Improving Data Reliability Using a Non-Compliance Detection Method versus Using Pharmacokinetic Criteria

  • Smita A. Kshirsagar
  • Terrence F. Blaschke
  • Lewis B. Sheiner
  • M. Krygowski
  • Edward P. Acosta
  • Davide Verotta
Article

Data from clinical trials present numerous problems for the data analyst. These include non-compliance with the prescribed dosing regimen and inaccurate recollection of dosing history by patients as well as mistakes in recording data. Several methods have been proposed to address these issues. One such technique by Lu et  al. (Selecting reliable pharmacokinetic data for explanatory analyses of clinical trials in the presence of possible noncompliance. J. Pharmacokinet. Pharmacodyn. 28:343–362 (2001)) identifies occasions in pharmacokinetic (PK) data where the preceding dosing history is likely to be unreliable. We used this method, implemented in the software program NONMEM (beta) VI, to clean a dataset containing indinavir (IDV) plasma concentrations from HIV-1 infected patients. The data was also cleaned by inspection in Microsoft Excel using clinical PK criteria. A one-compartment model with first order absorption and elimination was fit to both sets of cleaned data. IDV population PK parameters obtained from these analyses were similar to those reported previously. It is established that IDV nephrotoxicity is related to high IDV exposure. However, no relationships were found between any PK parameters and nephrotoxicity in the “compliance cleaned” dataset. In the “PK cleaned” dataset, the oral clearance and apparent volume were lower by 9.1% and 6.6%, respectively in patients with any type of nephrotoxicity and the maximum IDV concentration (Cmax) was 12.1% higher. In patients suffering from nephrolithiasis in particular, Cmax was 15.5% higher. Accordingly, the use of the non-compliance detection method did not improve the reliability of our dataset over the usual method of applying clinical criteria. In fact, analyses on the compliance-cleaned dataset missed some exposure-toxicity relationships. Thus, automated methods must be tested rigorously with ‘real life’ datasets, used with caution, and always in conjunction with clinical reasoning to avoid overlooking a signal in noisy data.

Keywords

non-compliance indinavir nephrotoxicity prior 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Lu J., Gries J.M., Verotta D., Sheiner L.B. (2001) Selecting reliable pharmacokinetic data for explanatory analyses of clinical trials in the presence of possible noncompliance. J. Pharmacokinet. Pharmacodyn. 28:343–362PubMedCrossRefGoogle Scholar
  2. 2.
    Sheiner L.B., Steimer J.L. (2000). Pharmacokinetic/pharmacodynamic modeling in drug development. Annu. Rev. Pharmacol. Toxicol. 40:67–95PubMedCrossRefGoogle Scholar
  3. 3.
    Peck C.C., Barr W.H., Benet L.Z., Collins J., Desjardins R.E., Furst D.E., Harter J.G., Levy G., Ludden T., Rodman J.H. (1994). Opportunities for integration of pharmacokinetics, pharmacodynamics, and toxicokinetics in rational drug J. Clin. Pharmacol. 34:111–119Google Scholar
  4. 4.
    Guidance for Industry on Population Pharmacokinetics (1999). Available at: http://www.fda.gov/cder/guidance/1852fnl.pdfGoogle Scholar
  5. 5.
    Aarons L., Balant L.P., Mentre F., Morselli P.L., Rowland M., Steimer J.L., Vozeh S. (1996). Practical experience and issues in designing and performing population pharmacokinetic/pharmacodynamic studies. Eur. J. Clin. Pharmacol. 49:251–254PubMedCrossRefGoogle Scholar
  6. 6.
    Vrijens B., Goetghebeur E. (1999). The impact of compliance in pharmacokinetic studies. Stat. Methods Med. Res. 8:247–262PubMedCrossRefGoogle Scholar
  7. 7.
    Urquhart J. (1994). Role of patient compliance in clinical pharmacokinetics. A review of recent research. Clin. Pharmacokinet. 27:202–215Google Scholar
  8. 8.
    Morris L.S., Schulz R.M. (1992). Patient compliance – an overview. J. Clin. Pharm. Ther. 17:283–295PubMedGoogle Scholar
  9. 9.
    Girard P., Blaschke T.F., Kastrissios H., Sheiner L.B. (1998). A Markov mixed effect regression model for drug compliance. Stat. Med. 17:2313–2333PubMedCrossRefGoogle Scholar
  10. 10.
    Kenna L.A., Sheiner L.B. (2004). Estimating treatment effect in the presence of non-compliance measured with error: precision and robustness of data analysis methods. Stat. Med. 23:3561–3580PubMedCrossRefGoogle Scholar
  11. 11.
    Soy D., Beal S.L., Sheiner L.B. (2004). Population one-compartment pharmacokinetic analysis with missing dosage data. Clin. Pharmacol. Ther. 76:441–451PubMedCrossRefGoogle Scholar
  12. 12.
    Mu S., Ludden T.M. (2003). Estimation of population pharmacokinetic parameters in the presence of non-compliance. J. Pharmacokinet. Pharmacodyn. 30:53–81PubMedCrossRefGoogle Scholar
  13. 13.
    Ten Have T.R., Joffe M., Cary M. (2003). Causal logistic models for non-compliance under randomized treatment with univariate binary response. Stat. Med. 22:1255–1283PubMedCrossRefGoogle Scholar
  14. 14.
    Sato T. (2001). A method for the analysis of repeated binary outcomes in randomized clinical trials with non-compliance. Stat. Med. 20:2761–2774PubMedCrossRefGoogle Scholar
  15. 15.
    Korhonen P.A., Laird N.M., Palmgren J. (1999). Correcting for non-compliance in randomized trials: an application to the ATBC Study. Stat. Med. 18:2879–2897PubMedCrossRefGoogle Scholar
  16. 16.
    Jonsson E.N., Wade J.R., Almqvist G., Karlsson M.O. (1997). Discrimination between rival dosing histories. Pharm. Res. 14:984–991PubMedCrossRefGoogle Scholar
  17. 17.
    Gulick R.M., Meibohm A., Havlir D., Eron J.J., Mosley A., Chodakewitz J.A., Isaacs R., Gonzalez C., McMahon D., Richman D.D., Robertson M., Mellors J.W. (2003). Six-year follow-up of HIV-1-infected adults in a clinical trial of antiretroviral therapy with indinavir, zidovudine, and lamivudine. Aids 17:2345–2349PubMedCrossRefGoogle Scholar
  18. 18.
    Olyaei A.J., deMattos A.M., Bennett W.M. (2000). Renal toxicity of protease inhibitors. Curr. Opin. Nephrol. Hypertens. 9:473–476PubMedCrossRefGoogle Scholar
  19. 19.
    Gentle D.L., Stoller M.L., Jarrett T.W., Ward J.F., Geib K.S., Wood A.F. (1997). Protease inhibitor-induced urolithiasis. Urology 50:508–511PubMedCrossRefGoogle Scholar
  20. 20.
    Bruce R.G., Munch L.C., Hoven A.D., Jerauld R.S., Greenburg R., Porter W.H., Rutter P.W. (1997). Urolithiasis associated with the protease inhibitor indinavir. Urology 50:513–518PubMedCrossRefGoogle Scholar
  21. 21.
    Dieleman J.P., Gyssens I.C., van der Ende M.E., de Marie S., Burger D.M. (1999). Urological complaints in relation to indinavir plasma concentrations in HIV-infected patients. Aids 13:473–478PubMedCrossRefGoogle Scholar
  22. 22.
    Dieleman J.P., Sturkenboom M.C., Jambroes M., Gyssens I.C., Weverling G.J., ten Veen J.H., Schrey G., Reiss P., Stricker B.H. (2002). Risk factors for urological symptoms in a cohort of users of the HIV protease inhibitor indinavir sulfate: the ATHENA cohort. Arch. Intern. Med. 162:1493–1501PubMedCrossRefGoogle Scholar
  23. 23.
    Dieleman J.P., van Rossum A.M., Stricker B.C., Sturkenboom M.C., de Groot R., Telgt D., Blok W.L., Burger D.M., Blijenberg B.G., Zietse R., Gyssens I.C. (2003). Persistent leukocyturia and loss of renal function in a prospectively monitored cohort of HIV-infected patients treated with indinavir. J. Acquir. Immune. Defic. Syndr. 32:135–1427DPubMedGoogle Scholar
  24. 24.
    Martinez E., Leguizamon M., Mallolas J., Miro J.M., Gatell J.M. (1999). Influence of environmental temperature on incidence of indinavir-related nephrolithiasis. Clin. Infect. Dis. 29:422–425PubMedGoogle Scholar
  25. 25.
    Saltel E., Angel J.B., Futter N.G., Walsh W.G., O’Rourke K., Mahoney J.E. (2000). Increased prevalence and analysis of risk factors for indinavir nephrolithiasis. J. Urol. 164:1895–1897PubMedCrossRefGoogle Scholar
  26. 26.
    Solas C., Basso S., Poizot-Martin I., Ravaux I., Gallais H., Gastaut J.A., Durand A., Lacarelle B. (2002). High indinavir Cmin is associated with higher toxicity in patients on indinavir-ritonavir 800/100 mg twice-daily regimen. J. Acquir. Immune. Defic. Syndr. 29:374–377PubMedGoogle Scholar
  27. 27.
    Sutherland S.E., Reigle M.D., Seftel A.D., Resnick M.I. (1997). Protease inhibitors and urolithiasis. J. Urol. 158:31–33PubMedCrossRefGoogle Scholar
  28. 28.
    Trainor L.D., Steinberg J.P., Austin G.W., Solomon H.M. (1998). Indinavir identification of patients at increased risk of developing nephrotoxicity. Arch. Pathol. Lab. Med. 122:256–259PubMedGoogle Scholar
  29. 29.
    Gagnon R.F., Tecimer S.N., Watters A.K., Tsoukas C.M. (2000). Prospective study of urinalysis abnormalities in HIV-positive individuals treated with indinavir. Am. J. Kidney Dis. 36:507–515PubMedGoogle Scholar
  30. 30.
    Kopp J.B., Falloon J., Filie A., Abati A., King C., Hortin G.L., Mican J.M., Vaughan E., Miller K.D. (2002). Indinavir-associated interstitial nephritis and urothelial inflammation: clinical and cytologic findings. Clin. Infect. Dis. 34:1122–1128PubMedCrossRefGoogle Scholar
  31. 31.
    Kopp J.B., Miller K.D., Mican J.A., Feuerstein I.M., Vaughan E., Baker C., Pannell L.K., Falloon J. (1997). Crystalluria and urinary tract abnormalities associated with indinavir. Ann. Intern. Med. 127:119–125PubMedGoogle Scholar
  32. 32.
    Wade J.R., Kelman A.W., Howie C.A., Whiting B. (1993). Effect of misspecification of the absorption process on subsequent parameter estimation in population analysis. J. Pharmacokinet. Biopharm. 21:209–222PubMedCrossRefGoogle Scholar
  33. 33.
    Gisleskog P.O., Karlsson M.O., Beal S.L. (2002). Use of prior information to stabilize a population data analysis. J. Pharmacokinet. Pharmacodyn. 29:473–505PubMedCrossRefGoogle Scholar
  34. 34.
    Beal S.L., Sheiner L.B.(eds) (1992). NONMEM Users Guide, NONMEM Project Group. University of California at San Francisco, San FranciscoGoogle Scholar
  35. 35.
    Gulick R.M., Smeaton L.M., D’Aquila R.T., Eron J.J., Currier J.S., Gerber J.G., Acosta E., Sommadossi J.P., Tung R., Snyder S., Kuritzkes D.R., Murphy R.L. (2001). Indinavir, nevirapine, stavudine, and lamivudine for human virus-infected, amprenavir-experienced subjects: AIDS Clinical Trials Group protocol 373. J. Infect. Dis. 183:715–721PubMedCrossRefGoogle Scholar
  36. 36.
    DiCenzo R., Forrest A., Fischl M.A., Collier A., Feinberg J., Ribaudo H., DiFrancecso R., Morse G.D. (2004). Pharmacokinetics of indinavir and nelfinavir in treatment-naive, human immunodeficiency virus-infected subjects. Antimicrob. Agents 48:918–923CrossRefGoogle Scholar
  37. 37.
    Fischl M.A., Ribaudo H.J., Collier A.C., Erice A., Giuliano M., Dehlinger M., Eron J.J., Jr., Saag M.S., Hammer S.M., Vella S., Morse G.D., Feinberg J.E., Denter L.M., Eshleman S.H. (2003). A randomized trial of 2 different 4-drug antiretroviral regimens versus a 3-drug regimen, in advanced human immunodeficiency virus disease. J. Infect. Dis. 188:625–634PubMedCrossRefGoogle Scholar
  38. 38.
    Pfister M., Labbe L., Lu J.F., Hammer S.M., Mellors J., Bennett K.K., Rosenkranz S. (2002). Sheiner L.B. Effect of coadministration of nelfinavir, indinavir, and saquinavir on the pharmacokinetics of amprenavir. Clin. Pharmacol. Ther. 72:133–141PubMedCrossRefGoogle Scholar
  39. 39.
    Pfister M., Labbe L., Hammer S.M., Mellors J., Bennett K.K., Rosenkranz S., Sheiner L.B. (2003). Population pharmacokinetics and pharmacodynamics of efavirenz, nelfinavir, and indinavir: Adult AIDS Clinical Trial Group Study 398. Antimicrob. Agents Chemother. 47:130–137PubMedCrossRefGoogle Scholar
  40. 40.
    Acosta E.P., Wu H., Hammer S.M., Yu S., Kuritzkes D.R., Walawander A. , Eron J.J., Fichtenbaum C.J., Pettinelli C., Neath D., Ferguson E., Saah A.J., Gerber J.G. (2004). Comparison of two indinavir/ritonavir regimens in the treatment of HIV-infected individuals. J. Acquir. Immune Defic. Syndr. 37:1358–1366PubMedCrossRefGoogle Scholar
  41. 41.
    Zhou X.J., Havlir D.V., Richman D.D., Acosta E.P., Hirsch M., Collier A.C., Tebas P., Sommadossi J.P. (2000). Plasma population pharmacokinetics and penetration into cerebrospinal fluid of indinavir in combination with zidovudine and lamivudine in HIV-1-infected patients. Aids 14:2869–2876PubMedCrossRefGoogle Scholar
  42. 42.
    van Heeswijk R.P., Veldkamp A.I., Hoetelmans R.M., Mulder J.W., Schreij G., Hsu A., Lange J.M., Beijnen J.H., Meenhorst P.L. (1999).The steady-state plasma pharmacokinetics of indinavir alone and in combination with a low dose of ritonavir in twice daily dosing regimens in HIV-1-infected individuals. Aids 13:F95–99PubMedCrossRefGoogle Scholar
  43. 43.
    Burger D.M., Hugen P.W., Aarnoutse R.E., Dieleman J.P., Prins J.M., van der Poll T., ten Veen J.H., Mulder J.W., Meenhorst P.L., Blok W.L., van der Meer J.T., Reiss P., Lange J.M. (2001). A retrospective, cohort-based survey of patients using twice-daily indinavir + ritonavir combinations: pharmacokinetics, safety, and efficacy. J. Acquir. Immune Defic. Syndr. 26:218–224PubMedCrossRefGoogle Scholar
  44. 44.
    Kakuda T.N., Page L.M., Anderson P.L., Henry K., Schacker T.W., Rhame F.S., Acosta E.P., Brundage R.C., Fletcher C.V. (2001). Pharmacological basis for concentration-controlled therapy with zidovudine, lamivudine, and indinavir. Antimicrob. Agents Chemother. 45:236–242PubMedCrossRefGoogle Scholar
  45. 45.
    Acosta E.P., Henry K., Baken L., Page L.M., Fletcher C.V. (1999). Indinavir concentrations and antiviral effect. Pharmacotherapy 19:708–712PubMedCrossRefGoogle Scholar
  46. 46.
    Csajka C., Marzolini C., Fattinger K., Decosterd L.A., Telenti A., Biollaz J., Buclin T. (2004). Population pharmacokinetics of indinavir in patients infected with human immunodeficiency virus. Antimicrob. Agents Chemother. 48:3226–3232PubMedCrossRefGoogle Scholar
  47. 47.
    Aarnoutse R.E., Wasmuth J.C., Fatkenheuer G., Schneider K., Schmitz K., de Boo T.M., Reiss P., Hekster Y.A., Burger D.M., Rockstroh J.K. (2003). Administration of indinavir and low-dose ritonavir (800/100 mg twice daily) with food reduces nephrotoxic peak plasma levels of indinavir. Antivir. Ther. 8:309–314PubMedGoogle Scholar
  48. 48.
    Sisson S. (2005). Trans-dimensional Markov chains: a decade of progress and future perspectives. J. Am. Statis. Assoc. 100:1077–1089CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2006

Authors and Affiliations

  • Smita A. Kshirsagar
    • 1
  • Terrence F. Blaschke
    • 1
    • 2
  • Lewis B. Sheiner
    • 4
    • 5
  • M. Krygowski
    • 6
  • Edward P. Acosta
    • 7
  • Davide Verotta
    • 3
    • 5
  1. 1.Department of MedicineStanford University Medical CenterStanfordUSA
  2. 2.Department of Molecular PharmacologyStanford University Medical CenterStanfordUSA
  3. 3.Departments of Epidemiology and BiostatisticsSan FranciscoUSA
  4. 4.Department of Laboratory MedicineUniversity of CaliforniaSan FranciscoUSA
  5. 5.Department of Biopharmaceutical SciencesUniversity of CaliforniaSan FranciscoUSA
  6. 6.Harvard School of Public HealthChestnut HillUSA
  7. 7.Division of Clinical PharmacologyUniversity of Alabama at BirminghamBirminghamUSA

Personalised recommendations