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CPT: Pharmacometrics & Systems Pharmacology

M S Chatterjee, J Elassaiss-Schaap, A Lindauer, D C Turner, A Sostelly, T Freshwater, K Mayawala, M Ahamadi, J A Stone, R de Greef, A G Kondic, D P de Alwis
Pembrolizumab is a potent immune-modulating antibody active in advanced melanoma, as demonstrated in the KEYNOTE-001, -002, and -006 studies. Longitudinal tumor size modeling was pursued to quantify exposure-response relationships for efficacy. A mixture model was first developed based on an initial dataset from KEYNOTE-001 to describe four patterns of tumor growth and shrinkage. For subsequent analyses, tumor size measurements were adequately described by a single consolidated model structure that captured continuous tumor size with a combination of growth and regression terms, as well as a fraction of tumor responsive to therapy...
November 29, 2016: CPT: Pharmacometrics & Systems Pharmacology
Thi-Huyen-Tram Nguyen, Mohamad-Samer Mouksassi, Nick Holford, Nidal Al-Huniti, Immanuel Freedman, Andrew C Hooker, Jyothy John, Mats O Karlsson, Diane R Mould, Juan José Pérez Ruixo, Elodie L Plan, Rada Savic, Johan G C van Hasselt, Benjamin Weber, Chenguang Zhou, Emmanuelle Comets, France Mentré
This article represents the first in a series of tutorials on model evaluation in nonlinear mixed effect models (NLMEM), from the ISoP Model Evaluation Group. Numerous tools are available for evaluation of NLMEM, with a particular emphasis on visual assessment. This first basic tutorial focuses on presenting graphical evaluation tools of NLMEM for continuous data. It illustrates graphs for correct or misspecified models, discusses their pros and cons and recalls the definition of metrics used. This article is protected by copyright...
November 24, 2016: CPT: Pharmacometrics & Systems Pharmacology
R G Hall, J G Pasipanodya, C Meek, R D Leff, M Swancutt, T Gumbo
Trimethoprim-sulfamethoxazole (TMP-SMX) is one of the most widely drugs on earth. The World Health Organization recommends it as an essential basic drug for all healthcare systems. Dosing is inconsistently based on weight, assuming linear relationships. Given that obesity is now a global "pandemic" it is vital that we evaluate the effect of obesity on trimethoprim-sulfamethoxazole concentrations. We conducted a prospective clinical experiment based on optimized design strategies and artificial intelligence algorithms and found that weight and body mass index (BMI) had a profound effect on drug clearance and volume of distribution, and followed nonlinear fractal geometry-based relationships...
November 21, 2016: CPT: Pharmacometrics & Systems Pharmacology
J Berkhout, J A Stone, K M Verhamme, M Danhof, T M Post
A previously established mechanism-based disease systems model for osteoporosis that is based on a mathematically reduced version of a model describing the interactions between osteoclast (bone removing) and osteoblast (bone forming) cells in bone remodeling has been applied to clinical data from women (n = 1,379) receiving different doses and treatment regimens of alendronate, placebo, and washout. The changes in the biomarkers, plasma bone-specific alkaline phosphatase activity (BSAP), urinary N-telopeptide (NTX), lumbar spine bone mineral density (BMD), and total hip BMD, were linked to the underlying mechanistic core of the model...
November 21, 2016: CPT: Pharmacometrics & Systems Pharmacology
M Ahamadi, T Freshwater, M Prohn, C H Li, D P de Alwis, R de Greef, J Elassaiss-Schaap, A Kondic, J A Stone
Pembrolizumab, a potent antibody against programmed death 1 (PD-1) receptor, has shown robust antitumor activity and manageable safety in patients with advanced solid tumors. Its pharmacokinetic (PK) properties were analyzed with population PK modeling using pooled data from the KEYNOTE-001, -002, and -006 studies of patients with advanced melanoma, non-small cell lung cancer (NSCLC), and other solid tumor types. Pembrolizumab clearance was low and the volume of distribution small, as is typical for therapeutic antibodies...
November 14, 2016: CPT: Pharmacometrics & Systems Pharmacology
L G Hutchinson, H-J Mueller, E A Gaffney, P K Maini, J Wagg, A Phipps, C Boetsch, H M Byrne, B Ribba
Experimental evidence suggests that antiangiogenic therapy gives rise to a transient window of vessel normalization, within which the efficacy of radiotherapy and chemotherapy may be enhanced. Preclinical experiments that measure components of vessel normalization are invasive and expensive. We have developed a mathematical model of vascular tumor growth from preclinical time-course data in a breast cancer xenograft model. We used a mixed-effects approach for model parameterization, leveraging tumor size data to identify a period of enhanced tumor growth that could potentially correspond to the transient window of vessel normalization...
November 14, 2016: CPT: Pharmacometrics & Systems Pharmacology
H Paik, B Chen, M Sirota, D Hadley, A J Butte
Drug repositioning has been based largely on genomic signatures of drugs and diseases. One challenge in these efforts lies in connecting the molecular signatures of drugs into clinical responses, including therapeutic and side effects, to the repurpose of drugs. We addressed this challenge by evaluating drug-drug relationships using a phenotypic and molecular-based approach that integrates therapeutic indications, side effects, and gene expression profiles induced by each drug. Using cosine similarity, relationships between 445 drugs were evaluated based on high-dimensional spaces consisting of phenotypic terms of drugs and genomic signatures, respectively...
November 14, 2016: CPT: Pharmacometrics & Systems Pharmacology
S B Duffull
The framework for systems pharmacology style models does not naturally sit with the usual scientific dogma of parsimony and falsifiability based on deductive reasoning. This does not invalidate the importance or need for overarching models based on pharmacology to describe and understand complicated biological systems. However, it does require some consideration on how systems pharmacology fits into the overall scientific approach.
November 12, 2016: CPT: Pharmacometrics & Systems Pharmacology
J Timmis, K Alden, P Andrews, E Clark, A Nellis, B Naylor, M Coles, P Kaye
This tutorial promotes good practice for exploring the rationale of systems pharmacology models. A safety systems engineering inspired notation approach provides much needed rigour and transparency in development and application of models for therapeutic discovery and design of intervention strategies. Structured arguments over a model's development, underpinning biological knowledge, and analyses of model behaviours, are constructed to determine the confidence that a model is fit for the purpose for which it will be applied...
November 11, 2016: CPT: Pharmacometrics & Systems Pharmacology
D Lu, L Gibiansky, P Agarwal, R C Dere, C Li, Y-W Chu, J Hirata, A Joshi, J Y Jin, S Girish
An integrated pharmacokinetics (PK) model that simultaneously describes concentrations of total antibody (Tab) and antibody-conjugated monomethyl auristatin E (acMMAE) following administration of monomethyl auristatin E (MMAE)-containing antibody-drug conjugates (ADCs) was developed based on phase I PK data with extensive sampling for two ADCs. Two linear two-compartment models that shared all parameters were used to describe the PK of Tab and acMMAE, except that the deconjugation rate was an additional clearance pathway included in the acMMAE PK model compared to Tab...
November 10, 2016: CPT: Pharmacometrics & Systems Pharmacology
E M Svensson, A-G Dosne, M O Karlsson
Albumin concentration and body weight are altered in patients with multidrug-resistant tuberculosis (MDR-TB) and change during the long treatment period, potentially affecting drug disposition. We here describe the pharmacokinetics (PKs) of the novel anti-TB drug bedaquiline and its metabolite M2 in 335 patients with MDR-TB receiving 24 weeks of bedaquiline on top of a longer individualized background regimen. Semiphysiological models were developed to characterize the changes in weight and albumin over time...
November 8, 2016: CPT: Pharmacometrics & Systems Pharmacology
A Lindauer, C R Valiathan, K Mehta, V Sriram, R de Greef, J Elassaiss-Schaap, D P de Alwis
Pembrolizumab, a humanized monoclonal antibody against programmed death 1 (PD-1), has a manageable safety profile and robust clinical activity against advanced malignancies. The lowest effective dose for evaluation in further dose-ranging studies was identified by developing a translational model from preclinical mouse experiments. A compartmental pharmacokinetic model was combined with a published physiologically based tissue compartment, linked to receptor occupancy as the driver of observed tumor growth inhibition...
November 8, 2016: CPT: Pharmacometrics & Systems Pharmacology
J Elassaiss-Schaap, S Rossenu, A Lindauer, S P Kang, R de Greef, J R Sachs, D P de Alwis
Evaluation of pharmacokinetic/pharmacodynamic (PK/PD) properties played an important role in the early clinical development of pembrolizumab. Because analysis of data from a traditional 3 + 3 dose-escalation design revealed several critical uncertainties, a model-based approach was implemented to better understand these properties. Based on anticipated scenarios for potency and PK nonlinearity, a follow-up study was designed and thoroughly evaluated. Execution of 14,000 virtual trials led to the selection and implementation of a robust design that extended the low-dose range by 200-fold...
November 8, 2016: CPT: Pharmacometrics & Systems Pharmacology
L Cheng, L Li
The Library of Integrated Cellular Signatures (LINCS) project provides comprehensive transcriptome profiling of human cell lines before and after chemical and genetic perturbations. Its L1000 platform utilizes 978 landmark genes to infer the transcript levels of 14,292 genes computationally. Here we conducted the L1000 data quality control analysis by using MCF7, PC3, and A375 cell lines as representative examples. Before perturbations, a promising 80% correlation in transcriptome was observed between L1000- and Affymetrix HU133A-platforms...
October 31, 2016: CPT: Pharmacometrics & Systems Pharmacology
P Kovalenko, A T DiCioccio, J D Davis, M Li, M Ardeleanu, Nmh Graham, R Soltys
An exploratory population pharmacokinetic model for functional dupilumab was developed. Data from healthy volunteers and patients with atopic dermatitis (AD) receiving intravenous or subcutaneous doses were integrated. The data included 197 participants (2,518 measurements of dupilumab in serum) from six phase I and II studies. The data were analyzed using stochastic approximation expectation-maximization and importance sampling methods. The best structural model was a two-compartment model with parallel linear and Michaelis-Menten elimination from the central compartment...
October 25, 2016: CPT: Pharmacometrics & Systems Pharmacology
A Tiwari, H Luo, X Chen, P Singh, I Bhattacharya, P Jasper, J E Tolsma, H M Jones, A Zutshi, A K Abraham
Understanding pharmacological target coverage is fundamental in drug discovery and development as it helps establish a sequence of research activities, from laboratory objectives to clinical doses. To this end, we evaluated the impact of tissue target concentration data on the level of confidence in tissue coverage predictions using a site of action (SoA) model for antibodies. By fitting the model to increasing amounts of synthetic tissue data and comparing the uncertainty in SoA coverage predictions, we confirmed that, in general, uncertainty decreases with longitudinal tissue data...
October 22, 2016: CPT: Pharmacometrics & Systems Pharmacology
L Pelligand, A Soubret, J N King, J Elliott, J P Mochel
The objective of this study was to model the pharmacokinetics (PKs) of robenacoxib in cats using a nonlinear mixed-effects (NLME) approach, leveraging all available information collected from cats receiving robenacoxib s.c. and/or i.v.: 47 densely sampled laboratory cats and 36 clinical cats sparsely sampled preoperatively. Data from both routes were modeled sequentially using Monolix 4.3.2. Influence of parameter correlations and available covariates (age, gender, bodyweight, and anesthesia) on population parameter estimates were evaluated by using multiple samples from the posterior distribution of the random effects...
October 22, 2016: CPT: Pharmacometrics & Systems Pharmacology
B Li, J Liu, Y Y Zhang, P Q Wang, Y N Yu, R X Kang, H L Wu, X X Zhang, Z Wang, Y Y Wang
Module-based methods have made much progress in deconstructing biological networks. However, it is a great challenge to quantitatively compare the topological structural variations of modules (allosteric modules [AMs]) under different situations. A total of 23, 42, and 15 coexpression modules were identified in baicalin (BA), jasminoidin (JA), and ursodeoxycholic acid (UA) in a global anti-ischemic mice network, respectively. Then, we integrated the methods of module-based consensus ratio (MCR) and modified Zsummary module statistic to validate 12 BA, 22 JA, and 8 UA on-modules based on comparing with vehicle...
October 19, 2016: CPT: Pharmacometrics & Systems Pharmacology
H B Mistry
No abstract text is available yet for this article.
October 12, 2016: CPT: Pharmacometrics & Systems Pharmacology
L Kuepfer, C Niederalt, T Wendl, J-F Schlender, S Willmann, J Lippert, M Block, T Eissing, D Teutonico
The aim of this tutorial is to introduce the fundamental concepts of physiologically-based pharmacokinetic/pharmacodynamic (PBPK/PD) modeling with a special focus on their practical implementation in a typical PBPK model building workflow. To illustrate basic steps in PBPK model building, a PBPK model for ciprofloxacin will be constructed and coupled to a pharmacodynamic model to simulate anti-bacterial activity of ciprofloxacin treatment. This article is protected by copyright. All rights reserved.
September 21, 2016: CPT: Pharmacometrics & Systems Pharmacology
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