Research ArticleComputational Medicine

Individualizing liver transplant immunosuppression using a phenotypic personalized medicine platform

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Science Translational Medicine  06 Apr 2016:
Vol. 8, Issue 333, pp. 333ra49
DOI: 10.1126/scitranslmed.aac5954
  • Fig. 1. PPD process guiding tacrolimus dosing for liver transplant patients.

    In this simulation, a patient after transplant was prescribed tacrolimus and other medications. The patient’s PPD curve (blue in select graphs) was calibrated using the trough levels from physician-guided standard-of-care dosing on days D(1) to D(3). The PPD curve was used to prospectively dose tacrolimus (red stars) to bring the patient’s trough levels into the target range of 6 to 8 ng/ml (gray regions). The numbers within the circles are the dosing days with the given tacrolimus doses and the resulting trough levels. (A) Original PPD calibrated curve (blue) using the trough levels from D(1) to D(3), with the recommended dose for D(4) (red star). (B) Following regimen changes, the PPD curve was recalibrated using the trough levels from three successive days after the regimen changes. During PPD recalibration, tacrolimus doses for the patient were preemptively selected on the basis of previous correlations. The recalibrated PPD curve (red) using the trough levels from D(5) to D(7) yielded D(8)’s recommended dose (red star). (C) 3D PPD tacrolimus and prednisone surface calibrated using the patient’s tacrolimus doses, prednisone doses, and trough levels from D(1) to D(11). Recommended tacrolimus dose is identified on the surface as noted by the green arrow.

  • Fig. 2. PPD-assisted personalized immunosuppression for patients PPD1 to PPD4.

    PPD curves (blue in select graphs) were calibrated for each patient using the trough levels from physician-guided standard-of-care dosing on D(−2) to D(0). The PPD curve was used to prospectively dose tacrolimus into the target range (gray regions in select graphs). Following regimen changes, PPD curves were recalibrated using the trough levels from at least three successive days after the regimen changes. During PPD recalibration, tacrolimus doses for PPD patients were preemptively selected on the basis of previous correlations. The numbers within the circles are the dosing days with the given tacrolimus doses (mg) and the resulting trough levels (ng/ml). (A) PPD1: Calibrated PPD curves using the trough levels from dosing days D(−2) to D(21), with the target range of 6 to 8 ng/ml. First PPD calibrated curve: D(−2) to D(0) (blue). PPD recalibration: A regimen change (green) for D(1), the recalibrated curve (orange) for D(2) to D(5), regimen changes (pink) for D(17) and D(18), and the second recalibrated curve (red) for D(19) to D(21). (B) PPD1 deviations between the trough levels and PPD-projected trough levels as a function of time between hemodialysis and the measured blood trough level. The numbers within the circles (blue) are the dosing days with hemodialysis performed before the trough level reading. (C) PPD2: Calibrated PPD curves using the trough levels from dosing days D(−2) to D(11), with the target ranges of 7 to 9 [D(2) only, not shown in gray], 8 to 10, and 9 to 11 ng/ml. First PPD calibrated curve for D(−2) to D(0) (blue). PPD recalibration: Regimen changes (orange) for D(4) to D(7) and the recalibrated curve (red) for D(8) to D(10). (D) PPD3: Calibrated PPD curves using the trough levels from dosing days D(−2) to D(9), with the target range of 8 to 10 ng/ml. First PPD calibrated curve for D(−2) to D(3) (blue). PPD recalibration: Regimen changes (orange and green) for D(4) to D(6) and regimen changes (red) for D(7) to D(9). D(12) was the follow-up trough level after PPD3’s discharge from the hospital. (E) PPD4: Calibrated PPD curves using the trough levels from dosing days D(−2) to D(22), with the target ranges of 4 to 6, 5 to 7, and 6 to 8 ng/ml. First PPD calibrated curve for D(−2) to D(1) (blue). PPD recalibration: The recalibrated curve (green) for D(2) to D(7), the second recalibrated curve (red) for D(8) to D(12), and the third recalibrated curve (orange) for D(13) to D(22).

  • Fig. 3. Physician-guided standard-of-care immunosuppression for control patients C1 to C4.

    (A to D) Tacrolimus was dosed according to physician-guided standard of care. The numbers of the dosing days within the circles for the given tacrolimus doses and the resulting trough levels with the target ranges are plotted. The colors of the circles correspond to the matching colored target ranges. (A) C1: Trough levels from D(−2) to D(19) were plotted with the target ranges of 8 to 10 ng/ml (pink) and 6.5 to 8.5 ng/ml (green). (B) C2: Trough levels from D(−2) to D(33) were plotted with the target ranges of 6 to 8 ng/ml (green), 6.5 to 8.5 ng/ml (not shown), and 8 to 10 ng/ml (pink). (C) C3: Trough levels from D(−2) to D(14) were plotted with the target ranges of 3.5 to 5.5 ng/ml (blue), 6 to 8 ng/ml (green), and 8 to 10 ng/ml (pink). (D) C4: Trough levels from D(−2) to D(18) were plotted with the target range of 8 to 10 ng/ml (pink).

  • Fig. 4. PPD-treated and clinical standard control-treated patients’ outcomes.

    (A and B) Recorded trough levels (ng/ml) were plotted against the date for each patient along with corresponding target ranges (gray regions) for control patients receiving the standard of care (A) and PPD-treated patients (B).

  • Fig. 5. Comparing PPD and control patients’ outcomes.

    Individual PPD (red-striped) and control patients’ (blue-striped) outcomes are shown. Green-shaded regions: Mean PPD (red solid) and control (blue solid) patients’ outcomes are shown. Data are means ± SEM (n = 4). (A) Number of postoperative days in the hospital until discharge. P values were determined by F test and Welch t test. (B) Number of days with trough level ≥2 ng/ml outside of the target range. P values were determined by Levene’s test and Wilcoxon rank sum test. (C) Ratio of the number of days with trough level ≥2 ng/ml outside of the target range to the total number of days of tacrolimus treatment. P values were determined by F test and Welch t test. (D) Ratio of the AUC outside of the target range to the total AUC. P values were determined by F test and Student’s t test.

  • Fig. 6. Retrospective PPD: PPD-guided dosing optimization of tacrolimus for C1.

    Retrospective PPD was conducted on C1 using the observed clinical doses and the measured trough levels to calibrate PPD curves and to identify the regimen changes. C1 retrospective PPD curves identified the tacrolimus dosages that could have brought the trough levels within the target ranges. (A) C1 calibrated PPD curves (blue, green, and red) using the trough levels from dosing days D(−2) to D(10). The numbers within the circles (blue, green, and red) are dosing days with the given tacrolimus doses (mg) and the resulting trough levels (ng/ml). The shaded regions (orange and blue) are the target ranges 8 to 10 ng/ml and 6.5 to 8.5 ng/ml. (B and C) PPD-optimized (red) and clinically observed (blue) trough levels (ng/ml) (B) and tacrolimus doses (mg) (C) plotted against the dosing days. The gray-shaded region is the target range. (D) PPD (red) and clinically observed control (blue) ratios of the AUC inside of the target range to the total AUC.

Supplementary Materials

  • www.sciencetranslationalmedicine.org/cgi/content/full/8/333/333ra49/DC1

    Subject clinical details

    Methods

    Fig. S1. The effect of cotrimoxazole and fluconazole dosing on patients’ trough levels.

    Fig. S2. PPD tacrolimus-prednisone interaction plots for patients PPD1, PPD2, and C1.

    Fig. S3. PPD tacrolimus-cotrimoxazole interaction plots for patient PPD4.

    Fig. S4. Retrospective PPD-guided tacrolimus and prednisone dosing optimization for patients C1 and C2.

    Table S1. Clinical summaries of control patients (C1 to C4) and PPD-guided patients (PPD1 to PPD4).

    Table S2. Data used for statistical comparisons in Fig. 5.

    Table S3. Patient-specific antibiotic and antifungal dosing changes and corresponding tacrolimus trough levels.

    Table S4. Patient-specific anti-inflammatory and immunosuppressant dosing changes and corresponding trough levels.

    Movie S1. Introduction to PPD and patient recalibration.

    Movie S2. Patient PPD2 recalibration tutorial.

    Movie S3. Patient PPD3 recalibration tutorial.

  • Supplementary Material for:

    Individualizing liver transplant immunosuppression using a phenotypic personalized medicine platform

    Ali Zarrinpar,* Dong-Keun Lee, Aleidy Silva, Nakul Datta, Theodore Kee, Calvin Eriksen, Keri Weigle, Vatche Agopian, Fady Kaldas, Douglas Farmer, Sean E. Wang, Ronald Busuttil, Chih-Ming Ho,* Dean Ho*

    *Corresponding author. E-mail: azarrinpar{at}mednet.ucla.edu (A.Z.); chihming{at}g.ucla.edu (C.-M.H.); dean.ho{at}ucla.edu (D.H.)

    Published 6 April 2016, Sci. Transl. Med. 8, 333ra49 (2016)
    DOI: 10.1126/scitranslmed.aac5954

    This PDF file includes:

    • Subject clinical details
    • Methods
    • Fig. S1. The effect of cotrimoxazole and fluconazole dosing on patients’ trough levels.
    • Fig. S2. PPD tacrolimus-prednisone interaction plots for patients PPD1, PPD2, and C1.
    • Fig. S3. PPD tacrolimus-cotrimoxazole interaction plots for patient PPD4.
    • Fig. S4. Retrospective PPD-guided tacrolimus and prednisone dosing optimization for patients C1 and C2.
    • Table S1. Clinical summaries of control patients (C1 to C4) and PPD-guided patients (PPD1 to PPD4).
    • Table S2. Data used for statistical comparisons in Fig. 5.
    • Table S3. Patient-specific antibiotic and antifungal dosing changes and corresponding tacrolimus trough levels.
    • Table S4. Patient-specific anti-inflammatory and immunosuppressant dosing changes and corresponding trough levels.

    [Download PDF]

    Other Supplementary Material for this manuscript includes the following:

    • Movie S1 (.mov format). Introduction to PPD and patient recalibration.
    • Movie S2 (.mov format). Patient PPD2 recalibration tutorial.
    • Movie S3 (.mov format). Patient PPD3 recalibration tutorial.

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