Age-dependent cyclosporine: Pharmacokinetics in marrow transplant recipients

We evaluated the effect of age on cyclosporine pharmacokinetics in 69 nonobese patients aged 10 months to 56 years (median 22 years) undergoing allogeneic bone marrow transplantation for treatment of aplastic anemia or hematologic malignancy. Cyclosporine pharmacokinetics were studied during the first 2 posttransplant weeks after an intravenous dose of 2.6 to 3.5 mg/kg. Serum cyclosporine concentrations were measured by HPLC. Cyclosporine concentration-time data were fitted to a two-compartment model with a nonlinear regression program. There was a significant inverse linear correlation between age and both total systemic clearance (CL) (r = 0.42; P < 0.001) and volume of distribution at steady-state (V_ss) (r = 0.33; P < 0.01). Mean (± SE) cyclosporine CL was 82 ± 21,45 ± 5, 38 ± 9,44 ± 8, and 20 ± 3 ml/min/kg and mean cyclosporine V_ss was 34 ± 11, 28 ± 10, 15 ± 4, 14 ± 5, and 4.7 ± 0.7 L/kg in patients 0 to 10 (n = 12), 11 to 20 (n = 19), 21 to 30 (n = 12), 31 to 4o (n = 17), and >40 (n = 9) years old, respectively. Patients 0 to 10 years old had a significantly higher cyclosporine CL than those 11 to 40 or >40 years old and also had a significantly larger V_ss than those >40 yrs old (P < 0.05). Age-related differences in CL or V_ss were also observed when these parameters were normalized by body surface area. Multiple stepwise regression showed that other factors, such as serum bilirubin, alkaline phosphatase, creatinine, or BUN, did not correlate with cyclosporine CL or V_ss. Thus since infants and children have a more rapid CL and larger V_ss than adults, they require larger cyclosporine doses to achieve comparable serum cyclosporine concentrations.