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

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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.

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References

  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. 28:343–362

    Article  PubMed  CAS  Google Scholar 

  2. Sheiner L.B., Steimer J.L. (2000). Pharmacokinetic/pharmacodynamic modeling in drug development. Annu. Rev. Pharmacol. Toxicol. 40:67–95

    Article  PubMed  CAS  Google Scholar 

  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. 34:111–119

    CAS  Google Scholar 

  4. Guidance for Industry on Population Pharmacokinetics (1999). Available at: http://www.fda.gov/cder/guidance/1852fnl.pdf

  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. 49:251–254

    Article  PubMed  CAS  Google Scholar 

  6. Vrijens B., Goetghebeur E. (1999). The impact of compliance in pharmacokinetic studies. Stat. Methods Med. Res. 8:247–262

    Article  PubMed  CAS  Google Scholar 

  7. Urquhart J. (1994). Role of patient compliance in clinical pharmacokinetics. A review of recent research. Clin. Pharmacokinet. 27:202–215

    CAS  Google Scholar 

  8. Morris L.S., Schulz R.M. (1992). Patient compliance – an overview. J. Clin. Pharm. Ther. 17:283–295

    PubMed  CAS  Google Scholar 

  9. Girard P., Blaschke T.F., Kastrissios H., Sheiner L.B. (1998). A Markov mixed effect regression model for drug compliance. Stat. Med. 17:2313–2333

    Article  PubMed  CAS  Google Scholar 

  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. 23:3561–3580

    Article  PubMed  Google Scholar 

  11. Soy D., Beal S.L., Sheiner L.B. (2004). Population one-compartment pharmacokinetic analysis with missing dosage data. Clin. Pharmacol. Ther. 76:441–451

    Article  PubMed  CAS  Google Scholar 

  12. Mu S., Ludden T.M. (2003). Estimation of population pharmacokinetic parameters in the presence of non-compliance. J. Pharmacokinet. Pharmacodyn. 30:53–81

    Article  PubMed  Google Scholar 

  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. 22:1255–1283

    Article  PubMed  Google Scholar 

  14. Sato T. (2001). A method for the analysis of repeated binary outcomes in randomized clinical trials with non-compliance. Stat. Med. 20:2761–2774

    Article  PubMed  CAS  Google Scholar 

  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. 18:2879–2897

    Article  PubMed  CAS  Google Scholar 

  16. Jonsson E.N., Wade J.R., Almqvist G., Karlsson M.O. (1997). Discrimination between rival dosing histories. Pharm. Res. 14:984–991

    Article  PubMed  CAS  Google Scholar 

  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 17:2345–2349

    Article  PubMed  CAS  Google Scholar 

  18. Olyaei A.J., deMattos A.M., Bennett W.M. (2000). Renal toxicity of protease inhibitors. Curr. Opin. Nephrol. Hypertens. 9:473–476

    Article  PubMed  CAS  Google Scholar 

  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 50:508–511

    Article  PubMed  CAS  Google Scholar 

  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 50:513–518

    Article  PubMed  CAS  Google Scholar 

  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 13:473–478

    Article  PubMed  CAS  Google Scholar 

  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. 162:1493–1501

    Article  PubMed  Google Scholar 

  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. 32:135–1427D

    PubMed  CAS  Google Scholar 

  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. 29:422–425

    PubMed  CAS  Google Scholar 

  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. 164:1895–1897

    Article  PubMed  CAS  Google Scholar 

  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. 29:374–377

    PubMed  CAS  Google Scholar 

  27. Sutherland S.E., Reigle M.D., Seftel A.D., Resnick M.I. (1997). Protease inhibitors and urolithiasis. J. Urol. 158:31–33

    Article  PubMed  CAS  Google Scholar 

  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. 122:256–259

    PubMed  CAS  Google Scholar 

  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. 36:507–515

    PubMed  CAS  Google Scholar 

  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. 34:1122–1128

    Article  PubMed  CAS  Google Scholar 

  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. 127:119–125

    PubMed  CAS  Google Scholar 

  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. 21:209–222

    Article  PubMed  CAS  Google Scholar 

  33. Gisleskog P.O., Karlsson M.O., Beal S.L. (2002). Use of prior information to stabilize a population data analysis. J. Pharmacokinet. Pharmacodyn. 29:473–505

    Article  PubMed  Google Scholar 

  34. Beal S.L., Sheiner L.B.(eds) (1992). NONMEM Users Guide, NONMEM Project Group. University of California at San Francisco, San Francisco

    Google Scholar 

  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. 183:715–721

    Article  PubMed  CAS  Google Scholar 

  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 48:918–923

    Article  CAS  Google Scholar 

  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. 188:625–634

    Article  PubMed  CAS  Google Scholar 

  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. 72:133–141

    Article  PubMed  CAS  Google Scholar 

  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. 47:130–137

    Article  PubMed  CAS  Google Scholar 

  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. 37:1358–1366

    Article  PubMed  CAS  Google Scholar 

  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 14:2869–2876

    Article  PubMed  CAS  Google Scholar 

  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:F95–99

    Article  PubMed  Google Scholar 

  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. 26:218–224

    Article  PubMed  CAS  Google Scholar 

  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. 45:236–242

    Article  PubMed  CAS  Google Scholar 

  45. Acosta E.P., Henry K., Baken L., Page L.M., Fletcher C.V. (1999). Indinavir concentrations and antiviral effect. Pharmacotherapy 19:708–712

    Article  PubMed  CAS  Google Scholar 

  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. 48:3226–3232

    Article  PubMed  CAS  Google Scholar 

  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. 8:309–314

    PubMed  CAS  Google Scholar 

  48. Sisson S. (2005). Trans-dimensional Markov chains: a decade of progress and future perspectives. J. Am. Statis. Assoc. 100:1077–1089

    Article  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Medicine, Stanford University Medical Center, Stanford, CA, USA

    Smita A. Kshirsagar & Terrence F. Blaschke

  2. Department of Molecular Pharmacology, Stanford University Medical Center, Stanford, CA, USA

    Terrence F. Blaschke

  3. Departments of Epidemiology and Biostatistics, San Francisco, CA, USA

    Davide Verotta

  4. Department of Laboratory Medicine, University of California, San Francisco, CA, USA

    Lewis B. Sheiner

  5. Department of Biopharmaceutical Sciences, University of California, San Francisco, CA, USA

    Lewis B. Sheiner & Davide Verotta

  6. Harvard School of Public Health, Chestnut Hill, MA, USA

    M. Krygowski

  7. Division of Clinical Pharmacology, University of Alabama at Birmingham, Birmingham, AL, USA

    Edward P. Acosta

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  1. Smita A. Kshirsagar
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  2. Terrence F. Blaschke
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  3. Lewis B. Sheiner
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  4. M. Krygowski
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  5. Edward P. Acosta
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  6. Davide Verotta
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Correspondence to Davide Verotta.

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Lewis B. Sheiner: Deceased

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Kshirsagar, S.A., Blaschke, T.F., Sheiner, L.B. et al. Improving Data Reliability Using a Non-Compliance Detection Method versus Using Pharmacokinetic Criteria. J Pharmacokinet Pharmacodyn 34, 35–55 (2007). https://doi.org/10.1007/s10928-006-9032-2

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  • DOI: https://doi.org/10.1007/s10928-006-9032-2

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