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Journal of Pharmacokinetics and Pharmacodynamics

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September 19, 2017: Journal of Pharmacokinetics and Pharmacodynamics
Matts Kågedal, Leonid Gibiansky, Jian Xu, Xin Wang, Divya Samineni, Shang-Chiung Chen, Dan Lu, Priya Agarwal, Bei Wang, Ola Saad, Neelima Koppada, Bernard M Fine, Jin Y Jin, Sandhya Girish, Chunze Li
Antibody-drug conjugates (ADCs) developed using the valine-citrulline-MMAE (vc-MMAE) platform, consist of a monoclonal antibody (mAb) covalently bound with a potent anti-mitotic toxin (MMAE) through a protease-labile vc linker. Recently, clinical data for a variety of vc-MMAE ADCs has become available. The goal of this analysis was to develop a platform model that simultaneously described antibody-conjugated MMAE (acMMAE) pharmacokinetic (PK) data from eight vc-MMAE ADCs, against different targets and tumor indications; and to assess differences and similarities of model parameters and model predictions, between different compounds...
September 16, 2017: Journal of Pharmacokinetics and Pharmacodynamics
Leonid Gibiansky, Ekaterina Gibiansky
The emerging discipline of mathematical pharmacology occupies the space between advanced pharmacometrics and systems biology. A characteristic feature of the approach is application of advance mathematical methods to study the behavior of biological systems as described by mathematical (most often differential) equations. One of the early application of mathematical pharmacology (that was not called this name at the time) was formulation and investigation of the target-mediated drug disposition (TMDD) model and its approximations...
September 16, 2017: Journal of Pharmacokinetics and Pharmacodynamics
Mengjie Li, Pritam Thapa, Pallavi Rajaputra, Moses Bio, Cody J Peer, William D Figg, Youngjae You, Sukyung Woo
The combination of photodynamic therapy (PDT) with anti-tumor agents is a complimentary strategy to treat local cancers. We developed a unique photosensitizer (PS)-conjugated paclitaxel (PTX) prodrug in which a PS is excited by near-infrared wavelength light to site-specifically release PTX while generating singlet oxygen (SO) to effectively kill cancer cells with both PTX and SO. The aim of the present study was to identify the determinants influencing the combined efficacy of this light-activatable prodrug, especially the bystander killing effects from released PTX...
September 14, 2017: Journal of Pharmacokinetics and Pharmacodynamics
Anne-Gaëlle Dosne, Martin Bergstrand, Mats O Karlsson
Quantifying the uncertainty around endpoints used for decision-making in drug development is essential. In nonlinear mixed-effects models (NLMEM) analysis, this uncertainty is derived from the uncertainty around model parameters. Different methods to assess parameter uncertainty exist, but scrutiny towards their adequacy is low. In a previous publication, sampling importance resampling (SIR) was proposed as a fast and assumption-light method for the estimation of parameter uncertainty. A non-iterative implementation of SIR proved adequate for a set of simple NLMEM, but the choice of SIR settings remained an issue...
September 8, 2017: Journal of Pharmacokinetics and Pharmacodynamics
Lambertus A Peletier, Johan Gabrielsson
Drug-discovery has become a complex discipline in which the amount of knowledge about human biology, physiology, and biochemistry have increased. In order to harness this complex body of knowledge mathematics can play a critical role, and has actually already been doing so. We demonstrate through four case studies, taken from previously published data and analyses, what we can gain from mathematical/analytical techniques when nonlinear concentration-time courses have to be transformed into their equilibrium concentration-response (target or complex) relationships and new structures of drug potency have to be deciphered; when pattern recognition needs to be carried out for an unconventional response-time dataset; when what-if? predictions beyond the observational concentration-time range need to be made; or when the behaviour of a semi-mechanistic model needs to be elucidated or challenged...
September 7, 2017: Journal of Pharmacokinetics and Pharmacodynamics
Marc Lavielle
The aim of this paper is to provide an overview of pharmacometric models that involve some latent process with Markovian dynamics. Such models include hidden Markov models which may be useful for describing the dynamics of a disease state that jumps from one state to another at discrete times. On the contrary, diffusion models are continuous-time and continuous-state Markov models that are relevant for modelling non observed phenomena that fluctuate continuously and randomly over time. We show that an extension of these models to mixed effects models is straightforward in a population context...
August 31, 2017: Journal of Pharmacokinetics and Pharmacodynamics
Hua He, Yanguang Cao
Conventional maximum tolerated doses (MTD) in chemotherapy are recently challenged by an alternative dosing method with low doses and high dosing frequency (LDHF). Still, it remains unclear which chemotherapies would potentially benefit from LDHF. The pharmacokinetic (PK) differences between MTD and LDHF are drug exposure magnitude (concentration) and exposure duration (time), two fundamental PK elements that are associated with the pharmacodynamics (PD) of chemotherapies. Here we hypothesized that quantitatively analyzing the contribution of each PK element to the overall cytotoxic effects would provide insights to the selection of the preferred chemotherapeutic dosing...
August 31, 2017: Journal of Pharmacokinetics and Pharmacodynamics
Erin J Mansell, Signe Schmidt, Paul D Docherty, Kirsten Nørgaard, John B Jørgensen, Henrik Madsen
Effective mathematical modelling of continuous subcutaneous infusion pharmacokinetics should aid understanding and control in insulin therapy. Thorough analysis of candidate model performance is important for selecting the appropriate models. Eight candidate models for insulin pharmacokinetics included a range of modelled behaviours, parameters and complexity. The models were compared using clinical data from subjects with type 1 diabetes with continuous subcutaneous insulin infusion. Performance of the models was compared through several analyses: R(2) for goodness of fit; the Akaike Information Criterion; a bootstrap analysis for practical identifiability; a simulation exercise for predictability...
August 22, 2017: Journal of Pharmacokinetics and Pharmacodynamics
Chuanpu Hu, Honghui Zhou, Amarnath Sharma
No abstract text is available yet for this article.
July 20, 2017: Journal of Pharmacokinetics and Pharmacodynamics
Leonid Gibiansky, Ekaterina Gibiansky
The paper extended the TMDD model to drugs with two identical binding sites (2-1 TMDD). The quasi-steady-state (2-1 QSS), quasi-equilibrium (2-1 QE), irreversible binding (2-1 IB), and Michaelis-Menten (2-1 MM) approximations of the model were derived. Using simulations, the 2-1 QSS approximation was compared with the full 2-1 TMDD model. As expected and similarly to the standard TMDD for monoclonal antibodies (mAb), 2-1 QSS predictions were nearly identical to 2-1 TMDD predictions, except for times of fast changes following initiation of dosing, when equilibrium has not yet been reached...
July 19, 2017: Journal of Pharmacokinetics and Pharmacodynamics
Michiel J van Esdonk, Jacobus Burggraaf, Piet H van der Graaf, Jasper Stevens
Pharmacodynamic modeling of pulsatile endogenous compounds (e.g. growth hormone [GH]) is currently limited to the identification of a low number of pulses. Commonly used pharmacodynamic models are not able to capture the complexity of pulsatile secretion and therefore non-compartmental analyses are performed to extract summary statistics (mean, AUC, Cmax). The aim of this study was to develop a new quantification method that deals with highly variable pulsatile data by using a deconvolution-analysis-informed population pharmacodynamic modeling approach...
August 2017: Journal of Pharmacokinetics and Pharmacodynamics
Eric A Strömberg, Andrew C Hooker
Optimizing designs using robust (global) optimality criteria has been shown to be a more flexible approach compared to using local optimality criteria. Additionally, model based adaptive optimal design (MBAOD) may be less sensitive to misspecification in the prior information available at the design stage. In this work, we investigate the influence of using a local (lnD) or a robust (ELD) optimality criterion for a MBAOD of a simulated dose optimization study, for rich and sparse sampling schedules. A stopping criterion for accurate effect prediction is constructed to determine the endpoint of the MBAOD by minimizing the expected uncertainty in the effect response of the typical individual...
August 2017: Journal of Pharmacokinetics and Pharmacodynamics
Fan Wu, Tycho Heimbach, Panos Hatsis, Hai-Ming Tang, Raviprakash Dugyala, Qin Yue, Tao Wang, Handan He
Drug-induced cardiotoxicity, including tachycardia and QT prolongation, remains a major safety concern that needs to be identified and its risk mitigated in early stages of drug development. In the present study, an integrated toxicokinetic-toxicodynamic (TK-TD) modeling approach within a nonlinear mixed-effect modeling framework is applied to investigate concurrent abnormal heart rate and QT changes in three beagle dogs, using a Novartis internal compound (NVS001) as the case example. By accounting for saturable drug absorption, circadian rhythms, drug-effect tolerance, and nonlinear rate-dependency of QT interval, the dynamic TK-TD model captures the experimentally observed drug effects on heart rate and QT interval across a wide dosing range of NVS001 in beagle dogs...
June 22, 2017: Journal of Pharmacokinetics and Pharmacodynamics
Chuanpu Hu, Bruce Randazzo, Amarnath Sharma, Honghui Zhou
Exposure-response modeling plays an important role in optimizing dose and dosing regimens during clinical drug development. The modeling of multiple endpoints is made possible in part by recent progress in latent variable indirect response (IDR) modeling for ordered categorical endpoints. This manuscript aims to investigate the level of improvement achievable by jointly modeling two such endpoints in the latent variable IDR modeling framework through the sharing of model parameters. This is illustrated with an application to the exposure-response of guselkumab, a human IgG1 monoclonal antibody in clinical development that blocks IL-23...
June 20, 2017: Journal of Pharmacokinetics and Pharmacodynamics
Chuanpu Hu, Omoniyi J Adedokun, Yang Chen, Philippe O Szapary, Christopher Gasink, Amarnath Sharma, Honghui Zhou
Informative exposure-response modeling of clinical endpoints is important in drug development to identify optimum dose and dosing regimens. Despite much recent progress in mechanism-based longitudinal modeling of clinical data, challenges remain in clinical trials of diseases such as Crohn's disease, where a commonly used composite endpoint Crohn's Disease Activity Index (CDAI) has considerable variation in its administration and scoring between different assessors and complex study designs typically include maintenance phases with randomized withdrawal re-randomizations and other response driven dose adjustments...
June 16, 2017: Journal of Pharmacokinetics and Pharmacodynamics
Vijay K Siripuram, Daniel F B Wright, Murray L Barclay, Stephen B Duffull
Identifiability is an important component of pharmacokinetic-pharmacodynamic (PKPD) model development. Structural identifiability is concerned with the uniqueness of the model parameters for a set of perfect input-output data and deterministic identifiability with the precision of parameter estimation given imperfect input-output data. We introduce two subcategories of deterministic identifiability, external and internal, and consider factors that distinguish between these forms. We define external deterministic identifiability as a function of externally controllable variables, i...
June 13, 2017: Journal of Pharmacokinetics and Pharmacodynamics
Hongshan Li, Jingyu Yu, Chao Liu, Jiang Liu, Sriram Subramaniam, Hong Zhao, Gideon M Blumenthal, David C Turner, Claire Li, Malidi Ahamadi, Rik de Greef, Manash Chatterjee, Anna G Kondic, Julie A Stone, Brian P Booth, Patricia Keegan, Atiqur Rahman, Yaning Wang
Pembrolizumab is a monoclonal antibody that targets the programmed death-1 receptor to induce immune-mediated clearance (CL) of tumor cells. Originally approved by the US Food and Drug Administration in 2014 for treating patients with unresectable or metastatic melanoma, pembrolizumab is now also used to treat patients with non-small-cell lung cancer, classical Hodgkin lymphoma, head and neck cancer, and urothelial cancer. This paper describes the recently identified feature of pembrolizumab pharmacokinetics, the time-dependent or time-varying CL...
June 1, 2017: Journal of Pharmacokinetics and Pharmacodynamics
Robert Andersson, Tobias Kroon, Joachim Almquist, Mats Jirstrand, Nicholas D Oakes, Neil D Evans, Michael J Chappel, Johan Gabrielsson
Nicotinic acid (NiAc) is a potent inhibitor of adipose tissue lipolysis. Acute administration results in a rapid reduction of plasma free fatty acid (FFA) concentrations. Sustained NiAc exposure is associated with tolerance development (drug resistance) and complete adaptation (FFA returning to pretreatment levels). We conducted a meta-analysis on a rich pre-clinical data set of the NiAc-FFA interaction to establish the acute and chronic exposure-response relations from a macro perspective. The data were analyzed using a nonlinear mixed-effects framework...
June 2017: Journal of Pharmacokinetics and Pharmacodynamics
Michael Weiss
Appropriate model selection is important in fitting oral concentration-time data due to the complex character of the absorption process. When IV reference data are available, the problem is the selection of an empirical input function (absorption model). In the present examples a weighted sum of inverse Gaussian density functions (IG) was found most useful. It is shown that alternative models (gamma and Weibull density) are only valid if the input function is log-concave. Furthermore, it is demonstrated for the first time that the sum of IGs model can be also applied to fit oral data directly (without IV data)...
June 2017: Journal of Pharmacokinetics and Pharmacodynamics
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