Integrating Dynamic Positron Emission Tomography and Conventional Pharmacokinetic Studies to Delineate Plasma and Tumor Pharmacokinetics of FAU, a Prodrug Bioactivated by Thymidylate Synthase

Li, Jing; Kim, Seongho; Shields, Anthony F.; Douglas, Kirk; McHugh, Christopher I.; Lawhorn-Crews, Jawana M.; Wu, Jianmei; Mangner, Thomas J.; LoRusso, Patricia

doi:10.1002/jcph.751

Cited by 3 publications

(1 citation statement)

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“…LPSO was, in fact, used to aid in the estimation of parameters in a complex PK model. 69 In this work, the objective was to integrate dynamic positron emission tomography and conventional plasma PK studies to characterize the plasma and tissue PKs of 1‐(2‐deoxy‐2‐fluoro‐beta‐d‐arabinofuranosyl) uracil (FAU) and 1‐(2‐deoxy‐2‐fluoro‐beta‐d‐arabinofuranosyl) 5‐methyluracil monophosphate (FMAU). An 8‐compartment model was used to simultaneously characterize the plasma and tissue pharmacokinetics of FAU and its active metabolite FMAU.…”

Section: Using Pso To Gain Insights Into Statistical Identifiability Issuesmentioning

confidence: 99%

Metaheuristics for pharmacometrics

Kim

Hooker

Shi

et al. 2021

CPT Pharmacom & Syst Pharma

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Metaheuristics is a powerful optimization tool that is increasingly used across disciplines to tackle general purpose optimization problems. Nature‐inspired metaheuristic algorithms is a subclass of metaheuristic algorithms and have been shown to be particularly flexible and useful in solving complicated optimization problems in computer science and engineering. A common practice with metaheuristics is to hybridize it with another suitably chosen algorithm for enhanced performance. This paper reviews metaheuristic algorithms and demonstrates some of its utility in tackling pharmacometric problems. Specifically, we provide three applications using one of its most celebrated members, particle swarm optimization (PSO), and show that PSO can effectively estimate parameters in complicated nonlinear mixed‐effects models and to gain insights into statistical identifiability issues in a complex compartment model. In the third application, we demonstrate how to hybridize PSO with sparse grid, which is an often‐used technique to evaluate high dimensional integrals, to search for D‐efficient designs for estimating parameters in nonlinear mixed‐effects models with a count outcome. We also show the proposed hybrid algorithm outperforms its competitors when sparse grid is replaced by its competitor, adaptive gaussian quadrature to approximate the integral, or when PSO is replaced by three notable nature‐inspired metaheuristic algorithms.

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Section: Using Pso To Gain Insights Into Statistical Identifiability Issuesmentioning

confidence: 99%

Metaheuristics for pharmacometrics

Kim

Hooker

Shi

et al. 2021

CPT Pharmacom & Syst Pharma

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Effects of capecitabine treatment on the uptake of thymidine analogs using exploratory PET imaging agents: 18F-FAU, 18F-FMAU, and 18F-FLT

et al. 2016

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BackgroundA principal goal for the use of positron emission tomography (PET) in oncology is for real-time evaluation of tumor response to chemotherapy. Given that many contemporary anti-neoplastic agents function by impairing cellular proliferation, it is of interest to develop imaging modalities to monitor these pathways. Here we examined the effect of capecitabine on the uptake of thymidine analogs used with PET: 3’-deoxy-3’-[18F]fluorothymidine (18F-FLT), 1-(2’-deoxy-2’-[18F]fluoro-β-D-arabinofuranosyl) thymidine (18F-FMAU), and 1-(2’-deoxy-2’-[18F]fluoro-β-D-arabinofuranosyl) uracil (18F-FAU) in patients with advanced cancer.MethodsFifteen patients were imaged, five with each imaging agent. Patients had been previously diagnosed with breast, colorectal, gastric, and esophageal cancers and had not received therapy for at least 4 weeks prior to the first scan, and had not been treated with any prior fluoropyrimidines. Subjects were imaged within a week before the start of capecitabine and on the second day of treatment, after the third dose of capecitabine. Tracer uptake was quantified by mean standard uptake value (SUVmean) and using kinetic analysis.ResultsPatients imaged with 18F-FLT showed variable changes in retention and two patients exhibited an increase in SUVmean of 172.3 and 89.9 %, while the other patients had changes ranging from +19.4 to -25.4 %. The average change in 18F-FMAU retention was 0.2 % (range -24.4 to 23.1) and 18F-FAU was -10.2 % (range -40.3 to 19.2). Observed changes correlated strongly with SUVmax but not kinetic measurements.ConclusionsThis pilot study demonstrates that patients treated with capecitabine can produce a marked increase in 18F-FLT retention in some patients, which will require further study to determine if this flare is predictive of therapeutic response. 18F-FAU and 18F-FMAU showed little change, on average, after treatment.Electronic supplementary materialThe online version of this article (doi:10.1186/s40644-016-0092-2) contains supplementary material, which is available to authorized users.

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Towards Improved Pharmacokinetic Models for the Analysis of Transporter-Mediated Hepatic Disposition of Drug Molecules with Positron Emission Tomography

Hernández-Lozano

Karch

Bauer

et al. 2019

AAPS J

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Positron emission tomography (PET) imaging with radiolabeled drugs holds great promise to assess the influence of membrane transporters on hepatobiliary clearance of drugs. To exploit the full potential of PET, quantitative pharmacokinetic models are required. In this study, we evaluated the suitability of different compartment models to describe the hepatic disposition of [ 11 C]erlotinib as a small-molecule model drug which undergoes transporter-mediated hepatobiliary excretion. We analyzed two different, previously published data sets in healthy volunteers, in which a baseline [ 11 C]erlotinib PET scan was followed by a second PET scan either after oral intake of unlabeled erlotinib (300 mg) or after intravenous infusion of the prototypical organic anion-transporting polypeptide inhibitor rifampicin (600 mg). We assessed a three-compartment (3C) and a four-compartment (4C) model, in which either a sampled arterial blood input function or a mathematically derived dual input function (DIF), which takes the contribution of the portal vein to the liver blood supply into account, was used. Both models provided acceptable fits of the observed PET data in the liver and extrahepatic bile duct and gall bladder. Changes in model outcome parameters between scans were consistent with the involvement of basolateral hepatocyte uptake and canalicular efflux transporters in the hepatobiliary clearance of [ 11 C]erlotinib. Our results demonstrated that inclusion of a DIF did not lead to substantial improvements in model fits. The models developed in this work represent a step forward in applying PET as a tool to assess the impact of hepatic transporters on drug disposition and their involvement in drug-drug interactions. Electronic supplementary material The online version of this article (10.1208/s12248-019-0323-0) contains supplementary material, which is available to authorized users.

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Integrating Dynamic Positron Emission Tomography and Conventional Pharmacokinetic Studies to Delineate Plasma and Tumor Pharmacokinetics of FAU, a Prodrug Bioactivated by Thymidylate Synthase

Cited by 3 publications

References 30 publications

Metaheuristics for pharmacometrics

Metaheuristics for pharmacometrics

Effects of capecitabine treatment on the uptake of thymidine analogs using exploratory PET imaging agents: 18F-FAU, 18F-FMAU, and 18F-FLT

Towards Improved Pharmacokinetic Models for the Analysis of Transporter-Mediated Hepatic Disposition of Drug Molecules with Positron Emission Tomography

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