Prediction of pharmacokinetic clearance and potential Drug-Drug interactions for omeprazole in the horse using<i>in vitro</i>systems

Shibany, Khaled A.; Pratt, Stefanie; Aldurdunji, Mohammed M.; Tötemeyer, Sabine; Paine, Stuart W.

doi:10.1080/00498254.2020.1764131

Cited by 4 publications

(3 citation statements)

References 27 publications

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“…As such, the half-life appears longer in the current study; and as the clearance is higher than in horses, it can be hypothesized that the longer half-life is related to a larger V d in donkeys. In vitro investigations could also be carried out to study donkeys' organ metabolism functions as done in horses [33].…”

Section: Discussionmentioning

confidence: 99%

Nonlinear Mixed-Effect Pharmacokinetic Modeling and Distribution of Doxycycline in Healthy Female Donkeys after Multiple Intragastric Dosing–Preliminary Investigation

Chapuis

Smith

French

et al. 2021

Animals

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Doxycycline (DXC) is a broad-spectrum antibacterial antimicrobial administered to horses for the treatment of bacterial infections which may also affect donkeys. Donkeys have a different metabolism than horses, leading to differences in the pharmacokinetics of drugs compared to horses. This study aimed to describe the population pharmacokinetics of DXC in donkeys. Five doses of DXC hyclate (10 mg/kg) were administered via a nasogastric tube, q12 h, to eight non-fasted, healthy, adult jennies. Serum, urine, synovial fluid and endometrium were collected for 72 h following the first administration. Doxycycline concentration was measured by competitive enzyme immunoassay. Serum concentrations versus time data were fitted simultaneously using the stochastic approximation expectation-maximization algorithm for nonlinear mixed effects. A one-compartment model with linear elimination and first-order absorption after intragastric administration, best described the available pharmacokinetic data. Final parameter estimates indicate that DXC has a high volume of distribution (108 L/kg) as well as high absorption (10.3 h−1) in donkeys. However, results suggest that oral DXC at 10 mg/kg q12 h in donkeys would not result in a therapeutic concentration in serum, urine, synovial fluid or endometrium by comparison to the minimum inhibitory concentration of common equine pathogens. Further studies are recommended to identify appropriate dosage and dosing intervals of oral DXC in donkeys.

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Section: Discussionmentioning

confidence: 99%

Nonlinear Mixed-Effect Pharmacokinetic Modeling and Distribution of Doxycycline in Healthy Female Donkeys after Multiple Intragastric Dosing–Preliminary Investigation

Chapuis

Smith

French

et al. 2021

Animals

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“…There is ample evidence that in vitro-in vivo differences in hepatocyte heterogeneity contribute significantly to IVIVE prediction discrepancies [3,4,30,31], yet the vCulture and vHuman experiments employed only homogeneous vHPCs. In doing so, we provide the necessary and essential foundation for future research that is needed to explore vCulture-vHuman differences caused by vHPC heterogeneity.…”

Section: Plos Onementioning

confidence: 99%

Utilizing virtual experiments to increase understanding of discrepancies involving in vitro-to-in vivo predictions of hepatic clearance

Krishnan

Smith²,

Ropella³

et al. 2022

PLoS ONE

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Predictions of xenobiotic hepatic clearance in humans using in vitro-to-in vivo extrapolation methods are frequently inaccurate and problematic. Multiple strategies are being pursued to disentangle responsible mechanisms. The objective of this work is to evaluate the feasibility of using insights gained from independent virtual experiments on two model systems to begin unraveling responsible mechanisms. The virtual culture is a software analog of hepatocytes in vitro, and the virtual human maps to hepatocytes within a liver within an idealized model human. Mobile objects (virtual compounds) map to amounts of xenobiotics. Earlier versions of the two systems achieved quantitative validation targets for intrinsic clearance (virtual culture) and hepatic clearance (virtual human). The major difference between the two systems is the spatial organization of the virtual hepatocytes. For each pair of experiments (virtual culture, virtual human), hepatocytes are configured the same. Probabilistic rules govern virtual compound movements and interactions with other objects. We focus on highly permeable virtual compounds and fix their extracellular unbound fraction at one of seven values (0.05–1.0). Hepatocytes contain objects that can bind and remove compounds, analogous to metabolism. We require that, for a subset of compound properties, per-hepatocyte compound exposure and removal rates during culture experiments directly predict corresponding measures made during virtual human experiments. That requirement serves as a cross-system validation target; we identify compound properties that enable achieving it. We then change compound properties, ceteris paribus, and provide model mechanism-based explanations for when and why measures made during culture experiments under- (or over-) predict corresponding measures made during virtual human experiments. The results show that, from the perspective of compound removal, the organization of hepatocytes within virtual livers is more efficient than within cultures, and the greater the efficiency difference, the larger the underprediction. That relationship is noteworthy because most in vitro-to-in vivo extrapolation methods abstract away the structural organization of hepatocytes within a liver. More work is needed on multiple fronts, including the study of an expanded variety of virtual compound properties. Nevertheless, the results support the feasibility of the approach and plan.

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“…There is ample evidence that in vitro-in vivo differences in hepatocyte heterogeneity contribute significantly to IVIVE prediction discrepancies [3,4,30,31], yet the vCulture and vHuman experiments employed only homogeneous vHPCs. This work provides the necessary and essential foundation for future research that is needed to explore in vitro-in vivo differences in vCompound Entry and removal rates caused by vHPC heterogeneity.…”

Section: Achieving and Failing To Achieve The Cross-system Validation Target Using Vcompound-2mentioning

confidence: 99%

Utilizing virtual experiments to increase understanding of discrepancies involving in vitro-in vivo predictions of hepatic clearance

Krishnan¹,

Smith²,

Ropella

et al. 2020

Preprint

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We demonstrate how results of virtual experiments can suggest mechanism-based explanations for IVIVE underpredictions of hepatic clearance. We use agent-oriented, discrete-event methods. We experiment on software analogies of rats and hepatocyte cultures dosed identically with objects that mimic two idealized compounds, vC1 (not cleared) and vC2 (removal maximized). Hepatocytes in cultures and rat livers interact identically with vC1 and vC2. The rules governing vC1 and vC2 movements and interactions with hepatocytes are the same in both systems. The two software systems are independent; to be useful in discovering plausible explanations of IVIVE inaccuracies, we require that, in the absence of hepatocyte exposure differences, the culture-to-rat scaling factor = 1.0 for all corresponding measures. The probability of cell entry (pEnter) maps directly to the unbound-fraction of drug used by IVIVE methods. For vC1 (vC2), we achieve that validation target for pEnter = 0.05-1.0 (1.0). However, for pEnter = 0.05-0.8, vC2 removal rates during culture experiments underpredicted corresponding removal rates in rats. The magnitude of the underpredictions increases with decreasing pEnter. For example, using pEnter = 0.1 (0.3), peak vC2 removal rates in culture experiments underpredict corresponding removal rates in rats by 3.2 (1.4) fold. Underpredictions are a consequence of the biomimetic periportal-to-pericentral organization of hepatocytes within virtual livers are absent in virtual cultures. In rats, pericentral hepatocytes do more of the vC2 removal work. The results suggest that using IVIVE methods that abstract away influential features of hepatocyte organization within livers may contribute to IVIVE underpredictions.Significance StatementFrom experiments on virtual (software) counterparts of rats and hepatocyte cultures, we learned that IVIVE underpredictions are a consequence of the biomimetic periportal-to-pericentral organization of hepatocytes within virtual livers being absent in virtual cultures. Using IVIVE methods that abstract away influential features of hepatocyte organization within livers may contribute in part to some IVIVE underpredictions.Visual Abstract

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Prediction of pharmacokinetic clearance and potential Drug-Drug interactions for omeprazole in the horse usingin vitrosystems

Cited by 4 publications

References 27 publications

Nonlinear Mixed-Effect Pharmacokinetic Modeling and Distribution of Doxycycline in Healthy Female Donkeys after Multiple Intragastric Dosing–Preliminary Investigation

Nonlinear Mixed-Effect Pharmacokinetic Modeling and Distribution of Doxycycline in Healthy Female Donkeys after Multiple Intragastric Dosing–Preliminary Investigation

Utilizing virtual experiments to increase understanding of discrepancies involving in vitro-to-in vivo predictions of hepatic clearance

Utilizing virtual experiments to increase understanding of discrepancies involving in vitro-in vivo predictions of hepatic clearance

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