FDA Approval Summary: Tocilizumab for Treatment of Chimeric Antigen Receptor T Cell-Induced Severe or Life-Threatening Cytokine Release Syndrome.

On August 30, 2017, the U.S. Food and Drug Administration approved Actemra (tocilizumab, Genentech, Inc., South San Francisco, CA) for the treatment of severe or life-threatening chimeric antigen receptor (CAR) T cell-induced cytokine release syndrome (CRS) in adults and in pediatric patients 2 years of age and older. The approval was based on a retrospective analysis of data for patients who developed CRS after treatment with CTL019 and KTE-C19 on prospective clinical trials. Evaluable patients had been treated with intravenous tocilizumab 8 mg/kg (12 mg/kg for patients <30 kg) for severe or life-threatening CRS; only the first episode of CRS was included in the analysis. The efficacy population for the CTL019 cohort included 24 male and 21 female patients (total 45 patients) of median age 12 years. The median time from the start of CRS to the first dose of tocilizumab was 4 days (range, 0-18 days). Patients were considered responders if CRS resolved within 14 days of the first dose of tocilizumab, if no more than 2 doses of tocilizumab were needed, and if no drugs other than tocilizumab and corticosteroids were used for treatment. Thirty-one patients (69%; 95% confidence interval, 53%-82%) achieved a response as defined. In an independent cohort of 15 patients with KTE-C19-induced CRS, 53% responded. Further study is needed to determine the optimal dose of tocilizumab and to confirm the safety of its use for treatment of patients with CAR T cell-induced CRS. IMPLICATIONS FOR PRACTICE: Severe or life-threatening chimeric antigen receptor (CAR) T cell-induced cytokine release syndrome (CRS) requires urgent treatment to prevent fatal outcomes. In two independent cohorts, the majority of patients with severe or life-threatening CAR T cell-induced CRS responded to treatment with one or two doses of tocilizumab in addition to advanced supportive care. More research is needed to determine the optimal dose and schedule of tocilizumab for treatment of CAR T cell-induced CRS.

Pediatric Cancer Drug Development: Leveraging Insights in Cancer Biology and the Evolving Regulatory Landscape to Address Challenges and Guide Further Progress.

The discovery and development of anticancer drugs for pediatric patients have historically languished when compared to both past and recent activity in drug development for adult patients, notably the dramatic spike of targeted and immune-oncology therapies. The reasons for this difference are multifactorial. Recent changes in the regulatory landscape surrounding pediatric cancer drug development and the understanding that some pediatric cancers are driven by genetic perturbations that also drive disparate adult cancers afford new opportunities. The unique cancer-initiating events and dependencies of many pediatric cancers, however, require additional pediatric-specific strategies. Research efforts to unravel the underlying biology of pediatric cancers, innovative clinical trial designs, model-informed drug development, extrapolation from adult data, addressing the unique considerations in pediatric patients, and use of pediatric appropriate formulations, should all be considered for efficient development and dosage optimization of anticancer drugs for pediatric patients.

FDA Approval Summary: Dabrafenib in Combination with Trametinib for BRAFV600E Mutation-Positive Low-Grade Glioma.

On March 16, 2023, the FDA approved dabrafenib in combination with trametinib (Tafinlar, Mekinist; Novartis Pharmaceuticals Corporation) for the treatment of pediatric patients with low-grade glioma (LGG) with a BRAFV600E mutation who require systemic therapy. FDA also approved oral formulations of both drugs suitable for patients who cannot swallow pills. This approval was based on the LGG cohort from study CDRB436G2201 (NCT02684058), a multicenter, open-label trial in which pediatric patients with LGG with a BRAFV600E mutation were randomly assigned 2:1 to dabrafenib plus trametinib (D+T) or carboplatin plus vincristine (C+V). The overall response rate (ORR) by independent review based on Response Assessment in Neuro-oncology LGG (2017) criteria was assessed in 110 patients randomly assigned to D+T (n = 73) or C+V (n = 37). ORR was 47% [95% confidence interval (CI), 35-59] in the D+T arm and 11% (95% CI, 3.0-25) in the C+V arm. Duration of response (DOR) was 23.7 months (95% CI, 14.5-NE) in the D+T arm and not estimable (95% CI, 6.6- NE) in the C+V arm. Progression-free survival (PFS) was 20.1 months (95% CI: 12.8, NE) and 7.4 months (95% CI, 3.6- 11.8) [HR, 0.31 (95% CI, 0.17-0.55); P < 0.001] in the D+T and C+V arms, respectively. The most common (>20%) adverse reactions were pyrexia, rash, headache, vomiting, musculoskeletal pain, fatigue, diarrhea, dry skin, nausea, hemorrhage, abdominal pain, and dermatitis acneiform. This represents the first FDA approval of a systemic therapy for the first-line treatment of pediatric patients with LGG with a BRAFV600E mutation.

Transfusions increase with nationally driven reimbursement changes of erythropoiesis stimulating agents for chemotherapy-induced anemia.

BACKGROUND: The Centers for Medicare and Medicaid Services (CMS) issued a national coverage determination (NCD) in July 2007, which imposed restrictions on the reimbursement of ESAs for Medicare and Medicaid beneficiaries. Since a majority of our patients are Medicare or Medicaid beneficiaries, we changed our clinical practice regarding the use of erythropoiesis stimulating agents (ESAs) to coincide with the NCD's reimbursement restriction. OBJECTIVE: To evaluate the number of transfusions in patients diagnosed with chemotherapy-induced anemia (CIA) receiving ESAs before and after the clinical practice was changed at the University of Illinois Medical Center (UIMC). METHODS: The medical records of all adult patients diagnosed with a nonmyeloid malignancy and CIA who received an ESA between July 2006 and June 2008 at the UIMC were evaluated. The patients were divided into two groups: patients in receipt of ESAs BEFORE (group 1) and AFTER (group 2). The number of transfusions, the response rates to chemotherapy and ESAs therapy, and overall survival were compared. RESULTS: Medical records for 110 patients were reviewed. More transfusions were given to patients AFTER we implemented the change in clinical practice (BEFORE 18 transfusions vs. AFTER 52 transfusions, p = 0.004). More patients responded to ESA therapy AFTER we implemented the change (67% vs. 83%, p = NS). The treatment response to chemotherapy and overall survival were similar between the two groups. CONCLUSION: The primary goal of reducing the number of transfusions in patients with CIA by administering ESAs cannot be met when clinical practice coincides with the NCD.

FDA Oncology Center of Excellence Project Renewal: Engaging the Oncology Community to Update Product Labeling for Older Oncology Drugs.

The FDA conducts independent reviews of scientific data obtained with investigational drug products to ensure that they are safe and effective. As a result of this process, FDA-approved product labeling is generated that is considered one of the most trusted sources of information for use of an approved drug. But FDA approval is only the beginning of the life cycle of a new drug; the first oncology drugs now have more than 7 decades of clinical experience in the postmarketing setting. Due, in part, to lack of incentives, some companies may not seek inclusion of new data, other than new safety information, in FDA-approved product labeling. Ensuring that product labeling provides adequate directions for use is important for all drugs, including older therapies that may form the backbone of many standard combination regimens for pediatric and adult cancers. Project Renewal is an FDA Oncology Center of Excellence pilot program that leverages expertise from the clinical and scientific oncology communities to review published literature and generate a drug-specific product report summarizing data that may support updates to FDA-approved product labeling. This article provides a broad overview of Project Renewal's collaborative pilot process for identifying and assessing literature supporting potential labeling updates, while engaging the oncology community to increase awareness of FDA's evidentiary standards and deliberative processes used when considering the addition of new indications and dosing regimens to product labeling.

FDA Approval Summary: Selumetinib for Plexiform Neurofibroma.

On April 10, 2020, the FDA approved selumetinib (KOSELUGO, AstraZeneca) for the treatment of pediatric patients 2 years of age and older with neurofibromatosis type 1 who have symptomatic, inoperable plexiform neurofibromas. Approval was based on demonstration of a durable overall response rate per Response Evaluation in Neurofibromatosis and Schwannomatosis criteria and supported by observed clinical improvements in plexiform neurofibroma-related symptoms and functional impairments in 50 pediatric patients with inoperable plexiform neurofibromas in a single-arm, multicenter trial. The overall reponse rate per NCI investigator assessment was 66% (95% confidence interval, 51-79) with at least 12 months of follow-up. The median duration of response was not reached, and 82% of responding patients experienced duration of response ≥12 months. Clinical outcome assessment endpoints provided supportive efficacy data. Risks of selumetinib are consistent with MAPK (MEK) inhibitor class effects, including ocular, cardiac, musculoskeletal, gastrointestinal, and dermatologic toxicities. Safety was assessed across a pooled database of 74 pediatric patients with plexiform neurofibromas and supported by adult and pediatric selumetinib clinical trial data in cancer indications. The benefit-risk assessment for selumetinib in patients with inoperable plexiform neurofibromas was considered favorable.

Effects of oral clotrimazole troches on the pharmacokinetics of oral and intravenous midazolam.

AIMS: The aim of the study was to determine the effects of oral clotrimazole troches on the pharmacokinetics of oral and intravenous midazolam in the plasma. METHODS: We conducted a randomized, open-label, four-way crossover study in 10 healthy volunteers. Each volunteer received oral midazolam 2 mg or intravenous midazolam 0.025 mg kg(-1) with and without oral clotrimazole troches 10 mg taken three times daily for 5 days. Each study period was separated by 14 days. Serial blood samples were collected up to 24 h after oral midazolam and 6 h after intravenous midazolam. Plasma concentrations for midazolam and its metabolite 1-hydroxymidazolam were measured and fitted to a noncompartmental model to estimate the pharmacokinetic parameters. RESULTS: Ten healthy volunteers aged 21-26 years provided written informed consent and were enrolled into the study. Clotrimazole decreased the apparent oral clearance of midazolam from 57 +/- 13 l h(-1)[95% confidence interval 48, 66] to 36 +/- 9.8 l h(-1) (95% confidence interval 29, 43) (P= 0.003). These changes were accompanied by a decrease in the area under the concentration-time curve (mean difference 22 microg h(-1) l(-1), P= 0.001) and bioavailability (mean difference 0.21, P= NS). There were no significant differences in the systemic clearance of midazolam with or without clotrimazole troches. CONCLUSIONS: Oral clotrimazole troches decreased the apparent oral clearance of midazolam; no significant differences in the systemic clearance of midazolam were found.

Influence of cyclooxygenase-1 genotype on ex vivo aspirin response in patients at risk for stroke.

BACKGROUND: We sought to determine whether cyclooxygenase-1 (PTGS1) genotype is associated with the ability of aspirin to inhibit platelet aggregation in patients at risk for stroke. METHODS: Blood and urine samples were collected from 60 subjects, including 28 African Americans, who were taking aspirin for primary or secondary stroke prevention. Samples were analyzed for the PTGS1 A-707G, PTGS1 P17L, and glycoprotein IIIa (ITGB3)P1(A1/A2) genotypes, ex-vivo platelet aggregation, serum cholesterol, plasma salicylate levels, and urinary 11-dehydrothromboxane B(2) (11-dhTxB(2)) concentrations. The association between PTGS1 A-707G and P17L genotypes and aspirin response, as assessed by ex vivo studies and 11-dhTxB(2) concentrations, was evaluated by statistical testing and nonlinear mapping. RESULTS: Salicylate concentrations, ITGB3 genotype distribution and 11-dhTxB(2) concentrations were similar among PTGS1 genotype groups. More subjects with the PTGS1 17PP versus PL genotype had incomplete ex-vivo inhibition of platelet aggregation by aspirin (57 vs. 20%; p = 0.04). Fifty-nine percent of subjects homozygous for both the PTGS -707A and 17P alleles, but none with both the PTGS1 -707G and 17L alleles had incomplete inhibition with aspirin; p = 0.04. Similarly, nonlinear mapping showed a direct relationship between the PTGS1 17P allele and decreased aspirin response. When analyzed separately by ethnicity, the association with the P17L genotype and aspirin response persisted in African Americans, but not Caucasians. CONCLUSIONS: Our data suggest that the PTGS1 P17L genotype contributes to response to aspirin as assessed by ex-vivo platelet aggregation. Our data further suggest that the association between PTGS1 genotype and aspirin response might vary by ethnicity.

Evaluation of the Modified Diet in Renal Disease equation for calculation of carboplatin dose.

BACKGROUND: Serum creatinine (SCr)-based formulas are used to estimate glomerular filtration rate (GFR) when calculating a dosage for carboplatin using the Calvert equation, but these formulas often underestimate measured GFR. The Modified Diet in Renal Disease (MDRD) equation appears to be a more accurate estimate of GFR in patients with chronic kidney disease, but this equation has not been studied extensively in patients with cancer. OBJECTIVE: To determine the absolute difference between the dose of carboplatin administered (traditional SCr-based formulas used to estimate GFR) and the dose calculated using the MDRD equation to estimate GFR and compare the frequencies of thrombocytopenia, neutropenia, and dosage modifications between subjects in whom the difference in dose was 20% or more (divergent) or less than 20% (nondivergent). METHODS: A retrospective analysis was conducted using data from patients who received carboplatin. Inclusion criteria were receipt of at least 2 doses of carboplatin, either as monotherapy or combination therapy, and documentation of desired area under the concentration-time curve (AUC). Patients were excluded if the baseline values needed to estimate GFR using the MDRD equation were not available. The absolute difference between the dose of carboplatin administered and that calculated using the MDRD equation was determined and, from this comparison, the subjects were divided into 2 groups (divergent vs nondivergent). RESULTS: The medical records of 186 adults who received more than 2 doses of carboplatin were included in the analysis. The doses were divergent in 89 (48%) patients. The mean target AUC values were 5.3 mg/mL/min and 5.1 mg/mL/min in the divergent and nondivergent groups, respectively, and most patients received cytotoxic regimens with a relatively low risk of febrile neutropenia. The frequencies of neutropenia, thrombocytopenia, and dosage modifications were similar between the 2 groups. Use of the MDRD equation to calculate the carboplatin dosage did not appear to result in a change in the frequency of myelosuppression or the need for dose modifications compared with traditional SCr-based formulas. CONCLUSIONS: The traditional SCr-based formulas for the calculation of carboplatin dosage should be used to estimate carboplatin dose until more data become available regarding the use of the MDRD equation in this population.

The pharmacokinetics of codeine and its metabolites in Blacks with sickle cell disease.

PURPOSE: We conducted a prospective, open-label study in 54 adult subjects with sickle cell disease to determine the relationship between morphine concentrations, cytochrome P450 (CYP) 2D6 genotype, and clinical outcomes. METHODS: A blood sample was obtained for genotyping and serial blood samples were drawn to measure codeine and its metabolites in the plasma before and after oral codeine sulfate 30 mg. Codeine and its metabolites were measured by liquid chromatography-tandem mass spectrometry (LC-MS). CYP2D6 genetic testing included four single nucleotide polymorphisms (SNP) indicative of three variant alleles: *17 (1023T); *29 (1659A, 3183A); and *41 (2988A) alleles. RESULTS: Thirty subjects (group I) had a mean (standard deviation) maximal morphine concentration of 2.0 (1.0) ng/ml. Morphine was not measurable in the remaining 24 subjects (group II). Nine (30%) subjects in group I and 11 (46%) subjects in group II carried a variant *17, *29, or *41 allele (p = 0.23); one (3%) subject in group I and 5 (21%) subjects in group II were homozygous for *17 or *29 allele (p = 0.07). Emergency room visits (group I 1.5 +/- 1.8 vs. group II 2.1 +/- 4.3, p = NS) did not differ based on metabolic status, but more hospital admissions (0.9 +/- 1.4 vs. 2.2 +/- 4.1, p = 0.05) were documented in patients with no measurable morphine concentrations. CONCLUSIONS: We conclude that Blacks with sickle cell disease without measurable plasma morphine levels after a single dose of codeine were not more likely to be a carrier of a single variant allele commonly associated with reduced CYP2D6 metabolic capacity; however, homozygosity for a variant CYP2D6 allele may result in reduced metabolic capacity. Furthermore, it appears that subjects without measurable morphine concentrations were more likely to be admitted to the hospital for an acute pain crisis.

Regulation of cytochrome P450 2C9 expression in primary cultures of human hepatocytes.

Cytochrome P450 2C9 (CYP2C9) expression is regulated by multiple nuclear receptors including the constitutive androstane receptor (CAR) and pregnane X receptor (PXR). We compared coregulation of CYP2C9 with CYP2B6 and CYP3A4, prototypical target genes for human CAR and PXR using human hepatocyte cultures treated for three days with the PXR activators clotrimazole, rifampin, and ritonavir; the CAR/PXR activator phenobarbital (PB); and the CAR-selective agonists CITCO, (6-(4-chlorophenyl)imidazo[2,1-beta][1,3]thiazole-5-carbaldehyde-O-(3,4-dichlorobenzyl)oxime) and phenytoin. Clotrimazole, rifampin, ritonavir, phenytoin, and phenobarbital induced CYP2C9 consistent with previous findings for CYP3A4. We observed EC(50) values of 519 microM (phenobarbital), 11 microM (phenytoin), and 0.75 microM (rifampin), similar to those for CYP3A4 induction. Avasimibe, a potent PXR activator, produced nearly identical concentration-dependent CYP2C9 and CYP3A4 activity profiles and EC(50) values. In 17 donors, rifampin increased mean basal CYP2C9 activity from 59 +/- 43 to 143 +/- 68 pmol/mg protein/min; fold induction ranged from 1.4- to 6.4-fold. Enzyme activity and mRNA measurements after rifampin, CITCO and PB treatment demonstrated potency and efficacy consistent with CYP2C9 regulation being analogous to CYP3A4 rather than CYP2B6. We demonstrate that hepatic CYP2C9 is differentially regulated by agonists of CAR and PXR, and despite sharing common regulatory mechanisms with CYP3A4 and CYP2B6; this enzyme exhibits an induction profile more closely aligned with that of CYP3A4.

FDA Approval Summary: (Daunorubicin and Cytarabine) Liposome for Injection for the Treatment of Adults with High-Risk Acute Myeloid Leukemia.

On August 3, 2017, the FDA granted regular approval to Vyxeos (also known as CPX-351; Jazz Pharmaceuticals), a liposomal formulation of daunorubicin and cytarabine in a fixed combination, for the treatment of adults with newly diagnosed therapy-related acute myeloid leukemia (t-AML) or acute myeloid leukemia (AML) with myelodysplasia-related changes (AML-MRC). Approval was based on data from Study CLTR0310-301, a randomized, multicenter, open-label, active-controlled trial comparing Vyxeos with a standard combination of daunorubicin and cytarabine ("7+3") in 309 patients 60-75 years of age with newly diagnosed t-AML or AML-MRC. Because of elemental copper concerns with the Vyxeos formulation, patients with Wilson disease were excluded from the study. Vyxeos demonstrated an improvement in overall survival (HR 0.69; 95% confidence interval, 0.52-0.90; P = 0.005) with an estimated median overall survival of 9.6 months compared with 5.9 months for the "7+3" control arm. The toxicity profile of Vyxeos was similar to that seen with standard "7+3" with the exception of more prolonged neutropenia and thrombocytopenia on the Vyxeos arm. Because the pharmacology of Vyxeos differs from that of other formulations of daunorubicin and cytarabine, labeling includes a warning against interchanging formulations during treatment. This is the first FDA-approved treatment specifically for patients with t-AML or AML-MRC.

Encephalopathy after high-dose Ifosfamide: a retrospective cohort study and review of the literature.

BACKGROUND: Encephalopathy occurs in 10-40% of patients treated with high-dose ifosfamide. Proposed risk factors for encephalopathy include hepatic or renal dysfunction, brain metastases, electrolyte imbalances and drug-drug interactions. OBJECTIVE: The purpose of this retrospective cohort study and literature review was to estimate the prevalence of encephalopathy, identify characteristics associated with encephalopathy and evaluate the effectiveness of methylthioninium chloride (methylene blue) in its prevention. STUDY DESIGN AND METHODS: A total of 19 patients received high-dose ifosfamide for soft tissue sarcoma during a 4-year period at our medical centre. Eight patients developed encephalopathy based on adverse drug event (ADE) reports submitted by a clinical pharmacist. These reports incorporate the Naranjo probability scale, which is used to assess the likelihood that a change in clinical status is the result of an ADE rather than the result of other factors, such as progression of disease. The demographics, concurrent medication therapy, co-existing illnesses and laboratory parameters were documented from the medical records. We also conducted a review of the literature by searching MEDLINE (1996-October 2007). MAIN OUTCOME AND RESULTS: A total of 19 patients received high-dose ifosfamide; eight patients experienced encephalopathy (group I, 42%) and 11 patients did not experience encephalopathy (group II, 58%). More women than men developed encephalopathy (group I, 87.5% vs group II, 27.3%). Serum albumin (group I, 3.1 +/- 0.3 vs group II, 3.6 +/- 0.3 g/dL), haemoglobin (10.5 +/- 1.5 vs 12.4 +/- 1.7 g/dL) and total bilirubin (0.5 +/- 0.2 vs 0.8 +/- 0.3 mg/dL) levels were substantially lower in patients with encephalopathy, whereas the ratio of actual bodyweight to the ideal bodyweight (1.4 +/- 0.3 vs 1.1 +/- 0.2) was substantially higher in these patients. Five (62.5%) patients received a subsequent cycle of high-dose ifosfamide; all of these patients received methylthioninium chloride to minimize the risk of encephalopathy. All of these patients developed encephalopathy. Other reports have found that hypoalbuminaemia is associated with encephalopathy and that methylthioninium chloride does not prevent ifosfamide-induced encephalopathy. CONCLUSIONS: In summary, female sex, low total bilirubin, albumin and haemoglobin levels, and obesity appear to be associated with ifosfamide-induced encephalopathy. Methylthioninium chloride did not appear to prevent encephalopathy with subsequent doses of high-dose ifosfamide.

Chemotherapy-induced anemia at an urban academic medical center: iron studies and supplementation.

OBJECTIVES: To determine the number of patients with chemotherapy-induced anemia receiving an erythropoiesis-stimulating agent (ESA) in whom iron studies were completed and iron supplementation was provided and to document the response rate of ESA therapy without parenteral iron at our medical center. DESIGN: Retrospective chart review. SETTING: Urban (Chicago) academic medical center between January 2004 and December 2005. PATIENTS: Ambulatory patients with a nonmyeloid malignancy receiving chemotherapy during a 2-year period in whom hemoglobin (Hb) was less than 11 grams/dL or ESA therapy was documented. INTERVENTION: Review of medical records. MAIN OUTCOME MEASURES: Number of patients reaching target Hb, time to reach target Hb, number of patients receiving a transfusion, number of patients with iron studies, and number of patients receiving iron supplementation. RESULTS: A total of 174 medical records were reviewed, and 50 patients met study criteria. Of these, 38 patients were treated with darbepoetin alfa, 11 patients were treated with epoetin alfa, and 1 patient was not treated with either agent. 20 patients achieved the target Hb level of 12 grams/dL within a median of 7 weeks (range 1-24 weeks). Only five patients treated with an ESA received iron supplementation, one responder and four nonresponders. Iron indices were measured in 20 patients (40%); 14 patients were candidates for iron therapy based on transferrin saturation, and 3 of these 14 patients received oral iron supplementation. Six responders and six nonresponders received a transfusion (25%). CONCLUSION: The overall response rate and time to Hb response were consistent with previous reports. Iron indices were not commonly measured before ESA therapy was started, and only a few patients were provided oral iron supplementation at our medical center.

Paclitaxel decreases the accumulation of gemcitabine and its metabolites in human leukemia cells and primary cell cultures.

BACKGROUND: We identified a drug-drug interaction between gemcitabine and paclitaxel in a clinical pharmacokinetic study. The purpose of the present study was to determine whether paclitaxel affected the uptake and accumulation of the parent drug gemcitabine and the formation of its metabolites after treatment of cells with gemcitabine in vitro. MATERIALS AND METHODS: The human leukemia cell line CEM was treated with 15 micoM 3H-gemcitabine, with and without paclitaxel, and the accumulation of radiolabeled gemcitabine was assessed up to one minute and one hour. Peripheral blood mononuclear cells (PMN) and hepatocytes were treated with gemcitabine, with or without paclitaxel, for specified amounts of time at three concentrations of gemcitabine, and the concentrations of gemcitabine and its metabolites were measured by liquid chromatography. RESULTS: In CEM cells, paclitaxel reduced the uptake and accumulation of gemctabine by 32% and 30%, respectively. In the hepatocytes, the mean concentrations of gemcitabine increased in the cell culture media 100%, 48% and 38% when treated with paclitaxel plus gemcitabine 5, 15 and 30 microM, respectively, compared to gemcitabine alone. The concentrations of the deaminated metabolite dFdU were significantly decreased in the cell culture media. In the PMN, the intracellular accumulation of active triphosphorylated metabolite dFdCTP was lower in cells treated with paclitaxel (up to 83%) compared to the control. CONCLUSION: Paclitaxel substantially reduced the uptake and accumulation of gemcitabine and the formation of its metabolites in vitro at clinically relevant concentrations.

Gemcitabine pharmacokinetics and interaction with paclitaxel in patients with advanced non-small-cell lung cancer.

PURPOSE: Gemcitabine administered at a fixed dose rate of 10 mg/m(2) per min has been reported to achieve plasma steady-state concentrations ranging from 10 to 20 microM in patients with acute leukemia. These concentrations have been shown to saturate the intracellular accumulation of the active triphosphate metabolite. We designed this pharmacokinetic study to assess the ability of a fixed dose rate of gemcitabine to achieve the desired steady-state concentration in the absence and presence of paclitaxel in patients with solid tumors. PATIENTS AND METHODS: A group of 14 patients with advanced non-small-cell lung cancer received paclitaxel 110 mg/m(2) over 3 h on days 1 and 8 and gemcitabine 800 mg/m(2) over 80 min on days 1 and 8 every 21 days. Patients received gemcitabine alone on cycle (C) 1, day (D) 1. Pharmacokinetic samples were collected at 0, 15, 30, 45, 60 and 80 min during infusion and 0.25, 0.5, 1, 2, 4, 6, and 8 h after infusion on C1D1, C1D8, C2D1, C4D1 and C6D1. RESULTS: Of 13 patients included in the pharmacokinetic analysis, 61% achieved the desired steady-state concentration (C(ss)) with gemcitabine alone (C1D1), whereas only 0 to 45% of patients achieved the desired C(ss) with paclitaxel and gemcitabine, depending on the treatment cycle. Paclitaxel significantly decreased systemic clearance (Cl(T); P=0.012) and volume of distribution (V(d); P=0.050) and significantly increased C(ss) ( P=0.009). Gemcitabine plasma pharmacokinetic parameters demonstrated great interpatient variability in the absence of paclitaxel (C(ss) 30%, Cl(T) 30%, V(d) 55%). Interpatient and intrapatient variability in gemcitabine pharmacokinetics were not observed when gemcitabine was administered in combination with paclitaxel (P>0.05). CONCLUSIONS: Gemcitabine plasma pharmacokinetic parameters are significantly altered in the presence of paclitaxel.

Oxaliplatin biotransformation and pharmacokinetics: a pilot study to determine the possible relationship to neurotoxicity.

BACKGROUND: Both oxaliplatin and ormaplatin undergo biotransformation to Pt(dach)Cl2 with studies suggesting a predictive relationship between systemic exposure to Pt(dach)Cl2 and the severity of the delayed sensory neuropathy associated with ormaplatin. Studies characterizing the pharmacokinetic parameters of oxaliplatin and Pt(dach)Cl2 in humans have not been reported. This study was conducted to characterize the pharmacokinetic parameters of oxaliplatin and Pt(dach)Cl2 and to determine the extent to which oxaliplatin undergoes biotransformation to Pt(dach)Cl2 in humans. MATERIALS AND METHODS: Ten adult patients with metastatic colon cancer received oxaliplatin with or without fluorouracil-based chemotherapy. Blood samples were obtained during cycles 1 and 2. Total platinum, oxaliplatin and Pt(dach)Cl2 in the plasma ultrafiltrate were measured using high performance liquid chromatography and atomic absorption spectrometry. All patients underwent a thorough neurological evaluation after each cycle. RESULTS: The median steady-state concentration (C(SS)) (interquartile range, 25% to 75%) for oxaliplatin 85 mg/m2 was 0.33 microg Pt/ml (0.28 to 0.38 microg Pt/ml). The area under the curve (AUC) was 0.79 microg Pt/ml/h (0.62 to 0.88 microg Pt/ml/h) and the elimination half-life was 0.32 h (0.27 to 0.46 h). The median C(SS) for Pt(dach)Cl2 was 0.008 microg Pt/ml (0.004 to 0.014 microg Pt/ml). The C(SS) ratio of oxaliplatin to Pt(dach)Cl2 was 31 (24 to 51). All patients reported acute cold-induced neuropathy following cycles 1 and 2. Only two patients reported delayed sensory neuropathy (grade 1). CONCLUSION: The parent drug oxaliplatin is the major active platinum complex detected in plasma ultrafiltrate for at least the first few hours following oxaliplatin infusion in humans. Therefore, the plasma biotransformation products of oxaliplatin are unlikely to contribute to its efficacy or toxicity. In particular, plasma Pt(dach)Cl2 is unlikely to significantly contribute to the delayed sensory neuropathy associated with oxaliplatin, since only a limited amount (<3%) of oxaliplatin undergoes biotransformation to Pt(dach)Cl2.

Epigenetics and oncology.

Epigenetic modifications play a critical role in the development of pediatric and adult cancers, contributing to the cumulative changes observed as normal cells undergo malignant transformation. These modifications have been studied to develop epigenome-targeted therapies and new diagnostic tools. The U.S. Food and Drug Administration has approved four epigenome-targeted anticancer drugs. Two are drugs that inhibit DNA methyltransferases: azacitidine and decitabine, and two are drugs that inhibit histone deacetylases: vorinostat and romidepsin. These initial successes demonstrate the potential effectiveness of epigenome-targeted therapies as monotherapy in hematologic malignancies, but newer studies are focused on combination therapy in many cancers. Epigenetic modifications have also been used to evaluate potential biomarkers to diagnose patients with cancer, identify patient populations likely to respond to specific anticancer therapies, and select reasonable dosages for investigational anticancer drugs, as observed with other newer targeted anticancer drugs. Although much has been learned about the relationship between the epigenome and cancer, many questions remain unanswered at this time. The next step is to continue to translate emerging epigenetic knowledge into anticancer drug development. In this review, we discuss the role of epigenetic modifications in the development of cancer and anticancer drug resistance, and we describe the progress and challenges associated with developing epigenome-targeted anticancer drugs and diagnostic tools that identify epigenetic modifications.