Stacey Tannenbaum

Asthma symptom re-emergence after omalizumab withdrawal correlates well with increasing IgE and decreasing pharmacokinetic concentrations

BACKGROUND Physicians have questioned whether omalizumab can be discontinued or the dose reduced after clinical improvement is seen in patients with severe asthma. OBJECTIVES To examine the relationships among omalizumab, free IgE, and clinical outcomes in a randomized, placebo-controlled trial in patients with severe persistent allergic asthma following a posology based on pretreatment total IgE and body weight. METHODS A pharmacokinetic-pharmacodynamic binding model was used to calculate free IgE, omalizumab, and total IgE concentrations during the 28-week treatment and 16-week follow-up of the INvestigation of Omalizumab in seVere Asthma TrEatment (INNOVATE) study. These were plotted against the mean changes in the total asthma symptom score, morning peak expiratory flow, and rescue medication use for physician-defined treatment responders and nonresponders. RESULTS The model accurately fitted omalizumab and free and total IgE, allowing reconstruction of the entire time course for each patient. Free IgE was rapidly suppressed below the 50 ng/mL (20.8 IU/mL) target, although there was a notable period before clinical measures stabilized. After treatment cessation, free IgE and omalizumab returned toward baseline and, after a delay, asthma symptoms re-emerged. Model-derived omalizumab and free IgE concentrations correlated well with changes in clinical outcomes, particularly in omalizumab-treated responders. Asthma symptoms exhibited different correlations during response onset compared with response offset (hysteresis), indicative of physiological time delays between changes in IgE levels and pulmonary function. CONCLUSION Omalizumab and free IgE correlated well with clinical symptoms. Reducing omalizumab doses below those in the dosing table cannot be recommended; the resulting increase in free IgE would cause a deterioration in asthma control.

Relationship between omalizumab pharmacokinetics, IgE pharmacodynamics and symptoms in patients with severe persistent allergic (IgE-mediated) asthma

AIMS Omalizumab, a subcutaneously administered anti-IgE antibody, is effective for moderate-to-severe persistent allergic asthma. The aims were to (i) describe the population pharmacodynamics of free IgE with a mechanism-based, nonlinear, omalizumab-IgE binding model; (ii) deduce a target-free IgE suppression level by correlation with clinical outcomes; and (iii) check the adequacy of current approved dosing tables and explore potential doses and regimens beyond. METHODS Concentration data (omalizumab, free and total IgE) were obtained from 1781 patients aged 12-79 years, in four sparsely sampled randomized, placebo-controlled studies and 152 subjects in a richly sampled single-dose study. NONMEM predictive performance across the range of bodyweights (39-150 kg) and baseline IgE (19-1055 IU ml(-1)) was checked by simulation. Predicted free IgE levels were correlated with time-averaged patient diary clinical outcomes. RESULTS The model accurately predicted observed omalizumab, free and total IgE concentrations. Free IgE concentrations correlated well with clinical signs and symptoms, allowing a target concentration of 14 ng ml(-1), at the midpoint of 4-week clinical observation periods, to be set for determining the dose and regimen for omalizumab. CONCLUSIONS The omalizumab-IgE binding model is predictive for free IgE and demonstrates a nonlinear time-dependent relationship between free IgE suppression and clinical outcomes in asthma. Although currently approved dosing tables are close to optimal, it should be possible to treat patients with higher levels of baseline IgE if higher doses can be administered.

Pharmacokinetic and Pharmacodynamic Properties of Canakinumab, a Human Anti-Interleukin-1β Monoclonal Antibody

Canakinumab is a high-affinity human monoclonal anti-interleukin-1β (IL-1β) antibody of the IgG1/κ isotype designed to bind and neutralize the activity of human IL-1β, a pro-inflammatory cytokine. Canakinumab is currently being investigated on the premise that it would exert anti-inflammatory effects on a broad spectrum of diseases, driven by IL-1β. This paper focuses on the analysis of the pharmacokinetic and pharmacodynamic data from the canakinumab clinical development programme, describing results from the recently approved indication for the treatment of cryopyrin-associated periodic syndromes (CAPS) under the trade name ILARIS®, as well as diseases such as rheumatoid arthritis, asthma and psoriasis.Canakinumab displays pharmacokinetic properties typical of an IgG1 antibody. In a CAPS patient weighing 70 kg, slow serum clearance (0.174 L/day) was observed with a low total volume of distribution at steady state (6.0 L), resulting in a long elimination half-life of 26 days. The subcutaneous absolute bioavailability was high (70%). Canakinumab displays linear pharmacokinetics, with a dose-proportional increase in exposure and no evidence of accelerated clearance or time-dependent changes in pharmacokinetics following repeated administration was observed. The pharmacokinetics of canakinumab in various diseases (e.g. CAPS, rheumatoid arthritis, psoriasis or asthma) are comparable to those in healthy individuals. No sex- or age-related pharmacokinetic differences were observed after correction for body weight.An increase in total IL-1β was observed in both healthy subjects and all patient populations following canakinumab dosing, reflecting the ability of canakinumab to bind circulating IL-1β. The kinetics of total IL-1β along with the pharmacokinetics of canakinumab were characterized by a population-based pharmacokinetic-binding model, where the apparent in vivo dissociation constant, signifying binding affinity of canakinumab to circulating IL-1β, was estimated at 1.07 ± 0.173 nmol/L in CAPS patients.During development of canakinumab a cell line change was introduced. Pharmacokinetic characterization was performed in both animals and humans to assure that this manufacturing change did not affect the pharmacokinetic/pharmacodynamic properties of canakinumab.

Canakinumab (ACZ885, a fully human IgG1 anti-IL-1β mAb) induces sustained remission in pediatric patients with cryopyrin-associated periodic syndrome (CAPS)

IntroductionCryopyrin-associated periodic syndrome (CAPS) represents a spectrum of three auto-inflammatory syndromes, familial cold auto-inflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), and neonatal-onset multisystem inflammatory disease/chronic infantile neurological cutaneous and articular syndrome (NOMID/CINCA) with etiology linked to mutations in the NLRP3 gene resulting in elevated interleukin-1β (IL-1β) release. CAPS is a rare hereditary auto-inflammatory disease, which may start early in childhood and requires a life-long treatment. Canakinumab, a fully human anti-IL-1β antibody, produces sustained selective inhibition of IL-1β. This study was conducted to assess the efficacy, safety, and pharmacokinetics of canakinumab in the treatment of pediatric CAPS patients.MethodsSeven pediatric patients (five children and two adolescents) with CAPS were enrolled in a phase II, open-label study of canakinumab in patients with CAPS. Canakinumab was administered at a dose of 2 mg/kg subcutaneously (s.c.) (for patients with body weight ≤ 40 kg) or 150 mg s.c. (for patients with body weight > 40 kg) with re-dosing upon each relapse. The primary efficacy variable was time to relapse following achievement of a complete response (defined as a global assessment of no or minimal disease activity and no or minimal rash and values for serum C-reactive protein (CRP) and/or serum amyloid A (SAA) within the normal range, < 10 mg/L).ResultsAll patients achieved a complete response within seven days after the first dose of canakinumab and responses were reinduced on retreatment following relapse. Improvements in symptoms were evident within 24 hours after the first dose, according to physician assessments. The estimated median time to relapse was 49 days (95% CI 29 to 68) in children who received a dose of 2 mg/kg. Canakinumab was well tolerated. One serious adverse event, vertigo, was reported, but resolved during treatment.ConclusionsCanakinumab, 2 mg/kg or 150 mg s.c., induced rapid and sustained clinical and biochemical responses in pediatric patients with CAPS.Trial registration numberClinicalTrials.gov: NCT00487708

Model‐Based Drug Development Survey Finds Pharmacometrics Impacting Decision Making in the Pharmaceutical Industry

During the past decade, the pharmaceutical industry has seen the increasing application of pharmacometrics approaches in drug development. However, the full potential of incorporating model‐based approaches in drug development and its impact on decision making has not been fully realized to date. In 2009, a survey on model‐based drug development (MBDD) was conducted (1) to further understand the current state of MBDD in the pharmaceutical industry and (2) to identify opportunities to realize the full potential of MBDD. Ten large and mid‐sized pharmaceutical companies provided responses to this survey. The results indicate that MBDD is achieving broad application in early and late development and is positively affecting both internal and regulatory decisions. Senior leadership (vice president and higher) within the companies indicated widely accepted utility for dose selection and gaining acceptance for study design and regulatory interactions but limited acceptance in discovery and commercial/pipeline decisions. Mounting appreciation for the impact of MBDD on internal and regulatory decision‐making bodes well for the future of the pharmacometric discipline and the growth of opportunities to realize the full potential of MBDD.

Simulation of Correlated Continuous and Categorical Variables using a Single Multivariate Distribution

Clinical trial simulations make use of input/output models with covariate effects; the virtual patient population generated for the simulation should therefore display physiologically reasonable covariate distributions. Covariate distribution modeling is one method used to create sets of covariate values (vectors) that characterize individual virtual patients, which should be representative of real subjects participating in clinical trials. Covariates can be continuous (e.g., body weight, age) or categorical (e.g., sex, race). A modeling method commonly used for incorporating both continuous and categorical covariates, the Discrete method, requires the patient population to be divided into subgroups for each unique combination of categorical covariates, with separate multivariate functions for the continuous covariates in each subset. However, when there are multiple categorical covariates this approach can result in subgroups with very few representative patients, and thus, insufficient data to build a model that characterizes these patient groups. To resolve this limitation, an application of a statistical methodology (Continuous method) was conceived to enable sampling of complete covariate vectors, including both continuous and categorical covariates, from a single multivariate function. The Discrete and Continuous methods were compared using both simulated and real data with respect to their ability to generate virtual patient distributions that match a target population. The simulated data sets consisted of one categorical and two correlated continuous covariates. The proportion of patients in each subgroup, correlation between the continuous covariates, and ratio of the means of the continuous covariates in the subgroups were varied. During evaluation, both methods accurately generated the summary statistics and proper proportions of the target population. In general, the Continuous method performed as well as the Discrete method, except when the subgroups, defined by categorical value, had markedly different continuous covariate means, for which, in the authors’ experience, there are few clinically relevant examples. The Continuous method allows analysis of the full population instead of multiple subgroups, reducing the number of analyses that must be performed, and thereby increasing efficiency. More importantly, analyzing a larger pool of data increases the precision of the covariance estimates of the covariates, thus improving the accuracy of the description of the covariate distribution in the simulated population.

Affiliation between the American Society of Pharmacometrics and the Journal of Pharmacokinetics and Pharmacodynamics

In 1982, the Journal of Pharmacokinetics and Pharmacodynamics first gave voice to the discipline of pharmacometrics [1] by providing a forum for the scholarly contributions that were seminal to the early development of this new field of study. In the intervening years, pharmacometrics has expanded far beyond its initial focus on the analysis of measurements (metrics) in pharmacokinetics and biopharmaceutics to become a quantitative science that encompasses a spectrum of activities from basic research into disease and mechanisms of drug action through the rational use of medicines in patient care [2]. During this time, the Journal has continued to serve as the intellectual home for new advances in pharmacokinetics and pharmacodynamics, as well as in pharmacometrics. Because of this history, the American Society of Pharmacometrics (ASoP) and the Journal of Pharmacokinetics and Pharmacodynamics have inaugurated an affiliation designating the Journal as an official publication of ASoP. This strategic partnership with the Journal of Pharmacokinetics and Pharmacodynamics is representative of ASoP’s mission to promote the central role of pharmacometrics in advancing the discovery, development, and utilization of new and existing medicines for the treatment and prevention of disease. This role is characterized by three concepts: (i) quantitative integration of multi-source data and knowledge through the application of clinical, biomedical, biological, engineering, statistical, and mathematical concepts, resulting in (ii) continuous methodological and technological innovation, supporting new scientific understanding and knowledge, which in turn (iii) impacts research, discovery, development, decision making, approval, and utilization of medicines [2]. Together with the Editor-in-Chief of the Journal, Professor William Jusko, we are happy to announce that Dr. Peter Bonate will be ASoP’s designated Associate Editor to the Journal of Pharmacokinetics and Pharmacodynamics. Peter’s own scholarly contributions to the field of pharmacometrics together with his extensive industry experience provide him with a unique perspective on the innovations needed to advance the methodologies and impact of pharmacometrics. Under Peter’s collaborative leadership, the affiliation between ASoP and the Journal of Pharmacokinetics and Pharmacodynamics will accelerate the Society’s efforts to serve its membership and advance its vision for the discipline of pharmacometrics.

Nonlinear Mixed Effects Modeling in Systems Pharmacology

Quantitative systems pharmacology (QSP) is the design and application of mathematical models to explain how drugs function at a systems level. Whereas traditional pharmacokinetic-pharmacodynamic modeling takes an empirical or mechanistic approach to modeling, QSP takes a holistic approach exploring whole biochemical and metabolic pathways and how drugs interact in those pathways. These models are often unidentifiable from any single set of data. Instead they are built using diverse datasets with many parameters fixed to mean values from different experiments resulting in models that are over-confident in their parameter values. Few models currently take into account these sources of variability in their parameter estimation. This chapter discusses nonlinear mixed effects models, a modeling approach that specifically accounts for sources of variability in a model, and their application to QSP.

The International Society of Pharmacometrics

In 2011, the American Society of Pharmacometrics (ASoP) was founded and over 600 members worldwide joined ASoP within 6 months. In 2012, ASoP evolved to the International Society of Pharmacometrics (ISoP) to reflect the increasing number of international members. ISoP’s growth continues and the Society currently represents over 900 members from almost 30 countries around the world. With this report, the officers and board directors of ISoP state the vision of the society, update on its activities, and invite more colleagues to join the journey for shaping the future of pharmacometrics (Fig. 1). From ASoP to ISoP, the vision and mission of the Society remains the same, that is: to promote the central role of pharmacometrics in advancing the discovery, development, and utilization of new medicines for the treatment and prevention of disease to improve human health and well-being. The Society is guided in this effort by three overarching themes of Integration, Innovation and Impact: (i) quantitative integration of multi-source data and knowledge through the application of clinical, biomedical, biological, engineering, statistical, and mathematical concepts, made possible by (ii) continuous methodological and technological innovation, and resulting in new scientific understanding and knowledge, which in turns (iii) impacts research, discovery, development, decision making, approval, and utilization of new medicines to prevent and treat disease [1]. Consistent with this mission, ISoP (i) serves as the sponsoring organization for the American Conference on Pharmacometrics (ACoP) and co-sponsors other International Conferences on Pharmacometrics such as the Population Approach Group of Australia & New Zealand (PAGANZ), International Symposium in Quantitative Pharmacology (ISQP) and the World Conference on Pharmacometrics (WCoP), (ii) offers a central organization for the integration of national and international pharmacometrics communities, initiatives, consortia, and educational activities, (iii) actively partners with other scientific and medical organizations such as the American Society of Clinical Pharmacology and Therapeutics (ASCPT) and institutes such as the Critical Path Institute (C-PATH), and (iv) provides resources, mentoring, leadership opportunities, educational services, to its members, especially to its trainee members [2]. An International Advisory Group has been formed to identify how ISoP can engage more effectively with the international pharmacometric and clinical community. Through its Education Committee it provides a source for finding training programs and linking trainees with mentors. In 2012, the Journal of Pharmacokinetics and Pharmacodynamics (JPKPD) entered into an affiliation with ISoP to accelerate the Society’s efforts to advance its vision for the discipline of pharmacometrics [3]. As part of that affiliation, the ISoP Publications Committee, in coordination with JPKPD editor Dr. William Jusko, named ISoP member Dr. Peter Bonate as Associate Editor and selected five Editorial Advisory Board Members. As part of ISoP’s commitment to its members, the Society will have themed issues in JPKPD each year and will solicit from its members articles throughout the year. In 2013, ISoP and JPKPD will publish a themed issue on Translational Modeling and Simulation in Neuroscience that will contain more than 10 articles. Later in the year, an ACoP 2013 Highlights issue will appear including an article on best practices in M. Pfister (&) D. E. Mager N. H. G. Holford B. Corrigan S. Tannenbaum R. Bruno L. Zhang Y. Wang D. Z. D’Argenio The International Society of Pharmacometrics (ISoP), 1200 Route 22E, Suite 2000, Bridgewater, NJ 08807, USA e-mail: mpfister@wequantify.com