Oral Targeted Therapies and Central Nervous System (CNS) Metastases.

The purpose of our review is to summarize the clinical activity of oral targeted agents against brain metastases. This includes BRAF inhibitors (dabrafenib and vemurafenib), human epidermal growth factor receptor inhibitors (lapatinib, gefitinib, erlotinib, and afatinib), multi-kinase angiogenesis inhibitors (sorafenib, sunitinib, pazopanib, and vandetanib), and ALK/c-MET (crizotinib) and ALK/IGF-1 (ceritinib) inhibitors. Effective systemic therapies are needed for long-term benefit in brain metastases and documentation of intracranial activity for many therapies is poor. Our review provides a summary of the literature with pertinent data for clinicians. This is needed as subjects with brain metastases are often prevented from enrolling in clinical trials and investigations focused on systemic therapies for brain metastases are rare.

Clinical pharmacokinetics of drugs in patients with heart failure: an update (part 2, drugs administered orally).

The purpose of the present review article is to update the information regarding pharmacokinetics of drugs in patients with heart failure that has accumulated since the last review article published in 1988 in Clinical Pharmacokinetics. Since this last review, our understanding of the pathophysiology of heart failure has changed from the cardio-renal model to the neuro-humoral model, and the pharmacologic approach to treatment of heart failure has been shifted from inotropic agents to those acting on the renin-angiotensin-aldosterone system. The pharmacologic agents now used for heart failure include many important classes of drugs, such as ACE inhibitors, angiotensin receptor blockers (antagonists) (ARBs), and mineralocorticoid receptor antagonists. In Part 1 of this review, we summarized the pharmacokinetic properties of relevant drugs administered intravenously. In Part 2, the present article, we describe pharmacokinetics of drugs following oral administration. For this purpose we conducted a systematic search of literature using MEDLINE, EMBASE, and Japan Centra Revuo Medicina (in Japanese). We retrieved a total of 110 relevant publications for 49 drugs and updated the information for ten drugs and provided new information for 31 drugs. We recognized that the pharmacokinetic data were obtained primarily from stable heart failure patients with moderate severity [New York Heart Association (NYHA) class II or III]. In addition, most patients were classified as heart failure with reduced ejection fraction. Furthermore, because most of the studies retrieved had no comparative groups of healthy subjects or patients without heart failure, historical controls from previous studies were used for comparisons. In Part 2, we also discuss the pharmacokinetics of active metabolites as well as parent drugs, because many drugs given by oral administration for the treatment of heart failure are prodrugs (e.g., ACE inhibitors and ARBs). The pharmacokinetic changes of drugs in patients with heart failure are discussed in the light of a physiologically based pharmacokinetic model. In addition, we discuss the effects of intestinal tissue heart failure-associated edema on drug absorption as it relates to the biopharmaceutical classification system, particularly for drugs demonstrating reduced systemic exposure as measured by the area under the plasma concentration-time curve after oral administration (AUCpo) in patients with heart failure as compared with healthy subjects. After review of the available data, it was seen that among patients with asymptomatic or compensated chronic heart failure there seemed to be no or minimal alterations in the maximum concentration (C max) and AUCpo of the included drugs, unless there was concurrent liver and/or renal dysfunction. In contrast, the AUCpo of at least 14 drugs (captopril, cilazaprilat, enalapril/enalaprilat, perindopril, carvedilol, candesartan, pilsicainide, felodipine, furosemide, enoximone, milrinone, flosequinan, molsidomine, and ibopamine) were suspected or documented to increase after oral administration by 50% or more in patients with symptomatic or decompensated heart failure.

Analyzing temozolomide medication errors: potentially fatal.

The EORTC-NCIC regimen for glioblastoma requires different dosing of temozolomide (TMZ) during radiation and maintenance therapy. This complexity is exacerbated by the availability of multiple TMZ capsule strengths. TMZ is an alkylating agent and the major toxicity of this class is dose-related myelosuppression. Inadvertent overdose can be fatal. The websites of the Institute for Safe Medication Practices (ISMP), and the Food and Drug Administration (FDA) MedWatch database were reviewed. We searched the MedWatch database for adverse events associated with TMZ and obtained all reports including hematologic toxicity submitted from 1st November 1997 to 30th May 2012. The ISMP describes errors with TMZ resulting from the positioning of information on the label of the commercial product. The strength and quantity of capsules on the label were in close proximity to each other, and this has been changed by the manufacturer. MedWatch identified 45 medication errors. Patient errors were the most common, accounting for 21 or 47% of errors, followed by dispensing errors, which accounted for 13 or 29%. Seven reports or 16% were errors in the prescribing of TMZ. Reported outcomes ranged from reversible hematological adverse events (13%), to hospitalization for other adverse events (13%) or death (18%). Four error reports lacked detail and could not be categorized. Although the FDA issued a warning in 2003 regarding fatal medication errors and the product label warns of overdosing, errors in TMZ dosing occur for various reasons and involve both healthcare professionals and patients. Overdosing errors can be fatal.

Clinical pharmacokinetics of drugs in patients with heart failure: an update (part 1, drugs administered intravenously).

Heart failure is one of the leading causes of death in developed countries, and its prevalence is expected to increase further in the coming years. While the pharmacokinetic changes observed in patients with heart failure have been reviewed twice in Clinical Pharmacokinetics, approximately a quarter century has passed since the latest article was published in 1988. Since then, many important classes of agents (e.g. ACE inhibitors, angiotensin receptor antagonists and inotropes) have been introduced for the treatment of heart failure. The aim of the present article is to update the information regarding the pharmacokinetics of these drugs. For this purpose we have made a systematic survey of literature using MEDLINE, EMBASE and Japan Centra Revuo Medicina (in Japanese) and found a total of 111 relevant publications for 58 drugs. Heart failure is a pathophysiological state where the damaged heart, from whatever causes, no longer pumps enough blood for the needs of body tissues at rest or during the normal daily activities. The spectrum of heart failure ranges from acute decompensated heart failure (including circulatory shock) to chronic compensated or decompensated heart failure. Because hypoperfusion of organs may influence drug absorption from the gastrointestinal tract, distribution into tissues and elimination either by the liver or kidneys, it is conceivable that the pharmacokinetics of many drugs may be altered in patients with heart failure. The pharmacokinetic changes of drugs in these patients in the light of a physiologically based pharmacokinetic model are discussed, since this model can interpret altered pharmacokinetics in terms of changes in the binding of drugs in plasma and tissue, blood flow to drug-eliminating organs and intrinsic activity of drug elimination. Pharmacokinetic changes of drugs after intravenous administration are described here in Part 1 and those after oral administration will be discussed in Part 2 in a later issue of the Clinical Pharmacokinetics. Reviewing the retrieved data, it was considered that patients with asymptomatic or compensated chronic heart failure seem to have no or minimal alterations in the pharmacokinetics of parenterally administered drugs as long as there was no concurrent liver and/or kidney dysfunction. In contrast, it was found that the systemic clearance of at least six drugs (i.e. milrinone, carperitide, molsidomine, theophylline, ciclosporin and hydralazine) was reduced after intravenous administration by 50 % or more in patients with acute decompensated heart failure or chronic severe heart failure (New York Heart Association class III or IV) as compared with healthy subjects. Because there is a paucity of information regarding the pharmacokinetics of drugs in patients with severe heart failure, close attention should be paid to monitoring the efficacy of these agents and their associated adverse effects.

Intra-CSF administration of chemotherapy medications.

Leptomeningeal carcinomatosis is a devastating complication of cancer and is likely increasing in incidence. The combination of widespread neuro-axial spread based on CSF flow and the blood-brain barrier (BBB) has favored immediate local delivery of antineoplastic agents. With the BBB, the leptomeninges can be a sanctuary site to systemic cancers and goal of therapy includes preventing involvement in this space. Current therapies with U.S. Food and Drug Administration (FDA) approval are limited to treat hematologic cancers. Although lacking FDA guidance, a wider array of therapies is available to treat solid tumors. We provide an updated examination on both well-established intra-CSF chemotherapies as well as agents having limited data, but reports of therapeutic benefit.

Efficacy of metformin and topiramate in prevention and treatment of second-generation antipsychotic-induced weight gain.

OBJECTIVE: To review the literature describing the efficacy of metformin and topiramate for the treatment of second-generation antipsychotic-induced weight gain. DATA SOURCES: Articles were identified by searching the MEDLINE database (from 1949 through January 2010) using the key words metformin, topiramate, antipsychotic, weight, weight gain, and obesity. STUDY SELECTION AND DATA EXTRACTION: All randomized, placebo-controlled trials of metformin and topiramate were selected for review. DATA SYNTHESIS: Weight gain due to second-generation antipsychotic use is a concern due to the risk of long-term metabolic and cardiovascular effects with these agents. These effects include obesity, hyperglycemia, and insulin resistance, all of which may contribute to diabetes and cardiovascular disease. Second-generation antipsychotics vary in the degree to which they cause weight gain, and dietary and lifestyle changes may not be feasible or sufficient in counter-acting this weight gain. Although other pharmacologic agents may be beneficial to prevent and treat antipsychotic-induced weight gain, metformin and topiramate have been the most extensively studied in this setting. Metformin acts peripherally to cause weight loss, while topiramate acts centrally. Review of 11 randomized, controlled trials demonstrates beneficial effects of metformin and topiramate in prevention and treatment of weight gain. Metformin is generally well tolerated and has been studied in pediatric patients, while topiramate is associated with more drug interactions and may possibly interfere with control of schizophrenia. CONCLUSIONS: Data for the use of metformin and topiramate in the treatment and prevention of second-generation antipsychotic-induced weight gain are limited. Both may be effective in helping patients lose weight via mechanisms that have yet to be clearly defined. The use of metformin results in greater weight loss than topiramate, and topiramate is associated with more risks and may compromise the treatment of schizophrenia. Treatment of antipsychotic-induced weight gain with metformin may be an option after lifestyle and dietary changes have failed.

Use of atypical antipsychotics in the treatment of autistic disorder.

OBJECTIVE: To review clinical trials and reports describing the efficacy and safety of atypical antipsychotics (olanzapine, ziprasidone, quetiapine, aripiprazole) in the treatment of autistic or other pervasive developmental disorders. DATA SOURCES: English-language publications from the MEDLINE database (1966-February 2007) including clinical trials, case reports, and retrospective series were reviewed. STUDY SELECTION AND DATA EXTRACTION: Relevant data were extracted from studies of selected atypical antipsychotics in the treatment of autistic disorder in children, adolescents, and adults. Most literature found was in the form of case reports or case series; however, several open-label and double-blind trials were also identified. DATA SYNTHESIS: Autistic disorder is a chronic neurodevelopmental disorder with limited treatment options. Nonpharmacologic approaches may be the most beneficial, but pharmacologic agents are needed for some patients with significant behavioral manifestations of the disorder. The atypical antipsychotics (olanzapine, ziprasidone, quetiapine, aripiprazole) have shown some efficacy in improving certain behavioral symptoms of autistic disorder--primarily aggressiveness, hyperactivity, and self-injurious behavior. Efficacy was based on observation or changes from baseline in behavioral rating scores. Data appear to be strongest for olanzapine compared with quetiapine, with several open-label trials suggesting its efficacy. Weight gain and sedation were frequently reported adverse events with both agents. Aripiprazole has demonstrated efficacy in limited case series, with minimal adverse effects reported. CONCLUSIONS: Atypical antipsychotics represent a treatment option for symptoms associated with autistic disorder. However, these drugs do not affect the core symptoms of autistic disorder and are associated with potentially significant adverse effects. In addition, there is a lack of randomized controlled trials to determine the true efficacy and long-term safety of these agents in the pediatric population.

Rituximab in the treatment of acquired hemophilia.

OBJECTIVE: To review published literature evaluating the use of rituximab for treatment of acquired hemophilia. DATA SOURCES: An English-language literature search was conducted using MEDLINE (1966-January 2006). References of identified articles were subsequently reviewed for additional data. Search terms included rituximab, acquired hemophilia, and inhibitors. DATA SYNTHESIS: Available data suggest that B-cell depletion by rituximab in patients with acquired hemophilia may contribute to the eradication of inhibitors to coagulation factors. B-cells have been shown to be essential in the development of autoimmunity or an acquired immune response. Beneficial effects of rituximab, after failure of established therapies, have been reported in case reports and one small, open-label trial. CONCLUSIONS: Although data are limited, administration of rituximab appears to be an effective option for treatment of patients with acquired hemophilia after established therapies have failed. Patients given rituximab experienced cessation of recurrent bleeding, normalization of factor VIII activity, and eradication of inhibitors. A complete response to rituximab (undetectable inhibitors, normalization of factor levels) generally occurred several weeks to months after initiation of therapy.

Continuous infusion of coagulation factor products.

OBJECTIVE: To review clinical information related to the use of continuous infusion factor products in patients with hemophilia. Specifically, case reports and open-label trials are summarized involving the use of factor VIII and recombinant factor VIIa for a variety of indications including surgical prophylaxis, acute bleeding, primary prevention, and management of inhibitors. In addition, issues surrounding the use of continuous infusion of factor products such as pharmacokinetic rationale, stability/sterility, and cost are reviewed. DATA SOURCES: Primary and review articles were identified through a MEDLINE search (1990-June 2001) and through secondary sources. STUDY SELECTION AND DATA EXTRACTION: All articles identified from the data sources were evaluated, and all information deemed relevant was included in this review. DATA SYNTHESIS: Data concerning the administration of factor products are primarily detailed in open-label trials and case reports. Comparisons between intermittent bolus injections and continuous infusion of factor products are limited and primarily compare continuous infusion regimens with historical controls. The rationale behind the continuous-infusion approach is linked to the pharmacokinetics of factor products administered via this route. Pharmacokinetic data reveal that, with continuous infusion of factor products, a reduction in clearance and a maintenance of factor serum concentrations are noted. CONCLUSIONS: Administration of factor products (factor VIII and recombinant factor VIIa) via continuous infusion has produced favorable hemostatic effects compared with intermittent bolus injections. The advantages of continuous infusion include maintenance of a constant factor concentration, thereby reducing risk of bleeding from excessively low trough concentrations, and a decrease in factor consumption related to a reduction in factor clearance with constant infusion. Manufacturers recommend using reconstituted factor products either immediately or within 1-3 hours after reconstitution; however, several studies have found the products to be stable and sterile for longer periods.