Clarithromycin substantially increases steady‐state bosentan exposure in healthy volunteers. (January 2014)

• Record Type: Journal Article
• Authors: Markert, Christoph; Schweizer, Yvonne; Hellwig, Regina; Wirsching, Theresia; Riedel, Klaus‐Dieter; Burhenne, Juergen; Weiss, Johanna; Mikus, Gerd; Haefeli, Walter E.
• Is Part Of: British journal of clinical pharmacology. Volume 77:Number 1(2014:Jan.)
• Page Start: 141
• Page End: 148
• Publication Date: 2014-01
• Subjects: Pharmacology -- Periodicals; Drugs -- Periodicals; 615.1
• DOI: 10.1111/bcp.12177
• Languages: English
• ISSNs: 0306-5251

Abstract

<abstract abstract-type="main"> <title> <x xml:space="preserve">Abstract</x> </title> <sec id="bcp12177-sec-0001" sec-type="section"> <title>Aims</title> <p>The aim of this study was to assess the effect of the cytochrome P450 (CYP) 3A4 and organic anion‐transporting polypeptide (OATP) 1B1 inhibitor clarithromycin on the pharmacokinetics of bosentan. We also aimed to evaluate the impact of <italic>CYP2C9</italic> and <italic>SLCO1B1</italic> (encoding for OATP1B1) genotypes and their combination.</p> </sec> <sec id="bcp12177-sec-0002" sec-type="section"> <title>Methods</title> <p>We assessed the effect of the OATP and CYP3A inhibitor clarithromycin on bosentan pharmacokinetics at steady state and concurrently quantified changes of CYP3A activity using midazolam as a probe drug. Sixteen healthy volunteers received therapeutic doses of bosentan (125 mg twice daily) for 14 days and clarithromycin (500 mg twice daily) concomitantly for the last 4 days, and bosentan pharmacokinetics was assessed on days 1, 10 and 14.</p> </sec> <sec id="bcp12177-sec-0003" sec-type="section"> <title>Results</title> <p>Clarithromycin significantly increased bosentan area under the plasma concentration–time curve of the dosing interval 3.7‐fold and peak concentration 3.8‐fold in all participants irrespective of the genotype. Clarithromycin also reduced CYP3A activity (midazolam clearance) in all participants; however, these changes were not correlated to the changes of bosentan clearance.</p> </sec> <sec id="bcp12177-sec-0004" sec-type="section"> <title>Conclusions</title> <p>Clarithromycin substantially increases the exposure to bosentan, suggesting that dose reductions may be necessary.</p> </sec> </abstract>