Dataset Information

Towards quantitation of the effects of renal impairment and probenecid inhibition on kidney uptake and efflux transporters, using physiologically based pharmacokinetic modelling and simulations.

ABSTRACT:

Background and objectives

The kidney is a major drug-eliminating organ. Renal impairment or concomitant use of transporter inhibitors may decrease active secretion and increase exposure to a drug that is a substrate of kidney secretory transporters. However, prediction of the effects of patient factors on kidney transporters remains challenging because of the multiplicity of transporters and the lack of understanding of their abundance and specificity. The objective of this study was to use physiologically based pharmacokinetic (PBPK) modelling to evaluate the effects of patient factors on kidney transporters.

Methods

Models for three renally cleared drugs (oseltamivir carboxylate, cidofovir and cefuroxime) were developed using a general PBPK platform, with the contributions of net basolateral uptake transport (T up,b) and apical efflux transport (T eff,a) being specifically defined.

Results and conclusion

We demonstrated the practical use of PBPK models to: (1) define transporter-mediated renal secretion, using plasma and urine data; (2) inform a change in the system-dependent parameter (?10-fold reduction in the functional 'proximal tubule cells per gram kidney') in severe renal impairment that is responsible for the decreased secretory transport activities of test drugs; (3) derive an in vivo, plasma unbound inhibition constant of T up,b by probenecid (?1 ?M), based on observed drug interaction data; and (4) suggest a plausible mechanism of probenecid preferentially inhibiting T up,b in order to alleviate cidofovir-induced nephrotoxicity.

SUBMITTER: Hsu V

PROVIDER: S-EPMC3927056 | biostudies-literature | 2014 Mar

REPOSITORIES: biostudies-literature

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Publications

Towards quantitation of the effects of renal impairment and probenecid inhibition on kidney uptake and efflux transporters, using physiologically based pharmacokinetic modelling and simulations.

Hsu Vicky V de L T Vieira Manuela M Zhao Ping P Zhang Lei L Zheng Jenny Huimin JH Nordmark Anna A Berglund Eva Gil EG Giacomini Kathleen M KM Huang Shiew-Mei SM

Clinical pharmacokinetics 20140301 3

<h4>Background and objectives</h4>The kidney is a major drug-eliminating organ. Renal impairment or concomitant use of transporter inhibitors may decrease active secretion and increase exposure to a drug that is a substrate of kidney secretory transporters. However, prediction of the effects of patient factors on kidney transporters remains challenging because of the multiplicity of transporters and the lack of understanding of their abundance and specificity. The objective of this study was to ...[more]

PMID: 24214317

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Project description:Plasma concentration of vitamin D3 metabolite 25-hydroxyvitamin D3 (25(OH)D3 ) is variable among individuals. The objective of this study is to establish an accurate model for 25(OH)D3 pharmacokinetics (PKs) to support selection of a suitable dose regimen for an individual. We collated vitamin D3 and 25(OH)D3 plasma PK data from reported clinical trials and developed a physiologically-based pharmacokinetic (PBPK) model to appropriately recapitulate training data. Model predictions were then qualified with 25(OH)D3 plasma PKs under vitamin D3 and 25(OH)D3 dose regimens distinct from training data. From data exploration, we observed the increase in plasma 25(OH)D3 after repeated dosing was negatively correlated with 25(OH)D3 baseline levels. Our final model included a first-order vitamin D3 absorption, a first-order vitamin D3 metabolism, and a nonlinear 25(OH)D3 elimination function. This structure explained the apparent paradox. Remarkably, the model accurately predicted plasma 25(OH)D3 following repeated dosing up to 1250 μg/d in the test set. It also made sensible predictions for large single vitamin D3 doses up to 50,000 μg in the test set. Model predicts 10 μg/d regimen may be ineffective for achieving sufficiency (plasma 25(OH)D3 ≥ 75 nmol/L) for a severely deficient individual (baseline 25(OH)D3 = 10 nmol/L), and it might take the same person over 200 days to reach sufficiency at 20 μg/d dose. We propose to personalize vitamin D3 supplementation protocol with this PBPK model. It would require measuring 25(OH)D3 baseline levels, which is not routinely performed under the current UK public health advice. STUDY HIGHLIGHTS: WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC? Vitamin D PK exhibits substantial inter-individual variability. Different officially recommended daily doses are confusing. WHAT QUESTION DID THIS STUDY ADDRESS? Is the UK's recommended 10 µg daily dose sufficient? Should everyone be given same dose? WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE? Our model accurately predicts plasma 25(OH)D under daily oral administration of vitamin D3 . The 10 µg daily vitamin D3 dose is insufficient for prophylaxis (plasma 25(OH)D at 75 nmol/L). HOW MIGHT THIS CHANGE DRUG DISCOVERY, DEVELOPMENT, AND/OR THERAPEUTICS? Combining blood test to measure 25(OH)D baseline with this PBPK model will help inform dosage selection and select follow-up date to improve effectiveness of Hypovitaminosis D treatment.

Dataset Information

Towards quantitation of the effects of renal impairment and probenecid inhibition on kidney uptake and efflux transporters, using physiologically based pharmacokinetic modelling and simulations.

Background and objectives

Methods

Results and conclusion

Publications

Towards quantitation of the effects of renal impairment and probenecid inhibition on kidney uptake and efflux transporters, using physiologically based pharmacokinetic modelling and simulations.

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