Pharmacokinetics, pharmacodynamics and clinical efficacy of omalizumab for the treatment of asthma.

INTRODUCTION: Omalizumab is a subcutaneously administrated monoclonal anti-IgE antibody indicated in adults, adolescents and children 6 years of age and older with moderate to severe allergic asthma uncontrolled by conventional pharmacological treatments and sensitization to at least one perennial allergen. Area covered: This drug evaluation summarizes published data on pharmacokinetic and pharmacodynamic properties of omalizumab, on clinical efficacy and safety, including real-world evidence, and provides a medico-economic evaluation of the drug. Expert opinion: Omalizumab represents an efficient therapeutic option for the management of patients with uncontrolled moderate/severe allergic asthma. It provides a significant reduction in the asthma exacerbation rate with a steroid-sparing effect, an improvement in quality of life in adults and adolescents, despite a lack of evidence about its efficacy specifically in severe allergic asthma. Clinical trials have demonstrated its efficacy in the pediatric population but further real-life evidence is expected to better characterize long-term effects in this population. There is still some debate about the optimal treatment duration but, to date, it is recommended not to stop the treatment as cessation has resulted in symptom recurrence. Omalizumab is an expensive treatment, but a key therapeutic option when used for uncontrolled severe allergic asthma.

Pharmacodynamic and pharmacokinetic assessment of fluticasone furoate + vilanterol for the treatment of asthma.

INTRODUCTION: The pharmacokinetic (PK) and pharmacodynamic (PD) effects of long-acting ß2-agonists and mostly inhaled corticosteroids (ICSs) shape the efficacy and safety of these agents in the treatment of asthma. In fact, the PK and PD characteristics of the drug largely determine the degree of pulmonary targeting Areas covered. In this review, we summarize the PK and PD properties of inhaled fluticasone furoate (FF) and vilanterol trifenatate (VI) and their fixed-dose combination (FDC) for the treatment of asthma Expert opinion. It is difficult to interpret the data that we have described because the preclinical and clinical development of FF/VI FDC was not really based on solid information on quantitative PK/PD approach. Unfortunately, for both FF and VI we only know concentrations in systemic blood, a compartment that is downstream of both target and non-target respiratory tissue. This lack of information does not allow us to understand the temporal relationship between the delivered dose and the drug concentration at the sites of action within the lungs. In addition, all studies performed with FF and VI did not address the fundamental issue that asthma can significantly alter lung deposition, absorption and also clearance of inhaled medicines.

Ethnic sensitivity assessment of pharmacokinetics and pharmacodynamics of omalizumab with dosing table expansion.

A three-part license expansion for omalizumab (Xolair(®)), humanized anti-IgE antibody, was recently made in Japan for paediatric use, additional higher doses and revised dosing frequency in allergic asthma. The dosing level and frequency of omalizumab are guided by a dosing table based on the total serum IgE and bodyweight. Nonlinear mixed-effect pharmacokinetic (PK) and pharmacodynamic (PD) modeling and simulation techniques described the binding between omalizumab and its target IgE. The population PKPD analysis was conducted using data from the nine studies included originally in the European application of dosing table expansion together with three Japanese clinical studies to assess the influence of the ethnicity. Statistically significant differences between the ethnic groups were detected. These were small, within or close to bioequivalence criteria. The model described the primary pharmacology in Caucasian and Japanese patients, both adult and paediatric, with simulations showing that the interplay between the clearance, volume and binding affinity parameters was such that there was no clinical impact of the Japanese ethnic differences on either drug PK or free IgE suppression and hence the required posology.

Assessment of endogenous, oral and inhaled steroid cross-reactivity in the Roche cortisol immunoassay.

BACKGROUND: Inhaled steroids are widely used for the treatment of asthma. Concerns over adrenal suppression when used at high doses or in combination with drugs such as ritonavir exist, requiring the measurement of serum cortisol. Herein, we investigate the cross-reactivity of the inhaled steroids betamethasone, fluticasone and beclomethasone in the Roche cortisol immunoassay, in addition to five other steroids. METHODS: Five replicates were produced from a serum pool for each of the eight steroids at a final concentration of 0.1 and 1 µg/mL. Each steroid was dissolved in 50% methanol, with 50% methanol of the same volume added to the control sample. The cross-reactivity of each steroid in the cortisol assay was calculated. RESULTS: There was no statistically or clinically significant cross-reactivity in the measurement of cortisol when fluticasone, beclomethasone or betamethasone were spiked at 0.1 and 1.0 µg/mL, except for beclomethasone at a concentration of 1 µg/mL (1490 nmol/L) with a cross-reactivity of 1.6%, which is unlikely to be clinically significant. At both steroid concentrations investigated, prednisolone, 17-hydroxyprogesterone and 11-deoxycortisol exhibited statistically significant cross-reactivities that were greater than the least significant change of the assay (13.1%), whereas dexamethasone and metyrapone did not. Mean inter-assay precision was 1.5% (405-1586 nmol/L). CONCLUSION: The cross-reactivity of the inhaled steroids; betamethasone, fluticasone and beclomethasone in the Roche cortisol immunoassay are unlikely to be clinically significant at the concentrations found in patients on therapeutic doses. This will enable confident assessment of adrenal status in patients at risk of adrenal suppression.

Substitution of theophylline slow-release formulations according to the rebate contracts in the German statutory health insurance.

On the basis of the rebate contracts between individual statutory health insurance funds and pharmaceutical enterprises, the generic substitution of prescribed medications is economically attractive and is advocated for statutory health insurees in Germany. In addition to the drugs whose substitution can be considered to be uncritical, rebate contracts also include controversial substances such as the bronchodilator theophylline (CAS 58-55-9), which has a narrow therapeutic range and should only be substituted under certain conditions. The objective of this article was to check the safety of the substitution of theophylline by means of a comparative evaluation of bioequivalence studies carried out on theophylline slow-release preparations. A systematic literature search was carried out in the MEDLINE database. The search terms used were combinations of the following key words: theophylline, generics, bioequivalence, substitution, brand and non-brand. In addition, a manual search was performed in the reference lists of the relevant articles. Only articles that were published between January 1, 1988 and August 30, 2008 were to be included. Five studies conformed to the inclusion and exclusion criteria. Two of the studies came to the conclusion that the preparations analysed were bioequivalent. In the remaining three studies there was no bioequivalence found between the preparations and the reference product. Because of the heterogeneity of study outcomes no metanalysis could be performed. On the basis of the studies analysed the conclusion can be drawn that a theophylline slow-release preparation should only be substituted under close monitoring by a physician because of the many factors which can adversely affect serum levels, such as the narrow therapeutic range of the active ingredient, the patient's metabolisation rate or the different galenics of the preparations. Nevertheless, the question remains as to whether the costs saved by the rebate contracts would not be significantly outweighed.

The preclinical testing strategy for the development of novel chemical entities for the treatment of asthma.

Identifying and developing novel chemical entities (NCE) for the treatment of asthma is a time-consuming process and liabilities that endanger the successful progression of a compound from research into the patient are found throughout all phases of drug discovery. In particular the failure of advanced compounds in clinical studies due to lack of efficacy and/or safety concerns is tremendously costly. Therefore, in order to try and reduce the failure rate in clinical trials various in vitro and in vivo tests are performed during preclinical development, to rapidly identify liabilities, eliminate high risk compounds and promote promising potential drug candidates. To achieve this objective, numerous prerequisites have to be met regarding the physico-chemical properties of the compound, and bioactivity or model systems are needed to rate the therapeutic potential of new compounds. Drug liabilities such as target and species specificity, formulation issues, pharmacokinetics as well as pharmacodynamics and the toxic potential of the compound have to be analyzed in great detail before a compound can enter a clinical trial. A particularly challenging aspect of developing novel NCEs for the treatment of asthma is choosing and setting up in vivo models believed to be predictive for human disease. Numerous companies have in the past and are currently developing NCEs targeting many different pathways and cells with the aim to treat asthma. However, currently the only NCE having a significant market share are long-acting beta-agonists (LABA), inhaled and orally active steroids and leukotriene receptor antagonists. In the past many novel NCE for the treatment of asthma were effective in animal models but failed in the clinic. In this review we outline the prerequisites of novel NCE needed for clinical development.

Anti-immunoglobulin E therapy with omalizumab for asthma.

OBJECTIVE: To evaluate data on anti-immunoglobulin E (anti-IgE) therapy for asthma. DATA SOURCES: Information was selected from PubMed from 1989 to May 2007 using the search term omalizumab and included randomized, controlled trials. These studies evaluated asthma treatment with omalizumab and focused on its efficacy, tolerability, and cost-effectiveness in this population. STUDY SELECTION AND DATA EXTRACTION: All randomized clinical trials were reviewed (23 were identified and 19 were included; 3 were not relevant and 1 contained duplicative data). Other articles using the search words anti-IgE therapy and cost-effectiveness were evaluated; relevant information was extracted. DATA SYNTHESIS: IgE-dependent mechanisms play an important role in the development and maintenance of airway inflammation in asthma. Omalizumab is a subcutaneously administered monoclonal anti-IgE antibody that reduces unbound IgE concentrations and promotes down-regulation of IgE receptors. Results from clinical trials in adults, adolescents, and children with poorly controlled IgE-mediated asthma have shown that omalizumab improves symptom control and allows patients to be managed with lower doses of inhaled corticosteroids (ICS). It has been well tolerated in clinical trials lasting as long as 52 weeks, but injection-site reactions are common (45% in omalizumab group vs 43% in placebo group) and anaphylaxis has occurred in 0.2% of patients. A consensus expert panel has recommended that omalizumab should be considered for patients 12 years of age or older with allergic asthma who are inadequately controlled on guideline-based therapy and require maintenance therapy with systemic corticosteroids or high-dose ICSs, or who have poor adherence to ICS therapy. CONCLUSIONS: Anti-IgE therapy provides an effective and generally safe approach to the treatment of patients with IgE-mediated asthma who are not adequately controlled by conventional guideline-based medications. However, the potential benefit must be weighed against the cost and inconvenience of this new therapy.

The potential role of roflumilast: the new phosphodiesterase-4 inhibitor.

OBJECTIVE: To review the pharmacology, pharmacokinetics, efficacy, and safety of roflumilast in the treatment of asthma and chronic obstructive pulmonary disease (COPD). DATA SOURCES: Studies, review articles, and meeting abstracts evaluating roflumilast were obtained from MEDLINE (1966-May 16, 2006), EMBASE (1980-May 16, 2006), and International Pharmaceutical Abstracts (1970-May 16, 2006) databases. Key terms used in all of the database searches were roflumilast, phosphodiesterase-4 inhibitor, asthma, chronic obstructive pulmonary disease, and COPD. Company Web sites were reviewed, and bibliographies of selected articles were evaluated for pertinent articles. STUDY SELECTION AND DATA EXTRACTION: In vitro, in vivo, and animal studies were selected, as were published human studies on the efficacy and safety of roflumilast. Due to limited published data on its safety, efficacy, pharmacokinetics, and drug interactions, meeting abstracts were also selected. Data retrieved from abstracts only is indicated in the references. DATA SYNTHESIS: Roflumilast is a phosphodiesterase-4 (PDE-4) inhibitor which, due to its selective inhibition of the PDE 4 isoenzyme, has potential antiinflammatory and antimodulatory effects in the pulmonary system. It has been studied as an oral tablet in doses of 250 or 500 microg/day. Animal data and clinical trials have demonstrated roflumilast's efficacy and safety as an antiinflammatory and antimodulatory agent for use in asthma and COPD, with no documented drug interactions and a favorable adverse effect profile. CONCLUSIONS: Roflumilast may be an additional option in the treatment of asthma and COPD due to its ease of administration and a seemingly favorable adverse event profile. However, more research is needed to solidify roflumilast's place in therapy.

Anti-IgE therapy with omalizumab in asthma and allergic rhinitis.

The pharmacology, efficacy, dosage, adverse effects, and economics of anti IgE (omalizumab) are discussed. Omalizumab is the generic name for the human/murine chimeric (recombinant humanized) monoclonal IgG antibody. Anti-IgE prevents IgE from attaching to effector cells, and thereby blunts IgE-mediated inflammatory responses. After subcutaneous administration its absorption is slow, reaching peak concentration in serum after an average of 7-8 days. At recommended doses, serum free IgE levels decrease within 1 hour following the first dose and are maintained between doses. Dose and dosing frequency are adjusted according to body mass and serum total IgE concentration before the start of treatment. Omalizumab administered subcutaneously is an effective treatment for add-on therapy in patients with poorly controlled, moderate-to-severe allergic asthma and allergic rhinitis (adults and adolescents > 12 years). It reduces the requirement for inhaled corticosteroids while protecting against disease exacerbation. Omalizumab is well tolerated, but the safety profile requires long-term assessment in adults as well as in children.

The combination of population pharmacokinetic studies.

Pharmacokinetic data consist of drug concentrations with associated known sampling times and are collected following the administration of known dosage regimens. Population pharmacokinetic data consist of such data on a number of individuals, possibly along with individual-specific characteristics. During drug development, a number of population pharmacokinetic studies are typically carried out and the combination of such studies is of great importance for characterizing the drug and, in particular, for the design of future studies. In this paper, we describe a model that may be used to combine population pharmacokinetic data. The model is illustrated using six phase I studies of the antiasthmatic drug fluticasone propionate. Our approach is Bayesian and computation is carried out using Markov chain Monte Carlo. We provide a number of simplifications to the model that may be made in order to ease simulation from the posterior distribution.

Zafirlukast. A review of its pharmacology and therapeutic potential in the management of asthma.

Zafirlukast is a competitive and selective leukotriene receptor antagonist indicated for the prophylaxis and treatment of chronic asthma. The rationale for the development of leukotriene antagonists was based on in vitro and in vivo data demonstrating the extensive role of the cysteinyl leukotrienes C4 (LTC4), D4 (LTD4) and E4 (LTE4) in the pathogenesis of asthma. Initial data have demonstrated an improvement in pulmonary function and symptom control and a reduction in the use of short-acting inhaled beta 2-adrenoceptor agonist therapy in patients with mild to moderate asthma treated with oral zafirlukast at the recommended dosage of 20 mg twice daily. Available data also suggest that zafirlukast may significantly reduce the incidence of asthma exacerbations. Data on the comparative efficacy of zafirlukast and existing antiasthma medications are limited. Results from 2 double-blind randomised studies comparing zafirlukast 20 mg twice daily with sodium cromoglycate aerosol or dry powder inhalation reported similar efficacy for both drugs. In a comparison with inhaled beclomethasone dipropionate (0.2 to 0.25 mg twice daily), improvements in morning peak expiratory flow rate, forced expiratory volume in 1 second and daytime symptom score were significantly less with zafirlukast 20 mg twice daily for 6 weeks. However, available data suggest that patient compliance and patient preference may be greater with oral zafirlukast 20 mg twice daily than with twice-daily inhaled corticosteroid therapy. Confounding results from 2 studies preclude any clear conclusions regarding the potential steroid-sparing effect of zafirlukast at the recommended dosage of 20 mg twice daily. Furthermore, Churg-Strauss syndrome has been reported in 6 patients who were being withdrawn from oral corticosteroid therapy while receiving treatment with oral zafirlukast. It is, therefore, recommended that zafirlukast-treated patients who require a reduction in their oral corticosteroid therapy are closely monitored. Zafirlukast is generally well tolerated. Reports of elevated liver enzymes in patients receiving high dosages of zafirlukast (80 mg twice daily) preclude the use of dosages exceeding 40 mg twice daily. Careful monitoring is necessary in zafirlukast-treated patients receiving concomitant therapy with drugs such as warfarin, terfenadine and erythromycin because of the potential for drug interactions. Thus, zafirlukast is a potentially useful addition to current antiasthma therapies in patients with mild to moderate asthma. Because zafirlukast is administered orally, it may be particularly beneficial in patients poorly compliant with asthma therapy as a result of poor inhaler technique. Further investigation of the efficacy of zafirlukast is expected to more clearly define its position in the management of asthma.