Quantification of CYP3A and Drug Transporters Activity in Healthy Young, Healthy Elderly and Chronic Kidney Disease Elderly Patients by a Microdose Cocktail Approach

Rattanacheeworn, Punyabhorn; Kerr, Stephen J.; Kittanamongkolchai, Wonngarm; Townamchai, Natavudh; Udomkarnjananun, Suwasin; Praditpornsilpa, Kearkiat; Thanusuwannasak, Thanundorn; Udomnilobol, Udomsak; Jianmongkol, Suree; Ongpipattanakul, Boonsri; Prueksaritanont, Thomayant; Avihingsanon, Yingyos; Chariyavilaskul, Pajaree

doi:10.3389/fphar.2021.726669

Cited by 14 publications

(12 citation statements)

References 49 publications

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“…Kirwan et al (2009) reported increased plasma concentrations of midazolam in patients with AKI compared to those in patients with normal kidney function (Kirwan et al, 2009). On the other hand, clinical pharmacokinetic change of midazolam in CKD patients compared with healthy control subjects was not observed or slightly reduced according to several clinical investigations (Nolin et al, 2009;Thomson et al, 2015;Rattanacheeworn et…”

Section: Mechanisms Underlying the Functional Changes In Hepatic Prot...mentioning

confidence: 99%

Emerging Roles of Uremic Toxins and Inflammatory Cytokines in the Alteration of Hepatic Drug Disposition in Patients with Kidney Dysfunction

Arakawa

Kato

2023

Drug Metab Dispos

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Patients with kidney dysfunction exhibit distinct pharmacokinetic profiles compared to those with normal kidney function. Hence, it is desirable to monitor the drug efficacy and toxicity caused by fluctuations in plasma drug concentrations associated with kidney dysfunction. Recently, pharmacokinetic information of drugs excreted mainly through the urine of patients with kidney dysfunction has been reported via drug labeling information. Pharmacokinetic changes in drugs mainly eliminated by the liver cannot be overlooked as drug metabolism and/or transport activity in the liver may also be altered in patients with kidney dysfunction; however, the underlying mechanisms remain unclear. To plan an appropriate dosage regimen, it is necessary to clarify the underlying processes of functional changes in pharmacokinetic proteins. In recent years, uremic toxins have been shown to reduce the activity and/or expression of renal and hepatic transporters.This inhibitory effect has been reported to be time-dependent. In addition, inflammatory cytokines, such as interleukin-6, released from immune cells activated by uremic toxins and/or kidney injury can reduce the expression levels of drug-metabolizing enzymes and transporters in human hepatocytes. In this mini-review, we have summarized the renal and hepatic pharmacokinetic changes as well as the potential underlying mechanisms in kidney dysfunction, such as the chronic kidney disease and acute kidney injury.

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Section: Mechanisms Underlying the Functional Changes In Hepatic Prot...mentioning

confidence: 99%

Emerging Roles of Uremic Toxins and Inflammatory Cytokines in the Alteration of Hepatic Drug Disposition in Patients with Kidney Dysfunction

Arakawa

Kato

2023

Drug Metab Dispos

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“… DDI prediction between DABE and CYP3A/P-gp inhibitors: ITZ (A) , RF (B,C) , CTC (D) , VP concomitantly (E) , and VP 1 h before DABE (F) from Prueksaritanont et al (2017) , Rattanacheeworn et al (2021) , Gouin-Thibault et al (2017) , and Hartter et al (2013) , respectively. Blue circles and blue lines represent the observed and simulated DAB levels for the control phase, respectively.…”

Section: Resultsmentioning

confidence: 99%

Assessing the relative contribution of CYP3A-and P-gp-mediated pathways to the overall disposition and drug-drug interaction of dabigatran etexilate using a comprehensive mechanistic physiological-based pharmacokinetic model

Udomnilobol,

Dunkoksung,

Sakares

et al. 2024

Front. Pharmacol.

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Dabigatran etexilate (DABE) is a clinical probe substrate for studying drug-drug interaction (DDI) through an intestinal P-glycoprotein (P-gp). A recent in vitro study, however, has suggested a potentially significant involvement of CYP3A-mediated oxidative metabolism of DABE and its intermediate monoester BIBR0951 in DDI following microdose administration of DABE. In this study, the relative significance of CYP3A- and P-gp-mediated pathways to the overall disposition of DABE has been explored using mechanistic physiologically based pharmacokinetic (PBPK) modeling approach. The developed PBPK model linked DABE with its 2 intermediate (BIBR0951 and BIBR1087) and active (dabigatran, DAB) metabolites, and with all relevant drug-specific properties known to date included. The model was successfully qualified against several datasets of DABE single/multiple dose pharmacokinetics and DDIs with CYP3A/P-gp inhibitors. Simulations using the qualified model supported that the intestinal CYP3A-mediated oxidation of BIBR0951, and not the gut P-gp-mediated efflux of DABE, was a key contributing factor to an observed difference in the DDI magnitude following the micro-versus therapeutic doses of DABE with clarithromycin. Both the saturable CYP3A-mediated metabolism of BIBR0951 and the solubility-limited DABE absorption contributed to the relatively modest nonlinearity in DAB exposure observed with increasing doses of DABE. Furthermore, the results suggested a limited role of the gut P-gp, but an appreciable, albeit small, contribution of gut CYP3A in mediating the DDIs following the therapeutic dose of DABE with dual CYP3A/P-gp inhibitors. Thus, a possibility exists for a varying extent of CYP3A involvement when using DABE as a clinical probe in the DDI assessment, across DABE dose levels.

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“…It is noteworthy that another two clinical studies showed less impact of renal impairment on rosuvastatin exposure 13,36 . Rattanacheeworn et al 36 .…”

Section: Discussionmentioning

confidence: 99%

“…It is noteworthy that another two clinical studies showed less impact of renal impairment on rosuvastatin exposure. 13,36 Rattanacheeworn et al 36 suggested aging rather than CKD disease effect plays a more important role in rosuvastatin PK. However, other studies reported no association between aging and rosuvastatin exposure.…”

Section: Discussionmentioning

confidence: 99%

Understanding Statin‐Roxadustat Drug–Drug‐Disease Interaction Using Physiologically‐Based Pharmacokinetic Modeling

Dong

Garcia

Huang

et al. 2023

Clin Pharma and Therapeutics

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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.

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Quantification of CYP3A and Drug Transporters Activity in Healthy Young, Healthy Elderly and Chronic Kidney Disease Elderly Patients by a Microdose Cocktail Approach

Cited by 14 publications

References 49 publications

Emerging Roles of Uremic Toxins and Inflammatory Cytokines in the Alteration of Hepatic Drug Disposition in Patients with Kidney Dysfunction

Emerging Roles of Uremic Toxins and Inflammatory Cytokines in the Alteration of Hepatic Drug Disposition in Patients with Kidney Dysfunction

Assessing the relative contribution of CYP3A-and P-gp-mediated pathways to the overall disposition and drug-drug interaction of dabigatran etexilate using a comprehensive mechanistic physiological-based pharmacokinetic model

Understanding Statin‐Roxadustat Drug–Drug‐Disease Interaction Using Physiologically‐Based Pharmacokinetic Modeling

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