Enzyme-inducing Antiseizure Drugs Research Articles

Reduced Bone Mineral Disease in Men with Epilepsy: a Cross-Sectional Study with 178 Subjects (P12-1.003)

<h3>Objective:</h3> To evaluate the bone mineral density (BMD) in men with epilepsy and correlate it with clinical data such as age, type of seizure, and anti-seizure drugs (ASD) use. <h3>Background:</h3> Little is known about the multifactorial underpinning mechanisms associated with the risk of developing a metabolic bone disease in men with epilepsy. <h3>Design/Methods:</h3> We evaluated 505 men previously diagnosed with epilepsy and exposed (minimum of 5 years) to previous or current enzyme-inducing antiseizure drugs (phenobarbital, phenytoin, carbamazepine) and valproic acid), followed at UNICAMP-Brazil in 2021. We identified 178 patients with BMD analysis (median age range, 50.5 (21–86 years). Individuals were split into two groups (young group [90 individuals, 21–49 years],; older group [89 subjects, 50–86 years],). The BMD test provided t-score indexes from the femoral neck, whole femur, and lumbar spine. Osteopenia and osteoporosis were defined with a t-score of −1.0 and lower than −2.5, respectively. We analyzed clinical data with analyzed SPSS22. We performed chi-square tests for categorical variables. <h3>Results:</h3> BMD was reduced in 107/179 men (59.7%). Unfortunately, high-levels of bone disease were identified in both young and older patients (p=0.09): young-group [37/90 normal (41.1%), 40/90 osteopenia (44.4%), 13/90 osteoporosis (14.4%)]; older-group [35/89 normal (39.3%), 30/89 osteopenia (33.7%), 24/89 osteoporosis (26.9%)]. As expected, the osteoporosis group (20.6% of patients) was older than the osteopenia group (p=0.011). About 90% of patients with abnormal BMD had focal epilepsy. Unfortunately, 33/53 (62%) operated patients presented abnormal BMD. <h3>Conclusions:</h3> we observed an elevated frequency of bone disease (regardless of the young age and surgical treatment) in men with epilepsy exposed to ASD. Our results suggest that ASD exposure is associated with early BMD reduction. Therefore, BMD evaluation and selection of appropriate ASD for PWE may be necessary to reduce the risk of fractures and related comorbidities. <b>Disclosure:</b> Dr. Marques has nothing to disclose. Miss Dias has received research support from CAPES. Miss Dias has received research support from FAPESP. Lucas Silva has nothing to disclose. Dr. Cendes has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for UCB Pharma. Dr. Cendes has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for UCB Biopharma. Dr. Cendes has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for United Medical – Brazil. Dr. Cendes has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Zodiac Pharma . Dr. Cendes has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Eurofarma – Brazil . Dr. Cendes has received personal compensation in the range of $500-$4,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Epilepsia. Dr. Cendes has received personal compensation in the range of $500-$4,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Frontiers in Neurology - Epilepsy. The institution of Dr. Cendes has received research support from São Paulo Research Foundation - FAPESP. The institution of Dr. Cendes has received research support from Conselho Nacional de Desenvolvimento Científico e Tecnológico - Brazil . The institution of Dr. Cendes has received research support from NIH. Clarissa Yasuda has nothing to disclose.

Antiseizure drugs and risk of developing smoking-related chronic obstructive pulmonary disease or lung cancer: A population-based case-control study.

To determine whether enzyme-inducing antiseizure drugs (ASDs) affect the risk of developing chronic obstructive pulmonary disease (COPD) or lung cancer in smokers. Cases of COPD and lung cancer and matched controls without these conditions were identified from a population of smokers with ≥1 prescription for any type of ASD in the Clinical Practice Research Datalink UK database of patients managed in primary care (1995-2016). A matched case-control study was performed utilising multivariate logistic regression analyses of exposure to enzyme-inducing ASDs compared to non-enzyme-inducing ASDs. The duration of ASD exposure and level of tobacco exposure were also assessed. We identified 5952 incident COPD and 1373 incident lung cancer cases, and 59 328 and 13 681 matched controls, respectively. Compared with never use, ever use of enzyme-inducing ASDs was associated with slightly decreased risk estimates of COPD (adjusted odds ratio: 0.85, 95% confidence interval: 0.81-0.89) and lung cancer (adjusted odds ratio: 0.82, 95% confidence interval: 0.73-0.92). These risk estimates were attenuated in heavy smokers. We found slightly decreased risk estimates of COPD and lung cancer among smokers taking enzyme-inducing ASDs and hypothesise that this may be related to induction of detoxification of tobacco-specific lung toxins.

Perampanel Pharmacokinetics in Children: Correlation of Dose With Serum Concentrations.

Enzyme-inducing antiseizure drugs taken concomitantly with perampanel are known to influence perampanel serum concentrations. In this study, we examined perampanel dosage, serum concentrations, and the effect of concomitant enzyme-inducing antiseizure drugs in children for a 3-year period. A retrospective chart review determined patient age, weight, perampanel serum concentration and prescribed dose, and concomitant drugs. Of 87 patients included in the study, 41 were prescribed an enzyme-inducing antiseizure drug. Although perampanel dosage did not differ between patients prescribed/not prescribed enzyme-inducing antiseizure drugs, serum concentrations were significantly lower in patients taking enzyme-inducing antiseizure drugs (average serum concentration for the enzyme-inducing antiseizure drug group was still above the previously reported efficacious serum concentration of 70 ng/mL). Although perampanel serum concentrations are negatively influenced by enzyme-inducing antiseizure drugs in children, it is likely that efficacy would be improved in patients not concomitantly prescribed enzyme-inducing antiseizure drugs because pediatric perampanel dosing is similar to that reported in prior adult efficacy trials.

Contraception for Women with Epilepsy

The purpose of this review is to summarize the current available literature on contraception for women with epilepsy, and to provide recommendations for women with epilepsy on enzyme-inducing anti-seizure drugs and on non-enzyme-inducing anti-seizure drugs. A recent study has confirmed the safety of the levonorgestrel-containing intrauterine device for women with epilepsy, with no effect on seizure control or anti-seizure drug levels. Other recent studies have found low serum etonogestrel or levonorgestrel levels in women on enzyme-inducing anti-seizure drugs and the etonogestrel or levonorgestrel implant, making this an unsuitable method for women on such drugs. Women with epilepsy have an especially compelling need to avoid unplanned pregnancy, as some common anti-seizure medications have teratogenic or detrimental neurocognitive effects on exposed children. Women on enzyme-inducing anti-seizure drugs and their physicians must be particularly aware of drug interactions with hormonal contraceptive methods.

Phase I trial of sorafenib in patients with recurrent or progressive malignant glioma

Sorafenib is an inhibitor of multiple kinases that has demonstrated antiproliferative and antiangiogenic activity in a number of in vitro and in vivo model systems. A phase I study was conducted to determine the maximum tolerated dose (MTD) of sorafenib in patients with recurrent malignant glioma. Sorafenib was given orally, twice a day (BID), continuously in 28-day cycles. The dose was escalated in 2 groups of patients stratified by use of enzyme-inducing antiseizure drugs (± EIASDs). Dose-limiting toxicity (DLT) was defined as any grades 3-4 nonhematological toxicity, grade 4 hematological toxicity, and febrile neutropenia. The number of evaluable patients enrolled in the +EIASD and -EIASD arms were 23 and 24, respectively. DLTs were predominantly dermatological and gastrointestinal effects, as observed in previous clinical trials of sorafenib. The MTD was 600 mg BID for patients receiving EIASDs and 800 mg BID for those who were not. The plasma pharmacokinetics of sorafenib were not significantly affected by the concurrent administration of EIASDs. The MTD of sorafenib given orally BID on a continuous basis was established as 600 mg BID in patients with malignant glioma who were concurrently receiving EIASDs and 800 mg BID in those who were not. Further evaluation is warranted of sorafenib at the recommended MTD against recurrent or progressive malignant glioma in combination with other molecularly targeted drugs or in the newly diagnosed setting concurrent with chemoradiation.

Osteoporosis in Men: Insights for the Clinician

Osteoporosis has finally been recognized as an important disorder in men. Men have osteoporotic fractures about 10 years later in life than women. Owing to increasing life expectancy, more fractures are predicted. Important risk factors for men include advancing age, smoking or chronic obstructive pulmonary disease, glucocorticoid therapy, and androgen deprivation therapy for prostate cancer. Other groups at risk for osteoporosis include those with alcohol abuse, men on enzyme-inducing antiseizure drugs, and those with malabsorption or history of surgery for peptic ulcer disease. History and physical examination will likely reveal secondary causes of osteoporosis. Some, but not all organizations, recommend screening for osteoporosis in men older than age 70. In the USA, The Department of Veterans Affairs recommends case finding rather than screening. Evaluation starts with bone mineral density testing by dual energy X-ray absorptiometry of the spine, hip, and in some cases forearm. A few laboratory tests can be helpful, including measurement of 25-hydroxyvitamin D. Most studies of osteoporosis therapy in men are small; but alendronate, risedronate, zoledronic acid, and teriparatide are FDA-approved to increase bone density in men with osteoporosis. A new potent antiresorptive agent, denosumab, increased bone density dramatically in men on androgen deprivation therapy and is approved for this indication in Europe. Recognition, diagnosis, and treatment of osteoporosis in men should lead to fewer fractures and probably fewer deaths.

Phase I and pharmacokinetic study of COL-3 in patients with recurrent high-grade gliomas

COL-3 is a chemically modified tetracycline that targets multiple aspects of matrix metalloproteinase regulation. This phase I clinical trial was conducted to determine the maximum tolerated dose (MTD) of COL-3 in adults with recurrent high-grade glioma, to describe the effects of enzyme-inducing antiseizure drugs (EIADs) on its pharmacokinetics, and to obtain preliminary evidence of activity. Adults with recurrent high-grade glioma were stratified by EIAD use. COL-3 was given orally daily without interruption until disease progression or treatment-related dose-limiting toxicity (DLT). Three patients in each EIAD group were evaluated at each dose level beginning with 25 mg/m(2)/day and escalated by 25 mg/m(2)/day. Toxicity, response, and pharmacokinetics were assessed. Thirty-three patients were evaluated. The MTD was 75 mg/m(2)/day in the -EIAD patients while one was not determined in +EIAD patients. The common toxicities observed were anemia, ataxia, diarrhea, hypokalemia, CNS hemorrhage, and myalgia. One partial response was observed. -EIAD patients tended to have a higher steady-state trough concentration that was apparent only at the 100 mg/m(2)/day dose level (P = 0.01). This study suggests that: (a) EIAD use does affect the pharmacokinetics of COL-3 at higher doses; and (b) there was not enough suggestion of single-agent activity to warrant further study in recurrent high-grade gliomas.

Phase II preradiation R115777 (tipifarnib) in newly diagnosed GBM with residual enhancing disease

Glioblastoma multiforme (GBM) is a lethal primary malignant brain tumor in adults. R115777 (tipifarnib) is an oral agent with antiproliferative effects, being a potent and selective inhibitor of farnesyltransferase. This multicenter, open-label phase II study was designed to evaluate the efficacy and safety of R115777 given after surgery and prior to radiation in patients with newly diagnosed and residual enhancing GBM. Following surgery, an MRI confirmed the presence of residual enhancing tumor. Patients on enzyme-inducing antiseizure drugs (EIASDs) received 600 mg twice per day, and those not on EIASDs received 300 mg twice per day. One to three monthly cycles of R115777 were administered, and radiation was initiated with progression or after three cycles. A cycle consisted of 3 weeks of continuous R115777 followed by a 1-week rest. MRI was done monthly. The primary end point was overall survival; secondary end points were tumor response rate and toxicity. A total of 28 confirmed GBM patients entered the study; 15 patients (54%) were on EIASDs. The overall median time of survival was 7.7 months. There were no tumor responses. Eight patients (29%) had stable disease as the best response. The study was stopped early due to progression of the disease in 12 patients (48%). A total of 24 patients (85%) were off study before the planned treatment schedule for radiation therapy. R115777 administered prior to radiation therapy in patients with newly diagnosed GBM and residual enhancing disease did not result in any measurable responses or improvement in survival. R115777 administered prior to radiation therapy is not recommended for patients with newly diagnosed GBM.

Phase I and pharmacokinetic study of karenitecin in patients with recurrent malignant gliomas

Karenitecin is a highly lipophilic camptothecin analogue with a lactone ring that is relatively resistant to inactivating hydrolysis under physiologic conditions. This phase I clinical trial was conducted to determine the maximum tolerated dose (MTD) of karenitecin in adults with recurrent malignant glioma (MG), to describe the effects of enzyme-inducing antiseizure drugs (EIASDs) on its pharmacokinetics, and to obtain preliminary evidence of activity. Karenitecin was administered intravenously over 60 min daily for 5 consecutive days every 3 weeks to adults with recurrent MG who had no more than one prior chemotherapy regimen. The continual reassessment method was used to escalate doses, beginning at 1.0 mg/m(2)/day, in patients stratified by EIASD use. Treatment was continued until disease progression or treatment-related dose-limiting toxicity (DLT). Plasma pharmacokinetics was determined for the first daily dose of karenitecin. Thirty-two patients (median age, 52 years; median KPS score, 90) were accrued. Seventy-eight percent had glioblastoma, and 22% had anaplastic glioma. DLT was reversible neutropenia or thrombocytopenia. The MTD was 2.0 mg/m(2) in daggerEIASD patients and 1.5 mg/m(2) in -EIASD patients. The mean (+/-SD) total body clearance of karenitecin was 15.9 +/- 9.6 liters/h/m(2) in daggerEIASD patients and 10.2 +/- 3.5 liters/h/m(2) in -EIASD patients (p = 0.02). No objective responses were observed in 11 patients treated at or above the MTD. The total body clearance of karenitecin is significantly enhanced by the concurrent administration of EIASDs. This schedule of karenitecin, a novel lipophilic camptothecin analogue, has little activity in recurrent MG.

Effect of phenytoin on celecoxib pharmacokinetics in patients with glioblastoma

Cyclooxygenase-2 (COX-2) expression has been linked to the prognosis, angiogenesis, and radiation sensitivity of many malignancies. Celecoxib, a selective COX-2 inhibitor, is predominantly eliminated by hepatic metabolism. This study was conducted to determine the effects of hepatic enzyme-inducing antiseizure drugs (EIASDs) on the pharmacokinetics of celecoxib. The safety of celecoxib administered with radiation for glioblastoma and the effect of the combined treatment on survival were also evaluated. Patients were stratified based on concomitant use of EIASDs. Celecoxib (400) mg was administered orally twice a day until tumor progression or dose-limiting toxicity. Standard radiation was administered without adjuvant chemotherapy. Sampling was performed to define the plasma concentration/time profile for the initial dose of celecoxib and steady-state trough concentrations. Thirty-five patients (22 +EIASD, 13 -EIASD) were enrolled. There were no significant differences in age, performance status, extent of surgery, or Mini Mental State Exam scores between the two cohorts. The treatment was well tolerated. All patients in the +EIASD arm were taking phenytoin. There were no significant differences in any celecoxib pharmacokinetic parameters between 15 +EIASD and 12 -EIASD patients. With 31 of 35 patients deceased, estimated median survival time for all patients was 12 months (+EIASD, 11.5 months; - EIASD, 16 months; p = 0.11). The pharmacokinetics of celecoxib is not significantly affected by the concomitant administration of phenytoin. Celecoxib administered during and after radiation is well tolerated. The potential difference in survival between the +EIASD and -EIASD groups deserves further evaluation.

The Effect of Enzyme-Inducing Antiseizure Drugs on the Pharmacokinetics and Tolerability of Procarbazine Hydrochloride

Procarbazine hydrochloride (PCB) is one of the few anticancer drugs with activity against high-grade gliomas. This study was conducted to determine if the maximum tolerated dose and pharmacokinetics of PCB are affected by the concurrent use of enzyme-inducing antiseizure drugs (EIASD). Adults with recurrent high-grade glioma were divided into cohorts who were (+) and were not (-) taking EIASDs. PCB was given orally for 5 consecutive days each month. Six patients were evaluated at each dose level beginning with 200 mg/m2/d and escalated using the modified continual reassessment method. Toxicity and response were assessed. Pharmacokinetic studies were done with a new electrospray ionization mass spectrometry assay. Forty-nine patients were evaluated. The maximum tolerated dose was 393 mg/m2/d for the +EIASD group and the highest dose evaluated in -EIASD patients was 334 mg/m2/d. Myelosuppression was the primary dose-limiting toxicity. Significant hepatic dysfunction occurred in three patients in the +EIASD cohort. Four partial responses (8%) and no complete responses were observed. PCB exhibited linear pharmacokinetics with no significant differences between the two cohorts. A marked increase in peak PCB levels was noted on day 5 relative to day 1, which was not attributable to drug accumulation. This study suggests that (a) EIASD use does not significantly affect the pharmacokinetics of PCB; (b) changes in the peak plasma concentration of PCB, consistent with decreased apparent oral clearance due to autoinhibition of hepatic metabolism, occur with daily dosing; and (c) severe hepatic dysfunction may accompany this administration schedule.

Pharmacokinetics of gimatecan, and orally administered camptothecin analogue, in patients with malignant gliomas

2039 Background: Gimatecan (GTN) is a lipophilic camptothecin analogue with excellent activity against in vivo tumor models when given orally (p.o.). This report describes the pharmacokinetics (PK) of GTN in a phase I trial in adults with recurrent malignant gliomas. Methods: GTN was given p.o. once a day for 5 days every 4 weeks. The dose was independently escalated in patients based upon whether or not enzyme inducing antiseizure drugs (EIASDs) were used concurrently. At least 3 patients were evaluated at each dose level. Sampling to define GTN plasma profiles for first and fifth daily doses was performed during cycle 1. Total GTN (intact lactone + carboxylate forms) was measured in plasma by HPLC with fluorescence detection (limit of detection, 1.0 ng/ml). PK parameters were estimated by noncompartmental methods and are reported as mean ± SD values. Results: PK data are available at 4 doses ranging from 0.33–1.23 mg/m2/day in 14 non-EIASD patients and from 0.33–1.60 mg/m2/day in 12 patients receiving EIASDs. There has been no dose limiting toxicity. GTN reached a peak concentration in plasma (Cmax) within 2 h for 90% of all doses (N = 51). In the non-EIASD group, GTN had a long terminal half-life of 57 ± 22 h and an apparent clearance (CL/f) of 1.2 ± 0.9 L/h. CL/f was not significantly associated with body surface area suggesting that flat dosing may be appropriate. In patients receiving 1.23 mg/m2/day (N= 5), there was only a 5-fold difference between the trough concentration 24 h after dose 1 (16 ± 5 ng/ml) and the Cmax for dose 5 (76 ± 21 ng/ml). The mean drug accumulation factor was 2.7 ± 0.6 based upon the 24 h area under the curve for doses 1 and 5. EIASDs had a marked effect on GTN PK, increasing CL/f by a factor of 2–10 and decreasing the apparent half-life to a similar extent. Conclusions: Treatment with well tolerated doses of GTN p.o. on a daily x 5 schedule provides prolonged systemic exposure to potentially effective drug levels. As with other anticancer agents, EIASDs significantly increased the clearance of GTN; greater doses will be required to achieve plasma levels that are comparable to patients not taking EIASDs. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Sigma-Tau Research Sigma-Tau Research

Pharmacokinetics of gimatecan, and orally administered camptothecin analogue, in patients with malignant gliomas

2039 Background: Gimatecan (GTN) is a lipophilic camptothecin analogue with excellent activity against in vivo tumor models when given orally (p.o.). This report describes the pharmacokinetics (PK) of GTN in a phase I trial in adults with recurrent malignant gliomas. Methods: GTN was given p.o. once a day for 5 days every 4 weeks. The dose was independently escalated in patients based upon whether or not enzyme inducing antiseizure drugs (EIASDs) were used concurrently. At least 3 patients were evaluated at each dose level. Sampling to define GTN plasma profiles for first and fifth daily doses was performed during cycle 1. Total GTN (intact lactone + carboxylate forms) was measured in plasma by HPLC with fluorescence detection (limit of detection, 1.0 ng/ml). PK parameters were estimated by noncompartmental methods and are reported as mean ± SD values. Results: PK data are available at 4 doses ranging from 0.33–1.23 mg/m2/day in 14 non-EIASD patients and from 0.33–1.60 mg/m2/day in 12 patients receiving EIASDs. There has been no dose limiting toxicity. GTN reached a peak concentration in plasma (Cmax) within 2 h for 90% of all doses (N = 51). In the non-EIASD group, GTN had a long terminal half-life of 57 ± 22 h and an apparent clearance (CL/f) of 1.2 ± 0.9 L/h. CL/f was not significantly associated with body surface area suggesting that flat dosing may be appropriate. In patients receiving 1.23 mg/m2/day (N= 5), there was only a 5-fold difference between the trough concentration 24 h after dose 1 (16 ± 5 ng/ml) and the Cmax for dose 5 (76 ± 21 ng/ml). The mean drug accumulation factor was 2.7 ± 0.6 based upon the 24 h area under the curve for doses 1 and 5. EIASDs had a marked effect on GTN PK, increasing CL/f by a factor of 2–10 and decreasing the apparent half-life to a similar extent. Conclusions: Treatment with well tolerated doses of GTN p.o. on a daily x 5 schedule provides prolonged systemic exposure to potentially effective drug levels. As with other anticancer agents, EIASDs significantly increased the clearance of GTN; greater doses will be required to achieve plasma levels that are comparable to patients not taking EIASDs. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Sigma-Tau Research Sigma-Tau Research