Sirolimus

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Sirolimus inhibits T-lymphocyte activation and proliferation that occurs in response to antigenic and cytokine (Interleukin [IL]-2, IL-4, and IL-15) stimulation by a mechanism that is distinct from that of other immunosuppressants. Sirolimus also inhibits antibody production. In cells, sirolimus binds to the immunophilin, FK Binding Protein-12 (FKBP-12), to generate an immunosuppressive complex. The sirolimus:FKBP-12 complex has no effect on calcineurin activity. This complex binds to and inhibits the activation of the mammalian target of rapamycin (mTOR), a key regulatory kinase. This inhibition suppresses cytokine-driven T-cell proliferation, inhibiting the progression from the G 1 to the S phase of the cell cycle. Mammalian target of rapamycin (mTOR) inhibitors such as sirolimus have been shown in vitro to inhibit production of certain growth factors that may affect angiogenesis, fibroblast proliferation, and vascular permeability. Studies in experimental models show that sirolimus prolongs allograft (kidney, heart, skin, islet, small bowel, pancreatico-duodenal, and bone marrow) survival in mice, rats, pigs, and/or primates. Sirolimus reverses acute rejection of heart and kidney allografts in rats and prolongs the graft survival in presensitized rats. In some studies, the immunosuppressive effect of sirolimus lasts up to 6 months after discontinuation of therapy. This tolerization effect is alloantigen-specific. In rodent models of autoimmune disease, sirolimus suppresses immune-mediated events associated with systemic lupus erythematosus, collagen-induced arthritis, autoimmune type I diabetes, autoimmune myocarditis, experimental allergic encephalomyelitis, graft-versus-host disease, and autoimmune uveoretinitis. Lymphangioleiomyomatosis involves lung tissue infiltration with smooth muscle-like cells that harbor inactivating mutations of the tuberous sclerosis complex (TSC) gene (LAM cells). Loss of TSC gene function activates the mTOR signaling pathway, resulting in cellular proliferation and release of lymphangiogenic growth factors. Sirolimus inhibits the activated mTOR pathway and thus the proliferation of LAM cells. 12.2 Pharmacodynamics Orally-administered sirolimus, at doses of 2 mg/day and 5 mg/day, significantly reduced the incidence of organ rejection in low- to moderate-immunologic risk renal transplant patients at 6 months following transplantation compared with either azathioprine or placebo [ see Clinical Studies ( 14.1 ) ]. There was no demonstrable efficacy advantage of a daily maintenance dose of 5 mg with a loading dose of 15 mg over a daily maintenance dose of 2 mg with a loading dose of 6 mg. Therapeutic drug monitoring should be used to maintain sirolimus drug levels within the target-range [ see Dosage and Administration ( 2.5 ) ]. 12.3 Pharmacokinetics Sirolimus pharmacokinetics activity have been determined following oral administration in healthy subjects, pediatric patients, hepatically impaired patients, and renal transplant patients. The pharmacokinetic parameters of sirolimus in low- to moderate-immunologic risk adult renal transplant patients following multiple dosing with sirolimus 2 mg daily, in combination with cyclosporine and corticosteroids, is summarized in Table 4. TABLE 4 MEAN ± SD STEADY STATE SIROLIMUS PHARMACOKINETIC PARAMETERS IN LOW-TO MODERATE-IMMUNOLOGIC RISK ADULT RENAL TRANSPLANT PATIENTS FOLLOWING SIROLIMUS 2 MG DAILY a,b a: In presence of cyclosporine administered 4 hours before sirolimus dosing. b: Based on data collected at months 1 and 3 post-transplantation. c: Average C min over 6 months. Multiple Dose (daily dose) Solution Tablets C max (ng/mL) 14.4 ± 5.3 15 ± 4.9 t max (hr) 2.1 ± 0.8 3.5 ± 2.4 AUC (ng•h/mL) 194 ± 78 230 ± 67 C min (ng/mL) c 7.1 ± 3.5 7.6 ± 3.1 CL/F (mL/h/kg) 173 ± 50 139 ± 63 Whole blood trough sirolimus concentrations, as measured by LC/MS/MS in renal transplant patients, were significantly correlated with AUC τ,ss . Upon repeated, twice-daily administration without an initial loading dose in a multiple-dose study, the average trough concentration of sirolimus increases approximately 2- to 3-fold over the initial 6 days of therapy, at which time steady-state is reached. A loading dose of 3 times the maintenance dose will provide near steady-state concentrations within 1 day in most patients [ see Dosage and Administration ( 2.3 , 2.5 ), Warning and Precautions ( 5.17 ) ]. Absorption Following administration of sirolimus oral solution, the mean times to peak concentration (t max ) of sirolimus are approximately 1 hour and 2 hours in healthy subjects and renal transplant patients, respectively. The systemic availability of sirolimus is low, and was estimated to be approximately 14% after the administration of sirolimus oral solution. In healthy subjects, the mean bioavailability of sirolimus after administration of the tablet is approximately 27% higher relative to the solution. Sirolimus tablets are not bioequivalent to the solution; however, clinical equivalence has been demonstrated at the 2 mg dose level. Sirolimus concentrations, following the administration of sirolimus oral solution to stable renal transplant patients, are dose-proportional between 3 and 12 mg/m 2 . Food Effects To minimize variability in sirolimus concentrations, both sirolimus oral solution and tablets should be taken consistently with or without food [ see Dosage and Administration ( 2 ) ]. In healthy subjects, a high-fat meal (861.8 kcal, 54.9% kcal from fat) increased the mean total exposure (AUC) of sirolimus by 23 to 35%, compared with fasting. The effect of food on the mean sirolimus C max was inconsistent depending on the sirolimus dosage form evaluated. Distribution The mean (± SD) blood-to-plasma ratio of sirolimus was 36 ± 18 in stable renal allograft patients, indicating that sirolimus is extensively partitioned into formed blood elements. The mean volume of distribution (Vss/F) of sirolimus is 12 ± 8 L/kg. Sirolimus is extensively bound (approximately 92%) to human plasma proteins, mainly serum albumin (97%), α 1 -acid glycoprotein, and lipoproteins. Metabolism Sirolimus is a substrate for both CYP3A4 and P-gp. Sirolimus is extensively metabolized in the intestinal wall and liver and undergoes counter-transport from enterocytes of the small intestine into the gut lumen. Inhibitors of CYP3A4 and P-gp increase sirolimus concentrations. Inducers of CYP3A4 and P-gp decrease sirolimus concentrations [ see Warnings and Precautions ( 5.20 ) and Drug Interactions ( 7 ) ]. Sirolimus is extensively metabolized by O-demethylation and/or hydroxylation. Seven (7) major metabolites, including hydroxy, demethyl, and hydroxydemethyl, are identifiable in whole blood. Some of these metabolites are also detectable in plasma, fecal, and urine samples. Sirolimus is the major component in human whole blood and contributes to more than 90% of the immunosuppressive activity. Excretion After a single dose of [ 14 C] sirolimus oral solution in healthy volunteers, the majority (91%) of radioactivity was recovered from the feces, and only a minor amount (2.2%) was excreted in urine. The mean ± SD terminal elimination half - life (t ½ ) of sirolimus after multiple dosing in stable renal transplant patients was estimated to be about 62 ± 16 hours. Sirolimus Concentrations (Chromatographic Equivalent) Observed in Phase 3 Clinical Studies The following sirolimus concentrations (chromatographic equivalent) were observed in phase 3 clinical studies for prophylaxis of organ rejection in de novo renal transplant patients [see Clinical Studies ( 14 ) ]. TABLE 5 SIROLIMUS WHOLE BLOOD TROUGH CONCENTRATIONS OBSERVED IN RENAL TRANSPLANT PATIENTS ENROLLED IN PHASE 3 STUDIES a: Months 4 through 12 b: Up to Week 2; observed CsA C min was 217 (56 to 432) ng/mL c: Week 2 to Week 26; observed CsA C min range was 174 (71 to 288) ng/mL d: Week 26 to Week 52; observed CsA C min was 136 (54.5 to 218) ng/mL Patient Population (Study number) Treatment Year 1 Year 3 Mean (ng/mL) 10 th to 90 th percentiles (ng/mL) Mean (ng/mL) 10 th to 90 th percentiles (ng/mL) Low-to-moderate risk (Studies 1 & 2) sirolimus (2 mg/day) + CsA 7.2 3.6 to 11 – – sirolimus (5 mg/day) + CsA 14 8 to 22 – – Low-to-moderate risk (Study 3) sirolimus + CsA 8.6 5 to 13 a 9.1 5.4 to 14 sirolimus alone 19 14 to 22 a 16 11 to 22 High risk (Study 4) sirolimus + CsA 15.7 11.8 11.5 5.4 to 27.3 b 6.2 to 16.9 c 6.3 to 17.3 d _ _ The withdrawal of cyclosporine and concurrent increases in sirolimus trough concentrations to steady-state required approximately 6 weeks. Following cyclosporine withdrawal, larger sirolimus doses were required due to the absence of the inhibition of sirolimus metabolism and transport by cyclosporine and to achieve higher target sirolimus trough concentrations during concentration-controlled administration [ see Dosage and Administration ( 2.1 ), Drug Interactions ( 7.1 ) ]. Lymphangioleiomyomatosis In a clinical trial of patients with lymphangioleiomyomatosis, the median whole blood sirolimus trough concentration after 3 weeks of receiving sirolimus tablets at a dose of 2 mg/day was 6.8 ng/mL (interquartile range 4.6 to 9 ng/mL; n = 37). Pharmacokinetics in Specific Populations Hepatic Impairment Sirolimus was administered as a single, oral dose to subjects with normal hepatic function and to patients with Child-Pugh classification A (mild), B (moderate), or C (severe) hepatic impairment. Compared with the values in the normal hepatic function group, the patients with mild, moderate, and severe hepatic impairment had 43%, 94%, and 189% higher mean values for sirolimus AUC, respectively, with no statistically significant differences in mean C max . As the severity of hepatic impairment increased, there were steady increases in mean sirolimus t 1/2 , and decreases in the mean sirolimus clearance normalized for body weight (CL/F/kg). The maintenance dose of sirolimus should be reduced by approximately one third in patients with mild-to-moderate hepatic impairment and by approximately one half in patients with severe hepatic impairment [ see Dosage and Administration ( 2.5 ) ]. It is not necessary to modify the sirolimus loading dose in patients with mild, moderate, and severe hepatic impairment. Therapeutic drug monitoring is necessary in all patients with hepatic impairment [ see Dosage and Administration ( 2.7 ) ]. Renal Impairment The effect of renal impairment on the pharmacokinetics of sirolimus is not known. However, there is minimal (2.2%) renal excretion of the drug or its metabolites in healthy volunteers. The loading and the maintenance doses of sirolimus need not be adjusted in patients with renal impairment [ see Dosage and Administration ( 2.6 ) ]. Pediatric Renal Transplant Patients Sirolimus pharmacokinetic data were collected in concentration-controlled trials of pediatric renal transplant patients who were also receiving cyclosporine and corticosteroids. The target ranges for trough concentrations were either 10 to 20 ng/mL for the 21 children receiving tablets, or 5 to 15 ng/mL for the one child receiving oral solution. The children aged 6 to 11 years (n = 8) received mean ± SD doses of 1.75 ± 0.71 mg/day (0.064 ± 0.018 mg/kg, 1.65 ± 0.43 mg/m 2 ). The children aged 12 to 18 years (n = 14) received mean ± SD doses of 2.79 ± 1.25 mg/day (0.053 ± 0.0150 mg/kg, 1.86 ± 0.61 mg/m 2 ). At the time of sirolimus blood sampling for pharmacokinetic evaluation, the majority (80%) of these pediatric patients received the sirolimus dose at 16 hours after the once-daily cyclosporine dose. See Table 6 below. TABLE 6 SIROLIMUS PHARMACOKINETIC PARAMETERS (MEAN ± SD) IN PEDIATRIC RENAL TRANSPLANT PATIENTS (MULTIPLE-DOSE CONCENTRATION CONTROL) a,b a: sirolimus coadministered with cyclosporine oral solution [MODIFIED] (e.g., Neoral ® Oral Solution) and/or cyclosporine capsules [MODIFIED] (e.g., Neoral ® Soft Gelatin Capsules).