Effect of cyclosporine coadministration on the pharmacokinetics of eltrombopag in healthy volunteers
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Eltrombopag is indicated in patients with severe aplastic anemia (SAA) refractory to prior immunosuppressive therapy. The combination of eltrombopag and immunosuppressive therapy (such as cyclosporine) is currently being evaluated in patients with treatment-naive SAA. Cyclosporine is a human breast cancer resistance protein (BCRP) inhibitor, and can potentially alter plasma exposure to eltrombopag, a BCRP substrate. This phase 1, open-label, randomized, 3-period, crossover study evaluated the effect of cyclosporine on the pharmacokinetics of eltrombopag in healthy adults.
Thirty-nine subjects were randomized to either single dose of eltrombopag 50 mg, cyclosporine 200 mg + eltrombopag 50 mg or cyclosporine 600 mg + eltrombopag 50 mg treatment groups. Eltrombopag pharmacokinetic parameters (Cmax, tmax, AUClast, AUCinf, %AUCex, t1/2, and CL/F) were determined using noncompartmental methods.
Geometric mean AUCinf, AUClast, and Cmax, were decreased by 18, 20, and 25%, respectively, for cyclosporine 200 mg + eltrombopag and by 24, 22, and 39%, respectively, for cyclosporine 600 mg + eltrombopag groups compared to the eltrombopag alone group. The median tmax was prolonged by ~ 1 h in both coadministration treatments. The geometric mean t1/2 was ≈ 21, ≈ 24, and ≈ 26 h, respectively, in cyclosporine 200 mg + eltrombopag, cyclosporine 600 mg + eltrombopag and eltrombopag alone groups. All the treatments were safe and well-tolerated. No serious adverse event or death was reported during the study.
These changes in exposure were not considered clinically meaningful as the dose of eltrombopag is adjusted using within-patient dose titration based on platelet counts.
KeywordsPharmacokinetics BCRP Severe aplastic anemia Eltrombopag Cyclosporine Interaction
This study (NCT02281370) was sponsored by GlaxoSmithKline. Eltrombopag became an asset of Novartis Pharma AG as of March 2, 2015. Medical editorial assistance was provided by Fatima Ambrin, PhD, Archana Rai, and Pranitha Manchanapalli, Pharm D of Novartis Business Services. Financial support for editorial assistance was provided by Novartis Pharmaceuticals Corporation.
BL and JZ contributed to study design, data collection, and data interpretation and performed the research. VA, KG, and TO contributed to data interpretation. All authors were involved with drafting the manuscript and approved the final version.
Compliance with ethical standards
Conflict of interest
VA, TO, and KG are employees of Novartis. JZ is an employee of PAREXEL International. BL is an employee of Quintiles.
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