Use Of Enzyme-inducing Antiepileptic Drugs Research Articles

Vitamin D deficiency in a Portuguese epilepsy cohort: who is at risk and how to treat.

The epilepsy-related risk factors for vitamin D deficiency, particularly the use of enzyme-inducing antiepileptic drugs (EIAEDs), and how to treat vitamin D deficiency in patients with epilepsy remain unclear. Our aims were to explore risk factors and the influence of EAIEDs in vitamin D status and to determine the efficacy of a daily dose of oral cholecalciferol (vitamin D3) in epileptic patients with vitamin D deficiency. Clinical data were collected and 25-hydroxyvitamin D (25(OH)D) serum levels were measured. All patients with vitamin D deficiency (25(OH)D ≤20ng/mL) or insufficiency (25(OH)D from 21-29 ng/mL) were treated with 6,670IU/day cholecalciferol for eight weeks and 25(OH)D was then remeasured. Descriptive and inferential statistics were employed. A total of 92 patients (44.6% males), with mean age of 41.0±14.8 years, were included. Measurements of 25(OH)D revealed that 79.3% patients had abnormal levels: 56.5% were vitamin D deficient and 22.8% were vitamin D insufficient. The statistically significant risk factors for vitamin D deficiency identified were: number of AEDs, treatment with EIAEDs, low sun exposure, high body mass index (BMI) and a high frequency of epileptic seizures. After treatment, 25(OH)D mean level increased by 98.99% (regardless of EIAED use or being overweight). In our sample, more than half of the adults with epilepsy showed 25(OH)D deficiency. Patients on EIAEDs had lower 25(OH)D levels. A daily dose of 6,670IU cholecalciferol successfully led to the correction of 25(OH)D levels. A higher dose in obese patients or in patients taking EIAEDs may not be warranted and this should be considered in future guidelines for routine vitamin D deficiency treatment.

Impact of enzyme-inducing anti-epilepsy drugs on lipid levels in elderly patients with epilepsy

It has been speculated that patients with epilepsy in elderly is increasing. The effect of enzyme-inducing antiepileptic drugs (EIAED) on lipid metabolism is well known. However, the study in elderly subjects has been rarely conducted. Furthermore, it has not been directly assessed whether EIAED use causes the change of lipid levels from normal range to abnormal range. Adult patients with epilepsy (235 on EIAED, 213 on non-EIAED) were divided by age (20−64, 65−74 and 75 over years old). Longitudinal change (before starting AED, in 3 and 6 months after starting AED) of serum total cholesterol (TC), triglyceride (TRIG), HDL cholesterol (HDL-C), LDL cholesterol (LDL-C) and non-HDL cholesterol (non-HDL-C) were retrospectively analyzed using mixed models. The risk of change of lipid levels from normal range to abnormal range was also assessed by logistic regression analysis.Comparison between patients with EIAED use (EIAED group) and patients with non-EIAED use (non-EIAED group) revealed significant differences. non-EIAED group was set as reference. Differences in least square mean (LSM), 95 % confidence interval (CI) and P value in analysis of LDL-C and non-HDL-C levels (1 × 10−2) were as follows: 0.23 (0.10 ∼ 0.36), P < 0.001, 0.22 (0.09 ∼ 0.33), P = 0.001 in patients with age 65-74. In patients of age over 75, those were 0.08 (0.01 ∼ 0.15), P = 0.038, 0.17 (0.07 ∼ 0.26), P < 0.001, respectively. In patients with age 65–74, odds ratios (ORs) (95 % CI) in change of TC, LDL and non-HDL-C level from normal range to abnormal range were 32.28 (1.83–567.05), 48.43 (2.69–869.05), 12.04 (1.29–111.88), respectively. In patients with age 75 over, odds ratios (ORs) (95 % CI) in change of TC, LDL and non-HDL-C level from normal range to abnormal range were 46.02 (2.77–762.89), 5.53 (1.27–23.94), 2.38 (1.01–10.76), respectively.EIAED use had significant impact on changes in lipid levels in elderly patients.Furthermore, we could assess the impact of switching AED from EIAED to levetiracetam (LEV) in 36 patients including elderly. Switching AED from EIAED to LEV had significant impact in reducing TC, TRIG, LDL-C and non-HDL-C in both younger adult and elderly patients.

Sexual function in people with epilepsy: Similarities and differences with the general population.

The potential impact of epilepsy on sexual function is important for patient welfare, but often neglected. This study explored the occurrences of different sexual problems in patients with both well-controlled and mostly refractory epilepsy, and compared these with equivalent information from the general population. Between 2015 and 2017, a total of 221 adult inpatients and outpatients, mostly with intractable epilepsy, at the National Centre for Epilepsy in Norway, and 78 outpatients with well-controlled epilepsy at Lillehammer hospital participated in a questionnaire survey on sexual function. Information on the individual patient's epilepsy was collected. The results were compared with equivalent data on sexual function from 1671 adult Norwegians in the general population. Patients with epilepsy reported a significantly higher frequency of problems with orgasm, dyspareunia, erectile dysfunction, and feelings of sexual deviance. However, reduced sexual desire, premature ejaculation/climax, and vaginal dryness occurred at similar frequencies in the general population. After controlling for gender, we found no significant association between sexual problems and seizure control or use of enzyme-inducing antiepileptic drugs. In both genders, feelings of sexual deviance were associated with lower quality of life. Fewer patients with epilepsy were satisfied with their sex lives. The perception of sex as an important part of daily life was similar among women with epilepsy and women from the general population, whereas significantly fewer men with epilepsy than men in the general population reported that sex was an important part of their daily lives. Women with mostly refractory epilepsy reported asking for help with their sexual problems significantly more often than women in the other groups. Some sexual problems occur significantly more often in patients with epilepsy than in the general population and feelings of sexual deviancy occur more frequently. No epilepsy-related factors could be identified as specific predictors.

Co-medication and potential drug interactions among patients with epilepsy

PurposeThis study aimed to analyze the extent of co-medication and to assess potential interactions between antiepileptic drugs (AEDs) and other drugs among patients with epilepsy. MethodsWe studied 663 consecutive patients with epilepsy seen in tertiary outpatient clinic. Data on epilepsy and current treatment with AED(s) were collected from structured interview and medical records. Other medications used regularly were classified according to the Anatomical Therapeutic Chemical classification system. Possible drug interactions between AEDs and other drugs were analyzed with the use of IBM Micromedex® database. ResultsStudied sample included 395 women; 54.5% of subjects were on monotherapy. Enzyme-inducing AED(s) were used by 127 patients (19.2%). Among 265 patients who used medications other than AEDs (40.0% of all subjects), potential major and moderate interactions between AEDs and other drugs were found in 80 patients (30.1%). Most prevalent major interactions included: ethinylestradiol/estradiol - valproate/oxcarbazepine/carbamazepine, sertraline-carbamazepine, and simvastatin-carbamazepine. A total number of currently used medications (OR = 1.26 [1.07–1.48] per one additional medication; p = 0.005) and the use of enzyme-inducing AEDs (OR = 2.78 [1.51–5.12]; p < 0.001) were independent predictors of interactions between AEDs and other drugs. ConclusionsCo-medication is common (40%) among patients with epilepsy. Potential major or moderate interactions between AED(s) and other drugs are noted in 30.1% of patients exposed to at least one medication other than AED (12.1% of the entire cohort). The risk of potential interactions increases with the number of medications used chronically and with the use of hepatic enzyme-inducing AEDs.

Quality of Antiepileptic Treatment Among Older Medicare Beneficiaries With Epilepsy: A Retrospective Claims Data Analysis.

Enzyme-inducing antiepileptic drugs (EI-AEDs) are not recommended for older adults with epilepsy. Quality Indicator for Epilepsy Treatment 9 (QUIET-9) states that new patients should not receive EI-AEDs as first line of treatment. In light of reported racial/ethnic disparities in epilepsy care, we investigated EI-AED use and QUIET-9 concordance across major racial/ethnic groups of Medicare beneficiaries. Retrospective analyses of 2008-2010 Medicare claims for a 5% random sample of beneficiaries 67 years old and above in 2009 augmented for minority representation. Logistic regressions examined QUIET-9 concordance differences by race/ethnicity adjusting for individual, socioeconomic, and geography factors. Epilepsy prevalent (≥1 International Classification of Disease-version 9 code 345.x or ≥2 International Classification of Disease-version 9 code 780.3x, ≥1 AED), and new (same as prevalent+no seizure/epilepsy events nor AEDs in 365 d before index event) cases. Use of EI-AEDs and QUIET-9 concordance (no EI-AEDs for the first 2 AEDs). Cases were 21% white, 58% African American, 12% Hispanic, 6% Asian, 2% American Indian/Alaskan Native. About 65% of prevalent, 43.6% of new cases, used EI-AEDs. QUIET-9 concordance was found for 71% Asian, 65% white, 61% Hispanic, 57% African American, 55% American Indian/Alaskan new cases: racial/ethnic differences were not significant in adjusted model. Beneficiaries without neurology care, in deductible drug benefit phase, or in high poverty areas were less likely to have QUIET-9 concordant care. EI-AED use is high, and concordance with recommendations low, among all racial/ethnic groups of older adults with epilepsy. Potential socioeconomic disparities and drug coverage plans may affect treatment quality and opportunities to live well with epilepsy.

Sexual problems in people with refractory epilepsy.

Sexual dysfunction is an important but often neglected aspect of epilepsy. The objective of this study was to explore the prevalence and types of sexual problems in patients with epilepsy and compare the results with similar data obtained from a representative sample of the general population. At the National Centre for Epilepsy in Norway, 171 of 227 consecutive adult inpatients and outpatients with epilepsy (response rate: 75.3%) and their neurologists participated in a questionnaire study about epilepsy and sexuality. The results were compared with data available from 594 adult Norwegians who had completed the same questionnaire. Patients with epilepsy had a significantly higher prevalence of sexual problems (women: 75.3% vs. 12.0%; men: 63.3% vs. 9.6%). The most commonly reported problems (>30%) were reduced sexual desire, orgasm problems, erection problems, and vaginal dryness. The patients reported considerable dissatisfaction regarding sexual functioning. Significantly more sexual problems were found in patients of both sexes with reduced quality of life and in women with symptoms of depression. We found no significant association between sexual problems and age of epilepsy onset, type of epilepsy, or use of enzyme-inducing antiepileptic drugs. Whereas age at sexual debut did not differ between the patients with epilepsy and the general population, men with epilepsy had a lower number of partners during the last 12months, and the proportion of women with a low frequency of intercourse was higher in the group with epilepsy. In conclusion, sexual problems are significantly greater in Norwegian patients with epilepsy than in the general adult population. As no single epilepsy type or treatment could be identified as a specific predisposing factor, it seems likely that there are multiple causes underlying our results, including both organic and psychosocial factors.

Antiepileptic drugs and the risk of ischaemic stroke and myocardial infarction: a population-based cohort study

ObjectivesHepatic enzyme-inducing antiepileptic drugs (AEDs) increase serum lipid levels and other atherogenic markers via the induction of cytochrome P450 and may therefore increase the risk of vascular events. We sought...

Costs Associated with the Use of Enzyme-Inducing Anti-Epileptic Drugs Versus Non-Enzyme-Inducing Anti-Epileptic Drugs: A Systematic Review

Costs Associated with the Use of Enzyme-Inducing Anti-Epileptic Drugs Versus Non-Enzyme-Inducing Anti-Epileptic Drugs: A Systematic Review

Use of antiepileptic drugs and lipid-lowering agents in the United States

IntroductionThe extent to which enzyme-inducing antiepileptic drugs (EIAEDs) are used as first-line treatment in the United States remains unknown. Studies suggest that EIAEDs produce elevation of serum lipids, which could require additional treatment. We assessed the current use of EIAED in monotherapy for epilepsy in the U.S., as well as the correlation between the use of EIAEDs and subsequent new prescriptions for HMG-CoA reductase inhibitors (“statins”) for hyperlipidemia. MethodsWe queried the MarketScan® databases between July 2009 and January 2013, covering 66million patients with commercial or supplemental Medicare insurance. We identified individuals who had a diagnosis of seizures, continuous enrollment in the database from 6months prior to 24months after the epilepsy diagnosis, no utilization of an AED or a statin prior to that diagnosis, and at least 1 new AED prescription. We tabulated the fraction of subjects who were prescribed EIAEDs (phenytoin, carbamazepine, or barbiturates) and those prescribed all other AEDs. Rates of new statin prescription between 1 and 24months after AED prescription were assessed among the two groups, restricted to those with no prior history of vascular disease who had lipid serology obtained subsequent to the new AED prescription. ResultsOf the 11,893 patients with newly treated epilepsy, 2425 (20.4%) were started on an EIAED, and 9468 (79.6%) were started on a noninducing AED. There was a consistent and significant trend for EIAEDs to be increasingly prescribed with increasing age (p<0.0001).Among patients meeting the criteria, 66 (13.3%) of 496 EIAED-treated patients and 178 (9.2%) of 1930 noninducing AED patients were newly prescribed a statin (p<0.007). This difference remained significant after accounting for age and gender (p=0.015). A patient who was started on an EIAED was 46% more likely to be subsequently prescribed a statin than a patient who was started on a noninducing AED (95% CI=1.08–1.98). ConclusionsEnzyme-inducing antiepileptic drug prescription for epilepsy appears to increase with increasing age in the U.S. despite the absence of a cogent rationale for this practice, suggesting a failure to appreciate the complications of EIAED therapy among U.S. physicians. Statins were more often prescribed to those newly treated with EIAEDs compared with those given noninducing AEDs. These preliminary data provide further evidence suggesting that EIAEDs elevate lipids in a clinically meaningful manner.

Statin medication in patients treated with antiepileptic drugs in Norway

The lipid-lowering response of statins metabolized by cytochrome P450 3A4 (CYP3A4) has previously been shown to be diminished by concurrent use of enzyme-inducing antiepileptic drugs (EIAEDs). The aim of this study was to compare statin prescription in patients receiving EIAEDs versus non-enzyme-inducing antiepileptic drugs (NEIAEDs), before and after introduction of prescribing restrictions for statins in Norway. The Norwegian Prescription Database was used to extract data on patients using antiepileptic drugs and statins during 2004 and 2008. Statin type and dose used were compared between patients treated with at least one EIAED (i.e., carbamazepine, phenobarbital, phenytoin, primidone) and those receiving NEIAEDs only (i.e., all other antiepileptic drugs). The number of included patients co-medicated with statins and AEDs was 4855 in 2004 and 9880 in 2008. Among these patients, 2827 and 3160, respectively, were treated with EIAEDs. The CYP3A4 statins (i.e., simvastatin, atorvastatin and lovastatin) accounted for 85% of all statins in 2004, increasing to 93% in 2008. There was no significant difference in the likelihood of being prescribed a CYP3A4 statin versus a non-CYP3A4 statin among patients receiving EIAEDs and NEIAEDs. The average daily dose of individual CYP3A4 statins was not different between the AED groups. The present study shows that the interaction risk between CYP3A4-metabolized statins and EIAEDs is largely overlooked in Norwegian clinical practice. To avoid therapeutic failure of statin treatment in patients using AEDs, implementation of strategies for systematic management of drug interactions is warranted.

A Phase I Trial of Tipifarnib With Radiation Therapy, With and Without Temozolomide, for Patients With Newly Diagnosed Glioblastoma

To determine the maximum tolerated dose (MTD) of tipifarnib in combination with conventional radiotherapy for patients with newly diagnosed glioblastoma. The MTD was evaluated in three patient cohorts, stratified based on concurrent use of enzyme-inducing antiepileptic drugs (EIAED) or concurrent treatment with temozolomide (TMZ): Group A: patients not receiving EIAED and not receiving TMZ; Group A-TMZ: patients not receiving EIAED and receiving treatment with TMZ; Group B: any patients receiving EIAED but not TMZ. After diagnostic surgery or biopsy, treatment with tipifarnib started 5 to 9 days before initiating radiotherapy, twice daily, in 4-week cycles using discontinuous dosing (21 out of 28 days), until toxicity or progression. For Group A-TMZ, patients also received TMZ daily during radiotherapy and then standard 5/28 days dosing after radiotherapy. Dose-limiting toxicity (DLT) was determined over the first 10 weeks of therapy for all cohorts. Fifty-one patients were enrolled for MTD determination: 10 patients in Group A, 21 patients in Group A-TMZ, and 20 patients in Group B. In the Group A and Group A-TMZ cohorts, patients achieved the intended MTD of 300 mg twice daily (bid) with DLTs including rash and fatigue. For Group B, the MTD was determined as 300 mg bid, half the expected dose. The DLTs included rash and one intracranial hemorrhage. Thirteen of the 20 patients evaluated in Group A-TMZ were alive at 1 year. Tipifarnib is well tolerated at 300 mg bid given discontinuously (21/28 days) in 4-week cycles, concurrently with standard chemo/radiotherapy. A Phase II study should evaluate the efficacy of tipifarnib with radiation and TMZ in patients with newly diagnosed glioblastoma and not receiving EIAED.

The association between antiepileptic drug and HMG-CoA reductase inhibitor co-medication and cholesterol management in patients with epilepsy

Pharmacokinetic interactions have been demonstrated in enzyme-inducing antiepileptic drugs (EIAEDs) and statins; however, their clinical significance is not well established. The purpose of this study was to evaluate the association of EIAEDs and non-enzyme-inducing antiepileptic drugs (NEIAEDs) on statin dose adjustments and low-density lipoprotein (LDL) cholesterol levels in patients with epilepsy. Retrospective insurance claims from 2000 to 2006 from the Ingenix Impact (formerly Integrated Health Care Information Services) database were analyzed. Two cohorts were compared, EIAEDs+statin and NEIAEDs+statin: 1118 patients were analyzed (58% men; 66% aged >55 years); 506 (45%) initiated with an EIAED. Outcomes assessed included statin dose adjustments and, for a subset of subjects, risk of mean LDL >100mg/dL during the 12-month follow-up period. Descriptive statistics were calculated and regression models estimated. Among the EIAED group, 72% initiated with phenytoin; among the NEIAED group, 57% initiated with gabapentin. For the EIAED group, the risk of upward statin dose adjustments was significantly greater (odds ratio=1.36; P=0.04) compared with the NEIAED group; similarly, the risk of having mean LDL >100mg/dL was significantly greater (odds ratio=41.22; P=0.005) and increased during the follow-up period (+26.6mg/dL; P=0.001) for the EIAED group. This study suggests that concomitant use of EIAEDs and statins may be associated with reduced clinical effectiveness of statins. Patients with epilepsy who use EIAEDs and statins concomitantly may require greater vigilance for optimal cholesterol management.

Phase II trial of bevacizumab and erlotinib in patients with recurrent malignant glioma

Vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR) signaling are established contributors to malignant glioma (MG) biology. We, therefore, evaluated bevacizumab, a humanized anti-VEGF monoclonal antibody, in combination with the EGFR tyrosine kinase inhibitor erlotinib, in this phase 2 study for recurrent MG patients (www.ClinicalTrials.gov, NCT00671970). Fifty-seven patients (n = 25, glioblastoma [GBM]; n = 32, anaplastic glioma [AG]) were enrolled. The primary endpoint was 6-month progression-free survival (PFS-6). Overall survival (OS), radiographic response, pharmacokinetics, and correlative biomarkers were the secondary endpoints. Patients were stratified based on the concurrent use of enzyme-inducing antiepileptic drugs (EIAEDs). Bevacizumab (10 mg/kg) was given intravenously every 2 weeks. Erlotinib was orally administered daily at 200 mg/day for patients not on EIAEDs and 500 mg/day for patients on EIAEDs. PFS-6 and median OS were 28% and 42 weeks for GBM patients and 44% and 71 weeks for AG patients, respectively. Twelve (48%) GBM patients and 10 (31%) AG patients achieved a radiographic response. Erlotinib pharmacokinetic exposures were comparable between EIAED and non-EIAED groups. Rash, mucositis, diarrhea, and fatigue were common but mostly grades 1 and 2. Among GBM patients, grade 3 rash, observed in 32%, was associated with survival benefit, whereas elevated hypoxia-inducible factor-2 alpha and VEGF receptor-2 levels were associated with poor survival. Bevacizumab plus erlotinib was adequately tolerated in recurrent MG patients. However, this regimen was associated with similar PFS benefit and radiographic response when compared with other historical bevacizumab-containing regimens.

Safety and efficacy of erlotinib in first-relapse glioblastoma: a phase II open-label study

Erlotinib, an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, is active in glioblastoma. We evaluated erlotinib efficacy in patients with first-relapse glioblastoma and assessed whether response was related to EGFR amplification and/or concomitant use of enzyme-inducing antiepileptic drugs (EIAEDs) in a phase II open-label study of glioblastoma patients in first relapse. Patients took erlotinib daily until progression. Starting dose was 150 mg for patients not taking EIAEDs and 300 mg for patients taking EIAEDs. Tumors were radiographically assessed every 8 weeks. Response was evaluated by investigators and confirmed by an independent radiology facility (IRF). The primary efficacy outcome was the objective response (OR) rate, according to the modified WHO criteria. Enrollment (n = 48) was terminated after a planned interim analysis due to an insufficient number of responses. The IRF confirmed 1 complete and 2 partial responses (PRs), for an OR rate of 6.3% (95% confidence interval [CI]: 1.7-17.0). Investigators determined 1 complete response and 3 PRs, median response duration of 7.0 months, 6-month progression-free survival (PFS) of 20% (95% CI: 10.0-32.4), and median survival of 9.7 months (95% CI: 5.9-11.6). Outcomes were not related to EGFR amplification or EIAED status. Diarrhea and rash were the most common adverse events (AEs); 23% of patients experienced grade 3-4 drug-related AEs. Despite the limited number of responses, 6-month PFS and median survival reached or exceeded the previously reported values for patients undergoing chemotherapy for recurrent glioblastoma. EGFR amplification was not associated with erlotinib activity. Given the large CIs and nonrandomized nature of the study, results should be interpreted cautiously.

Antiepileptic drug use, falls, fractures, and BMD in postmenopausal women: Findings from the women's health initiative (WHI)

Antiepileptic drugs (AEDs) are used increasingly in clinical practice to treat a number of conditions. However, the relationship between the use of these medications, particularly the newer AEDs, and fracture risk has not been well characterized. We used data from the Women's Health Initiative (WHI) to determine the relationship bewteen the use of AEDs and falls, fractures, and bone mineral density (BMD) over an average of 7.7 years of follow-up. We included 138,667 women (1,385 users of AEDs and 137,282 nonusers) aged 50 to 79 years in this longitudinal cohort analyses. After adjustment for covariates, use of AEDs was positively associated with total fractures [hazard ratio (HR) = 1.44, 95% confidence interval (CI) 1.30–1.61], all site-specific fractures including the hip (HR = 1.51, 95% CI 1.05–2.17), clinical vertebral fractures (HR = 1.60, 95% CI 1.20–2.12), lower arm or wrist fractures (HR = 1.40, 95% CI 1.11–1.76), and other clinical fractures (HR = 1.46, 95% CI 1.29–1.65) and two or more falls (HR = 1.62, 95% CI 1.50–1.74) but not with baseline BMD or changes in BMD (p ≥ .064 for all sites). Use of more than one and use of enzyme-inducing AEDs were significantly associated with total fractures (HR = 1.55, 95% CI 1.15–2.09 and HR = 1.36, 95% CI 1.09–1.69, respectively). We conclude that in clinical practice, postmenopausal women who use AEDs should be considered at increased risk for fracture, and attention to fall prevention may be particularly important in these women. © 2010 American Society for Bone and Mineral Research.

A phase I/II trial of enzastaurin in patients with recurrent high-grade gliomas

Enzastaurin, a potent inhibitor of protein kinase C-beta, inhibits angiogenesis and has direct cytotoxic activity against glioma cells in preclinical studies. Patients with recurrent high-grade gliomas were stratified by histology and use of enzyme-inducing antiepileptic drugs (EIAEDs). Patients on EIAED were treated on the phase I dose-escalation portion of the trial with evaluation of serum pharmacokinetics as the primary endpoint. Patients not on EIAED were treated on the phase II portion of the trial with radiographic response and progression-free survival (PFS) as primary objectives. Patients in phase I received enzastaurin 525-900 mg/d. Phase II patients received 500 or 525 mg/d. One hundred and eighteen patients were accrued to this trial. Therapy was well tolerated with thrombosis, thrombocytopenia, hemorrhage, and elevated alanine aminotransferase as the most commonly observed drug-associated grade 3 or higher toxicities. Patients on EIAED had serum enzastaurin exposure levels approximately 80% lower than those not on EIAED. Dose escalations up to 900 mg/d did not substantially increase serum exposure levels and a maximally tolerated dose was never reached. Twenty-one of 84 evaluable patients (25%) experienced an objective radiographic response. The 6-month PFS was 7% for patients with glioblastoma and 16% for patients with anaplastic glioma. Phosphorylation of glycogen synthase kinase-3 in peripheral blood mononuclear cells was identified as a potential biomarker of drug activity. Enzastaurin has anti-glioma activity in patients with recurrent high-grade glioma, but does not appear to have enough single-agent activity to be useful as monotherapy.

A Phase I Trial of Enzastaurin in Patients with Recurrent Gliomas

Enzastaurin is a selective inhibitor of protein kinase C beta. Prior phase I studies did not show increased drug exposures with escalating once daily administration. Limits from gastrointestinal absorption may be overcome by twice daily dosing, potentially improving antitumor effects. We conducted a phase I dose escalation study in 26 patients with recurrent malignant glioma, stratified by use of enzyme-inducing antiepileptic drugs, to investigate whether divided twice daily dosing results in higher exposures compared with once daily dosing. Phosphorylated glycogen synthase 3 beta was analyzed as a potential biomarker of enzastaurin activity. Enzastaurin was poorly tolerated at all dose levels evaluated (500, 800, and 1,000 mg total daily), with thrombocytopenia and prolonged QTc as dose-limiting toxicities. The average drug concentration of enzastaurin under steady-state conditions was doubled by twice daily dosing compared with daily dosing [1.990; 90% confidence interval (CI), 1.450-2.730]. Additionally, geometric mean ratios doubled with 800 versus 500 mg dosing for both daily (2.687; 90% CI, 1.232-5.860) and twice daily regimens (1.852; 90% CI, 0.799-4.292). Two patients achieved long-term benefit (over 150 weeks progression free). Higher and more frequent dosing of enzastaurin resulted in improved drug exposure but with unacceptable toxicity at the doses tested. Phosphorylated glycogen synthase 3 beta may be a useful biomarker of the biological activity of enzastaurin. Enzastaurin has activity in a subset of malignant glioma patients and warrants continued study in combination with other agents using a maximal once daily dose of 500 mg.

Phase II Trial of Single-Agent Bevacizumab Followed by Bevacizumab Plus Irinotecan at Tumor Progression in Recurrent Glioblastoma

To evaluate single-agent activity of bevacizumab in patients with recurrent glioblastoma. Patients with recurrent glioblastoma were treated with bevacizumab 10 mg/kg every 2 weeks. After tumor progression, patients were immediately treated with bevacizumab in combination with irinotecan 340 mg/m(2) or 125 mg/m(2) every 2 weeks, depending on use of enzyme-inducing antiepileptic drugs. Complete patient evaluations were repeated every 4 weeks. Forty-eight heavily pretreated patients were accrued to this study. Thromboembolic events (12.5%), hypertension (12.5%), hypophosphatemia (6%), and thrombocytopenia (6%) were the most common drug-associated adverse events. Six patients (12.5%) were removed from study for drug-associated toxicity (five thromboembolic events, one bowel perforation). Thirty-four patients (71%) and 17 patients (35%) achieved radiographic response based on Levin and Macdonald criteria, respectively. Median progression-free survival (PFS) was 16 weeks (95% CI, 12 to 26 weeks). The 6-month PFS was 29% (95% CI, 18% to 48%). The 6-month overall survival was 57% (95% CI, 44% to 75%). Median overall survival was 31 weeks (95% CI, 21 to 54 weeks). Early magnetic resonance imaging response (first 96 hours and 4 weeks) was predictive of long-term PFS, with the Levin criteria being more predictive than Macdonald criteria. Of 19 patients treated with bevacizumab plus irinotecan at progression, there were no objective radiographic responses. Eighteen patients (95%) experienced disease progression by the second cycle, and the median PFS was 30 days. We conclude that single-agent bevacizumab has significant biologic and antiglioma activity in patients with recurrent glioblastoma.

Antiepileptic drug use and rates of hip bone loss in older men

To test the hypotheses that older community dwelling men taking non-enzyme-inducing antiepileptic drugs (NEIAEDs) and those taking enzyme-inducing antiepileptic drugs (EIAEDs) have increased rates of hip bone loss. We ascertained antiepileptic drug (AED) use (interviewer-administered questionnaire with verification of use by containers) and measured hip bone mineral density (BMD) (using dual energy x-ray absorptiometry) at baseline and an average of 4.6 years later in a cohort of 4,222 older community-dwelling men enrolled in the Osteoporotic Fractures in Men study. Men were categorized as nonusers (no AED use at either examination, n = 4060), NEIAED user (use of NEIAED only at either examination, n = 100), or EIAED user (use of EIAED only at either examination, n = 62). After adjustment for multiple potential confounders (age, race, clinic site, health status, pain interfering with work or activity, physical activity, smoking status, alcohol use, total calcium intake, diabetes, chronic kidney disease, vitamin D supplement use, bisphosphonate use, selective serotonin reuptake inhibitor use, inability to rise from a chair, body mass index, and baseline BMD), the average rate of decline in total hip BMD was -0.35%/year among nonusers compared with -0.53%/year among NEIAED users (p = 0.04) and -0.46%/year among EIAED users (p = 0.31). Multivariable adjusted rate of loss was -0.60%/year among men taking NEIAED at both examinations, -0.51%/year among men taking NEIAED at one examination only, and -0.35%/year among nonusers (p for trend = 0.03). Findings were similar at hip subregions. Use of non-enzyme-inducing antiepileptic drugs was independently associated with increased rates of hip bone loss in this cohort of older community-dwelling men.

Plasma pharmacokinetics and cerebrospinal fluid concentrations of erlotinib in high-grade gliomas: A novel, phase I, dose escalation study

2054 Background: Erlotinib (ERL) is an inhibitor of epidermal growth factor receptor (EGFR) tyrosine kinase. EGFR is overexpressed in glioblastoma multiforme (GBM). The primary objectives of this study were to determine the maximum tolerated dose (MTD), dose limiting toxicity (DLT) and to evaluate plasma and cerebrospinal fluid (CSF) ERL concentrations using a novel every 72 hour ERL dosing schedule. Methods: Patients = 18 years of age with GBM or high grade glioma with evidence of disease progression following first line therapy (surgery/XRT/chemotherapy) and Karnofsky performance status = 60 % were included. Patients were stratified based on use of enzyme-inducing antiepileptic drugs (EIAED). Patients not on EIAED were initiated on ERL 450 mg PO every 72h, while those on EIAED were initiated on 900 mg PO every 72 h. Results: Six patients have been enrolled and assessed for safety, 5 for plasma PK and 3 for CSF concentrations. For ERL, the area under the plasma concentration versus time curve (AUC) was greater and the half-life longer in patients not receiving EIAED. However, the AUC of OSI-420, the major metabolite of ERL, was lower in patients not receiving EIAED. The OSI-420 AUC: ERL AUC ratio was increased 3 fold among patients receiving EIAED, indicative of increased hepatic metabolism and increased clearance. CSF concentrations were detectable and ranged from 1 to 3% of peak plasma concentrations. Neither group has experienced a DLT or reached the MTD. The most common side effects (grade 1/2) have been diarrhea (83%), rash (100%) and fatigue (33%). To date, there has been 1 partial response, 1 patient with stable disease and 4 patients with disease progression. The partial response and stable disease have occurred in patients with GBM. Conclusions: ERL is a well tolerated therapy. Patient enrollment and subsequent dose escalation is ongoing and updated results will be presented at the ASCO 2007 meeting. [Table: see text] No significant financial relationships to disclose.