Target-mediated Disposition Model Research Articles

Improving priors for human monoclonal antibody linear pharmacokinetic parameters by using half-lives from non-human primates

Obtaining a good prior for the linear pharmacokinetics of new monoclonal antibodies (mAbs) would be an advantage not only for designing first-in-human (FIH) studies but also for stabilizing fitting of data with non-linear target-mediated disposition models. We estimated the pharmacokinetics from FIH studies for five mAbs using a two-compartment model, both separately and together, using a simple pool, a third hierarchical level of random effects for between mAb differences and non-human-primate half-lives as a predictor covariate for said differences. There was good agreement between compounds for the rapidly accessible central volume of 2.9L (70kg human), but clearances and peripheral volumes differed with terminal half-lives ranging from 15 to 28 days. The simple pool of human studies gave inter-individual variability estimates of 32% coefficient of variation (CV) for clearance and 33% CV for peripheral volume, larger than for separate fits (13-26% CV and 15-35% CV for clearance and volume respectively). Using third level hierarchical random effects gave inter-individual variability estimates close to those of separate fits (24% and 16% CV respectively). The between-mAb differences became predictable if non-human primate body weight scaled terminal half-life estimates were included as covariates on clearance and peripheral volume. In conclusion, ignoring inter-mAb variation leads to inflated estimates of inter-individual variability and unrealistic simulations for FIH studies. However, by using 70kg body weight scaled terminal half-life estimates from non-human primates one can account for between-mAb differences and provide non-inflated priors for the linear pharmacokinetic parameters of new mAbs.

Target-mediated disposition population pharmacokinetics model of erythropoietin in premature neonates following multiple intravenous and subcutaneous dosing regimens

Routine erythropoietin (Epo) therapy for neonatal anemia is presently controversial due to its modest response. We speculate that an important contributor to this modest response is that previous clinical study designs were not driven by rigorous mechanistic and kinetic insights into the complex pharmacokinetics (PK) and pharmacodynamics (PD) of Epo in this population. To address this therapeutic opportunity, we conducted a prospective clinical study to investigate the PK of Epo in very-low-birth-weight (VLBW) premature neonates using a unique Epo dosing algorithm that accounts for complex neonatal erythropoietic physiology. Twenty-seven subjects received up to 10 intravenous or subcutaneous exogenous doses of Epo (600 or 1200 U/kg) during the first 4 weeks of life. Subjects were administered two doses of Epo 1200 U/kg on days 2 and 16, and eight doses of Epo 600 U/kg on days 4, 5, 6, 7, 9, 14, 15, and 28 following birth. We have developed for the first time a mechanistic, target-mediated disposition model that provides novel insights into the mechanisms driving Epo PK in VLBW neonates. Epo association rate, kon, was estimated to be 0.00610 pM-1h-1, and the dissociation rate koff was 0.112 h-1. Internalization of the Epo-target complex (kint) and the total receptor concentration (Rmax) were estimated to be 0.118 h-1 and 133 pM, respectively. Following s.c. administration, the absorption rate (ka) of Epo was 0.0738h-1 and bioavailability was 78.0%. Our mechanism-based population pharmacokinetic analysis provided quantitative insight into Epo kinetics in VLBW neonates; the information gained will assist in deriving dosing strategies for neonatal anemia and for neuroprotection efficacy studies.

Pharmacokinetic and pharmacodynamic relationship of AMG 811, an anti-IFN-γ IgG1 monoclonal antibody, in patients with systemic lupus erythematosus.

To investigate the relationships between AMG 811 exposure, concentration changes in serum IFN-γ, and IFN-γ-induced protein 10 (CXCL10), and to identify important contributions of baseline covariates to these relationships. A mechanism based pharmacokinetic (PK)-pharmacodynamic (PD) model was developed. A target mediated disposition model was used to describe AMG 811 and target IFN-γ interaction. CXCL10 was predicted to be driven by estimated free IFN-γ levels. For an average systemic lupus erythematosus (SLE) subject, the linear clearance (CL) of AMG 811 was 0.176 L/day, and the central (Vc) and peripheral (Vp) volumes of distribution were 1.48 and 2.12 L, respectively. Body weight was found to correlate with CL, Vc, Vp, and inter compartment clearance (Q); and age was found to correlate with Vc. The relationship between estimated free serum IFN-γ concentration levels and serum CXCL10 in logarithmic scales was best described by a linear model with slope and intercept estimated to be 0.197 and -0.3, respectively. The largest observed reduction of serum CXCL10 concentration was achieved at the highest AMG 811 dose tested (180 mg SC). This model enables simulations of AMG 811 PK-PD profiles under various dosing regimens to support future clinical studies.

Target-Mediated Disposition Model Describing the Dynamics of IL12 and IFNγ after Administration of a Mifepristone-Inducible Adenoviral Vector for IL-12 Expression in Mice

Interleukin-12 (IL12) is a cytokine with potential applications in the treatment of cancer given the potent immune response that it triggers, in part due to its ability to stimulate expression of interferon-γ (IFNγ). To avoid the toxicity associated with systemic exposure to IL12, a high-capacity adenoviral vector carrying a liver-specific, mifepristone-inducible IL12 expression system (HC-Ad/RUmIL12) has been developed. However, the maintenance of IL12 expression at therapeutic levels is compromised by the inhibitory effect of IFNγ on inducible systems. The aim of this work is to develop a semi-mechanistic model to characterize the relationship between IL12 and IFNγ in wild-type and knock-out mice for the IFNγ receptor treated with HC-Ad/RUmIL12 under different dosing regimens in order to better understand the key mechanisms controlling the system. Rapid binding was considered to account for target-mediated disposition exhibited by both cytokines (equilibrium dissociation constant were 18 and 2.28pM for IL12 and IFNγ, respectively). The final model included: (1) IFNγ receptor turnover, (2) irreversible free cytokine elimination from the serum compartment, (3) internalization of the IL12 receptor complex, (4) IL12 expression upregulated by the co-administration of the adenoviral vector and mifepristone and downregulated by the IFNγ receptor, and (5) synthesis of IFNγ controlled by the relative increments in the bound IL12. In conclusion, a model simultaneously describing the kinetics of IL12 and IFNγ in the context of gene therapy was developed and validated with additional data. The model was applied to design an experimental dosing protocol intended to maintain sustained therapeutic IL12 levels.

Theoretical Considerations of Target-Mediated Drug Disposition Models: Simplifications and Approximations

To clarify relationships among various types of target-mediated disposition (TMD) models including the Michaelis-Menten, quasi-steady-state (Qss), and rapid binding models and propose measures for the closeness of some models as approximations to the general TMD model (Mager and Jusko, J Pharmacokinet Pharmacodyn 28(6):507-532, 2001). Based on the classic singular perturbation theory by selecting appropriate scales of time, we derive requirements with which the Michaelis-Menten and Qss models are suitable approximations. Under the Qss assumption we show that other simplifications of the general TMD model can be similarly obtained as the Michaelis-Menten and Qss models. We compare these models by simulations using known application examples. The Michaelis-Menten and Qss models are direct simplifications of the general TMD model and, moreover, suitable approximations if certain specific requirements on the parameters are met. As a first attempt to quantify the closeness of some simplifications to the general TMD model, our work should provide a more rigorous basis for the theoretical and practical research of TMD models, which are important for investigating the pharmacokinetic-pharmacodynamic relationships of many biological compounds.

Target Mediated Disposition (TMD) Model Based Dose Selection for Fixed SC Doses of Anti-MAdCAM-1 Monoclonal Antibody (PF-00547659) in Crohnʼs Disease

Purpose: In inflammatory bowel disease (IBD), there is still a large unmet medical need despite the introduction of anti-TNFs and new mechanisms of action are needed particularly for patients who have failed other treatments. PF-00547659 is a fully human IgG2κ anti-human MAdCAM monoclonal antibody that binds to recombinant human MAdCAM to reduce lymphocyte homing to the gut and GI inflammation. Based upon the encouraging results of a phase IIa and pharmacokinetic (PK) study in ulcerative colitis (UC) (Vermiere S, Gut 2011), a large phase 2b study in Crohn's Disease (CD) was initiated. The PK properties of PF-00547659 are typical of those displayed by IgG2 monoclonal antibodies with target-mediated disposition exhibiting dose-dependent clearance and good SC bioavailability. The dose selection strategy for this CD study which desired fixed SC doses was based upon TMD Modeling in UC (Martin SW DDW 2009 W1042). Methods: The PK data from the UC study covering a wide range of IV and SC administered doses (0.01-10 mg/kg) provided sufficient information for mechanistic characterization of an antibody exhibiting nonlinear kinetics with high affinity for MAdCAM. The TMD model was used for simulation of 8 levels of fixed doses from 7.5 mg to 225 mg. The primary criteria for optimal doses was target suppression over 12 weeks. 500 monte-carlo simulations were performed including inter-subject and intra-subject variability. Results: Monthly SC doses of 75 mg provide greater than 95% target suppression over 12 weeks in 90% of subjects. Two additional doses of one half-log below (22.5 mg) and above (225 mg) were selected to provide information regarding the minimal and maximum effective suppression level necessary for efficacy in CD. The selected dose range has good separation in PK exposure, is within the range that was well tolerated and exhibited signs of clinical activity in UC (Figure).Figure: No Caption available.Conclusion: Based upon the simulation results, PF-00547659 SC monthly doses of 22.5 mg, 75 mg and 225 mg were selected for the phase 2b CD study. Doses above 22.5 mg SC inhibits > 90% of MAdCAM activity with the CI narrowing with increasing doses up to 225 mg SC which inhibits 99.8% of MAd-CAM activity. Disclosure: William Sandborn - Consultant Pfizer, Jason WIlliams - Pfizer Employee, Fabio Cataldi - Pfizer Employee, Gail Comer - Pfizer Employee. This research was supported by an industry grant from Pfizer.

New journal cover

The editors and publishers are pleased to display the new cover format for the Journal of Pharmacokinetics and Pharmacodynamics. Besides the dramatic change in colors, the cover is meant to reflect that physiology usually underlies both empirical and mechanistic models used in our field. We hope that readers and authors will appreciate that each issue of the cover will display a model or diagram selected from an article in the current issue. In the present case, the cover depicts a two-compartment model with Michaelis–Menten elimination and a target-mediated disposition model found in the article by Xiaoyu Yan, Wojciech Krzyzanski, and Donald E. Mager which compares recovery of pharmacokinetic parameters using these nonlinear systems. We wish to acknowledge our appreciation to Ms. Amanda Almon for creation of the basic cover graphics.

Integrated Cellular Bone Homeostasis Model for Denosumab Pharmacodynamics in Multiple Myeloma Patients

The purpose of this study is to couple a cellular bone homeostasis model with the pharmacokinetics (PK) and mechanism of action of denosumab, an inhibitor of receptor activator of nuclear factor-kappaB ligand, to characterize the time course of serum N-telopeptide (NTX), a bone resorption biomarker, following single escalating doses in multiple myeloma (MM) patients. Mean PK and median serum NTX temporal profiles were extracted from a previously conducted randomized, double-blind, double-dummy, active-controlled, multicenter study including 25 MM patients receiving escalating denosumab doses. Nonlinear denosumab PK profiles were well described by a target-mediated disposition model that includes rapid binding of drug to its pharmacological target. Fixed PK profiles were integrated into a previously reported theoretical cellular model of osteoblast-osteoclast interactions, and the NTX concentrations were linked to a resorbing active osteoclast (AOC) pool by a nonlinear transfer function. Reasonable fits were obtained for the NTX profiles from maximal likelihood estimation using the final model. Transfer function parameters, including the basal NTX level and the AOC concentration producing 50% of maximal NTX production, were estimated with good precision as 5.55 nM and 1.88 x 10(-5) pM. An indirect response model for inhibition of NTX production by denosumab was also used to characterize the data. Although this model adequately characterized the pharmacodynamic data, simulations conducted with the full model reveal that a cellular model coupled with clinical data has the distinct advantage of not only quantitatively describing data but also providing new testable hypotheses on the role of cellular system variables on drug response.