Clinical Pharmacokinetics

, Volume 45, Issue 3, pp 297–303 | Cite as

Effects of Chronic Renal Failure on the Pharmacokinetics of Ruboxistaurin and its Active Metabolite 338522

  • Stephen Wise
  • Eunice Yuen
  • Clark Chan
  • Yeo Kwee Poo
  • Lorraine Teng
  • Titus Lau
  • James Voelker
Original Research Article

Abstract

Background

Ruboxistaurin, a specific inhibitor of the ′1 and ′2 isoforms of protein kinase C, is currently in clinical development for the treatment of several diabetic microvascular complications. The major metabolite, N-desmethyl ruboxistaurin (metabolite 338522), is equipotent in its inhibitory activity. The elimination of ruboxistaurin and its metabolites is primarily through bile and the faecal route, with urinary excretion constituting only a minor route.

Objective

To assess the effects of chronic renal insufficiency on the pharmacokinetics of ruboxistaurin and metabolite 338522.

Methods

Six healthy subjects (creatinine clearance >80 mL/min/1.73m2) and six end-stage renal disease (ESRD) subjects requiring long-term haemodialysis were studied. All subjects received a single oral dose of ruboxistaurin 32mg followed by serial blood sampling up to 72 hours. ESRD subjects underwent haemodialysis approximately 58 hours after dosing, with blood samples obtained immediately before and after dialysis.

Results

No differences were observed in the pharmacokinetic parameters (area under the plasma concentration-time curve from time zero to infinity [AUCα], maximum plasma concentration [Cmax] and elimination half-life [t1/2]) of ruboxistaurin and metabolite 338522 between healthy and ESRD subjects Plasma concentrations of ruboxistaurin were below the lower limit of quantification by the time of haemodialysis. The predicted post-dialysis plasma concentrations of metabolite 338522 were not statistically different from the observed values (p = 0.163). Ruboxistaurin was well tolerated in both groups of subjects.

Conclusion

These results indicate that the kidney is not an important route of metabolism or excretion for ruboxistaurin and metabolite 338522. Based on the pharmacokinetic and tolerability findings, no formal dosage adjustment of ruboxistaurin should be required for patients with any degree of renal impairment who are undergoing haemodialysis.

Notes

Acknowledgements

This study was financially supported by Eli Lilly and Company, Indianapolis, IN, USA. With the exception of Dr Lau, all authors are employees of Eli Lilly and Company.

References

  1. 1.
    Jirousek MR, Gillig JR, Gonzalez CM, et al. (S)-13-[(Dimethylamino)methyl]-10,11,14,15-tetrahydro-4,9:16,21-dimetheno-1H,13H-dibenzo[e,k]pyrrolo[3,4-h][1,4,13] oxadiazacyclohexadecene-1,3(2H)-dione (LY333531) and related analogues: isozyme selective inhibitors of protein kinase Cβ. J Med Chem 1996 Jul; 39(14): 2664–71PubMedCrossRefGoogle Scholar
  2. 2.
    Aiello LP. The potential role of PKC beta in diabetic retinopathy and macular edema. Surv Opthalmol 2002 Dec; 47 Suppl. 2: S263–9CrossRefGoogle Scholar
  3. 3.
    Tuttle KR, Anderson PW. A novel potential therapy for diabetic nephropathy and vascular complications: protein kinase C beta inhibition. Am J Kidney Dis 2003 Sep; 42(3): 456–65PubMedCrossRefGoogle Scholar
  4. 4.
    Engel GL, Farid NA, Faul MM, et al. Salt form selection and characterization of ruboxistaurin mesylate monohydrate. Int J Pharm 2000 Apr 5; 198(2): 239–47PubMedCrossRefGoogle Scholar
  5. 5.
    Tesfamariam B, Brown ML, Deykin D, et al. Elevated glucose promotes generation of endothelium-derived vasoconstrictor prostanoids in rabbit aorta. J Clin Invest 1990 Mar; 85(3): 929–32PubMedCrossRefGoogle Scholar
  6. 6.
    Inoguchi T, Battan R, Handler E, et al. Preferential elevation of protein kinase C isoform and diacylglycerol levels in the aorta and heart of diabetic rats: differential reversibility to glycemic control by islet cell transplantation. Proc Natl Acad Sci U S A 1992 Nov; 89(22): 11059–63PubMedCrossRefGoogle Scholar
  7. 7.
    Ishii H, Jirousek MR, Koya D, et al. Amelioration of vascular dysfunctions in diabetic rats by an oral PKC beta inhibitor. Science 1996 May; 272(5262): 728–31PubMedCrossRefGoogle Scholar
  8. 8.
    Aiello LP, Bursell SE, Clermont A, et al. Vascular endothelial growth factor-induced retinal permeability is mediated by protein kinase C in vivo and suppressed by an orally effective beta-isoform-selective inhibitor. Diabetes 1997 Sep; 46(9): 1473–80PubMedCrossRefGoogle Scholar
  9. 9.
    Nakamura J, Kato K, Hamada Y, et al. A protein kinase C-beta-selective inhibitor ameliorates neural dysfunction in streptozotocin-induced diabetic rats. Diabetes 1999 Oct; 48(10): 2090–5PubMedCrossRefGoogle Scholar
  10. 10.
    Nonaka A, Kiryu J, Tsujikawa A, et al. PKC-beta inhibitor (LY333531) attenuates leukocyte entrapment in retinal micro-circulation of diabetic rats. Invest Ophthalmol Vis Sci 2000 Aug; 41(9): 2702–6PubMedGoogle Scholar
  11. 11.
    Koya D, Jirousek MR, Lin YW, et al. Characterization of protein kinase C beta isoform activation on the gene expression of transforming growth factor-beta, extracellular matrix components, and prostanoids in the glomeruli of diabetic rats. J Clin Invest 1997 Jul; 100(1): 115–26PubMedCrossRefGoogle Scholar
  12. 12.
    Molecule of the month: ruboxistaurin mesilate hydrate. Drug News Perspect 2003 Dec; 16(10): 691Google Scholar
  13. 13.
    Ring BJ, Gillespie JS, Binkley SN, et al. The interactions of a selective protein kinase C beta inhibitor with the human cytochromes P450. Drug Metab Dispos 2002 Sep; 30(9): 957–61PubMedCrossRefGoogle Scholar
  14. 14.
    Demolle D, de Suray JM, Vandenhende F, et al. LY333531 single escalating oral dose study in healthy volunteers [abstract]. Diabetologia 1998; 41 Suppl. 1: A283Google Scholar
  15. 15.
    Burkey JL, Campanale KM, O’Bannon DD, et al. Disposition of LY333531, a selective protein kinase C beta inhibitor, in the Fischer 344 rat and beagle dog. Xenobiotica 2002 Nov; 32(11): 1045–52PubMedCrossRefGoogle Scholar
  16. 16.
    Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron 1976; 16(1): 31–41PubMedCrossRefGoogle Scholar

Copyright information

© Adis Data Information BV 2006

Authors and Affiliations

  • Stephen Wise
    • 1
  • Eunice Yuen
    • 1
  • Clark Chan
    • 1
  • Yeo Kwee Poo
    • 1
  • Lorraine Teng
    • 1
  • Titus Lau
    • 2
  • James Voelker
    • 3
  1. 1.Lilly-NUS Centre for Clinical PharmacologyNational University of SingaporeSingapore
  2. 2.Renal Division, Department of MedicineNational University HospitalSingapore
  3. 3.Lilly Research LaboratoriesEli Lilly and CompanyIndianapolisUSA

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