Tumor necrosis factor-mediated disposition of infliximab in ulcerative colitis patients.

Ulcerative Colitis (UC) is an inflammatory bowel disease typically affecting the colon. Patients with active UC have elevated tumor necrosis factor (TNF) concentrations in serum and colonic tissue. Infliximab is a monoclonal antibody directed against TNF and binds with high affinity. Target-mediated drug disposition (TMDD) is reported for monoclonal antibodies meaning that their pharmacokinetics are affected by high target affinity. Here, a TMDD model is proposed to describe the interaction between infliximab and TNF in UC patients. Data from 20 patients with moderate to severe UC was used. Patients received standard infliximab induction therapy (5 mg kg-1) at week 0, followed by infusions at week 2 and 6. IFX, anti-drug antibodies and TNF serum concentrations were measured at day 0 (1 h after infusion), 1, 4, 7, 11, 14, 18, 21, 28 and 42. A binding model, TMDD model, and a quasi-steady state (QSS) approximation were evaluated using nonlinear mixed effects modeling (NONMEM). A two-compartment model best described the concentration-time profiles of infliximab. Typical clearance of infliximab was 0.404 L day-1 and increased with the presence of anti-drug antibodies and with lower albumin concentrations. The TMDD-QSS model best described the pharmacokinetic and pharmacodynamics data. Estimate for TNF baseline (Bmax was 19.8 pg mL-1 and the dissociation constant (Kss) was 13.6 nM. This model could eventually be used to investigate the relationship between suppression of TNF and the response to IFX therapy.

Linear pharmacokinetic parameters for monoclonal antibodies are similar within a species and across different pharmacological targets: A comparison between human, cynomolgus monkey and hFcRn Tg32 transgenic mouse using a population-modeling approach.

The linear pharmacokinetics (PK) of therapeutic monoclonal antibodies (mAbs) can be considered a class property with values that are similar to endogenous IgG. Knowledge of these parameters across species could be used to avoid unnecessary in vivo PK studies and to enable early PK predictions and pharmacokinetic/pharmacodynamic (PK/PD) simulations. In this work, population-pharmacokinetic (popPK) modeling was used to determine a single set of 'typical' popPK parameters describing the linear PK of mAbs in human, cynomolgus monkey and transgenic mice expressing the human neonatal Fc receptor (hFcRn Tg32), using a rich dataset of 27 mAbs. Non-linear PK was excluded from the datasets and a 2-compartment model was applied to describe mAb disposition. Typical human popPK estimates compared well with data from comparator mAbs with linear PK in the clinic. Outliers with higher than typical clearance were found to have non-specific interactions in an affinity-capture self-interaction nanoparticle spectroscopy assay, offering a potential tool to screen out these mAbs at an early stage. Translational strategies were investigated for prediction of human linear PK of mAbs, including use of typical human popPK parameters and allometric exponents from cynomolgus monkey and Tg32 mouse. Each method gave good prediction of human PK with parameters predicted within 2-fold. These strategies offer alternative options to the use of cynomolgus monkeys for human PK predictions of linear mAbs, based on in silico methods (typical human popPK parameters) or using a rodent species (Tg32 mouse), and call into question the value of completing extensive in vivo preclinical PK to inform linear mAb PK.

Extending a Systems Model of the APP Pathway: Separation of ß- and γ-Secretase Sequential Cleavage Steps of APP.

The abnormal accumulation of amyloid-ß (Aß) in the brain parenchyma has been posited as a central event in the pathophysiology of Alzheimer's disease. Recently, we have proposed a systems pharmacology model of the amyloid precursor protein (APP) pathway, describing the Aß APP metabolite responses (Aß40, Aß42, sAPPα, and sAPPß) to ß-secretase 1 (BACE1) inhibition. In this investigation this model was challenged to describe Aß dynamics following γ-secretase (GS) inhibition. This led an extended systems pharmacology model, with separate descriptions to characterize the sequential cleavage steps of APP by BACE1 and GS, to describe the differences in Aß response to their respective inhibition. Following GS inhibition, a lower Aß40 formation rate constant was observed, compared with BACE1 inhibition. Both BACE1 and GS inhibition were predicted to lower Aß oligomer levels. Further model refinement and new data may be helpful to fully understand the difference in Aß dynamics following BACE1 versus GS inhibition.

Influence of body composition on disposition of the highly fat distributed compound as analysed by physiologically based pharmacokinetic (PBPK) modeling and simulation.

A recent study suggested that the pharmacokinetics (PK) of highly fat distributed compounds can be affected by acute changes in the volume of adipose tissue. The present study investigates possible influences of body composition on the disposition of the highly lipophilic compound TAK-357 in two rat strains. Physiologically based PK (PBPK) modeling and simulation was applied on single and multiple dose PK data of TAK-357 in obese Wistar fatty rats and Wistar lean rats having approximately 45% and 13% body fat, respectively. The observed effects of an elevated fat mass in Wistar fatty rats on the plasma concentrations appeared to be partly compensated for by other differences between the two rat strains. A decrease in the tissue to blood partition coefficients under high body fat conditions was identified as another factor contributing to the difference in PK. A higher lipid content in the plasma in high body fat animals may result in relatively lower tissue to blood partition coefficients. PBPK-based simulations indicate that the plasma concentrations of lipophilic compounds in high body fat conditions can differ by up to two-times at steady-state. This confirms that there is only a small impact of body composition change on the plasma concentration of highly lipophilic drugs and that the need for therapeutic dose adjustments may be limited.

Impact of acute fat mobilisation on the pharmacokinetics of the highly fat distributed compound TAK-357, investigated by physiologically based pharmacokinetic (PBPK) modeling and simulation.

In a dog toxicokinetic study, an unusual plasma concentration increase of the highly lipophilic compound TAK-357 was observed 2 weeks after termination of a 2-week repeated dosing in one dog with acute body weight loss. The present study investigates the cause of this increase. A physiologically based pharmacokinetic (PBPK) model was constructed using the rat and dog pharmacokinetic data. Using the constructed model, the TAK-357 concentration profile in the case of body weight change was simulated. The PBPK model-derived simulation suggested that redistribution from adipose tissues to plasma due to a loss of body fat caused the observed concentration increase of TAK-357 in dog plasma. The analysis demonstrates that the disposition of a highly lipophilic and fat-distributed compound can be affected by acute changes in adipose tissue mass. PBPK modeling and simulation proved to be efficient tools for the quantitative hypothesis testing of apparently atypical PK phenomena resulting from acute physiological changes.

The application of mathematical modelling to the design of bispecific monoclonal antibodies.

Targeting multiple receptors with bispecific antibodies is a novel approach that may prevent the development of resistance to cancer treatments. Despite the initial promise, full clinical benefit of this technology has yet to be realized. We hypothesized that in order to optimally exploit bispecific antibody technology, thorough fundamental knowledge of their pharmacological properties compared to that of single agent combinations was needed. Therefore, we developed a mathematical model for the binding of bispecific antibodies to their targets that accounts for the spatial distribution of the binding receptors and the kinetics of binding, and is scalable for increasing valency. The model provided an adequate description of internal and literature-reported in vitro data on bispecific binding. Simulations of in vitro binding with the model indicated that bispecific antibodies are not always superior in their binding potency to combination of antibodies, and the affinity of bispecific arms must be optimized for maximum binding potency. Our results suggest that this tool can be used for the design and development of the next generation of anti-cancer bispecific compounds.

Systems Pharmacology Analysis of the Amyloid Cascade after ß-Secretase Inhibition Enables the Identification of an Aß42 Oligomer Pool.

The deposition of amyloid-ß (Aß) oligomers in brain parenchyma has been implicated in the pathophysiology of Alzheimer's disease. Here we present a systems pharmacology model describing the changes in the amyloid precursor protein (APP) pathway after administration of three different doses (10, 30, and 125 mg/kg) of the ß-secretase 1 (BACE1) inhibitor MBi-5 in cisterna magna ported rhesus monkeys. The time course of the MBi-5 concentration in plasma and cerebrospinal fluid (CSF) was analyzed in conjunction with the effect on the concentrations of the APP metabolites Aß42, Aß40, soluble ß-amyloid precursor protein (sAPP) α, and sAPPß in CSF. The systems pharmacology model contained expressions to describe the production, elimination, and brain-to-CSF transport for the APP metabolites. Upon administration of MBi-5, a dose-dependent increase of the metabolite sAPPα and dose-dependent decreases of sAPPß and Aß were observed. Maximal inhibition of BACE1 was close to 100% and the IC50 value was 0.0256 µM (95% confidence interval, 0.0137-0.0375). A differential effect of BACE1 inhibition on Aß40 and Aß42 was observed, with the Aß40 response being larger than the Aß42 response. This enabled the identification of an Aß42 oligomer pool in the systems pharmacology model. These findings indicate that decreases in monomeric Aß responses resulting from BACE1 inhibition are partially compensated by dissociation of Aß oligomers and suggest that BACE1 inhibition may also reduce the putatively neurotoxic oligomer pool.

Pharmacokinetic-pharmacodynamic modeling of alpha interferon response induced by a Toll-like 7 receptor agonist in mice.

Recombinant alpha interferon (IFN-alpha) is used in the treatment of hepatitis C virus (HCV)-infected patients but is not optimal in terms of efficacy or tolerability. Toll-like 7 receptor (TLR-7) agonists stimulate the innate immune system to produce, among other cytokines, IFN-alpha and are being evaluated as alternative drugs to treat HCV infection. This paper describes the application of pharmacokinetic-pharmacodynamic (PK-PD) modeling to understanding the behavior of a TLR-7 agonist [9-benzyl-8-hydroxy-2-(2-methoxyethoxy) adenine (BHMA)] in mice, using IFN-alpha as a biomarker. This is the first report of such a PK-PD model, and the conclusions may be of utility in the clinical development of TLR-7 agonists for HCV infection.

Mechanism-based pharmacodynamic modeling of S(-)-atenolol: estimation of in vivo affinity for the beta1-adrenoceptor with an agonist-antagonist interaction model.

The aim of this study was the development of an agonist-antagonist interaction model to estimate the in vivo affinity of S(-)-atenolol for the beta(1)-adrenoreceptor. Male Wistar-Kyoto (WKY) rats were used to characterize the interaction between the model drugs isoprenaline (to induce tachycardia) and S(-)-atenolol. Blood samples were taken to determine plasma pharmacokinetics. Reduction of isoprenaline-induced tachycardia was used as a pharmacodynamic endpoint. The pharmacokinetic-pharmacodynamic relationship of isoprenaline was first characterized with the operational model of agonism using the literature value for the affinity (K(A)) of isoprenaline (3.2 x 10(-8) M; left atria WKY rats). Resulting estimates for baseline (E(0)), maximal effect (E(max)), and efficacy (tau) were 374 (1.9%), 130 (5.9%), and 247 (33%) beats per minute, respectively. In addition, the interaction between isoprenaline and S(-)-atenolol was characterized using a pharmacodynamic interaction model based on the operational model of agonism that describes the heart rate response based on the affinity of the agonist (K(A)), the affinity of the antagonist (K(B)), the efficacy (tau), the maximal effect (E(max)), the Hill coefficient (n(H)), the concentrations of isoprenaline and atenolol, and the displacement of the endogenous agonist adrenaline. The estimated in vivo affinity (K(B)) of S(-)-atenolol for the beta(1) -receptor was 4.6 x 10(-8) M. The obtained estimate for in vivo affinity of S(-)-atenolol (4.6 x 10(-8) M) is comparable to literature values for the in vitro affinity in functional assays. In conclusion, a meaningful estimate of in vivo affinity for S(-)-atenolol could be obtained using a mechanism-based pharmacodynamic modeling approach.

Reproducible and time-dependent modification of serum protein binding in Wistar Kyoto rats.

INTRODUCTION: The theoretical basis of the influence of (alterations in) plasma protein binding on pharmacokinetics (PK) is well-established. In contrast, the impact of protein binding on pharmacodynamics has not been examined in a systematic manner. Here we present an experimental approach to modify serum protein levels and binding in the rat, in a robust, reproducible, and time-dependent manner. METHOD: Male Wistar Kyoto rats were divided into three different groups. The control group (n=4) did not receive treatment. In the cannulation(-) group (n=6) the rats were instrumented with three permanent blood cannulas. The rats in the cannulation(+) group received in addition to the cannulation a subcutaneous injection of turpentine oil of 100 microl/100 g bodyweight. The effects were characterized in terms of 1) the time course of serum levels of albumin and alpha(1)-acid glycoprotein (AGP), and 2) the effect on the ex vivo serum protein binding of S(-)-propranolol. RESULTS: In control rats the AGP serum concentration was stable at a value of 169+/-16 microg/ml. In the cannulation(-) group a maximum ten- to fifteen-fold increase in serum AGP concentration was observed at 48 h post surgery, followed by a gradual return back to baseline within 1 week. In the cannulation(+) group a similar concentration-time profile for AGP was found, but without a complete return to baseline within 1 week and with a much higher variability. Ex vivo, an increase in AGP serum concentration from 55 to 675 microg/ml resulted in a profound decrease in the free fraction of S(-)-propranolol from 14+/-0.6 to 1.9+/-0.3%. CONCLUSIONS: In conclusion, through cannulation alone the serum protein levels and binding were modified in a robust, reproducible and time-dependent manner. Therefore this experimental approach is suitable for the investigation of the influence of protein binding on both pharmacokinetics and pharmacodynamics.

Toward the prediction of CNS drug-effect profiles in physiological and pathological conditions using microdialysis and mechanism-based pharmacokinetic-pharmacodynamic modeling.

Our ultimate goal is to develop mechanism-based pharmacokinetic (PK)-pharmacodynamic (PD) models to characterize and to predict CNS drug responses in both physiologic and pathologic conditions. To this end, it is essential to have information on the biophase pharmacokinetics, because these may significantly differ from plasma pharmacokinetics. It is anticipated that biophase kinetics of CNS drugs are strongly influenced by transport across the blood-brain barrier (BBB). The special role of microdialysis in PK/PD modeling of CNS drugs lies in the fact that it enables the determination of free-drug concentrations as a function of time in plasma and in extracellular fluid of the brain, thereby providing important data to determine BBB transport characteristics of drugs. Also, the concentrations of (potential) extracellular biomarkers of drug effects or disease can be monitored with this technique. Here we describe our studies including microdialysis on the following: (1) the evaluation of the free drug hypothesis; (2) the role of BBB transport on the central effects of opioids; (3) changes in BBB transport and biophase equilibration of anti-epileptic drugs; and (4) the relation among neurodegeneration, BBB transport, and drug effects in Parkinson's disease progression.