Efficacy and safety of omalizumab for the treatment of refractory chronic spontaneous urticaria in Japanese patients: Subgroup analysis of the phase 3 POLARIS study.

BACKGROUND: Omalizumab, a humanized anti-IgE monoclonal antibody, proved efficacious and well tolerated in patients with chronic spontaneous urticaria (CSU) refractory to H1 antihistamines (H1AH) in the POLARIS study (NCT02329223), a randomized, double-blind, placebo-controlled trial in East Asian patients. However, data in Japanese patients, who have specific baseline characteristics (e.g., low angioedema incidence, different background medications) that may impact clinical outcomes, are lacking. This pre-specified analysis presents additional patient-level data over time, pharmacokinetic and pharmacodynamics data for omalizumab and IgE, and efficacy and safety data for omalizumab in Japanese patients. METHODS: Japanese patients (N = 105) were randomized 1:1:1 to omalizumab 300 mg, 150 mg, or placebo by subcutaneous injection every 4 weeks. Efficacy and safety were assessed primarily based on changes from baseline to Week 12 in weekly itch-severity scores (ISS7) and weekly urticaria activity scores (UAS7), and incidence of adverse events (AEs), respectively. Patient-level UAS7 data over time were also reviewed. RESULTS: At Week 12, least squares mean (LSM) changes from baseline in ISS7 were greater with omalizumab vs. placebo (-9.54 and -7.29 for omalizumab 300 mg and 150 mg, respectively, vs. placebo [-5.17]). Corresponding LSM changes from baseline in UAS7 were -21.61 and -15.59 (vs. placebo [-10.88]). Most responders in the omalizumab 300 mg group displayed improvement of disease activity within 2-4 weeks and had well-controlled symptoms during the treatment period. Overall AE incidence was similar across treatment arms. CONCLUSIONS: This subgroup analysis demonstrated that omalizumab is a well-tolerated, beneficial option for treatment of CSU in H1AH-refractory Japanese patients.

Omalizumab in patients with allergic (IgE-mediated) asthma and IgE/bodyweight combinations above those in the initially approved dosing table.

BACKGROUND: When first approved in the European Union (EU), the omalizumab dosing table had upper bodyweight and IgE limits of 150 kg and 700 IU/mL, respectively. In this study, we assessed the safety, pharmacokinetics (PK) and pharmacodynamics (PD) of omalizumab in patients with IgE/bodyweight combinations above those in the original dosing table. METHODS: A multicentre, open-label, parallel-group study assessed the safety, PK and PD of omalizumab in 32 patients with mild-to-moderate allergic (IgE-mediated) asthma. Patients received two subcutaneous injections of omalizumab at one of three dosage levels (450, 525, or 600 mg), chosen according to baseline IgE (300-2000 IU/mL) and bodyweight (40-150 kg), with a 14-day interval between injections. RESULTS: Overall, 69 adverse events (AEs), none of them serious, were reported by 26 (81.3%) patients. Analysis of laboratory measurements, vital signs and ECG data revealed no adverse findings of clinical relevance. The PK profile was consistent with previous data for lower doses. Mean maximum decrease of free IgE from screening was ≥99% for all three doses, and mean free IgE concentrations remained <25 ng/mL for at least 2 weeks after the second dose. The reductions in free IgE were consistent with levels previously associated with clinical improvements. CONCLUSIONS: The safety and PK/PD findings from this study are consistent with previous data, and supported the extension of the omalizumab dosing table to include those patients with higher IgE/bodyweight combinations. Clinical trial registry and registration number: clinicaltrials.gov (NCT00546143).

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 (FE(NO)) 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 FE(NO) 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.

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.

Pharmacokinetics of multiple inhaled NVA237 doses in patients with chronic obstructive pulmonary disease (COPD).

OBJECTIVE: NVA237 (glycopyrronium bromide) is a once-daily longacting muscarinic antagonist (LAMA) in development for the treatment of chronic obstructive pulmonary disease (COPD). This study investigated the pharmacokinetics (PK) of NVA237 following single and repeated once-daily inhalation in mild-tomoderate COPD patients. METHODS: In this double-blind, parallel-group study, COPD patients were randomized to a 14-day treatment with NVA237 (25, 50, 100 or 200 µg) or placebo. Plasma concentration-time profiles and urinary excretion of NVA237 were determined on Days 1 and 14. RESULTS: The median time to reach maximal plasma concentration (tmax) was 5 or 6.5 min postinhalation. At steady state (Day 14), total and maximum systemic exposure (AUC0-24, Cmax) to NVA237 and urinary excretion of unchanged drug (Ae0-24) was approximately dose proportional over the 50 - 200 µg dose range. The average exposure was 1.4- to 1.7- fold higher on Day 14 compared with Day 1. The mean terminal elimination half-life (t1/2) of NVA237 ranged between 13 and 22 h. Steady-state plasma concentrations were reached within 1 week of treatment. Renal clearance (CLR) was similar across doses both after single and repeated dosing, ranging between 17.4 and 20.6 l/h. Urinary excretion of NVA237 enantiomers ([3S,2R]- and [3R,2S]-stereoisomers) was similar with respect to the amount excreted within 24 h and the excretion rate. CONCLUSIONS: The pharmacokinetics of NVA237 were consistent between doses with limited systemic accumulation at steady state after repeated once-daily inhalation.

Single-dose pharmacokinetics of famciclovir in infants and population pharmacokinetic analysis in infants and children.

A multicenter, open-label study evaluated the single-dose pharmacokinetics and safety of a pediatric oral famciclovir (prodrug of penciclovir) formulation in infants aged 1 to 12 months with suspicion or evidence of herpes simplex virus infection. Individualized single doses of famciclovir based on the infant's body weight ranged from 25 to 175 mg. Eighteen infants were enrolled (1 to <3 months old [n = 8], 3 to <6 months old [n = 5], and 6 to 12 months old [n = 5]). Seventeen infants were included in the pharmacokinetic analysis; one infant experienced immediate emesis and was excluded. Mean C(max) and AUC(0-6) values of penciclovir in infants <6 months of age were approximately 3- to 4-fold lower than those in the 6- to 12-month age group. Specifically, mean AUC(0-6) was 2.2 microg h/ml in infants aged 1 to <3 months, 3.2 microg h/ml in infants aged 3 to <6 months, and 8.8 microg h/ml in infants aged 6 to 12 months. These data suggested that the dose administered to infants <6 months was less than optimal. Eight (44.4%) infants experienced at least one adverse event with gastrointestinal events reported most commonly. An updated pharmacokinetic analysis was conducted, which incorporated the data in infants from the present study and previously published data on children 1 to 12 years of age. An eight-step dosing regimen was derived that targeted exposure in infants and children 6 months to 12 years of age to match the penciclovir AUC seen in adults after a 500-mg dose of famciclovir.

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.

Formoterol delivered via a new multi-dose dry powder inhaler (Certihaler) is as effective and well tolerated as the formoterol dry powder inhaler (Aerolizer) in children with persistent asthma.

The Certihaler is a new multi-dose dry powder inhaler for the delivery of formoterol (Foradil), a long-acting beta(2)-agonist. This dose-ranging study compared the efficacy and safety of formoterol 5, 10, 15 and 30 microg and placebo administered via the Certihaler or formoterol 12 microg via a single-dose dry powder inhaler (Aerolizer) in children with persistent asthma. This was a randomized, placebo-controlled, double-blind, double-dummy, incomplete block crossover, dose-finding and pharmacokinetic study. Children (5-12 years, n = 77) received four of the active treatments twice weekly (BID) for 1 week separated by 1-week single-blind washouts. The primary efficacy variable was 12-h AUC of FEV(1) after 1 week's treatment. Secondary variables included serial 12-h FEV(1). A subset of patients (n = 37) participated in a pharmacokinetic analysis. All formoterol doses resulted in significant increases in 12-h AUC of FEV(1) compared with placebo, and there was no difference between active treatments. The onset of action of formoterol was <3 min for all active treatments. Doses of formoterol > or =10 microg via the Certihaler increased FEV(1) significantly for up to 12 h compared with placebo. The 5 microcg dose via the Certihaler and 12 microg dose via the Aerolizer had a significant effect up to 8 and 7 h post-dose, respectively. Urinary excretion of formoterol via the Certihaler increased in a dose-proportional manner. All formoterol doses were well tolerated, but some patients experienced tremor at the 15 and 30 microg doses. Despite the lack of significant differences between the active doses in the overall bronchodilation, formoterol 10 microg BID via the Certihaler was the dose that provided the best balance between efficacy and tolerability: its duration of action was sustained over 12 h, contrary to that the lower dose (5 microg BID), whereas its tolerability, especially with regard to tremor, was better than the higher doses (15 and 30 microg BID). Overall, Certihaler 10 microg BID was not significantly different from formoterol 12 microg BID via Aerolizer.