Guenther Hochhaus

Pharmacodynamics of omalizumab: implications for optimised dosing strategies and clinical efficacy in the treatment of allergic asthma.

SUMMARY Objective: Omalizumab (Xolair*), is a recombinant humanised monoclonal anti-immunoglobulin E (IgE) antibody, for the treatment of allergic asthma. This review describes how the correlation between clinical outcomes and a suitable surrogate marker (free serum IgE) led to the development of an individualised dosing strategy for omalizumab. It also demonstrates how subsequent studies using this dosing strategy were able to achieve low levels of IgE and clinical benefit. * Xolair is a registered trade name of Novartis Pharma AG, Basel, Switzerland and Genentech, South San Francisco, California, USA Data sources: Published articles and data on file (Novartis PharmaAG, Genentech). Results: Studies in patients with IgE-mediated diseases of the airways have shown that clinical benefit with omalizumab is observed when free IgE levels in serum are reduced to 50ng/ml (20.8 IU ml−1) or less (target 25 ng ml−1 (10.4IU ml−1)). The ability of omalizumab to reduce free IgE levels to such levels is dependent on dose, the patients weight and baseline IgE level. To simplify dosing, and ensure that free IgE reduction is achieved, an individualised tiered dosing table was developed from which patients with asthma, depending on weight and starting IgE level, receive omalizumab 150–375 mg by subcutaneous injection every 2 or 4 weeks. This dosing strategy has proved clinically efficacious for improving disease control in patients with allergic asthma, as shown by significantly lower exacerbation rates and decreased dependence on treatment with inhaled corticosteroids, along with improvements in symptoms, lung function and usage of rescue bronchodilators. Conclusions: The clinical efficacy of omalizumab has been optimised through the development of an individualised dosing table that emerged from an understanding of the pharmacodynamics of this agent.

Clinical Pharmacology of Pancreatic Enzymes in Patients with Cystic Fibrosis and In Vitro Performance of Microencapsulated Formulations

Improving protein and fat absorption in patients with cystic fibrosis relates to the amount of biologically active enzyme reaching the duodenum. Microencapsulated formulations are more effective than conventional products but differ in content, ability to retard acid inactivation and the pH at which they release enzymes. Contaminants in these products contribute to hyperuricosuria.

Pulmonary targeting of liposomal triamcinolone acetonide phosphate.

AbstractPurpose. To explore the use of triamcinolone acetonide phosphate liposomes as a pulmonary targeted drug delivery system. Methods. Triamcinolone acetonide phosphate liposomes composed of 1,2-distearoyl phosphatidylcholine and 1,2-distearoyl phosphatidyl glycerol and triamcinolone acetonide 21-phosphate dipotassium salt were prepared by dispersion and extruded through polycarbonate membranes. Encapsulation efficiency and in vitro stability at 37°C were assessed after size exclusion chromatography. TAP liposomes (TAP-lip) or TAP in solution (TAP-sol) were delivered to rats either by intratracheal instillation (IT) or intravenous (IV) administration. Pulmonary targeting was assessed by simultaneous monitoring of glucocorticoid receptor occupancy over time in lung (local organ) and liver (systemic organ) using an ex vivo receptor binding assay as a pharmacodynamic measure of glucocorticoid action. Results.In vitro studies in different fluids over 24 hours, showed that more than 75% of the TAP remained encapsulated in liposomes. Cumulative pulmonary effects after IT administration of TAP-lip were 1.6 times higher than liver receptor occupancy. In contrast, there was no difference in the pulmonary and hepatic receptor occupancy time profiles when TAP was administered intratracheally as a solution. No preferential lung targeting was observed when TAP-lip was administered IV. As indicated by the mean effect times, lung receptor occupancy was sustained only when TAP-lip was administered IT. Conclusions. Intratracheal administration of TAP-lip provided sustained receptor occupancy, and increased pulmonary targeting which was superior to IT administration of TAP-sol or IV administration of TAP-lip. The use of liposomes may represent a valuable approach to optimize sustained delivery of glucocorticoids to the lungs via topical administration.

Receptor binding studies of soft anticholinergic agents

Receptor binding studies were performed on 24 soft anticholinergic agents and 5 conventional anticholinergic agents using 4 cloned human muscarinic receptor subtypes. The measured pK i values of the soft anticholinergic agents ranged from 6.5 to 9.5, with the majority being in the range of 7.5 to 8.5. Strong correlation was observed between the pK is determined here and the pA 2 values measured earlier in guinea pig ileum contraction assays. The corresponding correlation coefficients (r 2) were 0.80, 0.73, 0.81, and 0.78 for pK i(m1), pK i(m2), pK i(m3), and pK i(m4), respectively. Quantitative structure-activity relationship (QSAR) studies were also performed, and good characterization could be obtained for the soft anticholinergics containing at least 1 tropine moiety in their structure. For these compounds, the potency as measured by the pK i values was found to be related to geometric, electronic, and lipophilicity descriptors. A linear regression equation using ovality (O e), dipole moment (D), and a calculated log octanol-water partition coefficient (QLogP) gave reasonably good descriptions (r=0.88) for the pK i(m3) values.

A Pharmacokinetic Simulation Tool for Inhaled Corticosteroids

The pharmacokinetic (PK) behavior of inhaled drugs is more complicated than that of other forms of administration. In particular, the effects of certain physiological (mucociliary clearance and differences in membrane properties in central and peripheral (C/P) areas of the lung), formulation (as it relates to drug deposition and particle dissolution rate), and patient-related factors (lung function; effects on C/P deposition ratio) affect the systemic PKs of inhaled drugs. The objectives of this project were (1) to describe a compartmental model that adequately describes the fate of inhaled corticosteroids (ICS) after administration while incorporating variability between and within subjects and (2) based upon the model, to provide a freely available tool for simulation of PK trials after ICS administration. This compartment model allows for mucociliary removal of undissolved particles from the lung, distinguishes between central and peripheral regions of the lung, and models drug entering the systemic circulation via the lung and the gastrointestinal tract. The PK simulation tool is provided as an extension package to the statistical software R (‘ICSpkTS’). It allows simulation of PK trials for hypothetical ICS and of four commercially available ICS (budesonide, flunisolide, fluticasone propionate, and triamcinolone acetonide) in a parallel study design. Simulated PK data and parameters agreed well with literature data for all four ICS. The ICSpkTS package is especially suitable to explore the effect of changes in model parameters on PK behavior and can be easily adjusted for other inhaled drugs.

Chronic blockade of hindbrain glucocorticoid receptors reduces blood pressure responses to novel stress and attenuates adaptation to repeated stress

Exogenous glucocorticoids act within the hindbrain to enhance the arterial pressure response to acute novel stress. Here we tested the hypothesis that endogenous glucocorticoids act at hindbrain glucocorticoid receptors (GR) to augment cardiovascular responses to restraint stress in a model of stress hyperreactivity, the borderline hypertensive rat (BHR). A 3- to 4-mg pellet of the GR antagonist mifepristone (Mif) was implanted over the dorsal hindbrain (DHB) in Wistar-Kyoto (WKY) and BHRs. Control pellets consisted of either sham DHB or subcutaneous Mif pellets. Rats were either subjected to repeated restraint stress (chronic stress) or only handled (acute stress) for 3-4 wk, then all rats were stressed on the final day of the experiment. BHR showed limited adaptation of the arterial pressure response to restraint, and DHB Mif significantly (P </= 0.05) attenuated the arterial pressure response to restraint in both acutely and chronically stressed BHR. In contrast, WKY exhibited a substantial adaptation of the pressure response to repeated restraint that was significantly reversed by DHB Mif. DHB Mif and chronic stress each significantly increased baseline plasma corticosterone concentration and adrenal weight and reduced the corticosterone response to stress in all rats. We conclude that endogenous corticosterone acts via hindbrain GR to enhance the arterial pressure response to stress in BHR, but to promote the adaptation of the arterial pressure response to stress in normotensive rats. Endogenous corticosterone also acts in the hindbrain to restrain corticosterone at rest but to maintain the corticosterone response to stress in both BHR and WKY rats.

Assessment of Glucocorticoid Lung Targeting by ex-Vivo Receptor Binding Studies in Rats

Triamcinolone acetonide (TA, 22 µg) was given to rats by intravenous (IV) injection or intratracheal (IT) instillation. Free glucocorticoid receptors were monitored over time in liver and lung using an ex-vivo receptor binding technique. After IV administration of a TA solution, the reduction of free receptors over time was very similar in lung and liver (AUCLung = 280 ± 47 %*h; AUCLiver = 320 ± 76 %*h). Intratracheal instillation of the same solution produced time profiles which mirrored those of IV injection (AUCLung = 260 ± 41 %*h; AUCLiver = 330 ± 50 %*h). The lack of lung targeting was also reflected in the failure to show any significant difference in the pulmonary targeting factor T (AUCLung/AUCLiver) between IV (T = 0.84 ± 0.18) and IT (T = 0.78 ± 0.03) administration. In contrast, a certain degree of lung specificity was observed after IT instillation of a glucocorticoid suspension (22 µg; AUCLung = 160 ± 135 %*h; AUCLiver = 65 ± 91 %*h, T = 2.3 ± 0.5) as indicated by significant differences in T between IV injection and IT instillation (p = 0.038). The method presented provides a means of simultaneously assessing pulmonary and systemic effects after different forms and routes of administration and might be of value in further studying multiple aspects of inhalation glucocorticoid therapy.

An interactive algorithm for the assessment of cumulative cortisol suppression during inhaled corticosteroid therapy

The objective of the study was to develop an algorithm based on a pharmacokinetic-pharmacodynamic (PK/PD) modeling approach to quantify and predict cumulative cortisol suppression (CCS) as a surrogate marker for the systemic activity of inhaled corticosteroid therapy. Two Excel spreadsheets, one for single dose and another for steady-state multiple doses of inhaled steroids, were developed for predicting CCS. Four of the commonly used inhaled steroids were chosen for the purposes of simulation: fluticasone propionate (EP), budesonide (BUD), flunisolide (FLU), and triamcinolone acetonide (TAA). Drug-specific PK and PD parameters were obtained from previous single- and multiple-dose studies. In cases in which multiple-dose data were not available, the single-dose data were extrapolated. The algorithm was designed to calculate CCS based on 5 input parameters: name of drug, dose, dosing interval, time(s) of dosing, and type of inhaler device. In addition, a generalized algorithm was set up to calculate CCS based on clearance, volume of distribution, absorption rate, protein binding, pulmonary deposition, oral bioavailability, and unbound EC50 of the corticosteroid of interest. The spreadsheet allowed predictions of CCS for single doses as well as steady-state conditions. A simple method has been developed that facilitates comparisons between various drugs and dosing regimens and has the potential to significantly reduce the number of comparative clinical trials to be performed for evaluating the short-term systemic activity of inhaled corticosteroids).

Bioequivalence of inhaled drugs: fundamentals, challenges and perspectives

Interest in bioequivalence (BE) of inhaled drugs derives largely from the desire to offer generic substitutes to successful drug products. The complexity of aerosol dosage forms renders them difficult to mimic and raises questions regarding definitions of similarities and those properties that must be controlled to guarantee both the quality and the efficacy of the product. Despite a high level of enthusiasm to identify and control desirable properties there is no clear guidance, regulatory or scientific, for the variety of aerosol dosage forms, on practical measures of BE from which products can be developed. As more data on the pharmaceutical and clinical relevance of various techniques, as described in this review, become available, it is likely that a path to the demonstration of BE will become evident. In the meantime, debate on this topic will continue.

Contrary to adult, neonatal rats show pronounced brain uptake of corticosteroids.

Neurotoxic adverse effects after systemic corticosteroid administration are elevated in preterm infants. To test whether this might be related to an immature blood-brain barrier (BBB) that permits corticosteroids to enter the brain and induce neurotoxic effects, this study assessed the differences in brain permeability of triamcinolone acetonide after intratracheal administration to neonatal (10- to 11-day-old) and adult rats. Triamcinolone acetonide (or the phosphate prodrug in the case of neonatal rats) was administered intratracheally to neonatal rats at doses of 2.5, 25, or 50 μg/kg and to adult rats at 100 μg/kg. An ex vivo receptor binding assay was used to monitor the cumulative brain and liver glucocorticoid receptor occupancies over 6 h. Brain and liver receptor occupancies in neonates were similar for the 25 and 50 μg/kg triamcinolone acetonide phosphate (brain/liver receptor occupancy ratio, 1.10 ± 0.14 and 0.87 ± 0.13, respectively), whereas some reduction in the brain permeability was seen at the lower dose. After intratracheal administration of 100 μg/kg triamcinolone acetonide to adult rats, receptor occupancies in the brain were significantly lower (brain/liver ratio, 0.21 ± 0.14; p < 0.001). The study demonstrated that glucocorticoids enter the brain of neonatal rats because of an immature BBB. The results of this study support the hypothesis that neurotoxic adverse effects in preterm infants after systemic corticosteroid administration might be related to an immature BBB.