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Journal of Pharmacokinetics and Pharmacodynamics

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https://www.readbyqxmd.com/read/28643108/integrated-tk-td-modeling-for-drug-induced-concurrent-tachycardia-and-qt-changes-in-beagle-dogs
#1
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
https://www.readbyqxmd.com/read/28634654/improvement-in-latent-variable-indirect-response-modeling-of-multiple-categorical-clinical-endpoints-application-to-modeling-of-guselkumab-treatment-effects-in-psoriatic-patients
#2
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
https://www.readbyqxmd.com/read/28623612/challenges-in-longitudinal-exposure-response-modeling-of-data-from-complex-study-designs-a-case-study-of-modeling-cdai-score-for-ustekinumab-in-patients-with-crohn-s-disease
#3
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
https://www.readbyqxmd.com/read/28612141/deterministic-identifiability-of-population-pharmacokinetic-and-pharmacokinetic-pharmacodynamic-models
#4
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
https://www.readbyqxmd.com/read/28573468/time-dependent-pharmacokinetics-of-pembrolizumab-in-patients-with-solid-tumor-and-its-correlation-with-best-overall-response
#5
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
https://www.readbyqxmd.com/read/28550375/exploring-inductive-linearization-for-pharmacokinetic-pharmacodynamic-systems-of-nonlinear-ordinary-differential-equations
#6
Chihiro Hasegawa, Stephen B Duffull
Pharmacokinetic-pharmacodynamic systems are often expressed with nonlinear ordinary differential equations (ODEs). While there are numerous methods to solve such ODEs these methods generally rely on time-stepping solutions (e.g. Runge-Kutta) which need to be matched to the characteristics of the problem at hand. The primary aim of this study was to explore the performance of an inductive approximation which iteratively converts nonlinear ODEs to linear time-varying systems which can then be solved algebraically or numerically...
May 26, 2017: Journal of Pharmacokinetics and Pharmacodynamics
https://www.readbyqxmd.com/read/28497294/a-two-step-deconvolution-analysis-informed-population-pharmacodynamic-modeling-approach-for-drugs-targeting-pulsatile-endogenous-compounds
#7
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...
May 11, 2017: Journal of Pharmacokinetics and Pharmacodynamics
https://www.readbyqxmd.com/read/28466367/model-based-meta-analysis-for-comparing-vitamin-d2-and-d3-parent-metabolite-pharmacokinetics
#8
Alanna S Ocampo-Pelland, Marc R Gastonguay, Matthew M Riggs
Association of Vitamin D (D3 & D2) and its 25OHD metabolite (25OHD3 & 25OHD2) exposures with various diseases is an active research area. D3 and D2 dose-equivalency and each form's ability to raise 25OHD concentrations are not well-defined. The current work describes a population pharmacokinetic (PK) model for D2 and 25OHD2 and the use of a previously developed D3-25OHD3 PK model [1] for comparing D3 and D2-related exposures. Public-source D2 and 25OHD2 PK data in healthy or osteoporotic populations, including 17 studies representing 278 individuals (15 individual-level and 18 arm-level units), were selected using search criteria in PUBMED...
May 2, 2017: Journal of Pharmacokinetics and Pharmacodynamics
https://www.readbyqxmd.com/read/28439684/impact-of-altered-endogenous-igg-on-unspecific-mab-clearance
#9
Saskia Fuhrmann, Charlotte Kloft, Wilhelm Huisinga
Immunodeficient mice are crucial models to evaluate the efficacy of monoclonal antibodies (mAbs). When studying mAb pharmacokinetics (PK), protection from elimination by binding to the neonatal Fc receptor (FcRn) is known to be a major process influencing the unspecific clearance of endogenous and therapeutic IgG. The concentration of endogenous IgG in immunodeficient mice, however is reduced, and this effect on the FcRn protection mechanism and subsequently on unspecific mAb clearance is unknown, yet of great importance for the interpretation of mAb PK data...
April 24, 2017: Journal of Pharmacokinetics and Pharmacodynamics
https://www.readbyqxmd.com/read/28421417/estimation-of-qt-interval-prolongation-through-model-averaging
#10
Peter L Bonate
The current method to analyze concentration-QT interval data, which is based on predictions conditional on a best model, fails to take into account the uncertainty of the model. Previous studies have suggested that failure to take into account model uncertainty using a best model approach can result in confidence intervals that are overly optimistic and may be too narrow. Theoretically, more realistic estimates are obtained using model-averaging where the overall point estimate and confidence interval are a weighted-average from a set of candidate models, the weights of which are equal to each model's Akaike weight...
April 18, 2017: Journal of Pharmacokinetics and Pharmacodynamics
https://www.readbyqxmd.com/read/28389762/analysis-of-opioid-consumption-in-clinical-trials-a-simulation-based-analysis-of-power-of-four-approaches
#11
Rasmus Vestergaard Juul, Joakim Nyberg, Mads Kreilgaard, Lona Louring Christrup, Ulrika S H Simonsson, Trine Meldgaard Lund
Inconsistent trial design and analysis is a key reason that few advances in postoperative pain management have been made from clinical trials analyzing opioid consumption data. This study aimed to compare four different approaches to analyze opioid consumption data. A repeated time-to-event (RTTE) model in NONMEM was used to simulate clinical trials of morphine consumption with and without a hypothetical adjuvant analgesic in doses equivalent to 15-62% reduction in morphine consumption. Trials were simulated with duration of 24-96 h...
April 7, 2017: Journal of Pharmacokinetics and Pharmacodynamics
https://www.readbyqxmd.com/read/28386710/the-effect-of-using-a-robust-optimality-criterion-in-model-based-adaptive-optimization
#12
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...
April 6, 2017: Journal of Pharmacokinetics and Pharmacodynamics
https://www.readbyqxmd.com/read/28357630/age-structured-population-model-of-cell-survival
#13
Wojciech Krzyzanski, Pawel Wiczling, Asfiha Gebre
Age-structured cell population model was introduced to describe cell survival. The impact of the environment on the cell population is represented by drug plasma concentration. A key model variable is the hazard of cell removal that is a subject to the environment effect. The model is capable of describing cohort and random labeling cell survival data. In addition, it accounts for cell loss due to labeling of cell sample, but it lacks ability to describe the effect of label elution on the survival data. The model was applied to red blood cell (RBC) survival data in two groups of Wistar rats obtained by two techniques: cohort labeling using (14)C-glycine (N = 4) and random labeling using biotin (N = 8)...
March 29, 2017: Journal of Pharmacokinetics and Pharmacodynamics
https://www.readbyqxmd.com/read/28224315/modeling-of-free-fatty-acid-dynamics-insulin-and-nicotinic-acid-resistance-under-acute-and-chronic-treatments
#14
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
https://www.readbyqxmd.com/read/28150181/empirical-models-for-fitting-of-oral-concentration-time-curves-with-and-without-an-intravenous-reference
#15
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
https://www.readbyqxmd.com/read/28132162/population-pharmacokinetics-and-pharmacodynamics-of-ionis-gcgrrx-an-antisense-oligonucleotide-for-type-2-diabetes-mellitus-a-red-blood-cell-lifespan-model
#16
Kenneth T Luu, Erin S Morgan, Sanjay Bhanot, Richard Geary, Anne Smith, Claudette Bethune, Lynnetta Watts, Scott Henry, Yanfeng Wang
IONIS-GCGRRx (ISIS 449884) is an antisense oligonucleotide inhibitor of the glucagon receptor (GCGR). The objective of this study was to evaluate the pharmacokinetics (PK) and pharmacodynamics (PD) of IONIS-GCGRRx via population-based modeling. The observed data were obtained from a Phase 1 (50, 100, 200, 300 and 400 mg) single- and multiple-dose study in healthy volunteers and a Phase 2 (100 and 200 mg) multiple-dose study in T2DM patients. The PK of IONIS GCGRRx was characterized by two primary systemic compartments and three absorption transit compartments with elimination out of the peripheral compartment...
June 2017: Journal of Pharmacokinetics and Pharmacodynamics
https://www.readbyqxmd.com/read/28353185/pk-pd-compass-bringing-infectious-diseases-pharmacometrics-to-the-patient-s-bedside
#17
Catharine C Bulik, Justin C Bader, Li Zhang, Scott A Van Wart, Christopher M Rubino, Sujata M Bhavnani, Kim L Sweeney, Paul G Ambrose
Antimicrobial stewardship programs face many challenges, one of which is a lack of guidance regarding antimicrobial dose, interval, and duration. There is no tool that considers patient demographic, pathogen susceptibility, and pharmacokinetic-pharmacodynamic (PK-PD) targets for efficacy in order to evaluate appropriate antimicrobial dosing regimens. The PK-PD Compass, an educational mobile application, was developed to address this unmet need. The application consists of a Monte Carlo simulation algorithm which integrates pharmacokinetic (PK) and PK-PD data, patient-specific characteristics, and pathogen susceptibility data...
April 2017: Journal of Pharmacokinetics and Pharmacodynamics
https://www.readbyqxmd.com/read/28299529/modeling-and-simulation-in-dose-determination-for-biodefense-products-approved-under-the-fda-animal-rule
#18
Kimberly L Bergman, K Krudys, S K Seo, J Florian
Development of effective medical countermeasures for biodefense is vital to United States biopreparedness and response in the age of terrorism, both foreign and domestic. A traditional drug development pathway toward approval is not possible for most biodefense-related indications, creating the need for alternative development pathways such as the FDA's Animal Rule. Under this unique regulatory mechanism, FDA-approval is based on adequate and well-controlled animal studies when it is neither ethical nor feasible to conduct human efficacy studies...
April 2017: Journal of Pharmacokinetics and Pharmacodynamics
https://www.readbyqxmd.com/read/28283865/editorial-to-the-themed-issue-on-focus-on-infectious-disease
#19
EDITORIAL
Peter Bonate
No abstract text is available yet for this article.
April 2017: Journal of Pharmacokinetics and Pharmacodynamics
https://www.readbyqxmd.com/read/28205025/the-multistate-tuberculosis-pharmacometric-model-a-semi-mechanistic-pharmacokinetic-pharmacodynamic-model-for-studying-drug-effects-in-an-acute-tuberculosis-mouse-model
#20
Chunli Chen, Fatima Ortega, Joaquin Rullas, Laura Alameda, Iñigo Angulo-Barturen, Santiago Ferrer, Ulrika Sh Simonsson
The Multistate Tuberculosis Pharmacometric (MTP) model, a pharmacokinetic-pharmacodynamic disease model, has been used to describe the effects of rifampicin on Mycobacterium tuberculosis (M. tuberculosis) in vitro. The aim of this work was to investigate if the MTP model could be used to describe the rifampicin treatment response in an acute tuberculosis mouse model. Sixty C57BL/6 mice were intratracheally infected with M. tuberculosis H37Rv strain on Day 0. Fifteen mice received no treatment and were sacrificed on Days 1, 9 and 18 (5 each day)...
April 2017: Journal of Pharmacokinetics and Pharmacodynamics
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