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01-04-2018 | Leading Article

Key Pharmacokinetic Essentials of Fixed-Dosed Combination Products: Case Studies and Perspectives

Authors: Ranjeet Prasad Dash, Rana Rais, Nuggehally R. Srinivas

Published in: Clinical Pharmacokinetics | Issue 4/2018

Abstract

Fixed-dose combinations are gaining popularity because they provide convenience while enhancing patient compliance. Literature examples suggest that many fixed-dose combinations are being rationalized and investigated for their potential utility in therapy. This article provides an introspection into the pharmacokinetic essentials that need to be considered prior to implementing a fixed-dose combination strategy. While the drug–drug interaction potential is an important question for the two drugs in a fixed-dose combination, the occurrence of a drug–drug interaction in itself is not a negative outcome for the proposed fixed-dose combination. However, the magnitude of a drug–drug interaction may require a re-assessment of the doses of the two drugs in a fixed-dose combination. Several case studies are provided and discussed to provide a broad perspective on the topic along with a representative framework and strategy on the development of fixed-dose combinations using key pharmacokinetic parameters.

Hennekens CH. Fixed-dose combination therapy with statins: strengths, limitations, and clinical and regulatory considerations. Am J Cardiovasc Drugs. 2008;8(3):155–60.CrossRefPubMed

World Health Organization. WHO Technical Report Series, No. 929, 2005. Guidelines for registration of fixed-dose combination medicinal products. Available from: http://www.who.int/medicines/areas/quality_safety/quality_assurance/GuidelinesRegistrationFixedDoseCombinationTRS929Annex5.pdf. Accessed 10 Jun 2017.

Hutchins V, Zhang B, Fleurence RL, Krishnarajah G, Graham J. A systematic review of compliance, treatment satisfaction and costs, in fixed-dose combination regimens in type 2 diabetes. Curr Med Res Opin. 2011;27(6):1157–68. doi:10.1185/03007995.2011.570745.CrossRefPubMed

Mukhejee J, Das A, Chakrabarty US, et al. Bioequivalence study of a fixed dose combination tablet containing rabeprazole and diclofenac sodium in healthy human subjects. Arzneimittelforschung. 2010;60(8):506–9. doi:10.1055/s-0031-1296319.

Sahoo BK, Das A, Agarwal S, et al. Pharmacokinetics and bioequivalence study of a fixed dose combination of rabeprazole and itopride in healthy Indian volunteers. Arzneimittelforschung. 2009;59(9):451–4. doi:10.1055/s-0031-1296424.PubMed

Bort R, Macé K, Boobis A, et al. Hepatic metabolism of diclofenac: role of human CYP in the minor oxidative pathways. Biochem Pharmacol. 1999;58(5):787–96. doi:10.1016/S0006-2952(99)00167-7.CrossRefPubMed

Miura M. Enantioselective disposition of lansoprazole and rabeprazole in human plasma. Yakugaku Zasshi. 2006;126(6):395–402. doi:10.1248/yakushi.126.395.CrossRefPubMed

Mushiroda T, Douya R, Takahara E, et al. The involvement of flavin-containing monooxygenase but not CYP3A4 in metabolism of itopride hydrochloride, a gastroprokinetic agent: comparison with cisapride and mosapride citrate. Drug Metab Dispos. 2000;28(10):1231–7.PubMed

Klotz U. Proton pump inhibitors: their pharmacological impact on the clinical management of acid-related disorders. Arzneimittelforschung. 2009;59(6):271–82. doi:10.1055/s-0031-1296397.PubMed

10.

Kishi T, Sunagawa K. Combination therapy of atorvastatin and amlodipine inhibits sympathetic nervous system activation and improves cognitive function in hypertensive rats. Circ J. 2012;76(8):1934–41. doi:10.1253/circj.CJ-12-0276.CrossRefPubMed

11.

Mancia G, Fagard R, Narkiewicz K, et al. 2013 ESH/ESC practice guidelines for the management of arterial hypertension. Blood Press. 2014;23(1):3–16. doi:10.3109/08037051.2014.868629.CrossRefPubMed

12.

Nwe HH, Bullman JN, Joshi SM, et al. The relative bioavailability of 2 prototype fixed-dose combination formulations for amlodipine and rosuvastatin in healthy white and Chinese subjects. Clin Pharmacol Drug Dev. 2016;5(2):131–40. doi:10.1002/cpdd.214.CrossRefPubMed

13.

Olsson AG, McTaggart F, Raza A. Rosuvastatin: a highly effective new HMG-CoA reductase inhibitor. Cardiovasc Drug Rev. 2002;20(4):303–28. doi:10.1111/j.1527-3466.2002.tb00099.x.CrossRefPubMed

14.

Zhu Y, Wang F, Li Q, et al. Amlodipine metabolism in human liver microsomes and roles of CYP3A4/5 in the dihydropyridine dehydrogenation. Drug Metab Dispos. 2014;42(2):245–9. doi:10.1124/dmd.113.055400.CrossRefPubMed

15.

Li Y, Jiang X, Lan K, et al. Pharmacokinetic properties of rosuvastatin after single-dose, oral administration in Chinese volunteers: a randomized, open-label, three-way crossover study. Clin Ther. 2007;29(10):2194–203. doi:10.1016/j.clinthera.2007.10.005.CrossRefPubMed

16.

MHRA. Amlodipine 5 mg tablets PL22903/0004 and amlodipine 10 mg tablets PL22903/0005 (amlodipine besilate). 2008. Available from: http://www.mhra.gov.uk/home/groups/par/documents/websiteresources/con028435.pdf. Accessed 21 Mar 2017.

17.

Chae DW, Son M, Kim Y, et al. Pharmacokinetics of a telmisartan/rosuvastatin fixed-dose combination: a single-dose, randomized, open-label, 2-period crossover study in healthy Korean subjects. Int J Clin Pharmacol Ther. 2015;53(10):883–9. doi:10.5414/CP202412.CrossRefPubMed

18.

Wienen W, Entzeroth M, van Meel JCA, et al. A review on telmisartan: a novel, long-acting angiotensin II-receptor antagonist. Cardiovasc Drug Rev. 2000;18(2):127–54. doi:10.1291/hypres.22.147.CrossRef

19.

Center for Drug Evaluation and Research. Application Number: NDA 20850. 1998. Available from: http://www.accessdata.fda.gov/drugsatfda_docs/nda/98/20850_MICARDIS_biopharmr_P1.pdf. Accessed 21 Mar 2017.

20.

Saah AJ, Winchell GA, Nessly ML, et al. Pharmacokinetic profile and tolerability of indinavir–ritonavir combinations in healthy volunteers. Antimicrob Agents Chemother. 2001;45(10):2710–5. doi:10.1128/AAC.45.10.2710-2715.2001.CrossRefPubMedPubMedCentral

21.

Kakuda TN, Opsomer M, Timmers M, et al. Pharmacokinetics of darunavir in fixed-dose combination with cobicistat compared with coadministration of darunavir and ritonavir as single agents in healthy volunteers. J Clin Pharmacol. 2014;54(8):949–57. doi:10.1002/jcph.290.CrossRefPubMed

22.

Klotz U. Clinical impact of CYP2C19 polymorphism on the action of proton pump inhibitors: a review of a special problem. Int J Clin Pharmacol Ther. 2006;44(7):297–302.CrossRefPubMed

23.

Qiao HL, Hu YR, Tian X, et al. Pharmacokinetics of three proton pump inhibitors in Chinese subjects in relation to the CYP2C19 genotype. Eur J Clin Pharmacol. 2006;62(2):107–12.CrossRefPubMed

24.

Dash RP, Rais R, Srinivas NR. Stereoselective and nonstereoselective pharmacokinetics of rabeprazole: an overview. Xenobiotica. 2017;6:1–11. doi:10.1080/00498254.2017.1307470 [Epub ahead of print].CrossRef

25.

Hill A, van der Lugt J, Sawyer W, et al. How much ritonavir is needed to boost protease inhibitors? Systematic review of 17 dose-ranging pharmacokinetic trials. AIDS. 2009;23(17):2237–45. doi:10.1097/QAD.0b013e328332c3a5.CrossRefPubMed

26.

von Hentig N, Müller A, Rottmann C, et al. Pharmacokinetics of saquinavir, atazanavir, and ritonavir in a twice-daily boosted double-protease inhibitor regimen. Antimicrob Agents Chemother. 2007;51(4):1431–9. doi:10.1128/AAC.00854-06.CrossRef

27.

Ruane PJ, Luber AD, Wire MB, et al. Plasma amprenavir pharmacokinetics and tolerability following administration of 1400 mg of fosamprenavir once daily in combination with either 100 or 200 mg of ritonavir in healthy volunteers. Antimicrob Agents Chemother. 2007;51(2):560–5. doi:10.1128/AAC.00560-06.CrossRefPubMed

28.

Kempf DJ, Marsh KC, Kumar G, et al. Pharmacokinetic enhancement of inhibitors of the human immunodeficiency virus protease by coadministration with ritonavir. Antimicrob Agents Chemother. 1997;41(3):654–60.PubMedPubMedCentral

29.

Greenblatt DJ, Harmatz JS. Ritonavir is the best alternative to ketoconazole as an index inhibitor of cytochrome P450-3A in drug-drug interaction studies. Br J Clin Pharmacol. 2015;80(3):342–50. doi:10.1111/bcp.12668.CrossRefPubMedPubMedCentral

30.

Nuedexta^® ‘DMQ-20/10’ prescribing information. Revised January 2016. Aliso Viejo (CA): Avanir Pharmaceuticals, Inc. 2016. Available from: http://www.drugs.com/pro/nuedexta.html. Accessed 9 Jun 2017.

31.

Duconge J, Ruaño G. Fixed-dose combination products and unintended drug interactions: urgent need for pharmacogenetic evaluation. Pharmacogenomics. 2015;16(15):1685–8. doi:10.2217/pgs.15.123.CrossRefPubMed

32.

Grün B, Kiessling MK, Burhenne J, et al. Trimethoprim-metformin interaction and its genetic modulation by OCT2 and MATE1 transporters. Br J Clin Pharmacol. 2013;76(5):787–96. doi:10.1111/bcp.12079.CrossRefPubMedPubMedCentral

33.

Christensen MM, Pedersen RS, Stage TB, et al. A gene-gene interaction between polymorphisms in the OCT2 and MATE1 genes influences the renal clearance of metformin. Pharmacogenet Genom. 2013;23(10):526–34.CrossRef

34.

Cho SK, Kim CO, Park ES, Chung JY. Verapamil decreases the glucose-lowering effect of metformin in healthy volunteers. Br J Clin Pharmacol. 2014;78(6):1426–32. doi:10.1111/bcp.12476.CrossRefPubMedPubMedCentral

35.

Kusuhara H, Ito S, Kumagai Y, et al. Effects of a MATE protein inhibitor, pyrimethamine, on the renal elimination of metformin at oral micro dose and at therapeutic dose in healthy subjects. Clin Pharmacol Ther. 2011;89(6):837–44. doi:10.1038/clpt.2011.36.CrossRefPubMed

36.

Bergman A, Ebel D, Liu F, et al. Absolute bioavailability of sitagliptin, an oral dipeptidyl peptidase-4 inhibitor, in healthy volunteers. Biopharm Drug Dispos. 2007;28(6):315–22.CrossRefPubMed

37.

Chen X, Zhao Q, Zhang J, Liu T, Jiang J, Hu P. An open-label, multiple-dose study to assess the pharmacokinetics and tolerability of sitagliptin/metformin fixed-dose combination (FDC) tablet in healthy Chinese adult subjects. Int J Clin Pharmacol Ther. 2016;54(9):705–11. doi:10.5414/CP202646.CrossRefPubMed

38.

Kakuda TN, Van De Casteele T, Petrovic R, et al. Bioequivalence of a darunavir/cobicistat fixed-dose combination tablet versus single agents and food effect in healthy volunteers. Antivir Ther. 2014;19(6):597–606. doi:10.3851/IMP2814.CrossRefPubMed

39.

Yasuda S, Higashi S, Murakami M, et al. Antacids have no influence on the pharmacokinetics of rabeprazole, a new proton pump inhibitor, in healthy volunteers. Int J Clin Pharmacol Ther. 1999;37(5):249–53.PubMed

40.

Zhai X, Hu K, Chen F, et al. Comparative bioavailability and tolerability of single and multiple doses of 2 diclofenac sodium sustained-release tablet formulations in fasting, healthy Chinese male volunteers. Curr Ther Res Clin Exp. 2013;75:53–8. doi: 10.1016/j.curtheres.2013.09.001.CrossRefPubMedPubMedCentral

41.

Yoon S, Lee H, Kim TE, et al. Comparative steady-state pharmacokinetic study of an extended-release formulation of itopride and its immediate-release reference formulation in healthy volunteers. Drug Des Devel Ther. 2014;8:123–8. doi:10.2147/DDDT.S53027.CrossRefPubMedPubMedCentral

Title: Key Pharmacokinetic Essentials of Fixed-Dosed Combination Products: Case Studies and Perspectives
Authors: Ranjeet Prasad Dash
Rana Rais
Nuggehally R. Srinivas
Publication date: 01-04-2018
Publisher: Springer International Publishing
Published in: Clinical Pharmacokinetics / Issue 4/2018
Print ISSN: 0312-5963
Electronic ISSN: 1179-1926
DOI: https://doi.org/10.1007/s40262-017-0589-2

At a glance: The STEP trials

Springer Medicine

Key Pharmacokinetic Essentials of Fixed-Dosed Combination Products: Case Studies and Perspectives

Abstract

At a glance: The STEP trials

Springer Medicine

Abstract

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