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Understanding Stati...
Understanding Statin-Roxadustat Drug–Drug-Disease Interaction Using Physiologically-Based Pharmacokinetic Modeling
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- Dong, Jin (author)
- Clinical Pharmacology and Quantitative Pharmacology, Clinical Pharmacology and Safety Sciences, R&D, AstraZeneca Gaithersburg Maryland USA
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- Garcia, Luna Prieto, 1988- (author)
- Uppsala universitet,Institutionen för farmaceutisk biovetenskap,Drug Metabolism and Pharmacokinetics, Research and Early Development Cardiovascular, Renal and Metabolism, BioPharmaceuticals, R&D, AstraZeneca Gothenburg Sweden,Translational Drug Discovery and Development
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- Huang, Yingbo (author)
- Department of Experimental and Clinical Pharmacology University of Minnesota Minneapolis Minnesota USA
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- Tang, Weifeng (author)
- Clinical Pharmacology and Quantitative Pharmacology, Clinical Pharmacology and Safety Sciences, R&D, AstraZeneca Gaithersburg Maryland USA
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- Lundahl, Anna (author)
- Drug Metabolism and Pharmacokinetics, Research and Early Development Cardiovascular, Renal and Metabolism, BioPharmaceuticals, R&D, AstraZeneca Gothenburg Sweden;Clinical Pharmacology and Quantitative Pharmacology, Clinical Pharmacology and Safety Sciences, R&D, AstraZeneca Gothenburg Sweden
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- Elebring, Marie (author)
- Drug Metabolism and Pharmacokinetics, Research and Early Development Cardiovascular, Renal and Metabolism, BioPharmaceuticals, R&D, AstraZeneca Gothenburg Sweden
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- Ahlström, Christine (author)
- Drug Metabolism and Pharmacokinetics, Research and Early Development Cardiovascular, Renal and Metabolism, BioPharmaceuticals, R&D, AstraZeneca Gothenburg Sweden
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- Vildhede, Anna (author)
- Drug Metabolism and Pharmacokinetics, Research and Early Development Cardiovascular, Renal and Metabolism, BioPharmaceuticals, R&D, AstraZeneca Gothenburg Sweden
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- Sjögren, Erik, 1977- (author)
- Uppsala universitet,Institutionen för farmaceutisk biovetenskap,Translational Drug Discovery and Development
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- Någård, Mats (author)
- Clinical Pharmacology and Quantitative Pharmacology, Clinical Pharmacology and Safety Sciences, R&D, AstraZeneca Gaithersburg Maryland USA
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(creator_code:org_t)
- John Wiley & Sons, 2023
- 2023
- English.
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In: Clinical Pharmacology and Therapeutics. - : John Wiley & Sons. - 0009-9236 .- 1532-6535. ; 114:4, s. 825-835
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Abstract
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- A different drug–drug interaction (DDI) scenario may exist in patients with chronic kidney disease (CKD) compared with healthy volunteers (HVs), depending on the interplay between drug–drug and disease (drug-drug-disease interaction (DDDI)). Physiologically-based pharmacokinetic (PBPK) modeling, in lieu of a clinical trial, is a promising tool for evaluating these complex DDDIs in patients. However, the prediction confidence of PBPK modeling in the severe CKD population is still low when nonrenal pathways are involved. More mechanistic virtual disease population and robust validation cases are needed. To this end, we aimed to: (i) understand the implications of severe CKD on statins (atorvastatin, simvastatin, and rosuvastatin) pharmacokinetics (PK) and DDI; and (ii) predict untested clinical scenarios of statin-roxadustat DDI risks in patients to guide suitable dose regimens. A novel virtual severe CKD population was developed incorporating the disease effect on both renal and nonrenal pathways. Drug and disease PBPK models underwent a four-way validation. The verified PBPK models successfully predicted the altered PKs in patients for substrates and inhibitors and recovered the observed statin-rifampicin DDIs in patients and the statin-roxadustat DDIs in HVs within 1.25- and 2-fold error. Further sensitivity analysis revealed that the severe CKD effect on statins PK is mainly mediated by hepatic BCRP for rosuvastatin and OATP1B1/3 for atorvastatin. The magnitude of statin-roxadustat DDI in patients with severe CKD was predicted to be similar to that in HVs. PBPK-guided suitable dose regimens were identified to minimize the risk of side effects or therapeutic failure of statins when co-administered with roxadustat.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Farmaceutiska vetenskaper (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Pharmaceutical Sciences (hsv//eng)
Keyword
- Farmakokinetik och läkemedelsterapi
- Pharmacokinetics and Drug Therapy
Publication and Content Type
- ref (subject category)
- art (subject category)
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- By the author/editor
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Dong, Jin
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Garcia, Luna Pri ...
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Huang, Yingbo
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Tang, Weifeng
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Lundahl, Anna
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Elebring, Marie
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Ahlström, Christ ...
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Vildhede, Anna
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Sjögren, Erik, 1 ...
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Någård, Mats
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- About the subject
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Basic Medicine
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and Pharmaceutical S ...
- Articles in the publication
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Clinical Pharmac ...
- By the university
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Uppsala University