Table VI. Cyclosporine exposure – efficacy studies.
Results are presented as mean±SD, unless otherwise specified
| Ref | Number of patients | Immonsuppressants | Sampling periods | Analytical method, exposure | Event (number of episodes) | Comments | |||
|---|---|---|---|---|---|---|---|---|---|
| HEART TRANSPLANTATION | |||||||||
|
| |||||||||
| [54] | 31 adults OHT 52±10 years |
Cyclosporine D adjusted on C0: | 244±178 days Median (range): 223 (22–582) |
HPLC-U Calculation of AUC: |
Routine surveillance EMB (ISHLT) | Trend for a significant relationship between C2 values and the incidence of rejection. | |||
| < M6 | 200–275 μg/L | AUC0-12: MAP-BE[1] or sparse-sample algorithms[2–4] | |||||||
| M6-M12 | 150–250 μg/L | AUC0-4: sparse-sample algorithm[5] | |||||||
| > M12 | 100–200 μg/L | ||||||||
| D = 194±57 mg BID (4.8±1.4 mg/kg BID) | C0 | 215±68 μg/L | Rejection (≥ grade 2) n = 3 patients; all had C2 < 1250 μg/L |
Number of patients experiencing rejection too small:
|
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| C2 | 949±204 μg/L | ||||||||
| AUC0-12 | 4,875±956 to 5,897±1,457 h.μg/L | ||||||||
| AUC0-4 | 2958±579 h.μg/L | ||||||||
| C0 | 242±62 μg/L (ns) | No rejection (< grade 2) | |||||||
| C2 | 1,359±474 μg/L (ns) | ||||||||
| AUC0-12 | 6,723±2,119 to 7,445±1,871 h.μg/L (ns) | ||||||||
| AUC0-4 | 3970±1150 h.μg/L vs. 2958±579 (ns) | ||||||||
|
| |||||||||
| [93] | 60 adults | Cyclosporine D adjusted on C0: | 3–60 months |
FPIA-AxSYM 4 AUC/patient = 240 AUC, calculated from C0, C2, C4, C6 |
At least one ARE grade 3A (ISHLT) in 20/60 patients | No difference between “rejection” and “no rejection” groups on mean C2. | |||
| Y1 | 300–400 μg/L | ||||||||
| Y2 | 200–250 μg/L | ||||||||
| Y3 | 150–180 μg/L | Constant absorbers, AUC CV < 15% (n = 21) | Acute rejection | Variability on absorption = risk factor for rejection. | |||||
| > Y3 | > 150 μg/L | AUC = 6,521 h.μg/L | n = 4 patients (19%) | ||||||
| ATG Corticosteroids until M12 AZA or MMF (n = 10) |
Inconstant absorbers, AUC CV > 15% (n = 39) | Acute rejection | |||||||
| AUC = 6,751 h.μg/L (ns) | n = 16 patients (41%), p < 0.05 | ||||||||
|
| |||||||||
| [55] | 10 children out of 50 in the global trial | SAND or NEO, D adjusted on C0 (and blood cell count): |
De novo ≥ 2 months |
HPLC/MS | Rejection: IMEG, echocardiography, TDE, BPAR (≥ grade 2 – ISHLT) | Prospective blinded analysis Small number of patients with rejection: study not powerful enough? Impossible to define different C2 target levels in relation to adjunctive immunosuppressants |
|||
| ≤ M1 | 200–300 μg/L | ROC analysis: best sensitivity and specificity for C2 < 600 μg/L – Se = 100%, Sp = 83%
|
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| > M1 | 150–200 μg/L | ||||||||
| (D: median, range) ATG AZA or MMF | |||||||||
| 8.1±6.3 years | D = 8.6 mg/kg (4–21) | 2.2±1.6 years | C2 | 345±163 μg/L | < Y1: 456±164 μg/L | Rejection (BPAR: n = 14) | Impossible to assess chronic rejection | ||
| Y1-Y2: 428±196 μg/L | n = 5 patients | ||||||||
| Y2-Y5: 244±147 μg/L | |||||||||
| Cmin | 213±29 μg/L | ||||||||
| Cmax | 467±38 μg/L | ||||||||
| AUC0-12 | 3,615±508 h.μg/L | ||||||||
| AUC0-4 | 1,498±132 h.μg/L | ||||||||
| 8.9±5.6 years | D = 7.9 mg/kg (3.7–24), ns | 2.4±1.8 years | C0: ns | No rejection | |||||
| C2 = 952±310 μg/L (p<0.001) | < Y1: 1,134±356μg/L | n = 5 patients | |||||||
| Y1-Y2: 996±266 μg/L | |||||||||
| Y2-Y5: 859±274 μg/L | |||||||||
| Cmin | 219±32 μg/L (ns) | ||||||||
| Cmax | 966±231 μg/L (p<0.001) | ||||||||
| AUC0-12 | 5,530±889 h.μg/L (p < 0.001) | ||||||||
| AUC0-4 | 2,713±536 h.μg/L (p<0.001) | ||||||||
|
| |||||||||
| HEART AND LUNG TRANSPLANTATION | |||||||||
|
| |||||||||
| [80] | 31 adults (12 CF) HL |
Cyclosporine median D (mg/kg/day)
|
< 3 months | SRIA | Treated ARE (66% BPAR) | Variability on C0: risk factor for subsequent rejection; no such relationship for C0 itself | |||
| Observed C0 (median): | < W3: 347.5 μg/L | If C0 CV > 40%: | |||||||
| W3-M3: 445.5 μg/L | RR = 1.51 (95%CI = 1.01–2.27) | ||||||||
|
| |||||||||
| [28] | 50 patients (9 CF) 19 SL, 9 DL, 22 HL |
NEO (n = 28) vs SAND (n = 22), D adjusted on C0 | 12 months |
EMIT 289 PK profiles |
Study designed to compare the PK of NEO vs SAND, not to establish a relationship between drug exposure and efficacy | ||||
| M1-M2 | 300–400 μg/L | ||||||||
| M3-M12 | 200–300 μg/L | C0 = 394 μg/L | Patients with at least one treated ARE | ||||||
| ATG, AZA, prednisolone | C0 = 449 μg/L (p = 0.042) | Patients with no ARE | Relationship C2, C6 or AUC0-6 – incidence of treated AR: ns | ||||||
|
| |||||||||
| [20] | 48 patients SL, DL, HL |
NEO (n = 27) vs SAND (n = 21), D adjusted on C0: | Weeks 1, 2, 3, 4, 13, 26, 39, 52 |
EMIT 341 AUC0-6 |
|||||
| M1-M2 | 300–400 μg/L | ARE frequency similar in the 3 C2 groups | |||||||
| M3-M12 | 200–300 μg/L | 3 groups based on C2 (μg/L) at M1: low, < 1000 (18); intermediate, 1000–1500 (16); high >1500 (14) | AR-free periods: Intermediate C2 (226 days) ≫ low C2 (197 days) and high C2 (191 days) (p<0.0001) |
||||||
| (CF patients: TID) ATG, AZA, prednisolone |
C2 | 875±546 μg/L | Median number of ARE > 2 | ||||||
| AUC0-6 | 4,036±1,904 h.μg/L | ||||||||
| C2 | 1,114±633 (p = 0.01) | Median number of ARE ≤ 2 | |||||||
| AUC0-6 | 4,870±2,182 (p = 0.01) | ||||||||
| C0 and C6: ns | |||||||||
ARE: Acute rejection episode – ATG: Antithymocyte globulin – AZA: Azathioprine – BPAR: Biopsy-proven acute rejection – CF: Cystic fibrosis – D: Dose – DL: Double lung transplantation – EMB: Endomyocardial biopsy – HL: Heart-lung transplantation – IMEG: Intramyocardial electrocardiogram – MAP-BE: Maximum a posteriori Bayesian estimation – MMF: mycophenolate mofetil – NEO: Neoral – OHT: Orthotopic heart transplantation – SAND: Sandimmune – SL: Single lung transplantation – TDE: Tissue Doppler echocardiography.