Sirolimus Other names: Rapamycin Sirolimus

Sirolimus inhibits T-cell activation induced by most stimuli, by blocking calcium-dependent and calcium-independent intracellular signal transduction. Studies demonstrated that its effects are mediated by a mechanism that is different from that of ciclosporin, tacrolimus, and other immunosuppressive agents.

Experimental evidence suggests that sirolimus binds to the specific cytosolic protein FKPB-12, and that the FKPB 12-sirolimus complex inhibits the activation of the mammalian Target Of Rapamycin (mTOR), a critical kinase for cell cycle progression. The inhibition of mTOR results in blockage of several specific signal transduction pathways. The net result is the inhibition of lymphocyte activation, which results in immunosuppression.

In animals, sirolimus has a direct effect on T- and B-cell activation, suppressing immune-mediated reactions, such as allograft rejection.

LAM involves lung tissue infiltration with smooth muscle-like cells that harbour 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.

Much of the general pharmacokinetic information was obtained using the sirolimus oral solution, which is summarised first. Information directly related to the tablet formulation is summarised specifically in the Oral tablet section.

Oral solution

Following administration of the sirolimus oral solution, sirolimus is rapidly absorbed, with a time to peak concentration of 1 hour in healthy subjects receiving single doses and 2 hours in patients with stable renal allografts receiving multiple doses. The systemic availability of sirolimus in combination with simultaneously administered ciclosporin is approximately 14%. Upon repeated administration, the average blood concentration of sirolimus is increased approximately 3-fold. The terminal half-life in stable renal transplant patients after multiple oral doses was 62 ± 16 hours. The effective half-life, however, is shorter and mean steady-state concentrations were achieved after 5 to 7 days. The blood to plasma ratio (B/P) of 36 indicates that sirolimus is extensively partitioned into formed blood elements.

Sirolimus is a substrate for both cytochrome P450 IIIA4 (CYP3A4) and P-glycoprotein. Sirolimus is extensively metabolised by O-demethylation and/or hydroxylation. Seven major metabolites, including hydroxyl, demethyl, and hydroxydemethyl, are identifiable in whole blood. Sirolimus is the major component in human whole blood and contributes to greater than 90% of the immunosuppressive activity. After a single dose of [¹⁴C] sirolimus in healthy volunteers, the majority (91.1%) of radioactivity was recovered from the faeces, and only a minor amount (2.2%) was excreted in urine.

Clinical studies of sirolimus did not include a sufficient number of patients above 65 years of age to determine whether they will respond differently than younger patients. Sirolimus trough concentration data in 35 renal transplant patients above 65 years of age were similar to those in the adult population (n=822) from 18 to 65 years of age.

In paediatric patients on dialysis (30% to 50% reduction in glomerular filtration rate) within age ranges of 5 to 11 years and 12 to 18 years, the mean weight-normalised CL/F was larger for younger paediatric patients (580 mL/h/kg) than for older paediatric patients (450 mL/h/kg) as compared with adults (287 mL/h/kg). There was a large variability for individuals within the age groups.

Sirolimus concentrations were measured in concentration-controlled studies of paediatric renal-transplant patients who were also receiving ciclosporin and corticosteroids. The target for trough concentrations was 10-20 ng/mL. At steady-state, 8 children aged 6-11 years received mean ± SD doses of 1.75 ± 0.71 mg/day (0.064 ± 0.018 mg/kg, 1.65 ± 0.43 mg/m²) while 14 adolescents aged 12-18 years received mean ± SD doses of 2.79 ± 1.25 mg/day (0.053 ± 0.0150 mg/kg, 1.86 ± 0.61 mg/m²). The younger children had a higher weight-normalised CL/F (214 mL/h/kg) compared with the adolescents (136 mL/h/kg). These data indicate that younger children might require higher bodyweight-adjusted doses than adolescents and adults to achieve similar target concentrations. However, the development of such special dosing recommendations for children requires more data to be definitely confirmed.

In mild and moderate hepatically impaired patients (Child-Pugh classification A or B), mean values for sirolimus AUC and t_1/2 were increased 61% and 43%, respectively, and CL/F was decreased 33% compared to normal healthy subjects. In severe hepatically impaired patients (Child-Pugh classification C), mean values for sirolimus AUC and t_1/2 were increased 210% and 170%, respectively, and CL/F was decreased by 67% compared to normal healthy subjects. The longer half-lives observed in hepatically impaired patients delay reaching steady-state.

Pharmacokinetic/pharmacodynamic relationship

The pharmacokinetics of sirolimus were similar in various populations, with renal function ranging from normal to absent (dialysis patients).

Oral tablet

The 0.5 mg tablet is not fully bioequivalent to the 1 mg, 2 mg and 5 mg tablets when comparing C_max. Multiples of the 0.5 mg tablets should therefore not be used as a substitute for other tablet strengths.

In healthy subjects, the mean extent of bioavailability of sirolimus after single-dose administration of the tablet formulation is about 27% higher relative to the oral solution. The mean C_max was decreased by 35%, and mean t_max increased by 82%. The difference in bioavailability was less marked upon steady-state administration to renal transplant recipients, and therapeutic equivalence has been demonstrated in a randomised study of 477 patients. When switching patients between oral solution and tablet formulations, it is recommended to give the same dose and to verify the sirolimus trough concentration 1 to 2 weeks later to assure that it remains within recommended target ranges. Also, when switching between different tablet strengths, verification of trough concentrations is recommended.

In 24 healthy volunteers receiving sirolimus tablets with a high-fat meal, C_max, t_max and AUC showed increases of 65%, 32%, and 23%, respectively. To minimise variability, sirolimus tablets should be taken consistently with or without food. Grapefruit juice affects CYP3A4-mediated metabolism and must, therefore, be avoided.

Sirolimus concentrations, following the administration of sirolimus tablets (5 mg) to healthy subjects as single doses are dose proportional between 5 and 40 mg.

Clinical studies of sirolimus did not include a sufficient number of patients above 65 years of age to determine whether they will respond differently than younger patients. Sirolimus tablets administered to 12 renal transplant patients above 65 years of age gave similar results to adult patients (n=167) 18 to 65 years of age.

Initial Therapy (2 to 3 months post-transplant)

In most patients receiving sirolimus tablets with a loading dose of 6 mg followed by an initial maintenance dose of 2 mg, whole blood sirolimus trough concentrations rapidly achieved steady-state concentrations within the recommended target range (4 to 12 ng/mL, chromatographic assay). Sirolimus pharmacokinetic parameters following daily doses of 2 mg sirolimus tablets administered in combination with ciclosporin microemulsion (4 hours prior to sirolimus tablets) and corticosteroids in 13 renal transplant patients, based on data collected at months 1 and 3 after transplantation, were: C_min,ss 7.39 ± 2.18 ng/mL; C_max,ss 15.0 ± 4.9 ng/mL; t_max,ss 3.46 ± 2.40 hours; AUC_τ,ss 230 ± 67 ng.h/mL; CL/F/WT, 139 ± 63 mL/h/kg (parameters calculated from LC-MS/MS assay results). The corresponding results for the oral solution in the same clinical study were C_min,ss 5.40 ± 2.50 ng/mL, C_max,ss 14.4 ± 5.3 ng/mL, t_max,ss 2.12 ± 0.84 hours, AUC_τ,ss 194 ± 78 ng.h/mL, CL/F/W 173 ± 50 mL/h/kg. Whole blood trough sirolimus concentrations, as measured by LC/MS/MS, were significantly correlated (r²=0.85) with AUC_τ,ss.

Based on monitoring in all patients during the period of concomitant therapy with ciclosporin, mean (10^th, 90^th percentiles) troughs (expressed as chromatographic assay values) and daily doses were 8.6 ± 3.0 ng/mL (5.0 to 13 ng/mL) and 2.1 ± 0.70 mg (1.5 to 2.7 mg), respectively.

Maintenance therapy

From month 3 to month 12, following discontinuation of ciclosporin, mean (10^th, 90^th percentiles) troughs (expressed as chromatographic assay values) and daily doses were 19 ± 4.1 ng/mL (14 to 24 ng/mL) and 8.2 ± 4.2 mg (3.6 to 13.6 mg), respectively. Therefore, the sirolimus dose was approximately 4-fold higher to account for both the absence of the pharmacokinetic interaction with ciclosporin (2-fold increase) and the augmented immunosuppressive requirement in the absence of ciclosporin (2-fold increase).

Lymphangioleiomyomatosis (LAM)

In a clinical trial of patients with LAM, 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 9.0 ng/mL; n=37). With concentration-control (target concentrations 5 to 15 ng/mL), the median sirolimus concentration at the end of 12 months of treatment was 6.8 ng/mL (interquartile range 5.9 to 8.9 ng/mL; n=37).

Adverse reactions not observed in clinical studies, but seen in animals at exposure levels similar to clinical exposure levels and with possible relevance to clinical use, were as follows: pancreatic islet cell vacuolation, testicular tubular degeneration, gastrointestinal ulceration, bone fractures and calluses, hepatic haematopoiesis, and pulmonary phospholipidosis.

Sirolimus was not mutagenic in the in vitro bacterial reverse mutation assays, the Chinese Hamster Ovary cell chromosomal aberration assay, the mouse lymphoma cell forward mutation assay, or the in vivo mouse micronucleus assay.

Carcinogenicity studies conducted in mouse and rat showed increased incidences of lymphomas (male and female mouse), hepatocellular adenoma and carcinoma (male mouse) and granulocytic leukaemia (female mouse). It is known that malignancies (lymphoma) secondary to the chronic use of immunosuppressive agents can occur and have been reported in patients in rare instances. In mouse, chronic ulcerative skin lesions were increased. The changes may be related to chronic immunosuppression. In rat, testicular interstitial cell adenomas were likely indicative of a species-dependent response to lutenising hormone levels and are usually considered of limited clinical relevance.

In reproduction toxicity studies decreased fertility in male rats was observed. Partly reversible reductions in sperm counts were reported in a 13-week rat study. Reductions in testicular weights and/or histological lesions (e.g. tubular atrophy and tubular giant cells) were observed in rats and in a monkey study. In rats, sirolimus caused embryo/foetotoxicity that was manifested as mortality and reduced foetal weights (with associated delays in skeletal ossification).