Population pharmacokinetic reanalysis of a Diazepam PBPK model: a comparison of Stan and GNU MCSim

Tsiros, Periklis; Dokoumetzidis, Aristides; Tsiliki, Georgia; Sarimveis, Haralambos

doi:10.1007/s10928-019-09630-x

Cited by 23 publications

(24 citation statements)

References 36 publications

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“…In this case, the ODE system is linear and can be solved analytically using the so-called matrix exponentials (Jackson, 2011;Jones et al, 2017), which can be quite computationally expensive (Tsiros et al, 2019).…”

Section: Background On Multistate Modelsmentioning

confidence: 99%

Multistate models of developmental toxicity: Application to valproic acid-induced malformations in the zebrafish embryo

Siméon

Beaudouin

Brotzmann

et al. 2021

Toxicology and Applied Pharmacology

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For the determination of acute toxicity of chemicals in zebrafish (Danio rerio) embryos, the OECD test guideline 236 stipulates a dose-response analysis of four lethal core endpoints and a quantitative characterization of abnormalities including their time-dependency. Routinely, the data are analysed at the different observation times separately. However, observations at a given time strongly depend on the previous effects and should be analysed jointly with them. To solve that problem, we developed multistate models for occurrence of developmental malformations and live events in zebrafish embryos exposed to eight concentrations of valproic acid (VPA) the first five days of life. Observations were recorded daily per embryo. We statistically infer on model structure and parameters using a numerical Bayesian framework. Hatching probability rate changed with time and we compared three forms of its time-dependence. A piecewise constant function of time adequately described the hatching data. The other transition rates were conditioned on the embryo body concentration of VAP, obtained using a physiologically-based pharmacokinetic model. VPA impacted mostly the malformation probability rate in hatched and non-hatched embryos. Malformation reversion probability rates were lowered by VPA.Direct mortality was low at the concentrations tested, but increased linearly with internal concentration.The model makes full use of data and gives a finer grain analysis of the teratogenic effects of VPA in zebrafish than the OECD-prescribed approach. We discuss the use the model for obtaining toxicological reference values suitable for inter-species extrapolation. A general result is that complex multistate models can be efficiently evaluated numerically.

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Section: Background On Multistate Modelsmentioning

confidence: 99%

Multistate models of developmental toxicity: Application to valproic acid-induced malformations in the zebrafish embryo

Siméon

Beaudouin

Brotzmann

et al. 2021

Toxicology and Applied Pharmacology

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show abstract

“…This approach is computationally intensive, but with the advancements in computing power and Markov chain Monte Carlo algorithms it is becoming more accessible. 16 Adaptive Bayesian approach has been studied for dose optimization. 17,18 The principle of this approach is that the prior distributions of the model parameters are updated sequentially over time with new data and their corresponding posterior distributions are used to perform simulation to obtain individualized dosage regimens.…”

Section: How Might This Change Drug Discovery Development And/or Thmentioning

confidence: 99%

“…Available information about model parameters can serve as priors in the analysis of new data to describe HGB response and ultimately to optimize doses in individual patients. This approach is computationally intensive, but with the advancements in computing power and Markov chain Monte Carlo algorithms it is becoming more accessible 16 …”

mentioning

confidence: 99%

Population Pharmacodynamic Modeling of Epoetin Alfa in End‐Stage Renal Disease Patients Receiving Maintenance Treatment Using Bayesian Approach

Nguyen

Meaney

Rao

et al. 2020

CPT Pharmacom & Syst Pharma

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The ability to control dosage regimens of erythropoiesis-stimulating agents (ESAs) to maintain a desired hemoglobin (HGB) target is still elusive. We utilized a Bayesian approach and informative priors to characterize HGB profiles, using simulated drug concentrations, in patients with end-stage renal disease receiving maintenance doses of epoetin alfa. We also demonstrated an adaptive Bayesian method, applied to individual patients, to improve the accuracy of HGB predictions over time. The results showed that sparse HGB data from daily clinical practice were characterized successfully. The adaptive Bayesian method effectively improved the accuracy of HGB predictions by updating the individual model with new data accounting for within-subject changes over time. The Bayesian approach presented leverages existing knowledge of the model parameters and has a potential utility in clinical practice to individualize dosage regimens of epoetin alfa and ESAs to achieve target HGB. Further studies are warranted to develop an application for practical use. Anemia is a common complication of end-stage renal disease (ESRD) associated with fatigue, weakness, dyspnea, increased morbidity, and mortality. 1 Recombinant human erythropoietin (EPO; epoetin alfa) is the first erythropoiesis-stimulating agent (ESA) introduced late 1980s for the treatment of anemia in patients with chronic kidney disease. 1 Since then, it has revolutionized anemia management, helping to prevent or minimize the use of blood transfusions and improve quality of life. 2,3 Despite its long history, the ability to control dosage regimen of epoetin alfa as well as other ESAs to maintain a target hemoglobin (HGB) concentration of 10-12 g/dL is still elusive. 4 HGB response is often observed with large oscillations and overshoots out of the desired range. 5,6 Furthermore, using high doses of ESAs to achieve the target HGB has been found associated with increased risks of death and cardiovascular events. 1 Therefore, individualized dosage regimen is recommended but sufficient guidelines are not available. 7,8 Extensive studies have been conducted in healthy volunteers and patients to characterize pharmacokinetics (PKs) and pharmacodynamics (PDs) of epoetin alfa. 9-13 However, the potential utilities of these studies have not been realized in clinical practice to individualize dosage regimen. There are challenges in bringing established PK/PD models into clinical use. These models are developed using rich data, including baseline information from individual subjects. However, in practice, only sparse HGB observations are collected, often once or twice a month, and PK data include only dose amounts without drug

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“…There are few published reports for the PBPK models for diazepam, which are focused on predicting its PK and DDIs in both humans and animals [ 34 , 35 , 36 ]. One study reported a PBPK model for diazepam to evaluate its DDIs with opioids (oxycodone, buprenorphine, and fentanyl) [ 35 ].…”

Section: Introductionmentioning

confidence: 99%

“…One study reported a PBPK model for diazepam to evaluate its DDIs with opioids (oxycodone, buprenorphine, and fentanyl) [ 35 ]. In contrast, another study aimed to develop a diazepam PBPK model by using different modeling and simulation tools after IV application only [ 34 ]. The third reported diazepam PBPK model was focused on the prediction of drug parameters in rats [ 36 ].…”

Section: Introductionmentioning

confidence: 99%

A Physiologically Based Pharmacokinetic Model for Predicting Diazepam Pharmacokinetics after Intravenous, Oral, Intranasal, and Rectal Applications

et al. 2021

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Diazepam is one of the most prescribed anxiolytic and anticonvulsant that is administered through intravenous (IV), oral, intramuscular, intranasal, and rectal routes. To facilitate the clinical use of diazepam, there is a need to develop formulations that are convenient to administer in ambulatory settings. The present study aimed to develop and evaluate a physiologically based pharmacokinetic (PBPK) model for diazepam that is capable of predicting its pharmacokinetics (PK) after IV, oral, intranasal, and rectal applications using a whole-body population-based PBPK simulator, Simcyp®. The model evaluation was carried out using visual predictive checks, observed/predicted ratios (Robs/pred), and the average fold error (AFE) of PK parameters. The Diazepam PBPK model successfully predicted diazepam PK in an adult population after doses were administered through IV, oral, intranasal, and rectal routes, as the Robs/pred of all PK parameters were within a two-fold error range. The developed model can be used for the development and optimization of novel diazepam dosage forms, and it can be extended to simulate drug response in situations where no clinical data are available (healthy and disease).

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Population pharmacokinetic reanalysis of a Diazepam PBPK model: a comparison of Stan and GNU MCSim

Cited by 23 publications

References 36 publications

Multistate models of developmental toxicity: Application to valproic acid-induced malformations in the zebrafish embryo

Multistate models of developmental toxicity: Application to valproic acid-induced malformations in the zebrafish embryo

Population Pharmacodynamic Modeling of Epoetin Alfa in End‐Stage Renal Disease Patients Receiving Maintenance Treatment Using Bayesian Approach

A Physiologically Based Pharmacokinetic Model for Predicting Diazepam Pharmacokinetics after Intravenous, Oral, Intranasal, and Rectal Applications

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