Evaluation of drug interactions of saxagliptin with sildenafil in healthy volunteers

Rania Y Mansour, Radwa ElBorolossy, Sara M Shaheen, Nagwa A Sabri, Rania Y Mansour, Radwa ElBorolossy, Sara M Shaheen, Nagwa A Sabri

Abstract

Purpose: The purpose of this study is to investigate the effect of sildenafil a CYP3A4 substrate and inhibitor on the pharmacokinetics and safety of saxagliptin.

Methods: Eighteen healthy volunteers were recruited in sequential; single-center study to determine pharmacokinetic parameters of saxagliptin and sildenafil, and (AUC0-∞), (AUC0-t); Cmax; tmax; t½, ke; ka were measured using validated LC-MS/MS method. Therapeutic doses were given as follows: Sildenafil 50 mg single dose on day one, then washout period from day two till day eight. Saxagliptin 5 mg once/day was given from day 9 till day 12; then on day 13, the two drugs were co-administered. Blood samples for pharmacokinetic analysis were collected on days 1 and 13 for sildenafil and on days 12 and 13 for saxagliptin.

Results: Saxagliptin ratios of T/R and 90% CI were 132.1% (122.7-142.3) for AUC0-t, and 167.6% (154.6-181.8) for Cmax. On the other hand, sildenafil pharmacokinetics were not affected. Gmax changed from 93.7 mg/dl to 95.6 mg/dl (P > 0.001) and AUCg0-t from 512.8 ng.h/ml to 532.75 ng.h/ml (P > 0.001) after co-administration of both drugs.

Conclusion: Sildenafil significantly affected the pharmacokinetic parameters of saxagliptin when co-administered.

Registration: This trial was registered at clinicaltrials.gov under identifier number: [NCT04170790] in November 2019.

Keywords: Diabetes; Drug interactions; Pharmacodynamics; Pharmacokinetics; Saxagliptin; Sexual dysfunction; Sildenafil.

Conflict of interest statement

The authors declare no competing interests.

The authors declare no competing interests.

© 2022. The Author(s).

Figures

Fig. 1
Fig. 1
Plasma concentration levels of Saxagliptin (ng/ml) alone and after concomitant administration of multiple oral doses of Saxagliptin 5mg tablet and single oral dose of Sildenafil 50mg Tablet
Fig. 2
Fig. 2
Saxagliptin Gmax after Multiple dose administration “Saxagliptin 5mg Tablet” and “Saxagliptin 5mg Tablet + Sildenafil 50mg Tablet” (P > 0.001)

References

    1. Rasool MF, Rehman AU, Imran I, Abbas S, Shah S, Abbas G, Khan I, Shakeel S, Ahmad Hassali MA, Hayat K (2020) Risk factors associated with medication errors among patients suffering from chronic disorders. Front Public Health 8. 10.3389/fpubh.2020.531038
    1. Zwart-van Rijkom JE, Uijtendaal EV, Ten Berg MJ, Van Solinge WW, Egberts AC. Frequency and nature of drug-drug interactions in a Dutch university hospital. Br J Clin Pharmacol. 2009;68(2):187–193. doi: 10.1111/j.1365-2125.2009.03443.x.
    1. Bucsa CD, Cazacu I, Farcas AM, Bojita M (2012) The prevalence of potential drug-drug interactions in the therapy of Romanian community pharmacy’s patients. Farmacia 60
    1. Gallelli L, Siniscalchi A, Palleria C, Mumoli L, Staltari O, Squillace A, Maida F, Russo E, Gratteri S, De Sarro G (2017) Adverse drug reactions related to drug administration in hospitalized patients. Curr Drug Saf 12(3). 10.2174/1574886312666170616090640
    1. Ryden L, Grant PJ, Anker SD, Berne C, Cosentino F, Danchin N, Deaton C, Escaned J, Hammes H, Huikuri H, et al. ESC guidelines on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with the EASD. Eur Heart J. 2014;35(27):1824–1824. doi: 10.1093/eurheartj/ehu076.
    1. Boulton DW. Clinical pharmacokinetics and pharmacodynamics of Saxagliptin, a Dipeptidyl peptidase-4 inhibitor. Clin Pharmacokinet. 2016;56(1):11–24. doi: 10.1007/s40262-016-0421-4.
    1. Su H, Boulton DW, Barros A, Wang L, Cao K, Bonacorsi SJ, Iyer RA, Humphreys WG, Christopher LJ. Characterization of the in vitro and in vivo metabolism and disposition and cytochrome P450 inhibition/Induction profile of saxagliptin in human. Drug Metab Dispos. 2012;40(7):1345–1356. doi: 10.1124/dmd.112.045450.
    1. Kajikawa M, Maruhashi T, Hidaka T, Matsui S, Hashimoto H, Takaeko Y, Nakano Y, Kurisu S, Kihara Y, Yusoff FM, Kishimoto S (2019) Effect of Saxagliptin on endothelial function in patients with type 2 diabetes: a prospective multicenter study. Sci Rep 9(1). 10.1038/s41598-019-46726-3
    1. Gareri P, Castagna A, Francomano D, Cerminara G, De Fazio P. Erectile dysfunction in the elderly: an old widespread issue with novel treatment perspectives. Int J Endocrinol. 2014;2014:1–15. doi: 10.1155/2014/878670.
    1. Cui K, Tang Z, Li CC, Wang T, Rao K, Wang SG, Liu JH, Chen Z. Lipoxin A4 improves erectile dysfunction in rats with type I diabetes by inhibiting oxidative stress and corporal fibrosis. Asian J Androl. 2018;20(2):166–172. doi: 10.4103/aja.aja_49_17.
    1. Jiann B (2014) Re: JinQiu Yuan, RenJie Zhang, ZuYao Yang, et al. Comparative effectiveness and safety of oral phosphodiesterase type 5 inhibitors for erectile dysfunction: a systematic review and network meta-analysis. EUR Urol 2013;63:902–12.Eur Urol Suppl 65(3), e40. 10.1016/j.eururo.2013.10.014
    1. Moncada I, Jara J, Subirá D, Castaño I, Hernández C. Efficacy of Sildenafil citrate at 12 hours after dosing: re-exploring the therapeutic window. Eur Urol. 2004;46(3):357–361. doi: 10.1016/j.eururo.2004.04.025.
    1. Hyland R, Roe EG, Jones BC, Smith DA. Identification of the cytochrome P450 enzymes involved in then-demethylation of sildenafil. Br J Clin Pharmacol. 2001;51(3):239–248. doi: 10.1046/j.1365-2125.2001.00318.x.
    1. Nichols DJ, Muirhead GJ, Harness JA. Pharmacokinetics of sildenafil after single oral doses in healthy male subjects: absolute bioavailability, food effects and dose proportionality. Br J Clin Pharmacol. 2002;53:5S–12S. doi: 10.1046/j.0306-5251.2001.00027.x.
    1. Lim D, Park K, Hwang W, Kim J, Kim B. Difference in protective effects of GIP and GLP-1 on endothelial cells according to cyclic adenosine monophosphate response. Exp Ther Med. 2017;13(5):2558–2564. doi: 10.3892/etm.2017.4279.
    1. Gumprecht J. Cardiovascular safety of dipeptidyl peptidase-4 (DPP-4) inhibitors. Clin Diabetol. 2016;4(6):238–242. doi: 10.5603/dk.2015.0027.
    1. Surendran S, Paul D, Pokharkar S, Deshpande A, Giri S, N., S. A lc-ms/Ms method for simultaneous estimation of a novel anti-diabetic combination of saxagliptin and dapagliflozin using a polarity switch approach: application to in vivo rat pharmacokinetic study. Anal Methods. 2019;11(2):219–226. doi: 10.1039/c8ay02087f.
    1. Patel CG, Li L, Girgis S, Kornhauser DM, Frevert EU, Boulton DW (2011) Two-way pharmacokinetic interaction studies between saxagliptin and cytochrome P450 substrates or inhibitors: simvastatin, diltiazem extended-release, and ketoconazole. Clin Pharmacol: Adv Appl 13. 10.2147/cpaa.s15227
    1. Balasubramanian R, Maideen NM. HMG-CoA reductase inhibitors (Statins) and their drug interactions involving CYP enzymes, P-glycoprotein and OATP transporters-an overview. Curr Drug Metab. 2021;22(5):328–341. doi: 10.2174/1389200222666210114122729.
    1. Lim PH, Moorthy P, Benton KG. The clinical safety of viagra. Ann N Y Acad Sci. 2002;962(1):378–388. doi: 10.1111/j.1749-6632.2002.tb04082.x.
    1. Krenzelok EP, Krenzelok E. Sildenafil: clinical toxicology profile. J Toxicol Clin Toxicol. 2000;38(6):645–651. doi: 10.1081/clt-100102015.
    1. Mason RP, Jacob RF, Kubant R, Walter MF, Bellamine A, Jacoby A, Mizuno Y, Malinski T. Effect of enhanced glycemic control with saxagliptin on endothelial nitric oxide release and CD40 levels in obese rats. J Atheroscler Thromb. 2011;18(9):774–783. doi: 10.5551/jat.7666.
    1. Raslan M, Eslam MS, Sara AR, Sabri NA (2022) Determination of Vardenafil in human plasma by lc/Ms/Ms and its clinical applications. Saudi J Med Pharm Sci 8(2), 53–61. 10.36348/sjmps.2022.v08i02.003
    1. Sara AR, Raslan M, Eslam MS, Sabri NA (2022) Virtual and on site vaccination clinics of COVID-19. Will it be applicable. Acta Sci Pharm Sci 141–144. 10.31080/asps.2022.06.0844

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