A whole body physiologically based pharmacokinetic model for the distribution of barbiturates in rats

Nestorov, Ivan; Blakey, Graham; Arundel, Philip A.; Aarons, Leon; Rowland, M.

doi:10.1016/s0928-0987(97)86266-5

Cited by 5 publications

(18 citation statements)

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“…The first method followed Nestorov's lumping principles for PBPK models 6 . This is consistent with other minimal PBPK models, which reduce the number of compartments to a few compartments with comparable blood flow rates 38,39 .…”

Section: Discussionsupporting

confidence: 54%

“…For the three‐compartment PBPK model, the lungs, venous, and arterial (serial tissues) compartments were lumped as one “central” compartment because they have similar and low time constants (Table 1). 6 …”

Section: Methodsmentioning

confidence: 99%

“…Formal or proper lumping is a method of model reduction, where each state of the original model contributes to only one state of the reduced system. 6 Tissues with identical structural positions and similar kinetic properties are lumped together. The reduced model with lumped compartments retains the kinetic behavior of the original model, and the associated parameters maintain their meaning.…”

Section: Introductionmentioning

confidence: 99%

“…[7][8][9][10][11][12] To lump parallel tissues, they should have similar time constants. 6 Additional model reduction approaches have been suggested for reducing PBPK models. 13,14 However, kinetic lumping approaches are typically tailor-made for each new compound as they are generally only valid locally for a specific set of parameter values.…”

Section: Introductionmentioning

confidence: 99%

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Investigation of simplified physiologically‐based pharmacokinetic models in rat and human

Yau

Olivares‐Morales

Ogungbenro

et al. 2023

CPT Pharmacom & Syst Pharma

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Whole-body physiologically-based pharmacokinetic (PBPK) models have many applications in drug research and development. It is often necessary to inform these models with animal or clinical data, updating model parameters, and making the model more predictive for future applications. This provides an opportunity and a challenge given the large number of parameters of such models. The aim of this work was to propose new mechanistic model structures with reduced complexity allowing for parameter optimization. These models were evaluated for their ability to estimate realistic values for unbound tissue to plasma partition coefficients (Kpu) and simulate observed pharmacokinetic (PK) data. Two approaches are presented: using either established kinetic lumping methods based on tissue time constants (drug-dependent) or a novel clustering analysis to identify tissues sharing common Kpu values or Kpu scalars based on similarities of tissue composition (drug-independent). PBPK models derived from these approaches were assessed using PK data of diazepam in rats and humans. Although the clustering analysis produced minor differences in tissue grouping depending on the method used, two larger groups of tissues emerged. One including the kidneys, liver, spleen, gut, heart, and lungs, and another including bone, brain, muscle, and pancreas whereas adipose and skin were generally considered distinct. Overall, a subdivision into four tissue groups appeared most physiologically relevant in terms of tissue composition. Several models were found to have similar abilities to describe diazepam i.v. data as empirical models. Comparability of estimated Kpus to experimental Kpu values for diazepam was one criterion for selecting the appropriate PK model structure. Study Highlights WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?Empirical models are frequently used to describe pharmacokinetic (PK) data but may have limited predictive utility (lack of physiological mechanisms). Wholebody physiologically-based PK (PBPK) models are particularly suited to integrateThis is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

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Section: Discussionsupporting

confidence: 54%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Investigation of simplified physiologically‐based pharmacokinetic models in rat and human

Yau

Olivares‐Morales

Ogungbenro

et al. 2023

CPT Pharmacom & Syst Pharma

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“…Organ lumping has been enacted to reduce the complexity of PBPK models. 7 Minimal PBPK (mPBPK) models offer a consolidation approach where only two or three groups of organs and tissues represent the whole body. 8 Blood flow through the grouped organs is partitioned using fractions of the cardiac output, and organ weights/volumes add up to the body mass.…”

Section: Introductionmentioning

confidence: 99%

Minimal physiologically‐based hybrid model of pharmacokinetics in pregnant women: Application to antenatal corticosteroids

Krzyzanski

Milad²,

Jobe

et al. 2023

CPT Pharmacom & Syst Pharma

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Minimal physiologically‐based pharmacokinetic (mPBPK) models are an alternative to full physiologically‐based pharmacokinetic (PBPK) models as they offer reduced complexity while maintaining the physiological interpretation of key model components. Full PBPK models have been developed for pregnancy, but a mPBPK model eases the ability to perform a “top‐down” meta‐analysis melding all available pharmacokinetic (PK) data in the mother and fetus. Our hybrid mPBPK model consists of mPBPK models for the mother and fetus with connection by the placenta. This model was applied to describe the rich PK data of antenatal corticosteroid betamethasone (BET) jointly with the limited data for dexamethasone (DEX) in the mother and fetus. Physiologic model parameters were obtained from the literature while drug‐dependent parameters were estimated by the simultaneous fitting of all available data for DEX and BET. Maternal clearances of DEX and BET confirmed the literature values, and the expected fetal‐to‐maternal plasma ratios ranged from 0.3 to 0.4 for both drugs. Simulations of maternal plasma concentrations for the dosing regimens of BET and DEX recommended by the World Health Organization based on our findings revealed up to 60% lower exposures than found in nonpregnant women and offers a means of devising alternative dosing regimens. Our hybrid mPBPK model and meta‐analysis approach could facilitate assessment of other classes of drugs indicated for the treatment of pregnant women.

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Development of a Generic Physiologically‐Based Pharmacokinetic Model for Lactation and Prediction of Maternal and Infant Exposure to Ondansetron via Breast Milk

Job

Dallmann

Parry

et al. 2022

Clin Pharma and Therapeutics

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Ondansetron is commonly used in breastfeeding mothers to treat nausea and vomiting. There is limited information in humans regarding safety of ondansetron exposure to nursing infants and no adequate study looking at ondansetron pharmacokinetics during lactation. We developed a generic physiologically‐based pharmacokinetic lactation model for small molecule drugs and applied this model to predict ondansetron transfer into breast milk and characterize infant exposure. Drug‐specific model inputs were parameterized using data from the literature. Population‐specific inputs were derived from a previously conducted systematic literature review of anatomic and physiologic changes in postpartum women. Model predictions were evaluated using ondansetron plasma and breast milk concentration data collected prospectively from 78 women in the Commonly Used Drugs During Lactation and infant Exposure (CUDDLE) study. The final model predicted breast milk and plasma exposures following a single 4 mg dose of intravenous ondansetron in 1,000 simulated women who were 2 days postpartum. Model predictions showed good agreement with observed data. Breast milk median prediction error (MPE) was 18.4% and median absolute prediction error (MAPE) was 53.0%. Plasma MPE was 32.5% and MAPE was 43.2%. The model‐predicted daily and relative infant doses were 0.005 mg/kg/day and 3.0%, respectively. This model adequately predicted ondansetron passage into breast milk. The calculated low relative infant dose indicates that mothers receiving ondansetron can safely breastfeed. The model building blocks and population database are open‐source and can be adapted to other drugs.

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A whole body physiologically based pharmacokinetic model for the distribution of barbiturates in rats

Cited by 5 publications

References 0 publications

Investigation of simplified physiologically‐based pharmacokinetic models in rat and human

Investigation of simplified physiologically‐based pharmacokinetic models in rat and human

Minimal physiologically‐based hybrid model of pharmacokinetics in pregnant women: Application to antenatal corticosteroids

Development of a Generic Physiologically‐Based Pharmacokinetic Model for Lactation and Prediction of Maternal and Infant Exposure to Ondansetron via Breast Milk

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