title: Sirolimus pharmacokinetics in early postmyeloablative pediatric blood and marrow transplantation.
abstract: This study examined the pharmacokinetics of sirolimus in pediatric allogeneic blood and marrow transplantation (BMT) recipients in the presence and absence of concomitant fluconazole. Forty pediatric BMT recipients received a daily oral dose of sirolimus and a continuous i.v. infusion of tacrolimus for graft-versus-host disease prophylaxis. Fluconazole was administered i.v. to 19 patients and orally to 6 patients. Full pharmacokinetic profiles of sirolimus within a single dosing interval were collected. Whole-blood sirolimus concentrations were measured by HPLC/mass spectrometry. Noncompartmental analysis was performed using WinNonlin. Nonlinear mixed-effects pharmacokinetic models were developed using NONMEM following standard procedures. The mean ± SD sirolimus trough level before the dose (C0) was 8.0 ± 4.6 ng/mL (range, 1.8-21.6 ng/mL). The peak concentration was 19.9 ± 11.8 ng/mL (range, 3.9-46.1 ng/mL), and the trough level 24 hours later (C24) was 9.1 ± 5.3 ng/mL (range, 1.0-19.1 ng/mL). The terminal disposition half-life (T1/2) was 24.5 ± 11.2 hours (range, 5.8-53.2 hours), and the area under the concentration-versus-time curve (AUC0-24) was 401.1 ± 316.3 ng·h/mL (range, 20.7-1332.3 ng·h/mL). In patients at steady state, C0 and C24 were closely correlated (R(2) = 0.77) with a slope of 0.99, indicating the achievement of steady state. C24 was 1.7-fold greater (P = .036) and AUC0-24 was 2-fold greater (P = .012) in Caucasian patients (n = 22) compared with Hispanic patients (n = 9). The average apparent oral clearance was 3-fold greater (P = .001) and the apparent oral volume of distribution was 2-fold greater (P = .018) in patients age ≤12 years compared with those age >12 years. C24 was significantly lower in patients (n = 10) who developed grade III-IV aGVHD (n = 10) than in those with grade 0-II aGVHD (n = 22) (6.1 ± 2.9 ng/mL versus 9.4 ± 5.5 ng/mL; P = .044). Dose-normalized sirolimus trough concentrations were significantly higher in patients receiving concomitant fluconazole therapy compared with those not receiving fluconazole (C0: 3.9 ± 2.5 versus 2.4 ± 1.5 ng/mL/mg, P = .030; C24: 4.8 ± 3.3 versus 2.5 ± 1.7 ng/mL/mg, P = .018). This pharmacokinetic study of sirolimus in pediatric patients documents a large interindividual variability in the exposure of sirolimus. Steady-state trough blood concentrations were correlated with drug exposure. Trough concentrations were higher with a concomitant use of fluconazole and were higher in Caucasian patients than in Hispanic patients. Oral clearance was greater in children age ≤12 years than in older children and adolescents. With therapeutic drug monitoring, the majority (79%) of sirolimus trough levels could be maintained within the target range (3-12 ng/mL). This study provides a rationale and support for dose adjustments of sirolimus based on steady-state blood concentrations aimed at achieving a target concentration to minimize toxicity and maximize therapeutic benefits in pediatric BMT recipients.
authors.affiliation: Division of Blood and Marrow Transplantation and Cellular Therapies, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, PA, USA. goyark@chp.edu
authors.forename: Rakesh K
authors.initials: RK
authors.lastname: Goyal
authors.forename: Kelong
authors.initials: K
authors.lastname: Han
authors.forename: Donna A
authors.initials: DA
authors.lastname: Wall
authors.forename: Michael A
authors.initials: MA
authors.lastname: Pulsipher
authors.forename: Nancy
authors.initials: N
authors.lastname: Bunin
authors.forename: Stephan A
authors.initials: SA
authors.lastname: Grupp
authors.forename: Sripal R
authors.initials: SR
authors.lastname: Mada
authors.forename: Raman
authors.initials: R
authors.lastname: Venkataramanan
mesh_terms: D000293:Adolescent; D000935:Antifungal Agents / Q000627:therapeutic use; D019540:Area Under Curve; D016026:Bone Marrow Transplantation; D002648:Child; D002675:Child, Preschool; D016903:Drug Monitoring; D005260:Female; D015725:Fluconazole / Q000627:therapeutic use; D006086:Graft vs Host Disease / Q000097:blood* / Q000517:prevention & control; D006207:Half-Life; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007166:Immunosuppressive Agents / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D008297:Male; D019653:Myeloablative Agonists / Q000627:therapeutic use; D020123:Sirolimus / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D016559:Tacrolimus / Q000627:therapeutic use; D019172:Transplantation Conditioning; D014184:Transplantation, Homologous; D055815:Young Adult
chemical_list: D000935:Antifungal Agents; D007166:Immunosuppressive Agents; D019653:Myeloablative Agonists; D015725:Fluconazole; D020123:Sirolimus; D016559:Tacrolimus