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Eltrombopag increases plasma rosuvastatin exposure in healthy volunteers.
Br J Clin Pharmacol. 2011 Aug; 72(2):321-9.BJ

Abstract

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

OATP1B1 is important for hepatic uptake of rosuvastatin and BCRP is important for rosuvastatin absorption and elimination. Eltrombopag inhibits OATP1B1 and BCRP in vitro at clinically relevant concentrations. Inhibition of these transporters could change cholesterol-lowering efficacy and increase the risk of exposure-dependent toxicities. To determine if co-administration of eltrombopag with rosuvastatin alters plasma rosuvastatin exposure, an open-label study was conducted in 42 healthy adult subjects.

WHAT THIS STUDY ADDS

Concomitant administration of eltrombopag with rosuvastatin was associated with increased rosuvastatin exposure via inhibition of drug transporters. The therapeutic index of HMG Co-A reductase inhibitors may be reduced by the concomitant use of eltrombopag. In subjects taking eltrombopag, a reduced dose of HMG Co-A reductase inhibitors may be needed.

AIM

Eltrombopag, an oral, nonpeptide thrombopoietin receptor agonist, inhibits the organic anion transporting polypeptide 1B1 (OATP1B1) and breast cancer resistance protein (BCRP) in vitro. OATP1B1 is important for hepatic uptake of rosuvastatin and inhibition of this transporter could reduce cholesterol-lowering efficacy and increase the risk of exposure-dependent toxicities. In contrast, BCRP is an efflux transporter and inhibition of this transporter could increase both hepatic and plasma rosuvastatin concentrations, resulting in increased efficacy and toxicity. To determine if co-administration of eltrombopag with rosuvastatin alters plasma rosuvastatin exposure, an open-label study was conducted in 42 healthy adult subjects.

METHODS

Subjects received rosuvastatin and eltrombopag orally: day 1, rosuvastatin 10 mg single dose; days 6 to 9, eltrombopag 75 mg once daily; day 10, eltrombopag 75 mg once daily and rosuvastatin 10 mg single dose. Adverse event assessments were performed daily and at the follow-up visit. Plasma samples for pharmacokinetic analysis were collected days 1 to 5 and days 10 to 14.

RESULTS

Co-administration of eltrombopag with rosuvastatin increased geometric mean (90% confidence interval) plasma rosuvastatin AUC(0,∞) by 55% (42%, 69%) and C(max) by 103% (82%, 126%) in the overall study population, with a larger interaction in the non-Asian compared with Asian subjects.

CONCLUSIONS

Concomitant administration of eltrombopag with rosuvastatin was associated with increased rosuvastatin exposure. The therapeutic index of HMG Co-A reductase inhibitors may be reduced by the concomitant use of eltrombopag. In subjects taking eltrombopag, a reduced dose of HMG Co-A reductase inhibitors may be needed.

Authors+Show Affiliations

GlaxoSmithKline, Five Moore Drive, Research Triangle Park, NC, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Clinical Trial
Journal Article

Language

eng

PubMed ID

21434975

Citation

Allred, Alicia J., et al. "Eltrombopag Increases Plasma Rosuvastatin Exposure in Healthy Volunteers." British Journal of Clinical Pharmacology, vol. 72, no. 2, 2011, pp. 321-9.
Allred AJ, Bowen CJ, Park JW, et al. Eltrombopag increases plasma rosuvastatin exposure in healthy volunteers. Br J Clin Pharmacol. 2011;72(2):321-9.
Allred, A. J., Bowen, C. J., Park, J. W., Peng, B., Williams, D. D., Wire, M. B., & Lee, E. (2011). Eltrombopag increases plasma rosuvastatin exposure in healthy volunteers. British Journal of Clinical Pharmacology, 72(2), 321-9. https://doi.org/10.1111/j.1365-2125.2011.03972.x
Allred AJ, et al. Eltrombopag Increases Plasma Rosuvastatin Exposure in Healthy Volunteers. Br J Clin Pharmacol. 2011;72(2):321-9. PubMed PMID: 21434975.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Eltrombopag increases plasma rosuvastatin exposure in healthy volunteers. AU - Allred,Alicia J, AU - Bowen,Carolyn J, AU - Park,Jung Wook, AU - Peng,Bin, AU - Williams,Daphne D, AU - Wire,Mary Beth, AU - Lee,Edmund, PY - 2011/3/26/entrez PY - 2011/3/26/pubmed PY - 2012/1/3/medline SP - 321 EP - 9 JF - British journal of clinical pharmacology JO - Br J Clin Pharmacol VL - 72 IS - 2 N2 - WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: OATP1B1 is important for hepatic uptake of rosuvastatin and BCRP is important for rosuvastatin absorption and elimination. Eltrombopag inhibits OATP1B1 and BCRP in vitro at clinically relevant concentrations. Inhibition of these transporters could change cholesterol-lowering efficacy and increase the risk of exposure-dependent toxicities. To determine if co-administration of eltrombopag with rosuvastatin alters plasma rosuvastatin exposure, an open-label study was conducted in 42 healthy adult subjects. WHAT THIS STUDY ADDS: Concomitant administration of eltrombopag with rosuvastatin was associated with increased rosuvastatin exposure via inhibition of drug transporters. The therapeutic index of HMG Co-A reductase inhibitors may be reduced by the concomitant use of eltrombopag. In subjects taking eltrombopag, a reduced dose of HMG Co-A reductase inhibitors may be needed. AIM: Eltrombopag, an oral, nonpeptide thrombopoietin receptor agonist, inhibits the organic anion transporting polypeptide 1B1 (OATP1B1) and breast cancer resistance protein (BCRP) in vitro. OATP1B1 is important for hepatic uptake of rosuvastatin and inhibition of this transporter could reduce cholesterol-lowering efficacy and increase the risk of exposure-dependent toxicities. In contrast, BCRP is an efflux transporter and inhibition of this transporter could increase both hepatic and plasma rosuvastatin concentrations, resulting in increased efficacy and toxicity. To determine if co-administration of eltrombopag with rosuvastatin alters plasma rosuvastatin exposure, an open-label study was conducted in 42 healthy adult subjects. METHODS: Subjects received rosuvastatin and eltrombopag orally: day 1, rosuvastatin 10 mg single dose; days 6 to 9, eltrombopag 75 mg once daily; day 10, eltrombopag 75 mg once daily and rosuvastatin 10 mg single dose. Adverse event assessments were performed daily and at the follow-up visit. Plasma samples for pharmacokinetic analysis were collected days 1 to 5 and days 10 to 14. RESULTS: Co-administration of eltrombopag with rosuvastatin increased geometric mean (90% confidence interval) plasma rosuvastatin AUC(0,∞) by 55% (42%, 69%) and C(max) by 103% (82%, 126%) in the overall study population, with a larger interaction in the non-Asian compared with Asian subjects. CONCLUSIONS: Concomitant administration of eltrombopag with rosuvastatin was associated with increased rosuvastatin exposure. The therapeutic index of HMG Co-A reductase inhibitors may be reduced by the concomitant use of eltrombopag. In subjects taking eltrombopag, a reduced dose of HMG Co-A reductase inhibitors may be needed. SN - 1365-2125 UR - https://www.unboundmedicine.com/medline/citation/21434975/Eltrombopag_increases_plasma_rosuvastatin_exposure_in_healthy_volunteers_ L2 - https://doi.org/10.1111/j.1365-2125.2011.03972.x DB - PRIME DP - Unbound Medicine ER -