Gengraf (Page 2 of 12)

Absorption

Cyclosporine (MODIFIED) has increased bioavailability compared to Sandimmune®. The absolute bioavailability of cyclosporine administered as Sandimmune® is dependent on the patient population, estimated to be less than 10% in liver transplant patients and as great as 89% in some renal transplant patients. The absolute bioavailability of cyclosporine administered as cyclosporine (MODIFIED) has not been determined in adults. In studies of renal transplant, rheumatoid arthritis and psoriasis patients, the mean cyclosporine AUC was approximately 20% to 50% greater and the peak blood cyclosporine concentration (Cmax ) was approximately 40% to 106% greater following administration of cyclosporine (MODIFIED) compared to following administration of Sandimmune®. The dose normalized AUC in de novo liver transplant patients administered cyclosporine (MODIFIED) 28 days after transplantation was 50% greater and Cmax was 90% greater than in those patients administered Sandimmune®. AUC and Cmax are also increased (cyclosporine [MODIFIED ] relative to Sandimmune®) in heart transplant patients, but data are very limited. Although the AUC and Cmax values are higher on cyclosporine (MODIFIED) relative to Sandimmune® , the predose trough concentrations (dose-normalized) are similar for the two formulations.

Following oral administration of cyclosporine (MODIFIED), the time to peak blood cyclosporine concentrations (Tmax ) ranged from 1.5 to 2.0 hours. The administration of food with cyclosporine (MODIFIED) decreases the cyclosporine AUC and Cmax . A high fat meal (669 kcal, 45 grams fat) consumed within one-half hour before cyclosporine (MODIFIED) administration decreased the AUC by 13% and Cmax by 33%. The effects of a low fat meal (667 kcal, 15 grams fat) were similar.

The effect of T-tube diversion of bile on the absorption of cyclosporine from cyclosporine (MODIFIED) was investigated in eleven de novo liver transplant patients. When the patients were administered cyclosporine (MODIFIED) with and without T-tube diversion of bile, very little difference in absorption was observed, as measured by the change in maximal cyclosporine blood concentrations from pre-dose values with the T-tube closed relative to when it was open: 6.9±41% (range -55% to 68%).

Pharmacokinetic Parameters ( mean ±SD )
Patient Population Dose/day 1 (mg/d) Dose/ weight (mg/kg/d) AUC 2 ( ng·hr /mL) C max (ng/mL) Trough 3 (ng/mL) CL/F (mL/min) CL/F (mL/min/kg)
De novo renaltransplant4 Week 4(N=37) 597±174 7.95±2.81 8772±2089 1802±428 361±129 593±204 7.8±2.9
Stable renaltransplant4 (N=55) 344±122 4.10±1.58 6035±2194 1333±469 251±116 492±140 5.9±2.1
De novo livertransplant5 Week 4(N=18) 458±190 6.89±3.68 7187±2816 1555±740 268±101 577±309 8.6±5.7
De novo rheumatoidarthritis6 (N=23) 182±55.6 2.37±0.36 2641±877 728±263 96.4±37.7 613±196 8.3±2.8
De novo psoriasis6 Week 4(N=18) 189±69.8 2.48±0.65 2324±1048 655±186 74.9±46.7 723±186 10.2±3.9
1 Total daily dose was divided into two doses administered every 12 hours2 AUC was measured over one dosing interval3 Trough concentration was measured just prior to the morning cyclosporine (MODIFIED) dose, approximately 12 hours after the previous dose4 Assay: TDx specific monoclonal fluorescence polarization immunoassay5 Assay: Cyclo-trac specific monoclonal radioimmunoassay6 Assay: INCSTAR specific monoclonal radioimmunoassay

Distribution

Cyclosporine is distributed largely outside the blood volume. The steady state volume of distribution during intravenous dosing has been reported as 3 to 5 L/kg in solid organ transplant recipients. In blood, the distribution is concentration dependent. Approximately 33% to 47% is in plasma, 4% to 9% in lymphocytes, 5% to 12% in granulocytes, and 41% to 58% in erythrocytes. At high concentrations, the binding capacity of leukocytes and erythrocytes becomes saturated. In plasma, approximately 90% is bound to proteins, primarily lipoproteins. Cyclosporine is excreted in human milk. (See PRECAUTIONS, Nursing Mothers)

Metabolism

Cyclosporine is extensively metabolized by the cytochrome P-450 3A enzyme system in the liver, and to a lesser degree in the gastrointestinal tract, and the kidney. The metabolism of cyclosporine can be altered by the coadministration of a variety of agents. (See PRECAUTIONS, Drug Interactions) At least 25 metabolites have been identified from human bile, feces, blood, and urine. The biological activity of the metabolites and their contributions to toxicity are considerably less than those of the parent compound. The major metabolites (M1, M9, and M4N) result from oxidation at the 1-beta, 9-gamma, and 4-N-demethylated positions, respectively. At steady state following the oral administration of Sandimmune® , the mean AUCs for blood concentrations of M1, M9, and M4N are about 70%, 21%, and 7.5% of the AUC for blood cyclosporine concentrations, respectively. Based on blood concentration data from stable renal transplant patients (13 patients administered cyclosporine [MODIFIED ] and Sandimmune® in a crossover study), and bile concentration data from de novo liver transplant patients (4 administered cyclosporine [MODIFIED ], 3 administered Sandimmune®), the percentage of dose present as M1, M9, and M4N metabolites is similar when either cyclosporine (MODIFIED) or Sandimmune® is administered.

Excretion

Only 0.1% of a cyclosporine dose is excreted unchanged in the urine. Elimination is primarily biliary with only 6% of the dose (parent drug and metabolites) excreted in the urine. Neither dialysis nor renal failure alters cyclosporine clearance significantly.

Drug Interactions

(See PRECAUTIONS, Drug Interactions) When diclofenac or methotrexate was coadministered with cyclosporine in rheumatoid arthritis patients, the AUC of diclofenac and methotrexate, each was significantly increased. (See PRECAUTIONS, Drug Interactions) No clinically significant pharmacokinetic interactions occurred between cyclosporine and aspirin, ketoprofen, piroxicam, or indomethacin.

Specific Populations

Renal Impairment

In a study performed in 4 subjects with end-stage renal disease (creatinine clearance <5 mL/min), an intravenous infusion of 3.5 mg/kg of cyclosporine over 4 hours administered at the end of a hemodialysis session resulted in a mean volume of distribution (Vdss) of 3.49 L/kg and systemic clearance (CL) of 0.369 L/hr/kg. This systemic CL (0.369 L/hr/kg) was approximately two thirds of the mean systemic CL (0.56 L/hr/kg) of cyclosporine in historical control subjects with normal renal function. In 5 liver transplant patients, the mean clearance of cyclosporine on and off hemodialysis was 463 mL/min and 398 mL/min, respectively. Less than 1% of the dose of cyclosporine was recovered in the dialysate.

Hepatic Impairment

Cyclosporine is extensively metabolized by the liver. Since severe hepatic impairment may result in significantly increased cyclosporine exposures, the dosage of cyclosporine may need to be reduced in these patients.

Pediatric Population

Pharmacokinetic data from pediatric patients administered cyclosporine (MODIFIED) or Sandimmune® are very limited. In 15 renal transplant patients aged 3 to 16 years, cyclosporine whole blood clearance after IV administration of Sandimmune® was 10.6±3.7 mL/min/kg (assay: Cyclo-trac specific RIA). In a study of 7 renal transplant patients aged 2 to 16, the cyclosporine clearance ranged from 9.8 to 15.5 mL/min/kg. In 9 liver transplant patients aged 0.6 to 5.6 years, clearance was 9.3±5.4 mL/min/kg (assay: HPLC).

In the pediatric population, cyclosporine (MODIFIED) also demonstrates an increased bioavailability as compared to Sandimmune®. In 7 liver de novo transplant patients aged 1.4 to 10 years, the absolute bioavailability of cyclosporine (MODIFIED) was 43% (range 30% to 68%) and for Sandimmune® in the same individuals absolute bioavailability was 28% (range 17% to 42%).

Pediatric Pharmacokinetic Parameters ( mean±SD )
Patient Population Dose/day (mg/d) Dose/weight (mg/kg/d) AUC 1 ( ng·hr /mL) C max (ng/mL) CL/F (mL/min) CL/F (mL/min/kg)
Stable liver transplant 2
Age 2 to 8, Dosed TID (N=9) 101±25 5.95±1.32 2163±801 629±219 285±94 16.6±4.3
Age 8 to 15, Dosed BID (N=8) 188±55 4.96±2.09 4272±1462 975±281 378±80 10.2±4.0
Stable liver transplant 3
Age 3, Dosed BID (N=1) 120 8.33 5832 1050 171 11.9
Age 8 to 15, Dosed BID (N=5) 158±55 5.51±1.91 4452±2475 1013±635 328±121 11.0±1.9
Stable renal transplant 3
Age 7 to 15, Dosed BID (N=5) 328±83 7.37±4.11 6922±1988 1827±487 418±143 8.7±2.9
1 AUC was measured over one dosing interval2 Assay: Cyclo-trac specific monoclonal radioimmunoassay3 Assay: TDx specific monoclonal fluorescence polarization immunoassay

Geriatric Population

Comparison of single dose data from both normal elderly volunteers (N=18, mean age 69 years) and elderly rheumatoid arthritis patients (N=16, mean age 68 years) to single dose data in young adult volunteers (N=16, mean age 26 years) showed no significant difference in the pharmacokinetic parameters.

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