high-performance liquid chromatograph. RESULTS: Ketoconazole competitively inhibited SN-38 glucuronidation. Among the UGT1A isoforms screened, ketoconazole showed the highest inhibitory effect on UGT1A1 and UGT1A9. The K(i) values were 3.3 +/- 0.8 micromol/L for UGT1A1 and 31.9 +/- 3.3 micromol/L for UGT1A9. CONCLUSIONS: These results show that ketoconazole is a potent UGT1A1 inhibitor, which seems the basis for increased exposure to SN-38 when coadministered with irinotecan.

Camptothecin↗
PubMed2005

Pharmacokinetics, pharmacodynamics and adherence to oral topotecan in myelodysplastic syndromes: a Cancer and Leukemia Group B study.

OBJECTIVE: To evaluate medication adherence, pharmacokinetics and exposure versus response relationships in patients with myelodysplastic syndromes (MDS). METHODS: Ninety adult patients with MDS received oral topotecan (1.2 mg/m2) either once a day for 10 days or twice a day for 5 days every 21 days for up to six cycles. Dosing histories were collected using electronic monitoring devices fitted to medication vials. Topotecan plasma concentrations were measured, and exposure was determined by a sparse sampling approach and Bayesian estimation methods. Relationships between exposure and clinical response and toxicity were evaluated using logistic regression. RESULTS: Overall adherence was excellent with 90% of patients taking the prescribed number of doses in cycle 1. Adherence did not differ between the two regimens. Topotecan pharmacokinetics were described using a one compartment open model with first order absorption and elimination. Pharmacokinetic parameter estimates did not differ between the once a day and twice a day dosing groups. While topotecan exposure was greater in the twice a day arm compared to the once a day arm due to drug accumulation, exposure did not correlate with clinical response. However, the probability of needing a platelet transfusion in the twice a day arm was significantly increased (by 35%) as a result of greater steady-state plasma topotecan concentrations. CONCLUSIONS: Adherence is high in patients with MDS receiving oral topotecan, whether the drug is prescribed once or twice daily. The optimal schedule cannot be determined from this study, as there was no evident relationship between any pharmacokinetic parameter and clinical response.

Administration, Oral↗