The Use of Transporter Probe Drug Cocktails for the Assessment of Transporter-Based Drug–Drug Interactions in a Clinical Setting—Proposal of a Four Component Transporter Cocktail

Ebner, Thomas; Ishiguro, Naoki; Taub, Mitchell E.

doi:10.1002/jps.24489

Cited by 60 publications

(59 citation statements)

References 50 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…used this combination to evaluate the inhibition potential of ravuconazole, the active form of the new antifungal drug fosravuconazole, for P‐gp, BCRP, OATP1B1, and OATP1B3, although they recognized the combination had not been validated clinically. Their basis for using of this combination was the clinical evidence that rosuvastatin does not affect the PK of digoxin and the in vitro evidences that suggested digoxin does not affect the PK of rosuvastatin . Our study results provide the clinical evidence to support the methods used in the Ishii et al .…”

Section: Discussionsupporting

confidence: 63%

“…A report has suggested the DDI between digoxin and rosuvastatin is unlikely, considering in vitro inhibitory effects and in vivo concentrations of digoxin and rosuvastatin at DDI site. 13 In addition, two in vitro studies have reported digoxin is not a substrate of BCRP, 14 OATP1B1, nor OATP1B3. 15 Therefore, the combination of digoxin and rosuvastatin has a potential to be used as a transporter probe cocktail in clinical DDI studies.…”

Section: No Effect Of Digoxin On Rosuvastatin Pkmentioning

confidence: 99%

“…Although there is no clinical study report that shows digoxin does not affect the PK of rosuvastatin, there are some pieces of supportive information to suggest lack of effect of digoxin on the PK of rosuvastatin. A report has suggested the DDI between digoxin and rosuvastatin is unlikely, considering in vitro inhibitory effects and in vivo concentrations of digoxin and rosuvastatin at DDI site . In addition, two in vitro studies have reported digoxin is not a substrate of BCRP, OATP1B1, nor OATP1B3 .…”

mentioning

confidence: 99%

See 2 more Smart Citations

No Effect of Digoxin on Rosuvastatin Pharmacokinetics in Healthy Subjects: Utility of Oita Combination for Clinical Drug–Drug Interaction Study

Otani

Wakuda

Imai

et al. 2019

Clinical Translational Sci

View full text Add to dashboard Cite

This study evaluated the utility of combination of digoxin (0.25 mg) and rosuvastatin (5 mg) as a new transporter (P‐glycoprotein/breast cancer resistance protein/organic anion‐transporting polypeptide (OATP)1B1/OATP1B3) probe cocktail (Oita combination) for drug–drug interaction (DDI) studies by demonstrating lack of DDI of digoxin on the pharmacokinetics (PKs) of rosuvastatin, as it was already known that rosuvastatin did not affect digoxin PK. This was an open‐label, two‐period study in which the primary end points were the geometric mean ratio (GMR) of the area under the plasma rosuvastatin concentration‐time curve from time zero to last (AUC last) after rosuvastatin administration combined with digoxin to that after rosuvastatin administration alone and its 90% confidence interval (CI). As the GMR of AUC last was 0.974 and its 90% CI was 0.911–1.042, it was judged that digoxin does not affect rosuvastatin PK. Results of this study have rationalized utility of the Oita combination as a transporter probe cocktail for clinical DDI studies.

show abstract

Section: Discussionsupporting

confidence: 63%

Section: No Effect Of Digoxin On Rosuvastatin Pkmentioning

confidence: 99%

mentioning

confidence: 99%

See 1 more Smart Citation

No Effect of Digoxin on Rosuvastatin Pharmacokinetics in Healthy Subjects: Utility of Oita Combination for Clinical Drug–Drug Interaction Study

Otani

Wakuda

Imai

et al. 2019

Clinical Translational Sci

View full text Add to dashboard Cite

show abstract

“…Moreover, a comprehensive update on the corresponding genotype/phenotype database was published last year . Meanwhile, rosuvastatin has been highlighted as a probe compound of choice for prospective clinical studies of OATP1B1‐ and OATP1B3‐associated drug interactions because it is relatively well tolerated in patients and not significantly metabolized (in contrast to simvastatin) such that observed interactions result solely from inhibition of transporters …”

Section: Oatp1b1 Phenotype Information Included As Systems Parametersmentioning

confidence: 99%

More Power to OATP1B1: An Evaluation of Sample Size in Pharmacogenetic Studies Using a Rosuvastatin PBPK Model for Intestinal, Hepatic, and Renal Transporter‐Mediated Clearances

Riedmaier

Burt

Abduljalil

2016

The Journal of Clinical Pharma

View full text Add to dashboard Cite

Rosuvastatin is a substrate of choice in clinical studies of organic anion‐transporting polypeptide (OATP)1B1‐ and OATP1B3‐associated drug interactions; thus, understanding the effect of OATP1B1 polymorphisms on the pharmacokinetics of rosuvastatin is crucial. Here, physiologically based pharmacokinetic (PBPK) modeling was coupled with a power calculation algorithm to evaluate the influence of sample size on the ability to detect an effect (80% power) of OATP1B1 phenotype on pharmacokinetics of rosuvastatin. Intestinal, hepatic, and renal transporters were mechanistically incorporated into a rosuvastatin PBPK model using permeability‐limited models for intestine, liver, and kidney, respectively, nested within a full PBPK model. Simulated plasma rosuvastatin concentrations in healthy volunteers were in agreement with previously reported clinical data. Power calculations were used to determine the influence of sample size on study power while accounting for OATP1B1 haplotype frequency and abundance in addition to its correlation with OATP1B3 abundance. It was determined that 10 poor‐transporter and 45 intermediate‐transporter individuals are required to achieve 80% power to discriminate the AUC0‐48h of rosuvastatin from that of the extensive‐transporter phenotype. This number was reduced to 7 poor‐transporter and 40 intermediate‐transporter individuals when the reported correlation between OATP1B1 and 1B3 abundance was taken into account. The current study represents the first example in which PBPK modeling in conjunction with power analysis has been used to investigate sample size in clinical studies of OATP1B1 polymorphisms. This approach highlights the influence of interindividual variability and correlation of transporter abundance on study power and should allow more informed decision making in pharmacogenomic study design.

show abstract

“…Another group recently proposed a 4‐probe transporter cocktail for the assessment of transporter‐based drug–drug interactions in humans based on in vitro data. Oral digoxin 0.25 mg (P‐gp), oral rosuvastatin 10 mg (BCRP and OATP), oral furosemide 5 mg (OAT), and oral metformin 500 mg (OCT, MATE) were the proposed probes for clinical evaluation …”

Section: Future Directionsmentioning

confidence: 99%

Evaluation of Proposed In Vivo Probe Substrates and Inhibitors for Phenotyping Transporter Activity in Humans

Momper

Tsunoda

Joseph

2016

The Journal of Clinical Pharma

View full text Add to dashboard Cite

Drug transporters are present in various tissues and have a significant role in drug absorption, distribution, and elimination. The International Transporter Consortium has identified 7 transporters of increasing importance from evidence of clinically significant transporter-mediated drug-drug interactions. The transporters are P-glycoprotein, breast cancer resistance protein, organic anion transporting polypeptide (OATP) 1B1, OATP1B3, organic cation transporter 2, organic anion transporters (OAT) 1, and OAT3. Decision trees were created based on in vitro experiments to determine whether an in vivo transporter-mediated drug-drug interaction study is needed. Phenotyping is a methodology that evaluates real-time in vivo transporter activity, whereby changes in a probe substrate or probe inhibitor reflect alternations in the activity of the specified transporter. In vivo probe substrates and/or probe inhibitors have been proposed for each aforementioned transporter. In vitro findings and animal models provide the strongest evidence regarding probe specificity. However, such findings have not conclusively correlated with human phenotyping studies. Furthermore, the extent of contribution from multiple transporters in probe disposition complicates the ability to discern if study findings are the result of a specific transporter and thus provide a recommendation for a preferred probe for a drug transporter.

show abstract

The Use of Transporter Probe Drug Cocktails for the Assessment of Transporter-Based Drug–Drug Interactions in a Clinical Setting—Proposal of a Four Component Transporter Cocktail

Cited by 60 publications

References 50 publications

No Effect of Digoxin on Rosuvastatin Pharmacokinetics in Healthy Subjects: Utility of Oita Combination for Clinical Drug–Drug Interaction Study

No Effect of Digoxin on Rosuvastatin Pharmacokinetics in Healthy Subjects: Utility of Oita Combination for Clinical Drug–Drug Interaction Study

More Power to OATP1B1: An Evaluation of Sample Size in Pharmacogenetic Studies Using a Rosuvastatin PBPK Model for Intestinal, Hepatic, and Renal Transporter‐Mediated Clearances

Evaluation of Proposed In Vivo Probe Substrates and Inhibitors for Phenotyping Transporter Activity in Humans

Contact Info

Product

Resources

About