Philip J. Lowe

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.

Physiologically Based Pharmacokinetic Modeling of FTY720 (2-Amino-2[2-(-4-octylphenyl)ethyl]propane-1,3-diol hydrochloride) in Rats After Oral and Intravenous Doses

FTY720 (2-amino-2[2-(-4-octylphenyl)ethyl]propane-1,3-diol hydrochloride) is a new sphingosine-1-phosphate receptor agonist being developed for multiple sclerosis and prevention of solid organ transplant rejection. A physiologically based pharmacokinetic model was developed to predict the concentration of FTY720 in various organs of the body. Single oral and intravenous doses of FTY720 were administered to male Wistar rats, with blood and tissue sampling over 360 h analyzed by liquid chromatography/tandem mass spectrometry. A well stirred model (perfusion rate-limited) described FTY720 kinetics in heart, lungs, spleen, muscle, kidneys, bone, and liver, with a permeability rate-limited model being required for brain, thymus, and lymph nodes. Tissue-to-blood partition coefficients (RT) ranged from 4.69 (muscle) to 41.4 (lungs). In lymph nodes and spleen, major sites for FTY720-induced changes in sequestration of lymphocytes, RT values were 22.9 and 34.7, respectively. Permeability-surface area products for brain, thymus, and lymph nodes were 39.3, 122, and 176 ml/min. Intrinsic hepatic clearance was 23,145 l/h/kg for the free drug in blood (fub 0.000333); systemic clearance was 0.748 l/h/kg and terminal half-life was 23.4 h. The fraction orally absorbed was 71%. The model characterized well FTY720 disposition for this extensive dosing and tissue collection study in the rat. On scaling the model to dogs and humans, good agreement was found between the actual and predicted blood concentration-time profiles. More importantly, brain concentrations in dogs were well predicted from those of the rat. In absolute terms, the predictions were slightly lower than observed values, just under a 1.5-fold deviation, but the model accurately predicted the terminal elimination of FTY720 from the brain.

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.

On the anticipation of the human dose in first-in-man trials from preclinical and prior clinical information in early drug development

The drug development process is divided into phases with decisions required on compound selection and promotion to each subsequent development phase. In preclinical drug development the main objective is to bring the compound into human trials and there is an inability of many preclinical information packages to predict clinical responses. Since clinical responses are functions of the dose, the human dose anticipation should be a key deliverable of any preclinical package of drug candidate. The human dose should be anticipated by integration of information from multiple sources, in vitro and in vivo, non-human and human, using a variety of methodologies and approaches. Prediction of human safe and active dose relies on the availability of validated animal models for effect. Although there are many exceptions to the rule, the paper defines a four-step approach for the anticipation of human dose for first-in-man trials: 1, characterization of non-human exposure–response relationships; 2, correction for interspecies differences; 3, diagnosing compound absorption, distribution, metabolism and excretion (ADME) properties and prediction of human pharmacokinetics; and 4, prediction of human dose–responses and dose selection for phase I protocols.

From Target Selection to the Minimum Acceptable Biological Effect Level for Human Study: Use of Mechanism-based PK/PD Modeling to Design Safe and Efficacious Biologics

In this paper, two applications of mechanism-based modeling are presented with their utility from candidate selection to first-in-human dosage selection. The first example is for a monoclonal antibody against a cytomegalovirus glycoprotein complex, which involves an antibody binding model and a viral load model. The model was used as part of a feasibility analysis prior to antibody generation, setting the specifications for the affinity needed to achieve a desired level of clinical efficacy. The second example is a pharmacokinetic–pharmacodynamic model based on a single-dose pharmacology study in cynomolgus monkey using data on pharmacokinetics, receptor occupancy, and the dynamics of target cell depletion and recovery. The model was used to estimate the MABEL, here defined as the minimum acceptable biological effect level against which a dose is selected for a first-in-human study. From these applications, we demonstrate that mechanism-based PK/PD binding models are useful for predicting human response to biologics compounds. Especially, such models have the ability to integrate preclinical and clinical, in vitro and in vivo information and facilitate rational decision making during various stages of drug discovery and translational research.

Population Pharmacokinetic and Pharmacodynamic Model-Based Comparability Assessment of a Recombinant Human Epoetin Alfa and the Biosimilar HX575

The aim of this study was to develop an integrated pharmacokinetic and pharmacodynamic (PK/PD) model and assess the comparability between epoetin alfa HEXAL/Binocrit (HX575) and a comparator epoetin alfa by a model‐based approach. PK/PD data—including serum drug concentrations, reticulocyte counts, red blood cells, and hemoglobin levels—were obtained from 2 clinical studies. In sum, 149 healthy men received multiple intravenous or subcutaneous doses of HX575 (100 IU/kg) and the comparator 3 times a week for 4 weeks. A population model based on pharmacodynamics‐mediated drug disposition and cell maturation processes was used to characterize the PK/PD data for the 2 drugs. Simulations showed that due to target amount changes, total clearance may increase up to 2.4‐fold as compared with the baseline. Further simulations suggested that once‐weekly and thrice‐weekly subcutaneous dosing regimens would result in similar efficacy. The findings from the model‐based analysis were consistent with previous results using the standard noncompartmental approach demonstrating PK/PD comparability between HX575 and comparator. However, due to complexity of the PK/PD model, control of random effects was not straightforward. Whereas population PK/PD model‐based analyses are suited for studying complex biological systems, such models have their limitations (statistical), and their comparability results should be interpreted carefully.

Applying physiological and biochemical concepts to optimize biological drug development.

Posology—the science of dose and regimen—is a critical part of drug development. It is concerned with ensuring that patients experience significant clinical benefit without intolerable adverse effects. It has become apparent, in the case of certain biologics, that one can directly quantitate occupancy or target capture and relate these to clinical responses. With mathematical models that integrate binding concepts with clinical effects, potential posologies can be quickly explored through simulation, thereby liberating research teams from the traditional constraints and simultaneously stimulating innovation.

Uptake of zinc(II)-phthalocyanine by HepG2 cells expressing the low-density lipoprotein receptor: studies with the liposomal formulation CGP55847

Hydrophobic photosensitizers readily intercalate into plasma lipoproteins. Some tumors acquire cholesterol from the circulation as a result of increased low density lipoprotein (LDL) receptor activity. Thus, circulating LDL may function as a vehicle for the delivery of bound Zn-Pc to cells within a tumor. Zn-Pc:LDL complexes, resulting from the interaction of LDL with the liposomal Zn-Pc formulation CGP55847, bind to the LDL receptor expressed on HepG2 cells but with reduced affinity in comparison to LDL. Confocal fluorescence microscopy facilitated the subcellular localization of Zn-Pc in microcolonies of HepG2 cells; the photosensitizer was distributed throughout the cellular membrane systems but was absent from the cell nucleus. Uptake of Zn-Pc in the presence of LDL was twofold greater than in the absence of the lipoprotein. These data suggest that the LDL uptake pathway may contribute to the localization of Zn-Pc in hyperproliferative tissue.

Revision of omalizumab dosing table for dosing every 4 instead of 2 weeks for specific ranges of bodyweight and baseline IgE

The dosing level and frequency of omalizumab are guided by a dosing table based on total serum immunoglobulin E (IgE) and bodyweight. Using a validated, mathematical simulation model (based on concentration data from 8 studies), we evaluated the impact of a revised omalizumab dosing table (every 4 weeks dosing regimen) on the pharmacokinetic and pharmacodynamic profiles of free and total IgE. Safety analysis, in patients with high levels of exposure to omalizumab, was done using data from the clinical and post-marketing databases. The model accurately predicted observed omalizumab, free and total IgE concentrations. After reaching steady-state, the average increase in exposure was 10%, even for patients with the highest concentrations at the upper 97.5th percentile. Free IgE suppression slightly increased in the initial phase, and slightly reduced at the trough of the dosing cycle, but average suppression remained similar for both regimens. The safety profile of omalizumab was similar for patients receiving higher or lower doses. Thus, doubling the dose of omalizumab, in a subset of patients receiving 225-300 mg of omalizumab (every 2 weeks dosing regimen) can efficiently suppress free IgE without compromising safety or efficacy.