Comparison of the pharmacokinetics and tolerability of HCP1004 (a fixed-dose combination of naproxen and esomeprazole strontium) and VIMOVO® (a marketed fixed-dose combination of naproxen and esomeprazole magnesium) in healthy volunteers

YoonJung Choi, HyeKyung Han, Dongseong Shin, Kyoung Soo Lim, Kyung-Sang Yu, YoonJung Choi, HyeKyung Han, Dongseong Shin, Kyoung Soo Lim, Kyung-Sang Yu

Abstract

Background: HCP1004 is a newly developed fixed-dose combination of naproxen (500 mg) and esomeprazole strontium (20 mg) that is used in the treatment of rheumatic diseases and can reduce the risk of nonsteroidal anti-inflammatory drug-associated ulcers. The aim of this study was to evaluate the pharmacokinetics (PK) and safety of HCP1004 compared to VIMOVO(®) (a marketed fixed-dose combination of naproxen and esomeprazole magnesium).

Subjects and methods: An open-label, randomized, two-treatment, two-sequence crossover, single-dose clinical study was conducted in 70 healthy volunteers. In each period, a reference (VIMOVO(®)) or test (HCP1004) drug was administered orally, and serial blood samples for PK analysis were collected up to 72 hours after dosing. To evaluate the PK profiles, the maximum plasma concentration (Cmax) and the area under the concentration-time curve from 0 to the last measurable time (AUC0-t) were estimated using a noncompartmental method. Safety profiles were evaluated throughout the study.

Results: Sixty-six of the 70 subjects completed the study. The Cmax (mean ± standard deviation) and AUC0-t (mean ± standard deviation) for naproxen in HCP1004 were 61.67 ± 15.16 µg/mL and 1,206.52 ± 166.46 h · µg/mL, respectively; in VIMOVO(®); these values were 61.85 ± 14.54 µg/mL and 1,211.44 ± 170.01 h · µg/mL, respectively. The Cmax and AUC0-t for esomeprazole in HCP1004 were 658.21 ± 510.91 ng/mL and 1,109.11 ± 1,111.59 h · ng/mL, respectively; for VIMOVO(®), these values were 595.09 ± 364.23 ng/mL and 1,015.12 ± 952.98 h · ng/mL, respectively. The geometric mean ratios and 90% confidence intervals (CIs) (HCP1004 to VIMOVO(®)) of the Cmax and AUC0-t of naproxen were 0.99 (0.94-1.06) and 1.00 (0.98-1.01), respectively. For esomeprazole, the geometric mean ratios (90% CI) for the Cmax and AUC0-t were 0.99 (0.82-1.18) and 1.04 (0.91-1.18), respectively. The overall results of the safety assessment showed no clinically significant issues for either treatment.

Conclusion: The PK of HCP1004 500/20 mg was comparable to that of VIMOVO(®) 500/20 mg for both naproxen and esomeprazole after a single oral dose. Both drugs were well-tolerated without any safety issues.

Trial registration: ClinicalTrials.gov NCT00938132.

Keywords: comparative pharmacokinetics; drug development; naproxen/esomeprazole.

Figures

Figure 1
Figure 1
Mean plasma concentration–time profiles of naproxen and esomeprazole. Notes: (A) Mean plasma concentration–time profiles of naproxen after a single dose of HCP1004 or VIMOVO®, and (B) mean plasma concentration–time profiles of esomeprazole after a single dose of HCP1004 or VIMOVO®. Abbreviations: N, number of subjects; hr, hours.
Figure 2
Figure 2
Individual changes in pharmacokinetic parameters. Notes: (A) Cmax of naproxen; (B) AUC0−t of naproxen; (C) Cmax of esomeprazole; and (D) AUC0−t of esomeprazole. Abbreviations: Cmax, maximum plasma concentration; AUC0−t, area under the concentration–time curve from time 0 to the last measurable time point.

References

    1. Haroutiunian S, Drennan DA, Lipman AG. Topical NSAID therapy for musculoskeletal pain. Pain Med. 2010;11(4):535–549.
    1. American College of Gastroenterology [webpage on the Internet] Understanding ulcers, NSAIDs and GI bleeding. Bethesda, MD: American College of Gastroenterology; [Accessed April 30, 2014]. Available from: .
    1. Singh G, Triadafilopoulos G. Epidemiology of NSAID induced gastrointestinal complications. J Rheumatol Suppl. 1999;56:18–24.
    1. Lanas A, García-Rodríguez LA, Arroyo MT, et al. Investigators of the Asociación Española de Gastroenterología (AEG) Effect of antisecretory drugs and nitrates on the risk of ulcer bleeding associated with nonsteroidal anti-inflammatory drugs, antiplatelet agents, and anticoagulants. Am J Gastroenterol. 2007;102(3):507–515.
    1. Lanza FL, Chan FK, Quigley EM, Practice Parameters Committee of the American College of Gastroenterology Guidelines for prevention of NSAID-related ulcer complications. Am J Gastroenterol. 2009;104(3):728–738.
    1. Cryer BL, Sostek MB, Fort JG, Svensson O, Hwang C, Hochberg MC. A fixed-dose combination of naproxen and esomeprazole magnesium has comparable upper gastrointestinal tolerability to celecoxib in patients with osteoarthritis of the knee: results from two randomized, parallel-group, placebo-controlled trials. Ann Med. 2011;43(8):594–605.
    1. Goldstein JL, Hochberg MC, Fort JG, Zhang Y, Hwang C, Sostek M. Clinical trial: the incidence of NSAID-associated endoscopic gastric ulcers in patients treated with PN 400 (naproxen plus esomeprazole magnesium) vs enteric-coated naproxen alone. Aliment Pharmacol Ther. 2010;32(3):401–413.
    1. Bangalore S, Kamalakkannan G, Parkar S, Messerli FH. Fixed-dose combinations improve medication compliance: a meta-analysis. Am J Med. 2007;120(8):713–719.
    1. VIMOVO® . Product Monograph. Mississauga, ON: AstraZeneca Canada Inc; 2011.
    1. U.S. Food and Drug Administration [webpage on the Internet] Esomeprazole strontium delayed-release capsules. Silver Spring, MD: U.S. Food and Drug Administration; 2013. [Accessed April 30, 2014]. Available from: .
    1. Parekh PJ, Oldfield EC, 4th, Johnson DA. Treatment of gastroesophageal reflux disease: two new oral formulations dexlansoprazole MR and esomezol (esomeprazole strontium) Expert Opin Pharmacother. 2014;15(9):1215–1222.
    1. Dhillon S. Naproxen/esomeprazole fixed-dose combination: for the treatment of arthritic symptoms and to reduce the risk of gastric ulcers. Drugs Aging. 2011;28(3):237–248.
    1. Wang-Smith L, Fort J, Zhang Y, Sostek M. Pharmacokinetics and relative bioavailability of a fixed-dose combination of enteric-c oated naproxen and non-enteric-coated esomeprazole magnesium. J Clin Pharmacol. 2012;52(5):670–680.
    1. U.S. Food and Drug Administration [webpage in the Internet]. Guidance for Industry Bioavailability and Bioequivalence Studies for Orally Administered Drug Products – General Considerations. [Accessed June 28, 2014]. Available from: .
    1. U.S. Food and Drug Administration [webpage on the Internet] Orange Book: Approved drug products with therapeutic equivalence evaluations. Silver Spring, MD: U.S. Food and Drug Administration; 2015. [Accessed June 28, 2014]. Available from: .
    1. Ma Q, Lu AY. Pharmacogenetics, pharmacogenomics, and individualized medicine. Pharmacol Rev. 2011;63(2):437–459.
    1. Ingelman-Sundberg M. Pharmacogenetics of cytochrome P450 and its applications in drug therapy: the past, present and future. Trends Pharmacol Sci. 2004;25(4):193–200.
    1. Yang JC, Lin CJ. CYP2C19 genotypes in the pharmacokinetics/pharmacodynamics of proton pump inhibitor-based therapy of Helicobacter pylori infection. Expert Opin Drug Metab Toxicol. 2010;6(1):29–41.
    1. Bae JW, Kim JH, Choi CI, et al. Effect of CYP2C9*3 allele on the pharmacokinetics of naproxen in Korean subjects. Arch Pharm Res. 2009;32(2):269–273.

Source: PubMed

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