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European Journal of Clinical Pharmacology

, Volume 74, Issue 12, pp 1605–1613 | Cite as

A pharmacokinetic drug-drug interaction study between pregabalin and tramadol in healthy volunteers

  • Soyoung Lee
  • Yun Kim
  • Janice Ji Sung Lee
  • Guangjin Im
  • Joo-Youn Cho
  • Jae-Yong Chung
  • Seonghae Yoon
Pharmacokinetics and Disposition

Abstract

Purpose

Combination therapy of pregabalin and tramadol is used to treat chronic neuropathic pain; however, the pharmacokinetic (PK) interactions of these drugs has not been studied. This study aimed to evaluate PK interactions between pregabalin and tramadol and the safety of combination therapy.

Methods

A randomized, open-label, multiple-dose, three-treatment, three-period, six-sequence cross-over study was conducted in healthy subjects. All subjects received the following three treatments for 4 days in each period: pregabalin 150 mg twice daily; tramadol extended-release (ER) 200 mg in the morning, and 100 mg in the evening; and co-administration of pregabalin 150 mg and tramadol ER 200 mg in the morning, and pregabalin 150 mg and tramadol ER 100 mg in the evening.

Results

A total of 21 subjects completed the study with no clinically significant safety issues. For pregabalin, the geometric mean ratio (GMR) (90% CI; confidence interval) of combination therapy to monotherapy for maximum concentration at steady state (Cmax,ss) and area under the concentration curve from 0 to dosing interval time at steady state (AUCτ,ss) were 0.8801 (0.8043–0.9632) and 1.0830 (1.0569–1.1098), respectively. The corresponding values for tramadol were 1.0177 (0.9839–1.0526) and 1.0152 (0.9896–1.0414), respectively. The GMR (90% CI) of combination therapy to monotherapy of O-desmethyl-tramadol for Cmax,ss and AUCτ,ss was 1.0465 (1.0095–1.0848) and 1.0361 (1.0001–1.0734), respectively.

Conclusions

There were no significant drug interactions between pregabalin and tramadol, considering that all of the 90% CI of PK measures were within the conventional bioequivalence range. Both drugs were well tolerated when administered concomitantly.

Keywords

Drug-drug interactions Pharmacokinetics Pregabalin Tramadol 

Notes

Authorship statement

Guarantor of the article: Seonghae Yoon.

Building the study concept: Yun Kim, Guangjin Im, Jae-Yong Chung, Seonghae Yoon.

Study design and acquisition of data: Yun Kim, Guangjin Im, Jae-Yong Chung, and Seonghae Yoon.

Data analysis and interpretation: Soyoung Lee, Yun Kim, Janice Ji Sung Lee, Guangjin Im, Joo-Youn Cho, Jae-Yong Chung, and Seonghae Yoon.

Drafting this manuscript: Soyoung Lee.

Final editing of the manuscript: Soyoung Lee, Yun Kim, Janice Ji Sung Lee, Guangjin Im, Joo-Youn Cho, Jae-Yong Chung, and Seonghae Yoon.

Funding information

This study was sponsored by SamChunDang Pharm. Co., Ltd., Seoul, Republic of Korea.

Compliance with ethical standards

This study was approved by the institutional review board of Seoul National University Bundang Hospital, Republic of Korea (no. B-1604-341-006) and registered with the Clinical Research Information Service (KCT 0002657). All subjects provided their written informed consent form prior to participating in this study. The study was conducted in compliance with the Declaration of Helsinki and followed the Guideline of Good Clinical Practice.

Conflict of interest

Janice Ji Sung Lee and Guangjin Im are employees of SamChunDang Pharm. Co., Ltd., Seoul, Republic of Korea, but the other authors have no competing interests to declare.

Supplementary material

228_2018_2543_MOESM1_ESM.docx (14 kb)
Online Resource 1 Determination of Plasma Pregabalin, Tramadol, and O-desmethyl tramadol Concentrations (DOCX 13 kb)
228_2018_2543_MOESM2_ESM.docx (101 kb)
Online Resource 2 Supplementary Fig. 1 Individual comparison of Cmax,ss and AUCτ,ss of pregabalin (a, d), tramadol (b, e) and O-desmethyl tramadol (c, f) between the monotherapy group and combination therapy group. (DOCX 101 kb)

References

  1. 1.
    Campbell JN, Meyer RA (2006) Mechanisms of neuropathic pain. Neuron 52(1):77–92CrossRefGoogle Scholar
  2. 2.
    Inoue S, Taguchi T, Yamashita T, Nakamura M, Ushida T (2017) The prevalence and impact of chronic neuropathic pain on daily and social life: a nationwide study in a Japanese population. Eur J Pain 21(4):727–737CrossRefGoogle Scholar
  3. 3.
    Yawn BP, Wollan PC, Weingarten TN, Watson JC, Hooten WM, Melton LJ III (2009) The prevalence of neuropathic pain: clinical evaluation compared with screening tools in a community population. Pain Med 10(3):586–593CrossRefGoogle Scholar
  4. 4.
    Torrance N, Smith BH, Bennett MI, Lee AJ (2006) The epidemiology of chronic pain of predominantly neuropathic origin. Results from a general population survey. J Pain 7(4):281–289CrossRefGoogle Scholar
  5. 5.
    Dworkin RH, O’connor AB, Backonja M, Farrar JT, Finnerup NB, Jensen TS, Kalso EA, Loeser JD, Miaskowski C, Nurmikko TJ (2007) Pharmacologic management of neuropathic pain: evidence-based recommendations. Pain 132(3):237–251CrossRefGoogle Scholar
  6. 6.
    O'Connor AB, Dworkin RH (2009) Treatment of neuropathic pain: an overview of recent guidelines. Am J Med 122(10):S22–S32CrossRefGoogle Scholar
  7. 7.
    Fink K, Dooley DJ, Meder WP, Suman-Chauhan N, Duffy S, Clusmann H, Göthert M (2002) Inhibition of neuronal Ca 2+ influx by gabapentin and pregabalin in the human neocortex. Neuropharmacology 42(2):229–236CrossRefGoogle Scholar
  8. 8.
    Dooley DJ, Donovan CM, Pugsley TA (2000) Stimulus-dependent modulation of [3H] norepinephrine release from rat neocortical slices by gabapentin and pregabalin. J Pharmacol Exp Ther 295(3):1086–1093PubMedGoogle Scholar
  9. 9.
    Bockbrader HN, Radulovic LL, Posvar EL, Strand JC, Alvey CW, Busch JA, Randinitis EJ, Corrigan BW, Haig GM, Boyd RA (2010) Clinical pharmacokinetics of pregabalin in healthy volunteers. J Clin Pharmacol 50(8):941–950CrossRefGoogle Scholar
  10. 10.
    Taylor CP, Angelotti T, Fauman E (2007) Pharmacology and mechanism of action of pregabalin: the calcium channel α 2–δ (alpha 2–delta) subunit as a target for antiepileptic drug discovery. Epilepsy Res 73(2):137–150CrossRefGoogle Scholar
  11. 11.
    Raffa RB, Friderichs E, Reimann W, Shank RP, Codd EE, Vaught JL, Jacoby HI, Selve N (1993) Complementary and synergistic antinociceptive interaction between the enantiomers of tramadol. J Pharmacol Exp Ther 267(1):331–340PubMedGoogle Scholar
  12. 12.
    Grond S, Sablotzki A (2004) Clinical pharmacology of tramadol. Clin Pharmacokinet 43(13):879–923CrossRefGoogle Scholar
  13. 13.
    Subrahmanyam V, Renwick AB, Walters DG, Young PJ, Price RJ, Tonelli AP, Lake BG (2001) Identification of cytochrome P-450 isoforms responsible for cis-tramadol metabolism in human liver microsomes. Drug Metab Dispos 29(8):1146–1155PubMedGoogle Scholar
  14. 14.
    Gillen C, Haurand M, Kobelt DJ, Wnendt S (2000) Affinity, potency and efficacy of tramadol and its metabolites at the cloned human μ-opioid receptor. Naunyn Schmiedeberg's Arch Pharmacol 362(2):116–121CrossRefGoogle Scholar
  15. 15.
    Althoff E (2015) Novartis deepens its industry leading pipeline with acquisition of Spinifex Pharmaceuticals, Inc. https://www.novartiscom/news/media-releases/novartis-deepens-its-industry-leading-pipeline-acquisition-spinifex
  16. 16.
    Bangalore S, Kamalakkannan G, Parkar S, Messerli FH (2007) Fixed-dose combinations improve medication compliance: a meta-analysis. Am J Med 120(8):713–719CrossRefGoogle Scholar
  17. 17.
    U.S. Food and Drug Administration, Center for Drug Evaluation and Research (CDER) (2012) Drug interaction studies-study design, data analysis, implications for dosing, and labeling recommendations. https://www.xenotech.com/regulatory-documents/2012/2012_guidance.aspx
  18. 18.
    Khandave SS, Sawant SV, Joshi SS, Bansal YK, Kadam SS (2010) Comparative bioequivalence studies of tramadol hydrochloride sustained-release 200 mg tablets. Drug design, development and therapy 4:367PubMedPubMedCentralGoogle Scholar
  19. 19.
    Filipe A, Almeida S, Pedroso PF, Neves R, Marques S, Sicard E, Massicotte J, Ortuno J (2015) Single-dose, randomized, open-label, two-way, crossover bioequivalence study of two formulations of pregabalin 300 mg hard capsules in healthy volunteers under fasting conditions. Drugs in R&D 15(2):195–201CrossRefGoogle Scholar
  20. 20.
    U.S. Food and Drug Administration (2004) Lyrica (pregabalin) Capsules Clinical Pharmacology Biopharmaceutics Review (s). https://www.accessdata.fda.gov/drugsatfda_docs/nda/2005/021724s000_ClinPharmR.pdf
  21. 21.
    Ben Menachem E (2004) Pregabalin pharmacology and its relevance to clinical practice. Epilepsia 45(s6):13–18CrossRefGoogle Scholar
  22. 22.
    U.S. Food and Drug Administration (2008) Ryzolt (tramadol) Extended-release tablets Clinical Pharmacology Biopharmaceutics Review (s). https://www.accessdata.fda.gov/drugsatfda_docs/nda/2008/021745s000_ClinPharmR.pdf
  23. 23.
    Karhu D, Fradette C, Potgieter MA, Ferreira MM, Terblanché J (2010) Comparative pharmacokinetics of a once daily tramadol extended release tablet and an immediate release reference product following single dose and multiple dose administration. J Clin Pharmacol 50(5):544–553CrossRefGoogle Scholar
  24. 24.
    Herbert MK, Weis R, Holzer P (2007) The enantiomers of tramadol and its major metabolite inhibit peristalsis in the guinea pig small intestine via differential mechanisms. BMC Pharmacol 7:5.  https://doi.org/10.1186/1471-2210-7-5 CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Bockbrader HN, Wesche D, Miller R, Chapel S, Janiczek N, Burger P (2010) A comparison of the pharmacokinetics and pharmacodynamics of pregabalin and gabapentin. Clin Pharmacokinet 49(10):661–669CrossRefGoogle Scholar
  26. 26.
  27. 27.
    Crighton IM, Martin PH, Hobbs GJ, Cobby TF, Fletcher AJ, Stewart PD (1998) A comparison of the effects of intravenous tramadol, codeine, and morphine on gastric emptying in human volunteers. Anesth Analg 87(2):445–449PubMedGoogle Scholar
  28. 28.
    Raouf M, Atkinson TJ, Crumb MW, Fudin J (2017) Rational dosing of gabapentin and pregabalin in chronic kidney disease. J Pain Res 10:275–278.  https://doi.org/10.2147/JPR.S130942 CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Mukae T, Fujita W, Ueda H (2016) P-glycoprotein inhibitors improve effective dose and time of pregabalin to inhibit intermittent cold stress-induced central pain. J Pharmacol Sci 131(1):64–67.  https://doi.org/10.1016/j.jphs.2016.01.002 CrossRefPubMedGoogle Scholar
  30. 30.
    Kanaan M, Daali Y, Dayer P, Desmeules J (2009) Uptake/efflux transport of tramadol enantiomers and O-desmethyl-tramadol: focus on P-glycoprotein. Basic Clin Pharmacol Toxicol 105(3):199–206.  https://doi.org/10.1111/j.1742-7843.2009.00428.x CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    van Seventer R, Feister HA, Young JP Jr, Stoker M, Versavel M, Rigaudy L (2006) Efficacy and tolerability of twice-daily pregabalin for treating pain and related sleep interference in postherpetic neuralgia: a 13 week, randomized trial. Curr Med Res Opin 22(2):375–384CrossRefGoogle Scholar
  32. 32.
    Satoh J, Yagihashi S, Baba M, Suzuki M, Arakawa A, Yoshiyama T, Shoji S (2011) Efficacy and safety of pregabalin for treating neuropathic pain associated with diabetic peripheral neuropathy: a 14 week, randomized, double blind, placebo controlled trial. Diabet Med 28(1):109–116CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Soyoung Lee
    • 1
  • Yun Kim
    • 1
  • Janice Ji Sung Lee
    • 2
  • Guangjin Im
    • 2
  • Joo-Youn Cho
    • 1
  • Jae-Yong Chung
    • 1
    • 3
  • Seonghae Yoon
    • 3
  1. 1.Department of Clinical Pharmacology and TherapeuticsSeoul National University College of MedicineSeoulRepublic of Korea
  2. 2.SamChunDang Pharm.Co.,Ltd.SeoulRepublic of Korea
  3. 3.Clinical Trials CenterSeoul National University Bundang HospitalSeongnamRepublic of Korea

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