Enzyme-inducing Drugs Research Articles

DTB Select: 11 | November 2016

Impact of hepatic enzyme-inducing drugs on levonorgestrel EHC ● New clinical rule to improve antibiotic prescribing to children ● The impact of nursery sickness policies on the treatment of conjunctivitis...

Variation in dose and plasma level of lamotrigine in patients discharged from a mental health trust.

The objectives of this study were to investigate the dose of lamotrigine when prescribed with an enzyme inhibitor or enzyme inducer in patients discharged from a mental health trust and to determine the corresponding lamotrigine plasma concentrations and the factors that may affect these. All patients discharged on lamotrigine between October 2007 and September 2012 were identified using the pharmacy dispensing database. We recorded demographic details, lamotrigine dose and plasma levels and coprescribed medication. During the designated period, 187 patients were discharged on lamotrigine of whom 117 had their plasma levels recorded. The mean lamotrigine daily dose was 226.1 mg (range 12.5-800 mg) and the mean plasma level 5.9 mg/l (range 0.8-18.1 mg/l). Gender, ethnicity, diagnosis and smoking status had no significant effect on dose or plasma levels. Patients taking an enzyme-inducing drug (n = 6) had significantly lower plasma levels [mean (SD) 3.40 (1.54) mg/l] than those not taking enzyme inducers [n = 111; 6.03 (3.13) mg/l; p = 0.043]. Patients taking an enzyme-inhibiting drug (n = 23) had significantly higher levels [7.47 (3.99) mg/l] than those not taking an inhibitor [n = 94; 5.52 (2.75) mg/l; p = 0.035]. No significant difference was found between the doses of lamotrigine in patients taking an enzyme inhibitor and those not taking one (p = 0.376). No significant difference was found between the doses of lamotrigine in patients taking an enzyme-inducing drug and those not taking any (p = 0.574). Current dosing recommendations indicate that lamotrigine doses should be halved in individuals taking enzyme inhibitors and doubled in those on enzyme inducers. In our survey these recommendations were rarely followed with the consequence that patients received too high or too low a dose of lamotrigine, respectively.

Decreased efficacy of an etonogestrel implant in a woman on antiepileptic medications: a case report

IntroductionMany antiepileptic drugs decrease the efficacy of combined hormonal contraceptives due to their inducing effect on cytochrome P450 liver metabolism. Less is known about the pharmacokinetics and outcomes of concomitant use of the etonogestrel implant and hepatic enzyme-inducing medications.Case presentationA 22-year-old Hispanic woman with a long-standing seizure disorder treated with carbamazepine for 9 years became pregnant after 25 months of etonogestrel implant use.ConclusionsHepatic enzyme-inducing drugs may reduce the efficacy of contraceptive implants. Contraceptive counseling for patients with medical co-morbidities requiring hepatic enzyme-inducing medications should include this information.

Imatinib plus hydroxyurea in pretreated nonprogressive glioblastoma (GBM): Long-term follow up of a single-center phase II study.

e13004 Background: GBM is malignant brain tumour with a median survival of 15.6 months. Dysregulated signalling of platelet derived growth factor receptors is suggested to play a role in pathogenesis. The combination of imatinib (I) plus hydroxyurea (HU) is known to be well tolerated and to show moderate efficacy in patients (pts) with recurrent GBM. Despite the aggressive course of GBM once starting progression, short periods of disease stabilisation after primary treatment or effective treatment of relapse can be observed. This Phase II study was initiated to analyse the efficacy of I plus HU as maintenance treatment (MT) in GBM pts. Methods: From December 2003 up to June 2005 30 pts were included. No enzyme-inducing anticonvulsive drugs were allowed. I (600 mg/day) and HU (1000 mg/day) were given as a continuous treatment. Blood cell counts were taken weekly and magnetic resonance imaging every 6 weeks. Primary endpoint (PE) was 6 and 12 months progression free survival (PFS), secondary endpoints (SE) were 5 years PFS and overall survival (OS). Results: All pts were eligible for PE and SE. 25 pts were male, 5 pts female, median age was 44 years (32 to 71). All pts had prior irradiation, 21 pts had prior temozolomide (T) containing therapy and 9 pts non-temozolomide containing therapy. 8 pts had none, 17 pts one and 5 pts two prior relapses. 25 pts had measurable disease, 4 of these pts achieved a partial response (PR), there was no complete remission, 5 pts had no evidence of disease. Median follow up is 90 months. Hematotoxicity grade 2 and 3 occurred in 11 out of 30 pts and required dose reduction of HU in 8 pts, dose reduction of I in 1 patient and G-CSF in 8 pts. PFS rate at 6, 12, 24 and 60 months were 60% (18/30), 40% (12/30), 17% (5/30) and 17% (5/30 ) respectively, OS rate at 6, 12, 24 and 60 months were 90% (27/30), 67% (20/30), 37% (11/30) and 17% (5/30). 4 pts are still alive without progression. Conclusions: Although I and HU did not demonstrate relevant efficacy in GBM and never reached admission status the reported study indicates impressive long-term survival data for I and HU as a continuous oral MT. Further studies should analyse more effective drugs like temozolomide as MT (proof of principle). Clinical trial information: STI571DE21.

Intravenous topiramate: Safety and pharmacokinetics following a single dose in patients with epilepsy or migraines taking oral topiramate

Although topiramate is widely prescribed for epilepsy and migraine, there is no intravenous product. We have developed an injectable topiramate formulation in which the drug is solubilized in a cyclodextrin matrix, Captisol(®) (Ligand Pharmaceuticals, Inc., La Jolla, CA). Our long-term goal is to evaluate intravenous topiramate for the treatment of neonatal seizures. Prior to studies in newborns, we carried out an investigation of injectable topiramate's safety and pharmacokinetics in adult patients. Twenty adult volunteers with epilepsy or migraine on stable, on maintenance topiramate therapy were given 25 mg of a stable-labeled intravenous topiramate over 10 min, followed by their usual oral doses. Vital signs were taken, electrocardiography studies (ECGs) were recorded, and the infusion sites were periodically examined prior to and up to 24 h after dosing. Blood samples were collected prior to administration and serially for 96 h thereafter. Plasma concentrations of both stable-labeled and regular topiramate were measured using liquid chromatography-mass spectrometry (LC-MS). Concentration-time data were analyzed using a noncompartmental approach with WinNonlin 5.2 (Pharsight Corporation, Mountain View, CA, U.S.A.). Seven patients experienced one or more of the following minor adverse events including nausea and vomiting (1), tingling around the lips (1), paresthesia in the arms and legs (1), and a mild vasovagal response with intravenous catheter placement (1). Included in the adverse events were four patients with epilepsy who had seizures consistent with their histories. There were no changes in heart rate, blood pressure, or ECG results, and there were no infusion site reactions. Pharmacokinetic parameters (mean ± standard deviation [SD]) determined following the intravenous dose included absolute bioavailability: 110 ± 16%, distribution volume: 0.79 ± 0.22 L/kg, clearance: 2.03 ± 1.07 L/h, and elimination half-life: 27.6 ± 9.7 h. Distribution volume, half-life, and clearance were significantly altered by enzyme-inducing drugs. A single 25-mg dose of intravenous topiramate caused minimal infusion site or systemic adverse effects in patients taking oral topiramate. Pharmacokinetic results show that oral topiramate is completely absorbed and that its steady-state elimination half-life is longer than previously assumed, which permits once or twice daily dosing even in the presence of enzyme-inducing drugs. The information from this study can inform the design of subsequent studies in adults, older children, and newborns, including controlled clinical trials intended to determine the efficacy and safety of intravenous topiramate for neonatal seizures.

Epilepsi hos eldre

Diagnostic work-up and treatment of patients who have developed epilepsy after the age of 65 can both be difficult. Epilepsy is one of the most common neurological conditions in the elderly, and the incidence of de novo geriatric epilepsy is rising. The aim of this review is to provide guidance on the management of epilepsy in this patient group. The review is based on a discretionary selection of original articles and reviews found in PubMed using the search term combination 'epilepsy' and 'elderly', and the authors' personal experience. The seizures, which are most commonly of the focal type, are not infrequently overlooked or misdiagnosed. Cerebrovascular disease is the underlying cause of about half of the cases. When selecting an anticonvulsant, it is important to take age-related physiological changes and comorbidities into consideration. Because elderly patients have a narrower therapeutic window than younger persons and greater susceptibility to cognitive and other side effects, a low starting dose and slower dose titration are particularly important. The results of studies of young epilepsy patients cannot be extrapolated to apply to elderly patients. More studies directly targeting this patient population are therefore needed. As a general rule, we do not recommend starting on enzyme-inducing drugs such as phenytoin, phenobarbital and carbamazepine, partly because of their high interaction potential.

Nicotine intake and smoking topography in smokers with bipolar disorder

Cigarette smoking behavior in bipolar disorder (BPD), including the effects of mood-stabilizing medications, has not been well characterized. We compared serum nicotine, nicotine metabolite levels, and smoking topography in 75 smokers with BPD to 86 control smokers (CON). For some comparisons, an additional control group of 75 smokers with schizophrenia (SCZ) were included. There were no differences between the BPD and CON groups in baseline smoking characteristics or serum nicotine or cotinine levels. Fifty-one smokers with BPD (68.9%) were taking one of the following mood stabilizers: valproic acid, lamotrigine, carbamazepine, oxcarbazepine, lithium, or topiramate. The 3-hydroxycotinine-to-cotinine ratio, a marker of cytochrome P450 2A6 (CYP2A6) metabolic activity, was significantly higher in BPD versus CON and versus SCZ (0.68 versus 0.49 versus 0.54; p =0.002). The difference between groups, however, was no longer significant when the analysis was repeated with those taking hepatic enzyme-inducing drugs (carbamazepine, oxcarbazepine, and topiramate) included as a covariate. The time between puffs, or interpuff interval (IPI), was shorter in BPD versus CON by an average of 3.0sec (p<0.05), although this was no longer significant when we removed smokers from the analysis of those taking hepatic enzyme inducers. Smokers with BPD are not different from CON on most measures of nicotine intake and smoking topography. We found an increased rate of nicotine metabolism in smokers taking mood stabilizers that are hepatic enzyme inducers, including carbamazepine, oxcarbazepine, and topiramate. Smokers with rapid nicotine metabolism might be expected to smoke more intensely to compensate for the more rapid disappearance of nicotine from the blood and brain, and may have more difficulty in quitting smoking, although this requires further study.

Implanon failure in an HIV-positive woman on antiretroviral therapy resulting in two ectopic pregnancies

This letter to the editor describes Implanon failure in an HIV-positive woman on antiretroviral therapy resulting in two ectopic pregnancies to provide information on antiretroviral drug interactions and contraceptive options. The author recommends that a more cautious approach should be taken in advising all women on long-term treatment with an enzyme-inducing drug to change to an unaffected contraceptive method such as the progestogen-only injectable copper or levonorgestrel-releasing intrauterine methods or the combined oral contraceptive pill. Furthermore the author recommends that due to the complexity of antiretroviral drug interactions and constant changes in the fields of HIV medicine and contraception clinicians may need to continually check various sources of information for current advice.

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.

Implanon® failure in an HIV-positive woman on antiretroviral therapy resulting in two ectopic pregnancies

Since its introduction in 1999, Implanon® remains one of the preferred contraceptive choices for many women as it offers a highly effective means of long-term contraception for three years that does not rely on adherence. Like all hormonal contraceptives, certain hepatic enzyme-inducing drugs may reduce its efficacy. We present an interesting case of an HIV-positive woman on antiretroviral therapy having tubal pregnancies on two separate occasions with Implanon in place.

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.

452 Novel in vivo imaging of acute chemotherapy-induced vascular toxicity

To estimate the maximum-tolerated dose (MTD); study the pharmacology of escalating doses of gefitinib combined with radiation therapy in patients ⩽21 years with newly diagnosed intrinsic brainstem gliomas (BSG) and incompletely resected supratentorial malignant gliomas (STMG); and to investigate epidermal growth factor receptor (EGFR) amplification and expression in STMG.Three strata were identified: stratum 1A – BSG; stratum IB – incompletely resected STMG not receiving enzyme-inducing anticonvulsant drugs (EIACD); and stratum II – incompletely resected STMG receiving EIACD. Dose escalation using a modified 3 + 3 cohort design was performed in strata IA and II. The initial gefitinib dosage was 100 mg/m2/d commencing with radiation therapy and the dose-finding period extended until 2 weeks post-radiation. Pharmacokinetics (PK) and biology studies were performed in consenting patients.Of the 23 eligible patients, 20 were evaluable for dose-finding. MTDs for strata IA and II were not established as accrual was halted due to four patients experiencing symptomatic intratumoral haemorrhage (ITH); two during and two post dose-finding. ITH was observed in 0 of 11 patients treated at 100 mg/m2/d, 1 of 10 at 250 mg/m2/d and 3 of 12 at 375 mg/m2/d. Subsequently a second patient at 250 mg/m2/d experienced ITH. PK analysis showed that the median gefitinib systemic exposure increased with dosage (p = 0.04). EGFR was over-expressed in 5 of 11 STMG and amplified in 4 (36%) samples.This trial provides clear evidence of EGFR amplification in a significant proportion of paediatric STMG and 250 mg/m2/d was selected for the phase II trial.

Clinical pharmacodynamics and pharmacokinetics of the antifungal extended‐spectrum triazole posaconazole: an overview

In recent years, the antifungal triazole posaconazole has become increasingly important for the prophylaxis and treatment of systemic mycoses. Although oral bioavailability of posaconazole can be enhanced by concomitant food intake and administration in divided daily doses, increased gastric pH or gut motility, as well as enzyme-inducing drugs, can result in lower plasma concentrations than expected. Whether therapeutic drug monitoring can reduce the risk of treatment failures by avoiding sub-therapeutic plasma concentrations needs further examination. Based on the ability of posaconazole to inhibit cytochrome P450 3A4, several drug interactions can be expected, especially with agents that undergo extensive first-pass effect through the gut and the liver. However, more information is needed regarding dose modifications during concomitant administration of posaconazole with drugs in certain categories, such as vinca alkaloids and retinoids, along with selected individual drugs such as everolimus.

Failure of Implanon&amp;reg; on antituberculous therapy

Implanon® a contraceptive implant is increasingly being used because of its efficacy and nonuser-dependent nature. However as for other steroid contraceptives its efficacy can be reduced by enzyme-inducing drugs such as antituberculous medication resulting in unplanned pregnancy. We present the case of a 27-year-old para 1 + 0 referred to us for termination of a pregnancy that resulted from failure of Implanon during concomitant treatment with Rifinah® (a rifampicin-isoniazid combination). All health care providers should be aware of the adverse effects of hepatic enzyme inducers on hormonal contraceptives obtain details of current contraceptive methods from women of reproductive age and refer them to contraceptive and reproductive health care professionals as appropriate for optimal management. This will ensure that such women do not experience the psychologic trauma of a termination of pregnancy.

A phase I and biology study of gefitinib and radiation in children with newly diagnosed brain stem gliomas or supratentorial malignant gliomas

Purpose To estimate the maximum-tolerated dose (MTD); study the pharmacology of escalating doses of gefitinib combined with radiation therapy in patients ⩽21 years with newly diagnosed intrinsic brainstem gliomas (BSG) and incompletely resected supratentorial malignant gliomas (STMG); and to investigate epidermal growth factor receptor (EGFR) amplification and expression in STMG. Patients and methods Three strata were identified: stratum 1A – BSG; stratum IB – incompletely resected STMG not receiving enzyme-inducing anticonvulsant drugs (EIACD); and stratum II – incompletely resected STMG receiving EIACD. Dose escalation using a modified 3 + 3 cohort design was performed in strata IA and II. The initial gefitinib dosage was 100 mg/m 2/d commencing with radiation therapy and the dose-finding period extended until 2 weeks post-radiation. Pharmacokinetics (PK) and biology studies were performed in consenting patients. Results Of the 23 eligible patients, 20 were evaluable for dose-finding. MTDs for strata IA and II were not established as accrual was halted due to four patients experiencing symptomatic intratumoral haemorrhage (ITH); two during and two post dose-finding. ITH was observed in 0 of 11 patients treated at 100 mg/m 2/d, 1 of 10 at 250 mg/m 2/d and 3 of 12 at 375 mg/m 2/d. Subsequently a second patient at 250 mg/m 2/d experienced ITH. PK analysis showed that the median gefitinib systemic exposure increased with dosage ( p = 0.04). EGFR was over-expressed in 5 of 11 STMG and amplified in 4 (36%) samples. Conclusion This trial provides clear evidence of EGFR amplification in a significant proportion of paediatric STMG and 250 mg/m 2/d was selected for the phase II trial.

Antiepileptic Drugs and Markers of Vascular Risk

The most-used treatments for epilepsy worldwide are older-generation drugs such as phenytoin, carbamazepine, phenobarbital, and valproic acid, which have prominent enzymatic effects. Our sense of comfort with these treatments is starting to fade, however, as more and more potential long-term consequences of these drugs come to light. Epidemiologic studies demonstrate that ischemic disease of the heart and brain is more common among patients with epilepsy. Enzyme-inducing drugs are associated with elevations in a host of surrogate markers of vascular risk, suggesting that they could be responsible for increased rates of cardiovascular and cerebrovascular disease. The enzyme-inhibiting drug valproate may have adverse consequences of its own pertaining to glucose and lipid metabolism. These effects stand in addition to those well established in the literature regarding bone metabolism, hormonal abnormalities, and drug-drug interactions. Because patients with epilepsy require medication for years, and often for life, it is difficult to justify the long-term use of these agents when there are capable alternatives. Many of the adverse effects of the older drugs appear to be rapidly reversible, prompting consideration of whether patients who are currently treated with these agents should be switched to alternative therapies, even in the absence of obvious side effects. Newer medications without effects on hepatic enzymes likely do not have these chronic metabolic consequences, and we recommend their use over older-generation drugs whenever possible.

Prevalence and Risk Factors for Vitamin D Insufficiency Among Children With Epilepsy

This cross-sectional study was designed to determine the prevalence of, and risk factors for, vitamin D insufficiency among children treated for epilepsy in a general pediatric neurology clinic. Included were 78 children with epilepsy, aged 3-17 years, treated by the authors between September 2008 and March 2009. Vitamin D levels and relevant risk factors were evaluated using multiple logistic regression. Of the 78 children, 41% were male and 81% were of European origin; the mean age was 11.64 + or - 4.37 years. 25-hydroxyvitamin D levels of <20 ng/mL were observed in 25% of the children and levels considered to be normal (>32 ng/mL) were observed in only 25%. Girls and children with elevated body mass index were at increased risk for low 25-hydroxyvitamin D. The odds ratio for low 25-hydroxyvitamin D was 4.07 for girls versus boys, with a 95% confidence interval of 1.18-13.97; for each 1-unit increase in body mass index, the odds ratio was 1.179, with a 95% confidence interval of 1.047-1.329. Use of newer antiepileptic drugs was not associated with altered risk, compared with older enzyme-inducing drugs. Vitamin D insufficiency was highly prevalent in this unselected population of children with epilepsy. Female sex and increased body mass index were significant risk factors for low vitamin D levels, but antiepileptic drug regimen was not.

Bone loss associated with use of antiepileptic drugs

Importance of the field: Epilepsy is a neurological disorder associated with several comorbidities, one of them being reduced bone health. As the bone loss most often is insidious and asymptomatic, they are usually not recognized, and thus untreated. The key message of this paper is to make clinicians aware of the problem.Areas covered in this review: This article reviews data from basic and clinical studies of bone loss associated with usage of antiepileptic drugs (AEDs) within the last 4 decades.What the reader will gain: The reader will learn that there is accumulating evidence of biochemical abnormalities indicating a disturbed bone metabolism, a decreased bone density and a 2 – 6 times increased risk of fractures among those with epilepsy compared to the general population. These findings most likely have many causes, both internal and external, but long-term use of AEDs seems to play an important role. Enzyme-inducing drugs, such as phenytoin, phenobarbital and carbamazepine, but also the enzyme inhibitor valproate, appear to have bone-depleting properties. Reduced bone density may be detected during the first 1 – 5 years of treatment. Although many theories have been launched, the exact mechanisms by which the the drugs affect bone architecture are not fully understood.Take home message: We recommend clinicians to promote osteoprotective behavior among their epilepsy patients; that is, sunlight exposure and weight-bearing exercise as well as avoidance of risk factors such as bone-depleting drugs other than AEDs, smoking and heavy alcohol consumption. Enzyme inducing drugs should be avoided, if possible. Bone mineral density screening should be assessed on an individual basis, taking risk factors for bone loss into account. All patients taking AEDs on long-term basis ought to have adequate amounts of dietary calcium and vitamin D, and those who have developed bone loss should in addition be given specific antiosteoporotic treatment.

A phase I trial of erlotinib in patients with nonprogressive glioblastoma multiforme postradiation therapy, and recurrent malignant gliomas and meningiomas

The objective of this phase I study was to determine the maximal tolerated dose (MTD) of erlotinib in patients with recurrent malignant gliomas (MGs) or recurrent meningiomas on enzyme-inducing antiepileptic drugs (EIAEDs). Dose escalation was by a standard 3 x 3 design. The initial starting dose of erlotinib was 150 mg daily. If no dose-limiting toxicity (DLT) was observed, then dose escalation occurs as follows: 200 mg/day, 275 mg/day, and then increased in 125 mg increments until the MTD was reached. The MTD was defined as the dose where < or = 1 of 6 patients experienced a DLT and the dose above had 2 or more DLTs. The MTD was 650 mg/day; the observed DLTs were grade 3 rash in 2 patients at 775 mg/day. Pharmacokinetic analysis showed a significant influence of EIAEDs on the metabolism of erlotinib when compared with our phase II data published separately. Primary toxicities were rash and diarrhea. The MTD of erlotinib in patients receiving EIAEDs is substantially higher than the standard dose of 150 mg. This has important implications for further development of this drug in the treatment of MG as well as the optimal management of patients with other malignancies such as NSCLC who are on enzyme-inducing drugs.