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Journal of Pharmacokinetics and Pharmacodynamics

Ahmad Y Abuhelwa, Stuart Mudge, Richard N Upton, David J R Foster
The aim of this study was to develop a population in vitro-in vivo pharmacokinetic model that simultaneously describe the absorption and accumulation kinetics of itraconazole (ICZ) and hydroxy-itraconazole (HICZ) in healthy subjects. The model integrated meta-models of gastrointestinal pH and gastrointestinal transit time and in vitro dissolution models of ICZ with the absorption and disposition kinetics of ICZ and HICZ. Mean concentration intravenous data, and single- and multi-dose oral data were used for model development...
November 17, 2017: Journal of Pharmacokinetics and Pharmacodynamics
Yasunori Aoki, Daniel Röshammar, Bengt Hamrén, Andrew C Hooker
Population model-based (pharmacometric) approaches are widely used for the analyses of phase IIb clinical trial data to increase the accuracy of the dose selection for phase III clinical trials. On the other hand, if the analysis is based on one selected model, model selection bias can potentially spoil the accuracy of the dose selection process. In this paper, four methods that assume a number of pre-defined model structure candidates, for example a set of dose-response shape functions, and then combine or select those candidate models are introduced...
November 4, 2017: Journal of Pharmacokinetics and Pharmacodynamics
Miro J Eigenmann, Nicolas Frances, Thierry Lavé, Antje-Christine Walz
Non-small cell lung cancer (NSCLC) patients greatly benefit from the treatment with tyrosine kinase inhibitors (TKIs) targeting the epidermal growth factor receptor (EGFR). However, emergence of acquired resistance inevitable occurs after long-term treatment in most patients and limits clinical improvement. In the present study, resistance to drug treatment in patient-derived NSCLC xenograft mice was assessed and modeling and simulation was applied to understand the dynamics of drug resistance as a basis to explore more beneficial drug regimen...
October 31, 2017: Journal of Pharmacokinetics and Pharmacodynamics
Rena J Eudy-Byrne, William Gillespie, Matthew M Riggs, Marc R Gastonguay
A hazard model of fracture was developed using individual patient data (IPD) from the NHANES (2005-2008) database and summary-level data from an aggregate dataset (AD). The AD was built by performing a comprehensive and systematic literature search of clinical studies published from 1995 to 2015, recording fracture rate and bone mineral density (BMD) for both treatment and placebo arms. The search resulted in a metadata set comprised of 21 studies investigating the effects of various bisphosphonates, teriparatide, denosumab, and raloxifene in 65,254 patients over a cumulative 56...
October 28, 2017: Journal of Pharmacokinetics and Pharmacodynamics
Stephen B Duffull, Andrew C Hooker
Optimal designs for nonlinear models are dependent on the choice of parameter values. Various methods have been proposed to provide designs that are robust to uncertainty in the prior choice of parameter values. These methods are generally based on estimating the expectation of the determinant (or a transformation of the determinant) of the information matrix over the prior distribution of the parameter values. For high dimensional models this can be computationally challenging. For nonlinear mixed-effects models the question arises as to the importance of accounting for uncertainty in the prior value of the variances of the random effects parameters...
October 24, 2017: Journal of Pharmacokinetics and Pharmacodynamics
Robert G Pearce, R Woodrow Setzer, Jimena L Davis, John F Wambaugh
Toxicokinetics (TK) provides critical information for integrating chemical toxicity and exposure assessments in order to determine potential chemical risk (i.e., the margin between toxic doses and plausible exposures). For thousands of chemicals that are present in our environment, in vivo TK data are lacking. The publicly available R package "httk" (version 1.8, named for "high throughput TK") draws from a database of in vitro data and physico-chemical properties in order to run physiologically-based TK (PBTK) models for 553 compounds...
October 14, 2017: Journal of Pharmacokinetics and Pharmacodynamics
Phuong Tran, Hee-Doo Yoo, Lien Ngo, Hea-Young Cho, Yong-Bok Lee
The objective of this study was to perform population pharmacokinetic (PK) analysis of gabapentin in healthy Korean subjects and to investigate the possible effect of genetic polymorphisms (1236C > T, 2677G > T/A, and 3435C > T) of ABCB1 gene on PK parameters of gabapentin. Data were collected from bioequivalence studies, in which 173 subjects orally received three different doses of gabapentin (300, 400, and 800 mg). Only data from reference formulation were used. Population pharmacokinetics (PKs) of gabapentin was estimated using a nonlinear mixed-effects model (NONMEM)...
October 10, 2017: Journal of Pharmacokinetics and Pharmacodynamics
Pantelis Sopasakis, Haralambos Sarimveis, Panos Macheras, Aristides Dokoumetzidis
We are witnessing the birth of a new variety of pharmacokinetics where non-integer-order differential equations are employed to study the time course of drugs in the body: this is dubbed "fractional pharmacokinetics". The presence of fractional kinetics has important clinical implications such as the lack of a half-life, observed, for example with the drug amiodarone and the associated irregular accumulation patterns following constant and multiple-dose administration. Building models that accurately reflect this behaviour is essential for the design of less toxic and more effective drug administration protocols and devices...
October 3, 2017: Journal of Pharmacokinetics and Pharmacodynamics
(no author information available yet)
No abstract text is available yet for this article.
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
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
Jon W Collins, J Heyward Hull, Julie B Dumond
Sparse tissue sampling with intensive plasma sampling creates a unique data analysis problem in determining drug exposure in clinically relevant tissues. Tissue exposure may govern drug efficacy, as many drugs exert their actions in tissues. We compared tissue area-under-the-curve (AUC) generated from bootstrapped noncompartmental analysis (NCA) methods and compartmental nonlinear mixed effect (NLME) modeling. A model of observed data after single-dose tenofovir disoproxil fumarate was used to simulate plasma and tissue concentrations for two destructive tissue sampling schemes...
December 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...
December 2017: Journal of Pharmacokinetics and Pharmacodynamics
(no author information available yet)
No abstract text is available yet for this article.
October 2017: Journal of Pharmacokinetics and Pharmacodynamics
(no author information available yet)
No abstract text is available yet for this article.
October 2017: Journal of Pharmacokinetics and Pharmacodynamics
Brenda Cirincione, Navin Goyal, Rene Bruno
No abstract text is available yet for this article.
October 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...
October 2017: Journal of Pharmacokinetics and Pharmacodynamics
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