Sirolimus - Sirolimus solution

Monitoring of sirolimus trough concentrations is recommended for all patients, especially in those patients likely to have altered drug metabolism, in patients ≥ 13 years who weigh less than 40 kg, in patients with hepatic impairment, when a change in the sirolimus oral solution dosage form is made, and during concurrent administration of strong CYP3A4 inducers and inhibitors [

].

Therapeutic drug monitoring should not be the sole basis for adjusting sirolimus oral solution therapy. Careful attention should be made to clinical signs/symptoms, tissue biopsy findings, and laboratory parameters.

When used in combination with cyclosporine, sirolimus trough concentrations should be maintained within the target-range [

]. Following cyclosporine withdrawal in transplant patients at low- to moderate-immunologic risk, the target sirolimus trough concentrations should be 16 to 24 ng/mL for the first year following transplantation. Thereafter, the target sirolimus concentrations should be 12 to 20 ng/mL.

The above recommended 24-hour trough concentration ranges for sirolimus are based on chromatographic methods. Currently in clinical practice, sirolimus whole blood concentrations are being measured by both chromatographic and immunoassay methodologies. Because the measured sirolimus whole blood concentrations depend on the type of assay used, the concentrations obtained by these different methodologies are not interchangeable [

]. Adjustments to the targeted range should be made according to the assay utilized to determine sirolimus trough concentrations. Since results are assay and laboratory dependent, and the results may change over time, adjustments to the targeted therapeutic range must be made with a detailed knowledge of the site-specific assay used. Therefore, communication should be maintained with the laboratory performing the assay. A discussion of different assay methods is contained in Clinical Therapeutics, Volume 22, Supplement B, April 2000 [].

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.

	Multiple Dose (daily dose)
	Solution	Tablets
Cmax(ng/mL)	14.4 ± 5.3	15.0 ± 4.9
tmax(hr)	2.1 ± 0.8	3.5 ± 2.4
AUC (ng•h/mL)	194 ± 78	230 ± 67
Cmin(ng/mL)c	7.1 ± 3.5	7.6 ± 3.1
CL/F (mL/h/kg)	173 ± 50	139 ± 63

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_minover 6 months.

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 [

].

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/m².

To minimize variability in sirolimus concentrations, sirolimus oral solution should be taken consistently with or without food []. 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_maxwas inconsistent depending on the sirolimus dosage form evaluated.







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%), α₁-acid glycoprotein, and lipoproteins.







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 []. 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.

After a single dose of [¹⁴C] 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.

The following sirolimus concentrations (chromatographic equivalent) were observed in phase 3 clinical studies for prophylaxis of organ rejection in

renal transplant patients [].

Patient Population (Study number)	Treatment	Year 1		Year 3
		Mean (ng/mL)	10thto 90thpercentiles (ng/mL)	Mean (ng/mL)	10thto 90thpercentiles 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 13a	9.1	5.4 to 14
	Sirolimus alone	19	14 to 22a	16	11 to 22
High risk (Study 4)	Sirolimus  + CsA	15.7	5.4 to 27.3b	–	–
		11.8	6.2 to 16.9c
		11.5	6.3 to 17.3d

a: Months 4 through 12

b: Up to Week 2; observed CsA C_minwas 217 (56 to 432) ng/mL

c: Week 2 to Week 26; observed CsA C_minrange was 174 (71 to 288) ng/mL

d: Week 26 to Week 52; observed CsA C_minwas 136 (54. to 218) ng/mL

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 [

].

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 9.0 ng/mL; n = 37).

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 [

]. 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 [].

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 [

].

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/m²). 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/m2). 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.

Age (y)	n	Body Weight (kg)	Cmax (ng/mL)	tmax,ss (h)	Cmin,ss (ng/mL)	AUCT,ss (ng•h/mL)	CL/Fc (mL/h/Kg)	CL/Fc (L/h/m2)
6 to 11	8	27 ± 10	22.1 ± 8.9	5.88 ± 4.05	10.6 ± 4.3	356 ± 127	214 ± 129	5.4 ± 2.8
12 to 18	14	52 ± 15	34.5 ± 12.2	2.7 ± 1.5	14.7 ± 8.6	466 ± 236	136 ± 57	4.7 ± 1.9

a: Sirolimus co-administered with cyclosporine oral solution [MODIFIED] (e.g., Neoral^®Oral Solution) and/or cyclosporine capsules

[MODIFIED] (e.g., Neoral^®Soft Gelatin Capsules).

b: As measured by Liquid Chromatographic/Tandem Mass Spectrometric Method (LC/MS/MS)

c: Oral-dose clearance adjusted by either body weight (kg) or body surface area (m²).

Table 7 below summarizes pharmacokinetic data obtained in pediatric dialysis patients with chronically impaired renal function.

Age Group (y)	n	tmax(h)	t1/2(h)	CL/F/WT(mL/h/kg)
5 to 11	9	1.1 ± 0.5	71 ± 40	580 ± 450
12 to 18	11	0.79 ± 0.17	55 ± 18	450 ± 232

* All subjects received sirolimus oral solution.

Clinical studies of sirolimus did not include a sufficient number of patients >65 years of age to determine whether they will respond differently than younger patients. After the administration of sirolimus oral solution or tablets, sirolimus trough concentration data in renal transplant patients >65 years of age were similar to those in the adult population 18 to 65 years of age.

Sirolimus clearance in males was 12% lower than that in females; male subjects had a significantly longer t_1/2than did female subjects (72.3 hours versus 61.3 hours). Dose adjustments based on gender are not recommended.

In the phase 3 trials for the prophylaxis of organ rejection following renal transplantation using sirolimus solution or tablets and cyclosporine oral solution [MODIFIED] (e.g., Neoral^®Oral Solution) and/or cyclosporine capsules [MODIFIED] (e.g., Neoral^®Soft Gelatin Capsules) [

], there were no significant differences in mean trough sirolimus concentrations over time between Black (n = 190) and non-Black (n = 852) patients during the first 6 months after transplantation.

Sirolimus is known to be a substrate for both cytochrome CYP3A4 and P-gp. The pharmacokinetic interaction between sirolimus and concomitantly administered drugs is discussed below. Drug interaction studies have not been conducted with drugs other than those described below.

Cyclosporine is a substrate and inhibitor of CYP3A4 and P-gp. Sirolimus should be taken 4 hours after administration of cyclosporine oral solution (MODIFIED) and/or cyclosporine capsules (MODIFIED). Sirolimus concentrations may decrease when cyclosporine is discontinued, unless the sirolimus dose is increased [].

In a single-dose drug-drug interaction study, 24 healthy volunteers were administered 10 mg sirolimus tablets either simultaneously or 4 hours after a 300-mg dose of Neoral^®Soft Gelatin Capsules (cyclosporine capsules [MODIFIED]). For simultaneous administration, mean C_maxand AUC were increased by 512% and 148%, respectively, relative to administration of sirolimus alone. However, when given 4 hours after cyclosporine administration, sirolimus C_maxand AUC were both increased by only 33% compared with administration of sirolimus alone.

In a single dose drug-drug interaction study, 24 healthy volunteers were administered 10 mg sirolimus oral solution either simultaneously or 4 hours after a 300 mg dose of Neoral^®Soft Gelatin Capsules (cyclosporine capsules [MODIFIED]). For simultaneous administration, the mean C_maxand AUC of sirolimus, following simultaneous administration were increased by 116% and 230%, respectively, relative to administration of sirolimus alone. However, when given 4 hours after Neoral^®Soft Gelatin Capsules (cyclosporine capsules [MODIFIED]) administration, sirolimus C_maxand AUC were increased by only 37% and 80%, respectively, compared with administration of sirolimus alone.

In a single-dose cross-over drug-drug interaction study, 33 healthy volunteers received 5 mg sirolimus oral solution alone, 2 hours before, and 2 hours after a 300 mg dose of Neoral^®Soft Gelatin Capsules (cyclosporine capsules [MODIFIED]). When given 2 hours before Neoral^®Soft Gelatin Capsules (cyclosporine capsules [MODIFIED]) administration, sirolimus C_maxand AUC were comparable to those with administration of sirolimus alone. However, when given 2 hours after, the mean C_maxand AUC of sirolimus were increased by 126% and 141%, respectively, relative to administration of sirolimus alone.

Mean cyclosporine C_maxand AUC were not significantly affected when sirolimus oral solution was given simultaneously or when administered 4 hours after Neoral^®Soft Gelatin Capsules (cyclosporine capsules [MODIFIED]). However, after multiple-dose administration of sirolimus given 4 hours after Neoral^®in renal post-transplant patients over 6 months, cyclosporine oral-dose clearance was reduced, and lower doses of Neoral^®Soft Gelatin Capsules (cyclosporine capsules [MODIFIED]) were needed to maintain target cyclosporine concentration.

In a multiple-dose study in 150 psoriasis patients, sirolimus 0.5, 1.5, and 3 mg/m²/day was administered simultaneously with Sandimmune^®Oral Solution (cyclosporine Oral Solution) 1.25 mg/kg/day. The increase in average sirolimus trough concentrations ranged between 67% to 86% relative to when sirolimus was administered without cyclosporine. The intersubject variability (% CV) for sirolimus trough concentrations ranged from 39.7% to 68.7%. There was no significant effect of multiple-dose sirolimus on cyclosporine trough concentrations following Sandimmune^®Oral Solution (cyclosporine oral solution) administration. However, the % CV was higher (range 85.9% to 165%) than those from previous studies.

Diltiazem is a substrate and inhibitor of CYP3A4 and P-gp; sirolimus concentrations should be monitored and a dose adjustment may be necessary []. The simultaneous oral administration of 10 mg of sirolimus oral solution and 120 mg of diltiazem to 18 healthy volunteers significantly affected the bioavailability of sirolimus. Sirolimus C_max, t_max, and AUC were increased 1.4-, 1.3-, and 1.6-fold, respectively. Sirolimus did not affect the pharmacokinetics of either diltiazem or its metabolites desacetyldiltiazem and desmethyldiltiazem.

Erythromycin is a substrate and inhibitor of CYP3A4 and P-gp; co-administration of sirolimus oral solution or tablets and erythromycin is not recommended []. The simultaneous oral administration of 2 mg daily of sirolimus oral solution and 800 mg q 8h of erythromycin as erythromycin ethylsuccinate tablets at steady state to 24 healthy volunteers significantly affected the bioavailability of sirolimus and erythromycin. Sirolimus C_maxand AUC were increased 4.4- and 4.2-fold respectively and t_maxwas increased by 0.4 hr. Erythromycin C_maxand AUC were increased 1.6- and 1.7-fold, respectively, and t_maxwas increased by 0.3 hr.

Ketoconazole is a strong inhibitor of CYP3A4 and P-gp; co-administration of sirolimus oral solution or tablets and ketoconazole is not recommended []. Multiple-dose ketoconazole administration significantly affected the rate and extent of absorption and sirolimus exposure after administration of sirolimus oral solution, as reflected by increases in sirolimus C_max, t_max, and AUC of 4.3-fold, 38%, and 10.9-fold, respectively. However, the terminal t_½of sirolimus was not changed. Single-dose sirolimus did not affect steady-state 12-hour plasma ketoconazole concentrations.

Rifampin is a strong inducer of CYP3A4 and P-gp; co-administration of sirolimus oral solution or tablets and rifampin is not recommended. In patients where rifampin is indicated, alternative therapeutic agents with less enzyme induction potential should be considered []. Pretreatment of 14 healthy volunteers with multiple doses of rifampin, 600 mg daily for 14 days, followed by a single 20-mg dose of sirolimus oral solution, greatly decreased sirolimus AUC and C_maxby about 82% and 71%, respectively.

Verapamil is a substrate and inhibitor of CYP3A4 and P-gp; sirolimus concentrations should be monitored and a dose adjustment may be necessary; []. The simultaneous oral administration of 2 mg daily of sirolimus oral solution and 180 mg q 12h of verapamil at steady state to 25 healthy volunteers significantly affected the bioavailability of sirolimus and verapamil. Sirolimus C_maxand AUC were increased 2.3- and 2.2-fold, respectively, without substantial change in t_max. The C_maxand AUC of the pharmacologically active S(-) enantiomer of verapamil were both increased 1.5-fold and t_maxwas decreased by 1.2 hr.

Clinically significant pharmacokinetic drug-drug interactions were not observed in studies of drugs listed below. Sirolimus and these drugs may be co-administered without dose adjustments.

• Acyclovir

• Atorvastatin

• Digoxin

• Glyburide

• Nifedipine

• Norgestrel/ethinyl estradiol (Lo/Ovral^®)

• Prednisolone

• Sulfamethoxazole/trimethoprim (Bactrim^®)

Co-administration of sirolimus with other known strong inhibitors of CYP3A4 and/or P-gp (such as voriconazole, itraconazole, telithromycin, or clarithromycin) or other known strong inducers of CYP3A4 and/or P-gp (such as rifabutin) is not recommended [

]. In patients in whom strong inhibitors or inducers of CYP3A4 are indicated, alternative therapeutic agents with less potential for inhibition or induction of CYP3A4 should be considered.

Care should be exercised when drugs or other substances that are substrates and/or inhibitors or inducers of CYP3A4 are administered concomitantly with sirolimus. Other drugs that have the potential to increase sirolimus blood concentrations include (but are not limited to):

• Calcium channel blockers: nicardipine.

• Antifungal agents: clotrimazole, fluconazole.

• Antibiotics: troleandomycin.

• Gastrointestinal prokinetic agents: cisapride, metoclopramide.

• Other drugs: bromocriptine, cimetidine, danazol, letermovir,

Other drugs that have the potential to decrease sirolimus concentrations include (but are not limited to):

• Anticonvulsants: carbamazepine, phenobarbital, phenytoin.

• Antibiotics: rifapentine.

Grapefruit juice reduces CYP3A4-mediated drug metabolism. Grapefruit juice must not be taken with or used for dilution of sirolimus [

].

St. John’s Wort () induces CYP3A4 and P-gp. Since sirolimus is a substrate for both cytochrome CYP3A4 and P-gp, there is the potential that the use of St. John’s Wort in patients receiving sirolimus could result in reduced sirolimus concentrations [].