Michael Looby

Pharmacokinetics of Lumiracoxib in plasma and synovial fluid

Backgroundumiracoxib is a new cyclo-oxygenase-2 (COX-2) selective inhibitor in development for the treatment of rheumatoid arthritis, osteoarthritis and acute pain.ObjectiveTo investigate the pharmacokinetics of lumiracoxib in plasma and knee joint synovial fluid from patients with rheumatoid arthritis.DesignOpen-label multiple-dose study evaluating the steady-state pharmacokinetics of lumiracoxib in plasma and synovial fluid after 7 days of treatment with lumiracoxib 400mg once daily.Patient populationMales and females aged 18–75 years with rheumatoid arthritis, having moderate to significant synovial fluid effusion of the knee.Outcome measuresFollowing a 7-day washout period for previous nonsteroidal anti-inflammatory drugs, 22 patients (17 female, 5 male) received lumiracoxib 400mg once daily for seven consecutive days. On day 7, following an overnight fast, a final dose of lumiracoxib was administered and serial blood and synovial fluid samples were collected for up to 28 hours. Lumiracoxib and its metabolites (4′-hydroxy-lumiracoxib and 5-carboxy-4′-hydroxy-lumiracoxib) were measured by validated high performance liquid chromatography-mass spectrometry methods. The steady-state pharmacokinetics of lumiracoxib were evaluated in plasma and synovial fluid by both a population pharmacokinetic model and noncompartmental analysis.ResultsLumiracoxib was rapidly absorbed (peak plasma concentration at 2 hours) and the terminal elimination half-life in plasma was short (6 hours). Lumiracoxib concentrations were initially higher in plasma than in synovial fluid; however, from 5 hours after administration until the end of the 28-hour assessment period, concentrations of lumiracoxib were higher in synovial fluid than in plasma. Peak drug concentration in synovial fluid occurred 3–4 hours later than the peak plasma concentration. The mean steady-state trough concentration of lumiracoxib in synovial fluid (454 μg/L) was approximately three times higher than the mean value in plasma (155 μg/L), and the area under the concentration-time curve from 12 to 24 hours after administration was 2.6-fold higher for synovial fluid than for plasma. Median lumiracoxib protein binding was similar in plasma and synovial fluid (range 97.9–98.3%). Concentrations of 4′-hydroxy-lumiracoxib, the active COX-2 selective metabolite, remained low in comparison with parent drug in both plasma and synovial fluid. The concentration of lumiracoxib in synovial fluid at 24 hours after administration would be expected to result in substantial inhibition of prostaglandin E2 formation.ConclusionThe kinetics of distribution of lumiracoxib in synovial fluid are likely to extend the therapeutic action of the drug beyond that expected from plasma pharmacokinetics. These data support the use of lumiracoxib in a once-daily regimen for the treatment of rheumatoid arthritis.

Characterization of the bronchodilatory dose response to indacaterol in patients with chronic obstructive pulmonary disease using model-based approaches

BackgroundIndacaterol is a once-daily long-acting inhaled β2-agonist indicated for maintenance treatment of moderate-to-severe chronic obstructive pulmonary disease (COPD). The large inter-patient and inter-study variability in forced expiratory volume in 1 second (FEV1) with bronchodilators makes determination of optimal doses difficult in conventional dose-ranging studies. We considered alternative methods of analysis.MethodsWe utilized a novel modelling approach to provide a robust analysis of the bronchodilatory dose response to indacaterol. This involved pooled analysis of study-level data to characterize the bronchodilatory dose response, and nonlinear mixed-effects analysis of patient-level data to characterize the impact of baseline covariates.ResultsThe study-level analysis pooled summary statistics for each steady-state visit in 11 placebo-controlled studies. These study-level summaries encompassed data from 7476 patients at indacaterol doses of 18.75-600 μg once daily, and showed that doses of 75 μg and above achieved clinically important improvements in predicted trough FEV1 response. Indacaterol 75 μg achieved 74% of the maximum effect on trough FEV1, and exceeded the midpoint of the 100-140 mL range that represents the minimal clinically important difference (MCID; ≥120 mL vs placebo), with a 90% probability that the mean improvement vs placebo exceeded the MCID. Indacaterol 150 μg achieved 85% of the model-predicted maximum effect on trough FEV1 and was numerically superior to all comparators (99.9% probability of exceeding MCID). Indacaterol 300 μg was the lowest dose that achieved the model-predicted maximum trough response.The patient-level analysis included data from 1835 patients from two dose-ranging studies of indacaterol 18.75-600 μg once daily. This analysis provided a characterization of dose response consistent with the study-level analysis, and demonstrated that disease severity, as captured by baseline FEV1, significantly affects the dose response, indicating that patients with more severe COPD require higher doses to achieve optimal bronchodilation.ConclusionsComprehensive assessment of the bronchodilatory dose response of indacaterol in COPD patients provided a robust confirmation that 75 μg is the minimum effective dose, and that 150 and 300 μg are expected to provide optimal bronchodilation, particularly in patients with severe disease.

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.

A novel model-based approach for dose determination of glycopyrronium bromide in COPD

BackgroundGlycopyrronium bromide (NVA237) is an inhaled long-acting muscarinic antagonist in development for treatment of COPD. This study compared the efficacy and safety of once-daily (OD) and twice-daily (BID) glycopyrronium bromide regimens, using a novel model-based approach, in patients with moderate-to-severe COPD.MethodsDouble-blind, randomized, dose-finding trial with an eight-treatment, two-period, balanced incomplete block design. Patients (smoking history ≥10 pack-years, post-bronchodilator FEV1 ≥30% and <80% predicted, FEV1/FVC <0.7) were randomized to one of 16 independent sequences for 28 days. Primary endpoint: mean trough FEV1 at Day 28.Results385 patients (mean age 61.2 years; mean post-bronchodilator FEV1 53% predicted) were randomized; 88.6% completed. All OD and BID dosing regimens produced dose-dependent bronchodilation; at Day 28, increases in mean trough FEV1 versus placebo were statistically significant for all regimens, ranging from 51 mL (glycopyrronium bromide 12.5 μg OD) to 160 mL (glycopyrronium bromide 50 μg BID). Pharmacodynamic steady-state was reached by Day 7. There was a small separation (≤37 mL) between BID and OD dose–response curves for mean trough FEV1 at steady-state in favour of BID dosing. Over 24 hours, separation between OD and BID regimens was even smaller (FEV1 AUC0-24h maximum difference for equivalent daily dose regimens: 8 mL). Dose–response results for FEV1 at 12 hours, FEV1 AUC0-12h and FEV1 AUC0-4h at steady-state showed OD regimens provided greater improvement over placebo than BID regimens for total daily doses of 25 μg, 50 μg and 100 μg, while the reverse was true for OD versus BID regimens from 12–24 hours. The 12.5 μg BID dose produced a marginally higher improvement in trough FEV1 versus placebo than 50 μg OD, however, the response at 12 hours over placebo was suboptimal (74 mL). Glycopyrronium bromide was safe and well tolerated at all doses.ConclusionsGlycopyrronium bromide 50 μg OD provides significant bronchodilation over a 24 hour period, and in terms of FEV1 AUC0-24h is not significantly different than the same total daily dose administered BID. Importantly, OD dosing may confer better patient adherence. The results are consistent with previous glycopyrronium bromide studies and support once-daily dosing of glycopyrronium bromide 50 μg in patients with moderate-to-severe COPD.Trial registrationClinicalTrials.gov: NCT01119950

Population Pharmacokinetics of Fingolimod Phosphate in Healthy Participants

Fingolimod (FTY720) is a sphingosine 1‐phosphate receptor (S1PR) modulator currently being evaluated for the treatment of multiple sclerosis. Fingolimod undergoes phosphorylation in vivo to yield fingolimod phosphate (fingolimod‐P), which modulates S1PRs expressed on lymphocytes and cells in the central nervous system. The authors developed a population model, using pooled data from 7 phase 1 studies, to enable characterization of fingolimod‐P pharmacokinetics following oral administration of fingolimod and to evaluate the impact of key demographic variables on exposure. The fingolimod‐P concentration‐time course after either single or multiple doses of fingolimod was described by a 2‐compartment model with first‐order apparent formation and elimination, lag time in the apparent formation, and dose‐dependent relative bioavailability and apparent central volume of distribution. Body weight and ethnicity were identified as demographic covariates correlated with the disposition of fingolimod‐P. Model predictions indicated no need for dose adjustment of fingolimod based on body weight; the effect of ethnicity on the disposition of fingolimod requires further investigation. The accurate prediction of the pharmacokinetic profile of fingolimod‐P determined empirically in 2 large phase 3 trials provides external validation of the model.

Benchmarking QSP Models Against Simple Models: A Path to Improved Comprehension and Predictive Performance

Quantitative Systems Pharmacology (QSP) models provide a means of integrating knowledge into a quantitative framework and, ideally, this integration leads to a better understanding of biology and better predictions of new experiments and clinical trials. In practice, these goals may be compromised by model complexity and uncertainty. To address these problems, we recommend that the predictive performance of QSP models be assessed through comparison with simpler models developed specifically for this purpose.

Visualizing Dose–Response When the Signal to Noise Ratio Is Low: The Bronchodilatory Response in Chronic Obstructive Pulmonary Disease

Spirometry is a safe, cheap, and easy-to-use methodology for the assessment of lung function. Spirometry biomarkers such as the forced expiratory volume in 1 second (FEV1) and the forced vital capacity (FVC) are commonly used in the diagnosis of conditions such as asthma and chronic obstructive pulmonary disease. In recent years, FEV1 in particular has also been used to support dose selection in bronchodilator drug development programs. Despite its convenience and objectivity as a measure of pulmonary function, FEV1 has a very low signal to noise ratio (SNR) as a marker of bronchodilator response. This problem is exacerbated when the biomarker is analyzed using traditional dose ranging study designs that do not provide an explicit and precise estimate of the dose response relationship. The combination of low SNR and imprecise methodology means that traditional dose finding activities for bronchodilators are inefficient and may lead to the selection of sub-optimal doses. Using graphics produced during the development of the novel long-acting β2-agonist, indacaterol, the issues outlined above are described and an alternative approach, built on a model-based characterization of the bronchodilatory dose response relationship is presented.