Effect of cyclosporine coadministration on the pharmacokinetics of eltrombopag in healthy volunteers
- 200 Downloads
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.
- 2.PROMACTA® (eltrombopag) [package insert]. Novartis Pharmaceuticals Co. East Hanover, NJ. https://www.pharma.us.novartis.com/sites/www.pharma.us.novartis.com/files/promacta.pdf. Accessed 29 Aug 2018
- 3.Bussel JB, Provan D, Shamsi T, Cheng G, Psaila B, Kovaleva L, Salama A, Jenkins JM, Roychowdhury D, Mayer B, Stone N, Arning M (2009) Effect of eltrombopag on platelet counts and bleeding during treatment of chronic idiopathic thrombocytopenic purpura: a randomised, double-blind, placebo-controlled trial. Lancet 373:641–648CrossRefGoogle Scholar
- 4.REVOLADE® (eltrombopag): [summary of product characteristics]. Novartis Europharm Ltd. Dublin, Ireland. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR__Product_Information/human/001110/WC500089964.pdf. Accessed 22 Aug 2018
- 7.Townsley DM, Scheinberg P, Winkler T, Desmond R, Dumitriu B, Rios O, Weinstein B, Valdez J, Lotter J, Feng X, Desierto M, Leuva H, Bevans M, Wu C, Larochelle A, Calvo KR, Dunbar CE, Young NS (2017) Eltrombopag added to standard immunosuppression for aplastic anemia. N Engl J Med 376:1540–1550CrossRefGoogle Scholar
- 10.Gupta A, Dai Y, Vethanayagam RR, Hebert MF, Thummel KE, Unadkat JD, Ross DD, Mao Q (2006) Cyclosporin A, tacrolimus and sirolimus are potent inhibitors of the human breast cancer resistance protein (ABCG2) and reverse resistance to mitoxantrone and topotecan. Cancer Chemother Pharmacol 58:374–383CrossRefGoogle Scholar
- 13.NEORAL® (cyclosporine) [package insert]. Novartis Pharmaceuticals Co. East Hanover, NJ. https://www.accessdata.fda.gov/drugsatfda_docs/label/2009/050715s027,050716s028lbl.pdf. Accessed 22 Aug 2018
- 16.Elsby R, Martin P, Surry D, Sharma P, Fenner K (2016) Solitary Inhibition of the breast cancer resistance protein efflux transporter results in a clinically significant drug-drug interaction with rosuvastatin by causing up to a 2-fold increase in statin exposure. Drug Metab Dispos 44(3):398–408CrossRefGoogle Scholar
- 17.Williams DD, Peng B, Bailey CK, Wire MB, Deng Y, Park JW, Collins DA, Kapsi SG, Jenkins JM (2009) Effects of food and antacids on the pharmacokinetics of eltrombopag in healthy adult subjects: two single-dose, open-label, randomized-sequence, crossover studies. Clin Ther 31(4):764–776CrossRefGoogle Scholar
- 21.Jenkins J, Williams D, Deng Y, Collins DA, Kitchen VS (2009) Eltrombopag, an oral thrombopoietin receptor agonist, has no impact on the pharmacokinetic profile of probe drugs for cytochrome P450 isoenzymes CYP3A4, CYP1A2, CYP2C9 and CYP2C19 in healthy men: a cocktail analysis. Eur J Clin Pharmacol 66(1):67–76CrossRefGoogle Scholar