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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 II. Cyclosporine pharmacokinetic parameters in cohort studies.

Results are expressed as mean±SD, unless otherwise specified

Ref Number of patients Post-transplant period Cyclosporine dose Co-administered immunosup-pressant Assay F, transfer k Vd/F (unless otherwise specified) CL/F (unless otherwise specified) t1/2 (h) (unless otherwise specified)
HEART TRANSPLANTATION
[23] 16 adults (out of 35 in the global trial) NEO N/R FPIA
TDx 		Non-compartmental PK analysis
Week 1 200±58 mg -- -- -- --
Week 2 159±40 mg F = 57±9% -- -- --
Week 52 162±37 mg -- -- -- --
[29] 20 male adults
58.8±10.2 years		 Stable
36.8±27.1 months		 NEO and SAND
1.14±0.4 mg/kg TID		 N/R
No corticosteroids		 FPIA
TDx 		2-compartment open model: 1-order absorption, 1-order elimination
k: h−1 V1, V2: L/kg CL: L.h−1/kg
SAND F = 66±16% V1 = 1.16±0.77 CL = 0.22±0.04 17.27±3.23
ka = 1.99±1.42 V2 = 5.38±1.37
k10 = 0.23±0.07
k12 = 0.37±0.14
k21 = 0.12±0.04
NEO F = 75±19% (p<0.001) V1 = 1.00±0.43 (ns) CL = 0.21±0.04 (ns) 18.83±3.58 (ns)
ka = 2.71±1.47 (p<0.05) V2 = 5.84±1.37 (ns)
k10 = 0.24±0.07 (ns)
k12 = 0.41±0.16 (ns)
k21 = 0.12±0.05 (ns)
After IV infusion V1 = 1.86±0.72 (ns) CL = 0.20±0.04 (ns) 17.68±4.29 (ns)
V2 = 5.58±1.57 (ns)
[19] 47 adults Stable NEO + SAND(1) N/R EMIT Non-compartmental PK analysis
D (mg/kg/day) t1/2 abs: h CL/F: L/h
54±12 years 49±19 months None 3.90±1.03 SAND t1/2 abs = 2.72±1.45 -- 46.7±21.1 --
n = 11 NEO t1/2 abs = 0.51±0.28 (p < 0.001) -- 31.8±9.5 (p<0.05) --
52±8 years 61±15 months DILT 2.98±0.64 SAND t1/2 abs = 1.44±1.16 -- 36.7±14.1 --
n = 11 NEO t1/2 abs = 0.58±0.62 (p < 0.05) -- 26.8±9.0 (p<0.05)
52±9 years 32±15 months KETO 0.79±0.27 SAND t1/2 abs = 1.65±1.22 -- 9.7±4.3 --
n = 13 NEO t1/2 abs = 0.67±0.34 (p < 0.01) -- 9.1±3.8 (ns) --
47±12 years 28±5 months DILT + KETO 0.90±0.54 SAND t1/2 abs = 1.81±1.09 -- 10.1±6.4 --
n = 12 NEO t1/2 abs = 1.07±0.57 (p < 0.05) -- 9.1±4.9 (ns) --
[30] 47 adults Stable (months) NEO + SAND(1) N/R EMIT 2-compartment PK analysis using ABBOTTBASE pharmacokinetic system (PKS); Structural model and PK parameters selected from a study in stable heart transplant recipients by Baraldo et al[29]
D (mg/kg/day) k: h−1 V1: L/kg CL: L.h−1/kg
49±19 None 3.90±1.03 F = 75% (fixed) V1 = 1 CL = 0.21 --
n = 11 ka = 2.7 h−1 (fixed) (CV = 43%) (CV = 19%)
k12 = 0.41 h−1 (CV = 39%)
61±15 DILT 2.98±0.64 k21 = 0.12 h−1 (CV = 42%)
n = 11
32±15 KETO 0.79±0.27 With no covariate:

  • r2 = 0.871 (p<0.001); bias% = 11.7; RMSE% = 13.4

  • Underestimation of AUC
n = 14
28±5 DILT + KETO 0.90±0.54 With “disposition factor”: (0.5 for CL if K or K+D; 0.76 for Vd if K+D)

  • r2 = 0.698 (p<0.001); bias% = 2.2; RMSE% = 16.6

  • Overestimation of AUC in patients on diltiazem

    Bayesian model: best sampling strategy: C0, C1, C2
n = 11
[21] 15 adults
48±10 years		 Clinically stable
5.2±4.4 years		 NEO
2.7±0.7 mg/kg/day
D adjusted on Cav = 200–300 μg/L		 ATG
AZA
Prednisolone		 FPIA
TDx 		Non-compartmental PK analysis using non linear regression program WinNonLin
Vd/F: mL/kg CL/F: mL.min−1/kg
-- 2,421±945 5.7±1.7 5.0±1.3
[31] 14 patients
de novo 		3 PK profiles/patient NEO
D adjusted on C0 		N/R FPIA
TDx 		Population exposure indices and PK parameters estimated using ITS method, CICLO 1.3
Absorption model based on a gamma distribution
MAT, SDAT: h A, B: L−1 λ1, λ2: h−1
t1/2(λ1), t1/2(λ2): h
Week 1 200±61.2 mg BID MAT = 1.25±0.40 A = 0.307±0.167 -- λ1 = 5.78±3.32
SDAT = 0.48±0.20 B = 0.637±0.267 λ2 = 0.47±0.17
t1/2(λ1) = 0.26±0.40
t1/2(λ2) = 1.90±1.09
Mont 3 152±36.0 mg BID (vs W1, p<0.05) MAT = 1.27±0.40 A = 0.771±0.630 -- λ1 = 3.18±2.19
SDAT = 0.45±0.19 B = 0.799±0.299 λ2 = 0.52±0.13
t1/2(λ1) = 0.28±0.13
t1/2(λ2) = 1.47±0.63
Year 1 164±40.1 mg BID MAT = 1.59±0.47 A = 0.690±0.445 -- λ1 = 2.595±1.368 (vs W1, p<0.05)
SDAT = 0.66±0.32 B = 0.783±0.229 λ2 = 0.529±0.097
t1/2(λ1) = 0.35±0.22
t1/2(λ2) = 1.36±0.27
LUNG TRANSPLANTATION
[66] 14 adults
8 SL, 6 DL		 Stable NEO
Steady-state		 N/R FPIA
TDx 		-- -- -- 9.52±5.71
HEART AND LUNG TRANSPLANTATION
[27] 22 adults(2) Month 1 D adjusted on C and clinical data AZA + prednisolone Pc NSRIA PK parameters estimated using a Bayesian program for parameter estimation [48]
Vd/F: L/kg CL/F: mL.min−1/kg
11 CF 16.7±7.2 mg/kg/day -- 7.2±5.3 3.5±1.3 --
11 non-CF 8.2±1.9 mg/kg/day (p<0.01) -- 4.3±2.2 (ns) 1.7±0.5 (p=0.003) --
[32] 19 adults Stable (no evidence of rejection within previous 3 months) NEO
D adjusted on C0 = 250–350 μg/L		 N/R EMIT PK parameters estimated using ITS method, CICLO 1.3; absorption described by a gamma distribution
3 consecutive PK profiles (P)/patient within 5 days
Parameters standardized to a 100-mg dose
MAT, SDAT: h V1/F: L CL/F: L/h λ1, λ2: h−1
F.A, F.B: L−1
9 CF
6 L, 3 HL		 250±76 mg BID (175–425) F set to 1 V1/F = 88±41 50±20 λ1 = 4.14±3.01
MAT = 1.00±0.21 F.A = 0.72±0.70 λ2 = 0.36±0.11
SDAT = 0.30±0.09 F.B = 0.68±0.34
10 non-CF
5 L, 5 HL		 175±52 mg BID (125–275)
p<0.025		 F set to 1 V1/F = 74±44 (ns) 50±14 (ns) λ1 = 2.16±1.75 (p < 0.01)
MAT = 1.13±0.28 (ns) F.A = 1.13±1.36 (ns) λ2 = 0.49±0.12 (p < 0.01)
SDAT = 0.37±0.15 (ns) F.B = 0.77±0.30 (ns)
(1)

Co-administration of enzyme inhibitors for minimum 2 years

(2)

Only adults except for 4 patients ≤ 16 years

ATG: Anti-thymocyte globulin – AZA: Azathioprine – C: concentration – CF: Cystic fibrosis – D: Dose – DILT: Diltiazem – DL: Double lung transplantation – F.A and F.B: estimated intravenous coefficients – f/up: follow-up – HL: Heart-lung transplantation – KETO: Ketoconazole – λ1, λ2: disposition rate constants – MAT: Mean absorption time – MMF: Mycophenolate mofetil – NEO: Neoral – N/R: not reported – SAND: Sandimmune – SDAT: Standard deviation of absorption time – SL: Single lung transplantation – V1: volume of central compartment – V2: volume of peripheral compartment.