Table 5. CsA and tacrolimus and their uses in experimental transplantation studies.
| Mechanism of action | Species | Plasma half-life (h) | Pharmacokinetics bioavailability/VD | Application form | Dosage examples | |
|---|---|---|---|---|---|---|
| Ciclosporine A (CsA) | ||||||
| Direct inhibition of calcineurin Selective inhibition of T-cell proliferation60 | Human | 24.0–93.0278 | Bioavailability: 61.9% CL: 29.6 L/h VD: 605 L279 | i.v., p.o.69 | • Initial dose: p.o. 2–12.5 (10.0) mg of P/kg per day, i.v. 1–20 (3.0) mg of CsA/kg per day q.d. or b.i.d. for 2–13 h, after 7–40 (21) days change to p.o. administration for 150–365 days, i.v. 15 mg of MTX/m2 on POD 1 and 10 mg of MTX/m2 on POD 3, 6 and 1169 | |
| Mouse | 4.1±0.6280 | At 2.6 mg/kg i.v.: CL: 0.015 L/kg/h VD: 0.07 L/kg280 | c.p.281 | • 35 mg of CsA/kg per day281 | ||
| Rat | 6.0–10.0282 19.4967 | CL: 0.20±0.04 L/kg/h MRT: 23.20±5.46 h VD: 4.54±0.68 L/kg67 | Implantation of CsA collagen matrix around the homograft,283 s.c.284, 285 | • 10 mg of CsA/kg per day284 • 1 mg of CsA/kg per day bound in collagen matrix283 | ||
| Dog | 8.567 | Poor oral absorption and bioavailability, preparations such as Neoral, Atopica and Sanimmune are not bioequivalent, Neoral achieves much higher blood levels than Atopica (veterinary-labeled oral product): rapid absorption, bioavailability of 23–45%, filled gastrointestinal tract reduces bioavailability by ~20%, high distribution in the liver, fat and lymphocytes212 CL: 6.96 L/h VD: 4.3 L/kg67 | conjunctival, p.o., topical,203 i.m., inhalation, i.v.251 | • 10 mg of CsA/kg/12 h, 2–3 mg of Az/kg/48 h, 0.5 mg of P/kg/12 h (then tapered off)286 • 10–25 mg of CsA/kg/12 h212 • Neoral: 5–10 mg of CsA/kg/12 h212 • Target trough levels: 100–500 ng/ml212 | ||
| Pig | 7.7±2.6287 8.1±1.5218 | Systemic availability: 18±6% CL: 0.87±0.11 L/kg/h VD: 6.5±1.7 L/kg In general: requires 2–4 times higher i.v. or oral dose of CsA than humans218 | i.m., i.v.,288, 289 p.o.72 | • 20 mg of CsA/kg per day288, 289 • 10 mg of CsA/kg per day288, 289 • Neonatal: 4 mg of CsA/kg per day, juvenile: 30 mg of CsA/kg per day72 | ||
| Sheep | 12.1±3.1290 | Abomasal bioavailability (6.4 mg/kg): 0.26±0.09 CL: 0.45±0.05 L/kg/h MRT: 9.6±4.1 h MAT (6.4 mg/kg): 4.7±11.1 h VD: 4.4±2.0 L/kg290 | i.v.,73 p.o. 290 | • 2–3 mg of CsA/kg per day b.i.d., 10 mg of Kc/kg b.i.d.73 | ||
| Tacrolimus (Tcr) | ||||||
| Indirect inhibition of calcineurin Binds to intracellular FK-binding protein Selective inhibition of T cell proliferation98, 99 | Human | In liver-transplanted patients: 12.1±4.7,291 12.0,292 5.5–16.6293 | Accumulation index during chronic therapy: 1.3 CL after p.o.: 0.21±0.08 L/kg/h VD after p.o.: 2.4±0.8 L/kg294 | p.o.295 | • 0.05 mg of Tcr/kg per day b.i.d.200 | |
| NHP | Baboon: 9.6±2.0 (at 10 mg/kg p.o.)293 | 10 mg/kg p.o.: peak plasma concentration of 8.1±1.0 ng/ml reached after 3.8±1.4 h293 | i.v.,296 p.o.104, 297 | • 4 mg of Tcr/kg per day104, 297 • 1 mg of Tcr/kg per day, 2 or 5 mg of ASKP1240/kg on POD 0, 3, 7, 11 and 14 and on POD 28–168 0.51 mg of Tcr/kg per day, 1 or 2.5 mg of ASKP1240/kg two times per week296 | ||
| Rat | 2.4±0.3 (at 1 mg), 2.5±0.3 (at 5 mg)298 | 100 times more potent than CsA at 1 mg/kg: CL: 0.42 L/kg/h VD: 4.62±0.03 L/kg298 | i.m.,293 i.v.,298 p.o.299 | • 0.1 mg of Tcr/kg per day or 1 mg of Tcr/kg per day299 | ||
| Dog | 9.0–13.2 (at 0.2 mg/kg i.v.), 5.6–7.9 (at 1 mg/kg p.o.)293 | Bioavailability after 1 mg/kg p.o.: 5–12% Peak plasma concentration (1.9–4.9 ng/ml) after 1–2 h at 0.2 mg kg i.v.: CL: 0.12–0.19 L/h i.m.: slow absorption, steady-state after 4.0–12.0 (continued up to 24.0)293 | i.m., i.v.,293 p.o.300 | • 0.5 mg of Tcr/kg per day, 5 mg of FTY720/kg per day300 | ||
| Pig | n.s.i. | n.s.i. | i.v. as continuous infusion,301 i.v.302 | • 0.1–0.2 mg of Tcr/kg for 12 days301 • 0.04 mg of Tcr/kg per day207 • 0.15 mg of Tcr/kg per day for 12 days103 | ||
| Sheep | n.s.i. | n.s.i. | i.v., p.o277 | • 2 days prior Tx: 0.02–0.15 mg of Tcr/kg per day p.o., 1.5 g of MMF per day p.o., perioperatively: 50 mg of ATG i.v. (DDI), 500 mg of MP i.v. 40 mg of MP per day p.o. on POD 1–15 (tapered off towards to 16 mg of MP per day) p.o.277 | ||
Abbreviations: ATG, antithymocyte globulin; Az, azathioprine; b.i.d., twice a day; CL, total plasma clearance; DDI, duration drip infusion; i.m., intramuscular; i.p., intraperitoneal; i.v., intravenous; Kc, ketoconazole; MAT, mean absorption time after oral dosing; MP, methylprednisolone; MRT, mean residence time; MTX, methotrexate; NHP, non-human primate; n.s.i., no sufficient information available; P, prednisolone; p.o., oral; POD, postoperative day; q.d., once a day; s.c., subcutaneous; Tx, transplantation; VD, volume of distribution.