Enzyme-inducing Antiepileptic Drugs Research Articles

Antiepileptic drugs in brain tumour patients

Seizures in brain tumour patients are common; therefore, most of the brain tumour patients require chronic treatment with antiepileptic drugs (AED). Also acute, and in some instances prophylactic, treatment may be necessary. Many AED either induce (mainly CYP3A4) or inhibit liver enzymes, and therefore affect the metabolism of drugs, such as chemotherapeutic agents or steroids. Chemotherapeutic agents, metabolized by CYP3A4 system are affected by enzyme-inducing AED (EIAED), are discussed.

Effect of bevacizumab (BEV) and irinotecan (CPT-11) on dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) in glioblastoma (GBM) patients

2026 Background: DCE-MRI can determine vascular permeability using Ktrans, a volume transfer constant of contrast agent between blood plasma and the extravascular extracellular space. We report a phase II trial to determine the correlation between vascular permeability and radiographic response in GBM patients treated with irinotecan and bevacizumab. Methods: Eligibility included 20 patients with recurrent GBM. Both agents were given every 14 days; bevacizumab at 10 mg/kg IV, and irinotecan at 340 mg/m2 for patients on enzyme inducing antiepileptic drugs (EIAED) and 125 mg/m2 for patients not on EIAED. Radiographic responses were assessed every 6 weeks. DCE-MRIs were performed before administration of chemotherapy, one day after treatment and after the first cycle. The primary endpoint was to examine the effect of bevacizumab and irinotecan treatment on vascular permeability as measured by percent change from baseline in Ktrans. Results: All 20 patients were enrolled, with a median age of 49.5 years. Best responses include one patient with complete response, nine with partial response (response rate=50%), nine patients with stable disease, and one with disease progression. A 6-month progression-free survival (PFS) of 65% and a 6-month overall survival (OS) of 85% were observed. Changes in Ktrans value were highly correlated with the percentage decline in tumor volume from baseline to end of cycle one (Spearman's rank correlation = 0.47; p=0.04). Using a two-sided t-test, borderline significant difference in mean Ktrans at 24 hours between responders and non-responders was obtained at six weeks (p=0.05). No DCE MRI measures at either 24 hours or 6 weeks were determined as predictors of PFS and OS. Fifteen patients discontinued therapy due to disease progression and two patients discontinued treatment due to toxicity (wound healing, n=1; pulmonary embolism, n=1). Conclusions: The utilization of DCE-MRI to determine a reduction in vascular permeability following a combination of bevacizumab and irinotecan is feasible and correlates with the degree of tumor volume decrease, but does not predict survival in this small study. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Genentech Genentech Genentech Genentech

A phase II trial with cetuximab, bevacizumab, and irinotecan for patients with primary glioblastomas and progression after radiation therapy and temozolamide

2056 Background: Recent data has shown that bevacizumab (B) and irinotecan (I) induces significant responses in recurrent GBM. Primary GBM is very often associated with amplification of EFGR (40–50%) and alterations in the EGFR gene. In vivo experiments have shown that cetuximab (C) increases apoptosis, decreases cell proliferation and decrease vascular endothelial growth factor expression in EGFR-amplified GBM cells in vitro. The use of the combination of C and I has shown a significantly higher response rate compared to irinotecan as monotherapy in colorectal cancer. In addition, adverse events (AE) have been acceptable and the BOND-2 study has shown the feasibility of combining C, B and I. In this phase II study we examine the safety and efficacy of CBI in recurrent GBM. Methods: Patients (pts) with recurrent GBM after standard primary treatment (surgery/biopsy, followed by radiotherapy and temozolamide) were included after signed informed consent and standard inclusion criteria. The pts received C 400 mg/m2 on day 1, followed by weekly C 250 mg/m2; B 10mg/kg every other week (first 10 pts received 5 mg/kg) and I 125 mg/m2 in pts not treated with enzyme inducing antiepileptic drugs (EIAED) or 340 mg/m2 in pts treated with EIAED, every other week. Evaluation was performed according to MacDonald criteria with MRI every 8 weeks and safety according to CTCAE v.3.0. Results: A total of 32 pts were included between August 2006 and January 2008. After safety analysis of the first 10 pts B was increased from 5 to 10 mg/kg and this regimen was well tolerated. 3 pts experienced grade III-IV allergic reaction during first C administration despite pre-medication. In January 2008, 27 were evaluable for response. One CR and 8 PR were observed (RR 33%) and 5 pts (19%) had minor responses (25–50% regression and clinical improvement). Median TTP was 24 weeks. Five pts had thromboembolic complications. Conclusions: The CBI regimen was well tolerated, with encouraging response rates, including 1 CR. However, the efficacy of the combination seems to be similar to BI alone, therefore is further evaluation of this regimen not planned. No significant financial relationships to disclose.

A phase I trial of gefitinib and sirolimus in adults with recurrent glioblastoma multiforme (GBM)

2088 Background: Glioblastoma multiforme (GBM) overexpresses the epidermal growth factor receptor (EGFR) and gefitinib is an EGFR tyrosine kinase inhibitor (TKI). The protein mammalian target of rapamycin (mTOR) also promotes GBM growth and rapamycin blocks the interaction of mTOR with its target proteins. Therefore, the novel therapeutic approach by combination of gefitinib (iressa), and sirolimus (rapamycin) should have a synergistic effect in treating GBM. A possible mechanism of EGFR TKI resistance may be targeted by mTOR antagonists. The primary objective is to evaluate the safety, toxicity of gefitinib and sirolimus with a secondary end point of determining time to tumor progression, overall survival and quality of life in recurrent GBM. Methods: Eligible patients aged 18 years or older with recurrent GBM, who were treated previously with surgery, radiation, chemotherapy with or without immunotherapy (vaccine) and KPS > 40% are eligible. Gefitinib is dosed at 500 mg/day with those receiving dexamethasone or enzyme inducing anti-epileptic drugs (EIAED) escalated to 1,000 mg/day. Sirolimus is dosed at 2 mg/day and adjusted to levels of 4–12 nanograms/ml. They were co-administered on a continuous oral daily dosing. Neurological exam, KPS, laboratory parameters and NCI CTC are initially obtained every 2 weeks and then monthly. MRI scans of the brain and FACT-Br are performed every two months. Results: To date 21 patients have enrolled and 18 are evaluable. There are 13 male and 5 female with a median age of 51.6 years (range 23–72 years), a median KPS of 60% (range 50–80%) and 12 patients were on EIAED. Diarrhea, rash and mucositis were the most common toxicities as expected. There were 3 patients with grade 3/4 non-hematological toxicities with rash, renal failure, hypotension, dyspnea, coagulopathy, and elevated LFT. One patient developed wound infection which was not related to these drugs. There were 2 (11%) minor response and 6 (33%) stable disease (range 1–18 months) with a clinical benefit of 44%. Conclusions: Oral daily co-administration of getifinib and sirolimus is safe, tolerable in this heavy treated group of patients with modest antitumor activity. The median progressive free survival time and time to tumor progression is to be determined. No significant financial relationships to disclose.

Combination of bevacizumab plus irinotecan in recurrent malignant gliomas (MG): A retrospective study of efficacy and safety

13011 Background: Recurrent MG have poor prognosis and low response rates to available treatments. Following data from Vredenburg´s phase II trial (pro ASCO 2005) some centres began to treat recurrent MG with bevacizumab and irinotecan. The aim of this study is to confirm efficacy and safety of this combination in non-selected consecutive patients (pts). Methods: Data from 6 Spanish hospitals was collected retrospectively. All pts were > 18 years, had to sign an informed consent and to present: histological documented MG; progression after radiation and temozolomide; measurable disease on MRI; have received at least 3 infusions of treatment schedule: Irinotecan 125mg/m2 and bevacizumab 10 mg/kg every 2 weeks for a maximum of a year. Response rate (RR) was determinate by MRI (performed every 6 cycles) using McDonald criteria. Progression free survival (PFS) and overall survival (OS) were calculated by Kaplan Meier method. Results: From August 2006 to October 2007, 44 consecutive pts (28 Glioblastoma, 11 Anaplastic Astrocitoma & 5 Anaplastic Oligoastrocitoma) were treated with this combination. Median age: 53 years (25–73). Median number of prior chemotherapy: 2 (1–4). Six cases had received irinotecan previously. Median KPS: 70% (60–100). Median Barthel Index: 100% (55–100). 26 pts received dexamethasone with median dosage: 4 mg (1–18). 29 were taking a non enzyme-inducing antiepileptic drug. Median cycles received: 9 (4–23) Toxicity grade 3–4: Asthenia in 6 pts; thrombocytopenia 1; neutropenia 1; mucositis 2 pts; thomboembolic complications (TEC) 3 pts, skin 1, haemorrhage out of CNS 2 pts and severe cognitive impairment 4 cases. Efficacy: 25 pts had response (4 complete response); 12 pts stable disease ≥ 3 months and 7 progression as best response. RR was 56.8% (95% CI [41–71.6]) Mean follow-up: 5.8 months (1.6–16.2). Mean PFS was 7.4 months (4,6–10,1). OS was 9.8 months (6.8–12.8). Conclusion: Our experience suggests that the combination of bevacizumab plus irinotecan in recurrent MG improves the RR, PFS and OS when compared with historical figures. However, this regimen is not free of severe toxicity (TEC and severe cognitive impairment) and requires a careful selection of patients. A phase 3 trials to validate this combination is needed. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Roche

A phase II trial (N0177) of erlotinib and temozolomide (TMZ) combined with radiation therapy (RT) in glioblastoma multiforme (GBM)

2016 Background: EGFR amplification in GBMs is a common occurrence and is associated with treatment resistance. Erlotinib, a selective inhibitor of EGFR, was combined with TMZ and RT in a phase II trial for GBMs. Methods: Adult patients not taking enzyme-inducing anticonvulsants after resection or biopsy of GBM were treated with erlotinib (150 mg daily) throughout the treatment protocol until progression. Erlotinib alone was delivered for 1 week, then concurrent with TMZ (75 mg mg/m2 daily) and RT (60 Gy), followed by up to 6 cycles of adjuvant TMZ (200 mg/m2, daily x 5d, q28 d). The primary endpoint was survival at 1 year with a planned sample size of 93 patients. Results: 97 eligible patients were accrued with 8 patients over 70 years old. By definition the primary endpoint was successfully met with over half the patients (61%) patients alive at 1 year and a median survival of 15 months. However, there was no sign of benefit when comparing N0177 with the radiation/TMZ arm of EORTC 26981: Recursive parti...

Phase II trial of erlotinib plus sirolimus for recurrent glioblastoma multiforme (GBM)

2062 Background: Erlotinib, an EGF receptor kinase inhibitor, has limited single-agent activity in recurrent GBM patients. The antiglioma activity of EGFR inhibitors is enhanced by inhibitors of the mammalian target of rapamycin (mTOR), such as sirolimus, in preclinical studies. Methods: This phase II study assesses the antitumor activity of erlotinib plus sirolimus among recurrent GBM patients. Eligibility criteria: histologically confirmed GBM; age ≥18 years; KPS ≥ 70%; adequate hepatic, renal, and bone marrow function and lack of prior EGFR or mTOR-directed therapy. Patients not on enzyme-inducing anticonvulsants (EIAC; phenytoin, carbamazepine, oxcarbazepine and phenobarbitol) receive 150 mg of erlotinib and 5 mg of sirolimus per day, while those on EIAC receive 500 mg of erlotinib and 10 mg of sirolimus per day. Patients are evaluated after every other 28-day cycle. The primary endpoint is 6-month progression-free survival. Results: To date 27 patients have enrolled with a median age of 53.2 years (r...

Phase II study of bevacizumab and erlotinib in patients with recurrent glioblastoma multiforme

13008 Background: Bevacizumab, a neutralizing monoclonal antibody to vascular endothelial growth factor (VEGF), has demonstrated promising radiographic response and promising survival benefit in combination with irinotecan in patients with recurrent glioblastoma multiforme (GBM). Erlotinib, an EGFR tyrosine kinase inhibitor, has shown anti-tumor activity in some glioma patients. Combination of bevacizumab and erlotinib has demonstrated safety and efficacy in several solid malignancies. In this study, we evaluate the combinatorial efficacy of bevacizumab and erlotinib in patients with recurrent GBM Methods: Twenty-five patients with recurrent GBM were enrolled. The primary outcome measure is 6 month progression-free survival. Radiographic response, pharmacokinetics and correlative biomarkers are secondary outcome measures. Patients are stratified based on concurrent use of enzyme-inducing anticonvulsants (EIAC). Bevacizumab is dosed at 10 mg/kg intravenously every two weeks. Erlotinib is orally administere...

Reproductive history, sexual behavior and use of contraception in women with epilepsy

BackgroundWomen with epilepsy experience more pregnancy-related risks than do their healthy peers. Guidelines recommend highly effective contraception. However, their contraceptive practices remain unknown. Study DesignWe conducted a cross-sectional questionnaire study among reproductive-age women (18–44 years) with epilepsy presenting for routine, outpatient visits to an urban, academic medical center. Our questionnaire, in English or Spanish, included demographic characteristics, reproductive history, antiepileptic drug use, sexual behavior and contraception. ResultsParticipants had a mean age of 32 years (S.D.=8), 32% spoke Spanish and described themselves as Hispanic. Participants reported a wide range of educational attainment, insurance payor and income.About half of the participants reported at least one pregnancy, and 50% of the 181 pregnancies reported were unplanned. Among the 53% who reported intercourse in the last month, 74% used contraception, 15% were pregnant, 5% did not want to use contraception, 3% sought pregnancy and 3% had hysterectomy. Of those using contraception, 53% used highly effective methods (sterilization, intrauterine device, hormonal pill, patch and injection), and 47% used less effective methods (condom, withdrawal, rhythm and spermicide). Among the 21 participants using hormonal methods, six concomitantly took enzyme-inducing antiepileptic drugs potentially increasing susceptibility to pregnancy. DiscussionIn this sample of women with epilepsy about half reported prior pregnancies; 50% were unplanned. Of those using contraception, only 53% used a highly effective method. Future studies should determine generalizability of these findings and explore reasons for inadequate family planning in women with epilepsy.

Phase II trial of irinotecan and thalidomide in adults with recurrent glioblastoma multiforme

This phase II study aimed at determining the efficacy and safety of irinotecan combined with thalidomide in adults with recurrent glioblastoma multiforme (GBM) not taking enzyme-inducing anticonvulsants (EIACs). Adult patients (> or =18 years) with recurrent GBM with up to three relapses following surgery and radiation therapy were eligible for this trial. The primary end point was rate of progression-free survival at 6 months (PFS-6); secondary end points were response rate, overall survival, and toxicity. Patients were treated in 6-week cycles with 125 mg/m(2) irinotecan weekly for 4 weeks followed by 2 weeks off treatment and 100 mg of thalidomide daily increased as tolerated to 400 mg/day. Of 32 evaluable patients, 8 (25%) were alive and progression free at 6 months. The median PFS was 13 weeks. One patient experienced a complete response, one a partial response, and 19 stable disease. Median overall survival time from entry into the study was 36 weeks, and the 1-year survival rate was 34%. Adverse events (grade 3 or 4) included diarrhea, abdominal cramps, lymphopenia, neutropenia, and fatigue. Two of the four deaths that occurred were possibly due to treatment-related toxicity. The combination of irinotecan, a cytotoxic agent, and thalidomide, an antiangiogenic agent, shows promising activity against recurrent GBM in patients not receiving EIACs and warrants further study. The results also provide support for similar strategies using combination therapies with newer targeted antiangiogenic agents to generate effective therapies against malignant gliomas.

Epilepsy-associated bone mineral density loss should be prevented

We read with interest Dr. Trevathan's1 editorial commenting on the study by Sheth et al.2 We agree with Sheth et al.'s conclusions and compare them to our findings. In addition, we would advocate for specific additional interventions based on current evidence.3,4 Problems in bone metabolism in patients on antiepileptic drugs (AEDs) are well known.3,4 Sheth et al. found that bone mineral density (BMD) was low in children on AEDs and that epilepsy duration was negatively correlated with BMD. We found that vitamin D levels were low in both adults and children on AEDs. Polytherapy in children and therapy duration and enzyme-inducing AEDs in adults were negatively correlated with BMD.3,4 In his editorial, Dr. Trevathan advocates early screening and intervention.1 We propose additional interventions.5,6

Retrospective Population Pharmacokinetic Analysis of Levetiracetam in Children and??Adolescents with Epilepsy

To characterize levetiracetam pharmacokinetics, identify significant covariate relationships and identify doses in children that achieve blood concentrations similar to those observed in adults. Nonlinear mixed-effects modelling was used to analyse pooled data collected from 228 children with epilepsy aged 3 months to 18 years in five trials of adjunctive levetiracetam therapy. Simulations were used to identify dosing regimens achieving levetiracetam steady-state peak and trough plasma concentrations similar to those attained in adults receiving the recommended starting dose for adjunctive therapy (500 mg twice daily). The covariates considered for inclusion in the base model were age, bodyweight, gender, race, body surface area (BSA), body mass index (BMI), creatinine clearance (CL(CR)), levetiracetam dose, concomitant antiepileptic drug (AED) by category (neutral, enzyme inducer, inhibitor, combination of inducer and inhibitor), and benzodiazepines. A one-compartment model with first-order absorption and elimination best characterized the data. The following significant covariates were identified: (i) age on the absorption rate constant (k(a)); (ii) bodyweight, dose, CL(CR) and concomitant enzyme-inducing AED on plasma oral clearance (CL/F); and (iii) bodyweight on the apparent volume of distribution after oral administration (V(d)/F). The main explanatory covariates were age on k(a), bodyweight on CL/F and V(d)/F, and enzyme-inducing AED on CL/F, of which bodyweight was the most influential covariate. Dosing can be carried out with either 10 mg/kg of oral solution twice daily in children weighing <50 kg and a 500-mg tablet twice daily in those weighing >50 kg or, when patients favour a solid formulation, 10 mg/kg of oral solution twice daily in children weighing <20 kg, a 250-mg tablet twice daily in those weighing 20-40 kg, and a 500-mg tablet twice daily in those weighing >40 kg. All of these doses achieved steady-state peak and trough plasma concentrations similar to those observed in adults following the recommended starting dose for adjunctive therapy (500 mg twice daily). The most influential covariate of levetiracetam pharmacokinetics in children is bodyweight. A starting dose of levetiracetam 10 mg/kg twice daily ensures the same exposure in children as does 500 mg twice daily in adults.

Sexual problems in males with epilepsy—An interdisciplinary challenge!

Sexual function can be altered in patients with different types of epileptic disorder, especially those with temporal lobe epilepsy. The awareness of sexual function disturbances, giving an enormous impact on someone's quality of life, should lead to therapeutic measures. The incidence, evaluation and therapeutic options are demonstrated and seen through the urologist's eyes.

Pharmacokinetic and Tumor Distribution Characteristics of Temsirolimus in Patients with Recurrent Malignant Glioma

To characterize the pharmacokinetics of temsirolimus and its major metabolite, sirolimus, in patients receiving enzyme-inducing antiepileptic drugs (EIAED) compared with patients receiving non-EIAEDs. An additional objective was to determine whether concentrations of temsirolimus or sirolimus were achieved in brain tumor tissue. Patients with recurrent malignant gliomas not receiving EIAEDs initially received temsirolimus weekly at a dose of 250 mg i.v. The dose was subsequently reduced to 170 mg due to intolerable side effects. For patients taking EIAEDs, the starting dose of temsirolimus was 250 mg with standard dose escalation until the maximal tolerated dose was established. Ten whole blood samples were obtained over a period of 24 h after administration of temsirolimus for pharmacokinetic assessments. Patients eligible for cytoreductive surgery received temsirolimus before tumor resection. Whole blood and tumor tissue were obtained for analysis. Significant differences in the pharmacokinetic variables for temsirolimus and sirolimus were observed between the two patient groups at a comparable dose level of 250 mg. For patients receiving EIAEDs, the systemic exposure to temsirolimus was lower by 1.5-fold. Likewise, peak concentrations and exposure to sirolimus were lower by 2-fold. Measurable concentrations of temsirolimus and sirolimus were observed in brain tumor specimens. The average tissue to whole blood ratio for temsirolimus was 1.43 and 0.84 for sirolimus. Drugs that induce cytochrome P450 3A4, such as EIAEDs, significantly affect the pharmacokinetics of temsirolimus and its active metabolite, sirolimus. Total exposure to temsirolimus and sirolimus was lower in the EIAED group at the maximum tolerated dose of 250 mg compared with the non-EIAED group at the maximum tolerated dose of 170 mg. However, brain tumor tissue concentrations of temsirolimus and sirolimus were relatively comparable in both groups of patients at their respective dose levels. Correlative analyses of the tissue for the inhibition of the key regulators (p70S6 kinase and 4E-binding protein 1) of mammalian target of rapamycin are necessary to define the therapeutic significance of the altered exposure to temsirolimus.

Adjunctive lamotrigine for partial seizures in patients aged 1 to 24 months

This randomized, double-blind, placebo-controlled trial was conducted to assess the efficacy and tolerability of adjunctive lamotrigine for the treatment of partial seizures in infants aged 1 to 24 months. The study used a responder-enriched design in which all patients received adjunctive lamotrigine during an open-label phase (n = 177; maximum maintenance dose 5.1 mg/kg/day for those on non-enzyme-inducing antiepileptic drugs [AEDs] or valproate and 15.6 mg/kg/day for those on enzyme-inducing AEDs). Patients meeting response criteria were randomly assigned to double-blind treatment for up to 8 weeks with continued lamotrigine (n = 19) or to withdrawal from lamotrigine (placebo; n = 19) while background AEDs were maintained. The proportion of treatment failures (patients who met escape criteria or withdrew before completing the double-blind phase) was lower with lamotrigine (58%) than with placebo (84%). This finding was not significant in the primary analysis (two-sided chi(2) test [primary endpoint]). A post hoc sensitivity analysis of the primary endpoint was also performed (p = 0.045 by one-sided, mid-p corrected Fisher exact test). The median time to meet escape criteria was longer with lamotrigine (42 days) than with placebo (22 days) (p = 0.059). During the last 28 days of the open-label phase, 53% of the patients had a >or=50% reduction in frequency of partial seizures with lamotrigine. Additional reduction in partial seizure frequency was observed during the double-blind phase compared with the last 4 weeks of the open-label phase among those randomly assigned to lamotrigine (32% with a >or=25% reduction) but not those randomly assigned to placebo (5% with a >or=25% reduction). Lamotrigine was well tolerated, with an adverse event profile comparable to that observed in older pediatric patients. Lamotrigine was well tolerated, and the data indicate that it may be efficacious in the treatment of partial seizures in infants aged 1 to 24 months.

Importance of monotherapy in women across the reproductive cycle

Special treatment considerations are warranted in women with epilepsy, particularly those of childbearing age. Treatment guidelines generally recommend the use of antiepileptic drug (AED) monotherapy at the lowest dose possible during pregnancy. The UK Epilepsy and Pregnancy Register reported that the risk for major congenital malformations is higher with AED polytherapy than with monotherapy (6.0% vs 3.7%, respectively) and that valproate carries the highest individual risk. The AEDs that induce hepatic cytochrome CYP450 enzymes carry particular concern both before and after pregnancy. Hepatic enzyme inducers alter steroid metabolism in women receiving oral contraceptives, increase the risk for contraceptive failure, and interfere with calcium absorption and vitamin D metabolism, thus increasing the risk for osteoporosis and fractures. Vitamin K deficiency is another potential consequence of treatment with a hepatic enzyme-inducing AED, increasing the risk for coagulopathy and neonatal intraparenchymal and intracerebral hemorrhage during the first 24 hours of life. Supplemental vitamin K therapy during the last month of pregnancy is warranted. Preconceptional and gestational folate supplementation may also be warranted to prevent neural tube malformation related to AED treatment. Because AED pharmacokinetics may be altered during pregnancy, plasma AED concentrations should be measured before conception and monthly during pregnancy to prevent seizure breakthrough.

HPLC evaluation of clinical and pharmacological factors reported to cause false-positive carbohydrate-deficient transferrin (CDT) levels

BackgroundCarbohydrate-deficient transferrin (CDT) is an alcohol biomarker used for detection and follow-up of excessive alcohol consumption. This HPLC study evaluated some clinical conditions and medications previously suggested to interfere with and cause non-alcohol related elevations of CDT. MethodsSerum samples were collected from patients with end-stage liver disease (n=50), type 2 diabetes mellitus (n=46), cystic fibrosis (n=24), an elevated C-reactive protein level (CRP>100 mg/L; n=15), and from patients taking enzyme inducing or non-enzyme inducing antiepileptic drugs (n=43). Subjects with known or suspected alcohol-related problems were excluded. A sensitive and specific HPLC candidate CDT reference method was used to determine the relative amount of disialotransferrin to total transferrin. ResultsOf the 178 samples, 9 (5%) had a %disialotransferrin level ≥1.8% (>97.5th percentile) and were considered CDT positive. The highest frequency of elevated results was found in patients with end-stage liver disease (12%, n=6), including 3 with hemochromatosis, 1 with hepatitis C, 1 with autoimmune hepatitis and 1 with unspecified liver disease and cirrhosis. The other elevated %disialotransferrin results were from 2 patients taking enzyme-inducing antiepileptic drugs and 1 with type 2 diabetes. Five of 8 examined %disialotransferrin positive samples were also positive for ethyl glucuronide (EtG). ConclusionThis HPLC study found an overall low frequency of elevated %disialotransferrin levels in the clinical conditions and medications examined. Previous reports of frequent false-positive CDT results thus seem to be connected with the analytical methodology used rather than representing true clinical or pharmacological interferences.

Phase I Study of Temozolomide and Irinotecan for Recurrent Malignant Gliomas in Patients Receiving Enzyme-Inducing Antiepileptic Drugs: A North American Brain Tumor Consortium Study

To determine the maximum tolerated dose of irinotecan when administrated with temozolomide every 28 days, in patients with recurrent malignant glioma who were also receiving CYP450 enzyme-inducing antiepileptic drugs (EIAED), and to characterize the pharmacokinetics of irinotecan and its metabolites. The study was also intended to assess whether temozolomide affects the conversion of irinotecan to SN-38. Patients with recurrent malignant glioma received a fixed dose of temozolomide (150 mg/m(2)) daily for 5 days from days 1 to 5 every 28 days, and an i.v. infusion of irinotecan on days 1 and 15 of each cycle. The starting dose of irinotecan was 350 mg/m(2), which was escalated to 550 mg/m(2) in 50-mg/m(2) increments. The plasma pharmacokinetics of irinotecan and its active metabolite, SN-38, were determined during the infusion of irinotecan on cycle 1, day 1. Thirty-three patients were enrolled into the study and treated. Thirty-one patients were evaluable for both tumor response and toxicity and two patients were evaluable for toxicity only. Common toxicities included neutropenia and thrombocytopenia, nausea, vomiting, and diarrhea. Dose-limiting toxicities were grade 3 diarrhea and nausea/vomiting. The maximum tolerated dose for irinotecan was determined to be 500 mg/m(2). The recommended phase II dose of irinotecan in combination with temozolomide for patients receiving EIAEDs is 500 mg/m(2), administrated every 15 days on a 28-day schedule. This study also confirmed that concomitant administration of EIAEDs increases irinotecan clearance and influences SN-38 disposition. No pharmacokinetic interaction was observed between temozolomide and irinotecan.

Serum Concentrations of Pregabalin in Patients With Epilepsy: The Influence of Dose, Age, and Comedication

Pregabalin (PGB) is a new antiepileptic drug (AED) approved for adjunctive therapy for partial seizures with and without generalized tonic-clonic seizures and for the treatment of peripheral neuropathic pain in adults. PGB does not bind to plasma proteins and is excreted predominantly unchanged by the kidneys. Previous studies indicated that PGB shows no relevant interactions with other AEDs. The aim of this study was to investigate the influence of PGB dose, patient age, and comedication on the serum concentration of PGB. In total, 198 samples of 167 (adult) inpatients who fulfilled the inclusion criteria (eg, trough concentration, body weight available) were investigated. A patient was considered twice only if the comedication had been changed. The PGB serum concentration (mg/L) in relation to PGB dose/body weight (mg/kg) per day (level-to-dose ratio, LDR, [(mg/L)/(mg/kg)=kg/L]) was calculated and compared for the most frequent drug combinations (n=97). Analysis of covariance (using age as covariate) carried out on the log-transformed data showed that comedication had a slight but significant (P = 0.02) effect on PGB serum concentrations. The median LDR of PGB was 0.29 for PGB + oxcarbazepine (n=16), 0.31 for PGB + carbamazepine (n=20), 0.35 for PGB + levetiracetam (n=11), 0.35 for PGB + lamotrigine (n=15), and 0.39 for PGB + valproic acid + lamotrigine (n=35). Regression analysis including all 198 samples indicated (in accordance with analysis of covariance) that PGB concentrations were lower in combination with enzyme-inducing AEDs (phenytoin, carbamazepine, oxcarbazepine) and were age-dependent (higher in older patients). The PGB dose-concentration relationship was nearly linear (r=0.68, P<0.0001). However, patients on the same PGB dosage per body weight had rather different PGB trough concentrations, which could be explained only in part by age and comedication. The increase of PGB serum concentrations in older patients is in accordance with expectations for drugs that are predominantly renally excreted. Unexpectedly and in contrast to other studies, our data indicate that comedication with enzyme-inducing antiepileptic drugs (eg, carbamazepine) can moderately decrease PGB serum concentrations (about 20% to 30%). Further studies should clarify the effect of age and interactions on PGB concentrations.

Homocysteine Levels in Epileptic Children Receiving Antiepileptic Drugs

The aim of this study is to investigate the homocysteine, folic acid, and vitamin B(12) levels in epileptic children receiving antiepileptic drugs. A total of 25 children with idiopathic epilepsy (8 valproate, 11 carbamazepine, and 6 oxcarbazepine) and 10 healthy children were included in the study. The mean homocysteine, folic acid, and vitamin B(12) levels in the study group were 7.57 +/- 3.78 micromol/L (normal = 5-15 micromol/L), 10.19 +/- 4.05 ng/mL (normal = 3.0-17 ng/mL), and 428.20 +/- 256.12 pg/mL (normal = 193-983 pg/mL), respectively. The differences between the mean plasma homocysteine, folic acid, and vitamin B(12) levels of the study and control groups were not significant (P = .522; P = .855; P = .798, respectively). However, plasma homocysteine levels were higher than the normal cutoff point accepted for childhood in 4 (16%) of the study patients. Out of these 4 children, 3 were from the carbamazepine group and 1 was from the valproate group. Although the number of the study patients is limited, the authors recommend assessment of plasma homocysteine, serum vitamin B(12), and folic acid levels in children receiving enzyme-inducing antiepileptic drugs.