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A microfluidic system that replicates pharmacokinetic (PK) profiles in vitro improves prediction of in vivo efficacy in preclinical models.

ABSTRACT: Test compounds used on in vitro model systems are conventionally delivered to cell culture wells as fixed concentration bolus doses; however, this poorly replicates the pharmacokinetic (PK) concentration changes seen in vivo and reduces the predictive value of the data. Herein, proof-of-concept experiments were performed using a novel microfluidic device, the Microformulator, which allows in vivo like PK profiles to be applied to cells cultured in microtiter plates and facilitates the investigation of the impact of PK on biological responses. We demonstrate the utility of the device in its ability to reproduce in vivo PK profiles of different oncology compounds over multiweek experiments, both as monotherapy and drug combinations, comparing the effects on tumour cell efficacy in vitro with efficacy seen in in vivo xenograft models. In the first example, an ERK1/2 inhibitor was tested using fixed bolus dosing and Microformulator-replicated PK profiles, in 2 cell lines with different in vivo sensitivities. The Microformulator-replicated PK profiles were able to discriminate between cell line sensitivities, unlike the conventional fixed bolus dosing. In a second study, murine in vivo PK profiles of multiple Poly(ADP-Ribose) Polymerase 1/2 (PARP) and DNA-dependent protein kinase (DNA-PK) inhibitor combinations were replicated in a FaDu cell line resulting in a reduction in cell growth in vitro with similar rank ordering to the in vivo xenograft model. Additional PK/efficacy insight into theoretical changes to drug exposure profiles was gained by using the Microformulator to expose FaDu cells to the DNA-PK inhibitor for different target coverage levels and periods of time. We demonstrate that the Microformulator enables incorporating PK exposures into cellular assays to improve in vitro-in vivo translation understanding for early therapeutic insight.

SUBMITTER: Singh D

PROVIDER: S-EPMC9135222 | biostudies-literature | 2022 May

REPOSITORIES: biostudies-literature

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A microfluidic system that replicates pharmacokinetic (PK) profiles in vitro improves prediction of in vivo efficacy in preclinical models.

Singh Dharaminder D Deosarkar Sudhir P SP Cadogan Elaine E Flemington Vikki V Bray Alysha A Zhang Jingwen J Reiserer Ronald S RS Schaffer David K DK Gerken Gregory B GB Britt Clayton M CM Werner Erik M EM Gibbons Francis D FD Kostrzewski Tomasz T Chambers Christopher E CE Davies Emma J EJ Montoya Antonio Ramos AR Fok Jacqueline H L JHL Hughes David D Fabre Kristin K Wagoner Matthew P MP Wikswo John P JP Scott Clay W CW

PLoS biology 20220526 5

Test compounds used on in vitro model systems are conventionally delivered to cell culture wells as fixed concentration bolus doses; however, this poorly replicates the pharmacokinetic (PK) concentration changes seen in vivo and reduces the predictive value of the data. Herein, proof-of-concept experiments were performed using a novel microfluidic device, the Microformulator, which allows in vivo like PK profiles to be applied to cells cultured in microtiter plates and facilitates the investigat ...[more]

PMID: 35617197

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Project description:Pasteurella multocida can invade and translocate through endothelial cells and result in vascular-system infection, which can cause severe economic losses in the poultry industry. Antibacterial therapy (especially florfenicol) plays an important part in controlling P. multocida infection. To preserve the effect of florfenicol, in vivo pharmacokinetic/pharmacodynamic (PK/PD) modeling of florfenicol against three P. multocida strains in duck was established. Then, the efficacy of the currently marketed dose, a rational dosage regimen for populations, and the PK/PD cutoff were predicted through Monte Carlo simulations (MCSs). The area under the concentration-time curve from 0 to 24 h/minimum inhibitory concentration (AUC0-24 h /MIC) was the optimal PK/PD parameter. The PK/PD surrogate values of florfenicol against P. multocida were similar using different organs as the PD target, but varied in different strains. For the florfenicol-sensitive strain 0825Y1, when the AUC0-24 h /MIC reached 117.54 and 108.19, florfenicol showed a bactericidal effect in the liver and lung, respectively. For the florfenicol-sensitive strain 0901J1, the corresponding value was 78.39 and 54.30, respectively. For the florfenicol-resistant strain JY160110, florfenicol could attain a maximum effect of 1 - log10 reduction in bacteria in the liver and lung when the AUC0-24 h /MIC reached 2.03 and 2.06, respectively. The PK/PD-based prediction for the population dose indicated a poor effect for the low end of the currently marketed dose (40 mg/kg body weight per day), but a robust effect for the high end of the currently marketed dose (60 mg/kg body weight per day) with a target attainment rate of 92.79% and 81.44% against P. multocida in mainland China and worldwide, respectively. The recommended dose optimized by MCSs was 52 mg/kg body weight in mainland China. The PK/PD cutoff of florfenicol against P. multocida at the low end and high end of the current daily dose (40 and 60 mg/kg body weight) and predicted daily dose in mainland China (52 mg/kg body weight) was 0.25, 4, and 0.5 μg/ml, respectively. These results suggested that more than one strain should be involved for PK/PD modeling and contributed to rational use of florfenicol in populations. We also provided fundamental data for determination of florfenicol breakpoints in poultry.

Dataset Information

A microfluidic system that replicates pharmacokinetic (PK) profiles in vitro improves prediction of in vivo efficacy in preclinical models.

Publications

A microfluidic system that replicates pharmacokinetic (PK) profiles in vitro improves prediction of in vivo efficacy in preclinical models.

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