Advertisement

Investigational New Drugs

, Volume 32, Issue 5, pp 913–927 | Cite as

Design of informative renal impairment studies: evaluation of the impact of design stratification on bias, precision and dose adjustment error

  • J. G. Coen van HasseltEmail author
  • Jan H. M. Schellens
  • Jos H. Beijnen
  • Alwin D. R. Huitema
PHASE I STUDIES

Summary

Purpose Renal impairment (RI) studies are conducted to estimate the impact of RI on pharmacokinetics (PK). In some disease areas, these studies can be difficult to conduct, for instance due to the limited number of eligible patients. The objective of this analysis was to evaluate bias and precision of population PK parameters, and the dose adjustment error (DAE) for RI studies i) with different levels of study design imbalance in the stratification of subjects across RI categories, and ii) that include additional patients in the control arm of RI studies, that may be available from previously conducted PK studies. Methods Study designs were simulated and re-estimated using a hypothetical 2-compartmental PK model with varying magnitude of the fraction of renal elimination (FR) and magnitude of between-subject variability (BSV). The DAE was computed based on the difference between the theoretical necessary dose adjustment versus the empirical estimated dose adjustment to reach a similar exposure as controls. Results Although some design imbalance may still lead to DAEs of acceptable magnitude (DAE < −11.05–14.44 inter-quartile range, IQR), at least some patients are necessary in the more severe RI groups. When 100 additional patients with normal renal function were included in a sub-informative design, the DAE changed from < −7.63–16.64 IQR to < −8.89−8.69 IQR. Conclusions We quantified the impact of study design imbalance on bias and precision of PK parameters and DAE, as may occur for RI studies in some indications. Adding additional data from earlier studies to the analysis dataset improves the bias and precision of PK parameters.

Keywords

Renal impairment Study design Pharmacokinetics Simulation Modelling 

Notes

Conflict of interest

The authors declare no conflict of interest.

References

  1. 1.
    U.S. Food and Drug Administration (2010) Guidance for industry pharmacokinetics in patients with impaired renal function study design, data analysis, and impact on dosing and labeling. Analysis. http://www.fda.gov/downloads/Drugs/Guidances/UCM204959.pdf.
  2. 2.
    Ibrahim S, Honig P, Huang SM et al (2000) Clinical pharmacology studies in patients with renal impairment: past experience and regulatory perspectives. J Clin Pharmacol 40:31–38CrossRefPubMedGoogle Scholar
  3. 3.
    Zhang Y, Zhang L, Abraham S et al (2009) Assessment of the impact of renal impairment on systemic exposure of new molecular entities: evaluation of recent new drug applications. Clin Pharmacol Ther 85:305–311CrossRefPubMedGoogle Scholar
  4. 4.
    Committee for medicinal products for human use, European Medicines Agency (2004) Note for guidance on the evaluation of the pharmacokinetics of medicinal products in patients with impaired renal function. http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500003123.pdf.
  5. 5.
    Kubitza D, Becka M, Mueck W et al (2010) Effects of renal impairment on the pharmacokinetics, pharmacodynamics and safety of rivaroxaban, an oral, direct Factor Xa inhibitor. Br J Clin Pharmacol 70:703–712PubMedCentralCrossRefPubMedGoogle Scholar
  6. 6.
    Lobo ED, Heathman M, Kuan H-Y et al (2010) Effects of varying degrees of renal impairment on the pharmacokinetics of duloxetine: analysis of a single-dose phase I study and pooled steady-state data from phase II/III trials. Clin Pharmacokinet 49:311–321CrossRefPubMedGoogle Scholar
  7. 7.
    Rahman A, White RM (2006) Cytotoxic anticancer agents and renal impairment study: the challenge remains. J Clin Oncol 24:533–536CrossRefPubMedGoogle Scholar
  8. 8.
    Clinicaltrials.gov.Google Scholar
  9. 9.
    Green B, Greenwood M, Saltissi D et al (2005) Dosing strategy for enoxaparin in patients with renal impairment presenting with acute coronary syndromes. Br J Clin Pharmacol 59:281–290PubMedCentralCrossRefPubMedGoogle Scholar
  10. 10.
    Beal SL, Sheiner LB, Boeckman AJ, Bauer RJ (2009) NONMEM user's guides (1989-2009). Icon Development Solutions, Ellicott CityGoogle Scholar
  11. 11.
    Lindbom L, Ribbing J, Johnsson E (2004) Perl-speaks-NONMEM (PsN) - A Perl module for NONMEM related programming. Comput Method Prog Biomed 75:85–94CrossRefGoogle Scholar
  12. 12.
    R Development Core Team (2011) R: A language and environment for statistical computing. Vienna, AustriaGoogle Scholar
  13. 13.
    Devriese LA (2011) Pharmacokinetics of novel anticancer drugs and dynamics of circulating tumor cells in early clinical studies. Utrecht University, Netherlands, p 45–66. http://dspace.library.uu.nl/handle/1874/212943
  14. 14.
    Lal R, Sukbuntherng J, Luo W et al (2012) Clinical pharmacokinetics of gabapentin after administration of gabapentin enacarbil extended-release tablets in patients with varying degrees of renal function using data from an open-label, single-dose pharmacokinetic study. Clin Ther 34:201–213CrossRefPubMedGoogle Scholar
  15. 15.
    Li Z, Tenhoor C, Marbury T et al (2011) Pharmacokinetics and pharmacodynamics of tonapofylline in subjects with severe renal impairment and in elderly subjects. Int J Clin Pharmacol Ther 49:563–570CrossRefPubMedGoogle Scholar
  16. 16.
    Galsky MD, Camacho LH, Chiorean EG et al (2012) Phase I study of the effects of renal impairment on the pharmacokinetics and safety of satraplatin in patients with refractory solid tumors. Ann Oncol 23:1037–1044CrossRefPubMedGoogle Scholar
  17. 17.
    Bethke TD, Hartmann M, Hünnemeyer A et al (2011) Influence of renal impairment on the pharmacokinetics of oral roflumilast: an open-label, parallel-group, single-center study. Int J Clin Pharmacol Ther 49:491–499CrossRefPubMedGoogle Scholar
  18. 18.
    Cawello W, Ahrweiler S, Sulowicz W et al (2012) Single dose pharmacokinetics of the transdermal rotigotine patch in patients with impaired renal function. Br J Clin Pharmacol 73:46–54PubMedCentralCrossRefPubMedGoogle Scholar
  19. 19.
    Graefe-Mody U, Friedrich C, Port A et al (2011) Effect of renal impairment on the pharmacokinetics of the dipeptidyl peptidase-4 inhibitor linagliptin(*). Diabetes Obes Metab 13:939–946CrossRefPubMedGoogle Scholar
  20. 20.
    Peeters P, Bockbrader H, Spaans E et al (2011) Asenapine pharmacokinetics in hepatic and renal impairment. Clin Pharmacokinet 50:471–481CrossRefPubMedGoogle Scholar
  21. 21.
    Gschwend S, Ebert W, Schultze-Mosgau M, Breuer J (2011) Pharmacokinetics and imaging properties of Gd-EOB-DTPA in patients with hepatic and renal impairment. Invest Radiol 46:556–566CrossRefPubMedGoogle Scholar
  22. 22.
    Kosaka T, Hosokawa K, Shime N et al (2012) Effects of renal function on the pharmacokinetics and pharmacodynamics of prophylactic cefazolin in cardiothoracic surgery. Eur J Clin Microbiol Infect Dis 31:193–199CrossRefPubMedGoogle Scholar
  23. 23.
    Tomkinson H, Kemp J, Oliver S et al (2011) Pharmacokinetics and tolerability of zibotentan (ZD4054) in subjects with hepatic or renal impairment: two open-label comparative studies. BMC Clin Pharmacol 11:3PubMedCentralCrossRefPubMedGoogle Scholar
  24. 24.
    Schmid K, Pascual S, Gil EG et al (2010) Pharmacokinetics and safety of aclidinium bromide, A muscarinic antagonist, in adults with normal or impaired renal function: a phase I, open-label, single-dose clinical trial. Clin Ther 32:1798–1812CrossRefPubMedGoogle Scholar
  25. 25.
    Bauman JW, Antal JM, Adams LM et al (2012) Effect of hepatic or renal impairment on the pharmacokinetics of casopitant, a NK-1 receptor antagonist. Invest New Drugs 30:662–671CrossRefPubMedGoogle Scholar
  26. 26.
    Nichols AI, Richards LS, Behrle JA et al (2011) The pharmacokinetics and safety of desvenlafaxine in subjects with chronic renal impairment. Int J Clin Pharmacol Ther 49:3–13CrossRefPubMedGoogle Scholar
  27. 27.
    Shiffman ML, Pol S, Rostaing L et al (2011) Efficacy and pharmacokinetics of adefovir dipivoxil liquid suspension in patients with chronic hepatitis B and renal impairment. J Clin Pharmacol 51:1293–1301CrossRefPubMedGoogle Scholar
  28. 28.
    Bruderer S, Sasu B, Tsvitbaum N, Dingemanse J (2011) Influence of severe renal impairment on the pharmacokinetics of clazosentan. J Clin Pharmacol 51:413–421CrossRefPubMedGoogle Scholar
  29. 29.
    Bauman JW, Vincent CT, Peng B et al (2011) Effect of hepatic or renal impairment on eltrombopag pharmacokinetics. J Clin Pharmacol 51:739–750CrossRefPubMedGoogle Scholar
  30. 30.
    Stangier J, Rathgen K, Stähle H, Mazur D (2010) Influence of renal impairment on the pharmacokinetics and pharmacodynamics of oral dabigatran etexilate: an open-label, parallel-group, single-centre study. Clin Pharmacokinet 49:259–268CrossRefPubMedGoogle Scholar
  31. 31.
    Smith JP, Weller S, Johnson B et al (2010) Pharmacokinetics of acyclovir and its metabolites in cerebrospinal fluid and systemic circulation after administration of high-dose valacyclovir in subjects with normal and impaired renal function. Antimicrob Agents Chemother 54:1146–1151PubMedCentralCrossRefPubMedGoogle Scholar
  32. 32.
    Jacobsen LV, Hindsberger C, Robson R, Zdravkovic M (2009) Effect of renal impairment on the pharmacokinetics of the GLP-1 analogue liraglutide. Br J Clin Pharmacol 68:898–905PubMedCentralCrossRefPubMedGoogle Scholar
  33. 33.
    Smith W, Swan S, Marbury T, Henney H (2010) Single-Dose pharmacokinetics of sustained-release fampridine (Fampridine-SR) in healthy volunteers and adults with renal impairment. J Clin Pharmacol 50:151–159CrossRefPubMedGoogle Scholar
  34. 34.
    Khosravan R, Toh M, Garrett M et al (2010) Pharmacokinetics and safety of sunitinib malate in subjects with impaired renal function. J Clin Pharmacol 50:472–481CrossRefPubMedGoogle Scholar
  35. 35.
    Small DS, Wrishko RE, Ernest CS et al (2009) Prasugrel pharmacokinetics and pharmacodynamics in subjects with moderate renal impairment and end-stage renal disease. J Clin Pharm Ther 34:585–594CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • J. G. Coen van Hasselt
    • 1
    • 2
    • 4
    Email author
  • Jan H. M. Schellens
    • 1
    • 3
  • Jos H. Beijnen
    • 2
    • 3
  • Alwin D. R. Huitema
    • 2
  1. 1.Department of Clinical PharmacologyThe Netherlands Cancer InstituteAmsterdamThe Netherlands
  2. 2.Department of PharmacyNetherlands Cancer InstituteAmsterdamThe Netherlands
  3. 3.Faculty of Science, Department of Pharmaceutical Sciences, Division of Pharmacoepidemiology & Clinical PharmacologyUtrecht UniversityUtrechtThe Netherlands
  4. 4.Division of Pharmacology, Leiden Academic Centre for Drug ResearchLeiden UniversityLeidenThe Netherlands

Personalised recommendations