Maraviroc is a substrate for OATP1B1 in vitro and maraviroc plasma concentrations are influenced by SLCO1B1 521 T>C polymorphism

Marco Siccardi, Antonio D'Avolio, Silvia Nozza, Marco Simiele, Lorena Baietto, Francesca Romana Stefani, Darren Moss, Wai San Kwan, Antonella Castagna, Adriano Lazzarin, Andrea Calcagno, Stefano Bonora, David Back, Giovanni Di Perri, Andrew Owen

Research output: Contribution to journalArticle

Abstract

Background: Organic anion transporting polypeptides (OATPs) are emerging as major determinants of pharmacokinetics for numerous drugs, with the 1B1 isoform-mediating hepatic uptake. The 521 T>C polymorphism has been correlated earlier with higher plasma concentrations of several drugs and the aim of this study was to determine whether this polymorphism influences trough concentrations of maraviroc. Methods: The uptake of maraviroc by OATP1B1 was assessed using a heterologous Xenopus laevis oocyte expression system and quantified using a novel liquid chromatography-mass spectrometry method. Regression analyses were conducted to identify factors associated with maraviroc Ctrough in 59 patients treated with maraviroc at 150, 300, or 600 mg twice daily. Results: Maraviroc was identified as a substrate for OATP1B1 with a Km of 33.9 μmol/l. A dose of 600 mg of etravirine or efavirenz [odds ratio (OR)=0.22, 95% confidence interval (95% CI): 0.06-0.76; P=0.016] and SLCO1B1 521 heterozygosity were both associated with maraviroc Ctrough, above the suggested target concentration of 50 ng/ml (OR=20.3, 95% CI: 2.2-182; P=0.007). Conclusion: These findings show the importance of OATP1B1 for variability in maraviroc pharmacokinetics. Furthermore, the SLCO1B1 521 T>C polymorphism maybe useful in predicting higher plasma concentrations but these data should be confirmed before prospective clinical studies to define the clinical usefulness.

Original languageEnglish
Pages (from-to)759-765
Number of pages7
JournalPharmacogenetics and Genomics
Volume20
Issue number12
DOIs
Publication statusPublished - Dec 2010

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Keywords

  • maraviroc
  • pharmacogenetics
  • pharmacokinetics
  • SLCO1B1
  • uptake transporter

ASJC Scopus subject areas

  • Genetics
  • Molecular Biology
  • Molecular Medicine
  • Genetics(clinical)

Cite this

Siccardi, M., D'Avolio, A., Nozza, S., Simiele, M., Baietto, L., Stefani, F. R., Moss, D., Kwan, W. S., Castagna, A., Lazzarin, A., Calcagno, A., Bonora, S., Back, D., Di Perri, G., & Owen, A. (2010). Maraviroc is a substrate for OATP1B1 in vitro and maraviroc plasma concentrations are influenced by SLCO1B1 521 T>C polymorphism. Pharmacogenetics and Genomics, 20(12), 759-765. https://doi.org/10.1097/FPC.0b013e3283402efb