Guenther Kaiser

Omalizumab Protects against Allergen- Induced Bronchoconstriction in Allergic (Immunoglobulin E-Mediated) Asthma

Background: Omalizumab has been shown to suppress responses to inhaled allergens in allergic asthma patients with pretreatment immunoglobulin E (IgE) ≤700 IU/ml. To extend current dosing tables, we evaluated the potential of high omalizumab doses to block allergen-induced bronchoconstriction in patients with higher IgE levels. Methods: Asthmatic adults (18–65 years; body weight 40–150 kg) were divided into groups according to screening IgE (group 1: 30–300 IU/ml; group 2: 700–2,000 IU/ml) and randomized 2:1 to omalizumab/placebo every 2 or 4 weeks for 12–14 weeks. Allergen bronchoprovocation (ABP) testing was performed before treatment and at weeks 8 and 16. The primary efficacy endpoint, the early-phase allergic response (EAR), was defined as the maximum percentage drop in forced expiratory volume in 1 s during the first 30 min after ABP. Serum free IgE was determined as a pharmacodynamic endpoint, and the exhaled fractional concentration of nitric oxide (FENO) was an exploratory endpoint. Results: Fifty patients were included in the study. Omalizumab improved EAR; at week 8, EAR was 23.1% for placebo, 9.3% in group 1 (p = 0.018 versus placebo) and 5.6% in group 2 (p < 0.001). At week 16, EAR was 20%, 11.8% (p = 0.087) and 5.1% (p < 0.001), respectively. Free IgE decreased in groups 1 and 2 and remained <50 ng/ml in all patients during weeks 6–16. Omalizumab completely suppressed FENO increases after ABP in both groups. Conclusions: Omalizumab blocked early asthmatic responses over a broad range of IgE/body weight combinations. Extending the dosing tables enables omalizumab to benefit a wider range of patients.

Determination of the pharmacokinetics of glycopyrronium in the lung using a population pharmacokinetic modelling approach

AIMS Glycopyrronium bromide (NVA237) is a once-daily long-acting muscarinic antagonist recently approved for the treatment of chronic obstructive pulmonary disease. In this study, we used population pharmacokinetic (PK) modelling to provide insights into the impact of the lung PK of glycopyrronium on its systemic PK profile and, in turn, to understand the impact of lung bioavailability and residence time on the choice of dosage regimen. METHODS We developed and validated a population PK model to characterize the lung absorption of glycopyrronium using plasma PK data derived from studies in which this drug was administered by different routes to healthy volunteers. The model was also used to carry out simulations of once-daily and twice-daily regimens and to characterize amounts of glycopyrronium in systemic compartments and lungs. RESULTS The model-derived PK parameters were comparable to those obtained with noncompartmental analysis, confirming the usefulness of our model. The model suggested that the lung absorption of glycopyrronium was dominated by slow-phase absorption with a half-life of about 3.5 days, which accounted for 79% of drug absorbed through the lungs into the bloodstream, from where glycopyrronium was quickly eliminated. Simulations of once-daily and twice-daily administration generated similar PK profiles in the lung compartments. CONCLUSIONS The slow absorption from the lungs, together with the rapid elimination from the systemic circulation, could explain how once-daily glycopyrronium provides sustained bronchodilatation with a low incidence of adverse effects in patients with chronic obstructive pulmonary disease. Its extended intrapulmonary residence time also provides pharmacokinetic evidence that glycopyrronium has the profile of a once-daily drug.

Population pharmacokinetics and optimal design of paediatric studies for famciclovir

AIMS To develop a population pharmacokinetic model for penciclovir (famciclovir is a prodrug of penciclovir) in adults and children and suggest an appropriate dose for children. Furthermore, to develop a limited sampling design based on sampling windows for three different paediatric age groups (1-2, 2-5 and 5-12 years) using an adequate number of subjects for future pharmacokinetic studies. METHODS Penciclovir plasma data from six different adult and paediatric studies were supplied by Novartis. Population pharmacokinetic modelling was undertaken in NONMEM version VI. Simulations in MATLAB were used to select an oral paediatric dose that gives similar exposure to 500 mg in adults. Optimal sampling times and sampling windows were obtained in MATLAB and simulations in NONMEM were used to select adequate sample sizes for three paediatric age groups. RESULTS A two-compartment, first-order absorption model with an absorption lag time, allometric weight models on V(1), V(2) and Q, and an allometric weight model, age and creatinine clearance as covariates on CL adequately describe the pharmacokinetics of penciclovir in adults and children. Estimated CL (l h(-1) 70 kg(-1)) and V(ss) (l.70 kg(-1)) were 31.2 and 83.1, respectively. An oral dose of 10 mg kg(-1) body weight in children was predicted to give similar exposure as 500 mg in adults. A single sampling windows design (0.25-0.4, 0.5-1, 1.25-1.75, 2.75-3.5 and 7.25-8 h) for five samples per subject and 10 subjects in each of the paediatric age groups is recommended for future studies. CONCLUSIONS A population pharmacokinetic model of penciclovir in adults and children has been developed. A prospective study design, including dose adjustment, cohort size and blood sampling design has been recommended.

Safety, tolerability and pharmacokinetics of single escalating doses of indacaterol, a once-daily beta2-agonist bronchodilator, in subjects with COPD.

OBJECTIVES To assess the safety and tolerability of 4 doses of indacaterol, a once-daily beta2-agonist, in subjects with chronic obstructive pulmonary disease (COPD). The 24-h bronchodilator effect and pharmacokinetics of indacaterol were also investigated. METHODS 16 subjects aged 43 - 72 years with mild/moderate COPD were each given single doses of indacaterol of 400, 1,000, 2,000 and 3,000 µg, via a single-dose dry powder inhaler. RESULTS Changes from predose (400, 1,000, 2,000, 3,000 µg doses, respectively) were as follows. Maximum mean decreases in fasting (up to 2 h post-dose) serum potassium were 0.12, 0.30, 0.38, 0.26 mmol/l; maximum mean increases (up to 2 h post-dose) in fasting serum glucose were 0.12, 0.40, 0.87, 1.01 mmol/l. The maximum increase in heart rate (by 3, 6, 12, 13 beats/min, respectively) was within 1 h post-dose. No clinically significant electrocardiogram abnormalities were reported. Most adverse events were mild or moderate, with none considered serious or leading to withdrawal. Indacaterol was rapidly absorbed and displayed multiphasic disposition kinetics. The terminal elimination phase with a half-life of 50 - 63 h could only be seen for doses of 1,000 µg or higher. Mean systemic exposure to indacaterol (AUC0-24) increased by ~ 9-fold from 400 to 3,000 µg. CONCLUSION Even at doses far in excess of the therapeutic range, indacaterol had minimal systemic effects; such changes would be considered within safe limits for a single dose.

Effect of cimetidine, a model drug for inhibition of the organic cation transport (OCT2/MATE1) in the kidney, on the pharmacokinetics of glycopyrronium.

OBJECTIVE Glycopyrronium (NVA237), a novel once-daily long-acting muscarinic antagonist (LAMA), has recently been approved for maintenance treatment of COPD. This study evaluated the effect of organic cation transporter inhibition on inhaled glycopyrronium disposition using cimetidine as a probe inhibitor. METHODS In this open-label, two-period, two-sequence, crossover study, 20 healthy subjects received two treatments. A single dose of 100 μg glycopyrronium was inhaled alone and on Day 4 of a 6-day treatment with oral cimetidine 800 mg b.i.d. Trough plasma concentrations of cimetidine were determined throughout cimetidine dosing. Plasma concentrations and urinary excretion of glycopyrronium were determined up to 72 hours post glycopyrronium dose. The primary pharmacokinetics (PK) parameters were plasma peak concentration (Cmax), AUC up to the last measured concentration (AUClast), and renal clearance (CLr) of glycopyrronium. RESULTS Cimetidine trough concentrations indicated that PK steady state of cimetidine was reached prior to single dose inhalation of glycopyrronium. Inhalation of glycopyrronium in the presence of cimetidine resulted in an increase in total systemic exposure (AUClast) of glycopyrronium by 22% (geometric mean ratio 1.22; 90% CI: 1.12 - 1.32). This exposure increase correlated with a slight decrease of 23% in CLr (geometric mean ratio 0.77; 90% CI: 0.70 - 0.85). Cmax was not affected. Both treatments were safe and well tolerated without any deaths or severe adverse events. CONCLUSION Based on the magnitude of the PK changes seen in this study, no relevant drug interaction is expected when glycopyrronium is co-administered with cimetidine or other inhibitors of the organic cation transport.