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. Author manuscript; available in PMC: 2013 Jun 11.
Published in final edited form as: Clin Pharmacokinet. 2009;48(7):419–462. doi: 10.2165/11317230-000000000-00000

Table VIII.

Cyclosporine TDM or concentration-controlled studies

Ref Study Patients Time post-transplant Immunosuppressants Analytical method, exposure index and target Evaluated endpoints and results Comments
HEART TRANSPLANTATION
[59] Prospective study
Consecutive patients, randomized in 2 groups		 20 adults < 1 year SAND EMIT BPAR: ISHLT classification
Group I
53±8 years
n = 10		 11±2 months Thymoglobuline
AZA
Prednisone		 D adjusted on C0 = 150–250 μg/L Efficacy:

  • BPAR: 50% (grade I: 70/172 biopsies: 40.7%)
Others:

  • Cyclosporine D at end of f/up : 3.5±1 mg/kg/day

  • Mean cyclosporine D adjustment/patient: 1/month

  • Total cyclosporine cost: 5,106±1,045 CDN $

Group II
58±4 years
n = 10		 10±3 months D adjusted on C6 = 150–250 μg/L Efficacy:

  • BPAR: 50% (grade I: 47/111 biopsies: 29.7%, p=0.04)

  • Left VEF and graft atherosclerosis similar in both groups
Toxicity:

  • Renal function similar in both groups (SCr, GFR)

Others:

  • Cyclosporine D at end of f/up : 2.6±0.6 mg/kg/day (p=0.002)

  • Mean cyclosporine D adjustment/patient: 1/month

  • Total cyclosporine cost: 3,589±1,116 CDN $ (p=0.005)

[56] Prospective study
Randomization to C0 or C2 monitoring
Follow-up: 6 months		 30 adults Stable, ≥ 1 year
No BPAR in previous 6 months
SCr < 250 μmol/L		 NEO (Week 0: conversion from SAND to NEO)

Thymoglobuline
AZA
Prednisone		 EMIT Routine biopsies and after each dose reduction
No instance of BPAR ≥ grade 2 (ISHLT classification)		 No comparison of outcome between two groups based on monitored exposure index: this study rather looked for a correlation between a single time-point concentration and AUC0-4 and AUC0-12
Group I
59±7 years
n = 15

  • Week 2: D adjusted on C0 = 100–200 μg/L

  • ≥ Week 6: D adjusted on C2 = 300–600 μg/L

 D increase in 8 patients after the first visit
D reduction in all patients after the second visit

  • C0 = 147±39 μg/L

  • C1 = 762±385 μg/L

  • C2 = 835±320 μg/L

  • C4 = 379±138 μg/L

  • AUC0-4 (Trap) = 2,467±804 h.μg/L
Group II
56±9 years
n = 15

  • Week 2: D adjusted on C2 = 200–400 μg/L

  • ≥ Week 6: D adjusted on C2 = 300–600 μg/L

 D reduction after the first visit

  • C0 = 102±35 μg/L (p = 0.0001)

  • C1 = 621±402 μg/L (ns)

  • C2 = 555±271 μg/L (p = 0.01)

  • C4 = 218±83 μg/L (p = 0.001)

  • AUC0-4 (Trap) = 1,723±808 h.μg/L (p = 0.02)
[10] Longitudinal follow-up of all patients followed at heart transplantation clinic 2-phase study 114 adults
57±9 years		 Stable, ≥ 1 year NEO

ATG (most patients)
Cyclosporine
monotherapy (7.9%)
or + AZA + prednisone (40.3%)
or + AZA (36%)
or + prednisone (15.8%)		 EMIT Primary endpoint: clinical benefit = composite measure

  • Positive cardiac outcomes (no mortality, no acute rejection, no decrease in LVEF > 10%), and

  • Positive renal outcomes (absence of increase in SCr > 10%)

 Limitation: sequential longitudinal assessment of two strategies for NEO D adjustment in the same patients
Phase 1 (10±4 months) D adjusted on C2 = 300–600 μg/L Primary endpoint:

  • Clinical benefit: 69.3%
Initial Secondary endpoints:

  • Incidence of acute rejection: 0.87%

  • Incidence of mortality: 7.9%

  • Incidence of increase in SCr > 10%: 18.1%
D = 2.6±0.8 mg/kg/day C0 = 136±42 μg/L
C2 = 776±316 μg/L
Final
D = 1.9±0.6 mg/kg/day C0 = 87±36 μg/L
C2 = 422±153 μg/L
Phase 2 (10±2 months) Dose adjusted on Primary endpoint:

  • Clinical benefit: 43.3%

    RR = 1.6 (p = 10−5)
C0 = 100–200 μg/L
Initial
D = 1.9±0.6 mg/kg/day C0 = 86±35 μg/L Secondary endpoints:

  • Incidence of acute rejection: 0.96% (ns)

  • Incidence of mortality: 9.6% (ns)

  • Incidence of increase in SCr > 10%: 48.9%

    RR = 0.37 (p<10−4)

  • LVEF: stable across both time periods
C2 = 428±159 μg/L
Final
D = 2.4±0.6 mg/kg/day C0 = 134±46 μg/L
C2 = 592±156 μg/L
[22] Prospective analysis of 2 consecutive periods De novo
f/up: 4 years		 NEO
In absence of ARE, D decreased if SCr increased > 20% from baseline

ATG, MMF, prednisone		 EMIT Efficacy

  • Routine EMB: ARE ≥ grade 3A (ISHLT classification)

  • Echocardiography

  • Coronary angiography

    Toxicity

  • Renal function: SCr, ClCr (Cockroft-Gault), GFR

 MMF D: group 1 ≠ 2 D/kg different at M1
13 adults
54±9 years		 Group I (MMF D: 1 g BID)

  • < M9: D adjusted on C0

    < M3: 200–300 μg/L

    M4-M6: 150–250 μg/L

    M6-M9: 100–200 μg/L

  • > M9: D adjusted on C2 =400–600 μg/L

 Efficacy

  • Incidence of ARE ≥ grade 3A

    • Month 6: 38.5%

    • Month 12: 38.5%

    • Month 24: 46%

    • Month 36: 54%

  • Time to acute rejection: 363±462 days

  • 3 deaths

  • LVEF: 58±5 (M3) to 60±5% (M12)

  • Incidence of graft atherosclerosis at M12: 11%
9 adults
53±12 years		 Group II (MMF D: 1.5 g BID)

  • D adjusted on C2

    < M3: 600–800 μg/L

    M4-M6: 500–700 μg/L

    > M6: 400–600 μg/L

 Efficacy

  • Incidence of ARE ≥ grade 3A (ns)

    • Month 6: 11%

    • Month 12: 44%

    • Month 24: 56%

    • Month 36: 56%

  • Time to acute rejection: 344±237 days (ns)

  • No death

  • LVEF: 59±2 (M36) to 61±2% (M24) (ns)

  • Incidence of graft atherosclerosis at M12: 0% (ns)

    Toxicity:

  • Renal function, incidence of infections: ns
[86] 2-phase prospective study
Paired determination of C0 and C2
Investigators blinded to exposure index		 58 adults
56±11 years		 2.03±1.28 years (0.3–3.6) Cyclosporine
ATG or basiliximab
Prednisone
AZA or MMF		 FPIA-TDx Toxicity:

  • Incidence of life-threatening infections

  • Renal dysfunction (SCr, ClCr)

    Efficacy

  • BPAR ≥ grade 2 (ISHLT)

 Short follow-up in both phases.

C0 or C2 values in the whole population for each phase: N/R.

No monitoring of MPA levels.
Phase I (6 months): D adjusted on C0

  • M3-M6: 300–350 μg/L

  • M6-M12: 250–300 μg/L

  • M12-M24: 200–250 μg/L

  • >M24: 150–200 μg/L

 Toxicity

  • 8 infection episodes

  • Renal function deterioration in 2 patients

    Efficacy:

  • ARE ≥ grade 3, 7/58 patients

  • Rejection vs no rejection:

    C0 = 195±121 vs 197±100, ns

    C2 = 777±326 vs 1,015±422, p=0.022
Phase II (6 months): D adjusted on C2 associated with no rejection during phase I

  • M3-M6: 1,403±285

  • M6-M12: 1,175±215

  • M12-M24: 947±170

  • >M24: 824±120

 Toxicity

  • 6 infection episodes (ns)

  • Renal function deterioration in 1 patient; no difference in SCr and calculated ClCr

Efficacy:

  • ARE ≥ grade 3, 6/56 patients (ns)

  • Rejection vs no rejection:

    C0 = 204±85 vs 209±138, ns

    C2 = 765±297 vs 967±470, p=0.03
[51] Prospective randomized controlled study
f/up: 6 months		 125 adults Stable, > 1 year Cyclosporine CEDIA Short follow-up duration.

Low incidence of AR after the first year post-transplant.

Study not powered to detect a small possible effect of C2 vs C0 monitoring on AR.
Group I
n = 62
55±10 years		 6.4±2.8 years ± Prednisone
± MMF or AZA		 D adjusted on C0 = 80–120 μg/L Primary endpoint

  • Decrease of cyclosporine D: 11 mg/day

Secondary endpoints

  • Deaths: 1 patient

  • ARE: no suspicion

  • Infections: 9.7%

  • ClCr: + 0.54 mL/min
Group II
n = 63
55±9 years		 6.4±2.5 years D adjusted on C2 = 300–600 μg/L Primary endpoint

  • Decrease of cyclosporine D: 26 mg/day (p = 0.0025) – C0 in target range

Secondary enpoints

  • Deaths: 1 patient

  • ARE: no suspicion

  • Infections: 15.9% (p = 0.14)

  • ClCr: −0.16 mL/min (p = 0.61)
HEART AND LUNG TRANSPLANTATION
[88] Single center study using historic controls Intent-to-treat analysis De novo Cyclosporine EMIT Larger proportion of DL (p < 0.01) and of CF patients (p < 0.01) in C2 vs C0 group.
Transplantation between 1989 and 2000 338 patients
124 SL, 150 DL, 64 HL		 ATG(1)
AZA
Prednisolone		 C0 group
Target: N/R		 Primary endpoint : efficacy (ISHLT classification)

  • Freedom from AR:

    M3: 51% – M6: 45% – M12: 41%

  • Freedom from BOS:

    Y1: 87% – Y3: 53% – Y5: 36%

  • Actuarial survival:

    30-days: 93% – Y1: 83% – Y3: 66% – Y5 : 55%

Secondary endpoint: toxicity

  • Chronic renal failure within 5 years: 18 patients
Transplantation between 2001 and 2002 50 patients
3 SL, 44 DL, 3 HL		 f/up: 16–1,790 days (1,185±426) AZA (n = 15) or MMF (n = 35)
Prednisolone		 C2 group Primary endpoint : efficacy (ISHLT classification)

  • 15 patients with ARE (23 episodes/171 TBB)

    18/23 episodes within 2 weeks of subtherapeutic level

  • 12 patients with ARE/25 with C2 subtherapeutic levels

  • Freedom from AR (p = 0.001)

    M3: 74% – M6: 69% – M12: 69%

  • Freedom from BOS (p = 0.002)

    Y1: 98% – Y3: 79% – Y5: 59%

  • Actuarial survival (p = 0.029)

    30-days: 98% – Y1: 94% – Y3: 82% – Y5 : 77%

Secondary endpoint: toxicity

  • Chronic renal failure in one patient, with SCr > 250 mg/L (needed dialysis and renal transplantation); (p > 0.10)

  • SCr = 122±64 mg/L
Day 0–2 > 800
Day 2–7 > 1,200
Day 8–30 1,200–1,700
Day 30–60 1,200–1,500
Day 61–90 800–1,200
Day 91–180 700–1,000
Day 181–365 600–900
Day >365 600–800
LUNG TRANSPLANTATION
[92] Sequential groups 36 adults (17 CF)
DL		 De novo
f/up: 3 months		 Cyclosporine
Prednisolone		 EMIT C0 group older than C2 group

Baseline SCr lower in C0 group

Associated immunosuppressants different between the 2 groups
n = 18 AZA (n = 14) or MMF (n = 4) D adjusted on C0
Week 1: 450 μg/L
Month 3: 250 μg/L		 Efficacy

  • FEV1 at M3: no difference

  • AR (A and B): similar rates in both groups (numbers: N/R)

  • Survival at M3: 100%
n = 18 AZA (n = 2) or MMF (n = 16) D adjusted on C2
Week 1: 1,200 μg/L
Month 3: 800 μg/L		 Toxicity

  • SCr: greater increase from baseline in C0 group

  • Infections: similar rates in both groups (1.85 vs. 1.79 events per 100 patients-days)
[87] Uncontrolled single-center pilot study 15 adults with renal dysfunction (5 CF)
5 SL, 10 DL		 3.5±2.7 years (0.2–9.0) Cyclosporine

AZA (n = 10) or MMF (n = 5)
Prednisolone		 EMIT

Switch from C0 to C2 monitoring
C2 = 300–600 μg/L		 Primary endpoint

  • Renal function improvement at 3 and 12 months: SCr = 0.20±0.07 mmol/L at baseline to 0.15±0.05 mmol/L at M3 (p < 0.001)

Secondary endpoint

  • Stable lung function except for 1 ARE

Cyclosporine D (mg/kg/day) divided by two within 3 months:6.4±7.3 to 3.9±3.7 at M3 (p = 0.031) to 3.1±2.7 at M12 (p = 0.041)
(1)

Patients transplanted before 1995

AR: Acute rejection – ARE: Acute rejection episode – ATG: Antithymocyte globulin – AZA: Azathioprine – BOS: Bronchiolitis obliterans syndrome – BPAR: Biopsy proven acute rejection – ClCr: Creatinine clearance – D: dose – EMB: Endomyocardial biopsy – f/up: Follow-up – GFR: Glomerular filtration rate – LVEF: Left ventricular ejection fraction – M: Month – MMF: Mycophenolate mofetil – NEO: Neoral – N/R: not reported – SAND: Sandimmune – SCr: Serum creatinine – TBB: Transbronchial biopsy – Y: Year.