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Pharmacokinetics of Sirolimus (Rapamycin) in Subjects With Mild to Moderate Hepatic Impairment

From the Departments of Clinical Pharmacology (Dr Zimmerman, Ms Harper, Dr Parker, Mr Matschke) and Mass Spectrometry (Dr Lim), Wyeth Research, Collegeville, Pennsylvania; and SFBC, Miami, Florida (Dr Lasseter, Ms Dilzer).

Address for reprints: James J. Zimmerman, PhD, Clinical Pharmacology, Wyeth Research, 500 Arcola Road, Collegeville, PA 19426.

	ABSTRACT

TOP ABSTRACT METHODS RESULTS DISCUSSION ACKNOWLEDGEMENTS REFERENCES

 
Eighteen adult subjects with mild to moderate hepatic impairment and 18 healthy control subjects were given a single 15-mg dose of sirolimus by oral solution. Mean whole-blood sirolimus weight-normalized oral-dose clearances (CL/F) were significantly decreased (P = .02) in subjects with mild to moderate hepatic impairment by -31.8% and -36.0%, respectively, compared with controls. There were no significant differences in mean sirolimus C_max and t_max values among groups. The observed decreases in CL/F may be relevant in renal transplant patients with mild to moderate hepatic impairment, based on the close similarity of sirolimus CL/F in controls and previously studied stable renal transplant patients receiving multiple-dose administration of sirolimus and cyclosporine. There was considerable overlap in the CL/F values of hepatic-impaired subjects and controls, suggesting that whole-blood sirolimus trough concentrations in renal transplant patients exhibiting mild to moderate hepatic impairment be initially monitored to assess the need for dose adjustments.

Key Words: Sirolimus • hepatic insufficiency • pharmacokinetics • immunosuppressive agents

Similar to the immunosuppressive agents CsA and tacrolimus, systemically absorbed sirolimus is eliminated primarily by metabolism and is a substrate for the hepatic⁵ and intestinal⁶ cytochrome P450 3A4 enzymes in vitro. The clearance of tacrolimus is reduced in persons with liver disease.^7,8 Because some kidney transplant subjects receiving sirolimus may have impaired liver function, this study was performed to assess the effect of hepatic impairment on the single-dose pharmacokinetics of sirolimus.

	METHODS

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Subjects
The subjects enrolled for this study included 18 adults with Child-Pugh grades A and B hepatic impairment⁹ and 18 healthy adults who were matched by gender, age (within 5 years), weight (within 10%), and smoking habit to the subjects with hepatic impairment. Each subject limited the consumption of caffeine-containing products (<300 mg/d) and avoided alcoholic beverages from 48 hours before sirolimus administration until the end of the study (day 14). Women of childbearing potential were not pregnant before sirolimus administration and used a medically acceptable, nonhormonal birth control method from the screening visit through the end of the study.

Subjects with hepatic impairment had chronic liver disease as assessed by liver biopsy (13 subjects) and/or physical signs consistent with Child-Pugh classification (eg, measurements for ascites, encephalopathy, bilirubin, albumin, and prothrombin time). Subjects were medically stable for at least 1 month before sirolimus administration and had no laboratory test values outside the normal limits, except for values related to hepatic impairment. Medications necessary for management of the subject's liver disease and associated conditions, as well as low-dose estrogen, progestin, or estrogen-progestin combination therapy for hormone replacement, were permitted if the regimens were stable for at least 2 weeks before sirolimus administration. The use of any recreational or investigational drug and treatment with any known substrates, inducers, or inhibitors of CYP3A4 were not allowed within 30 days before sirolimus administration.

Clinical Study
This open-label, single-dose pharmacokinetic study was performed by Clinical Pharmacology Associates (Miami, Fla). Each subject fasted overnight for a minimum of 10 hours before sirolimus administration. A 15-mg dose of sirolimus (Rapamune®) was prepared by transferring 3 mL of a nonaqueous oral solution (5 mg/mL) to a cup, adding 120 mL of room temperature water, and mixing. After sirolimus administration, the subjects remained at the unit for 144 hours and returned for blood sample collections and safety evaluations at 216 hours and 312 hours.

Venous blood samples (3 mL) were collected at each of the following time points relative to dosing: 0 (pre-dose), 0.33, 0.67, 1, 2, 3, 5, 8, 12, 24, 48, 72, 96, 120, 144, 216, and 312 hours. A duplicate set of blood samples was drawn for preparation of plasma by centrifugation (3 mL) on the same time schedule through 24 hours after dosing. All samples were stored frozen at -70°C until analyzed.

Bioanalysis
Whole-blood and plasma samples were assayed for sirolimus concentrations by Wyeth Research (Princeton, NJ) using validated high-performance liquid chromatographic tandem mass spectrometry (LC/MS/MS) methods,¹⁰ which included a linear range of 0.1 to 50 ng/mL and a sensitivity of 0.1 ng/mL in either whole blood or plasma. The in-process quality control (QC) samples in whole blood showed a mean interday bias ranging from -2.5% to +1.8%, and the mean interday imprecision (% coefficient of variation [CV]) ranged from 10.3% to 18.9%. The corresponding values for interday bias and imprecision for QC samples in plasma ranged from -10.0% to -4.7% and from 6.8% to 8.7%, respectively.

Pharmacokinetic Analyses
The values of peak concentration (C_max) and time of peak concentration (t_max) were read directly from the blood or plasma semilogarithmic concentration-time profiles. Other pharmacokinetic parameters were calculated using standard noncompartmental equations.¹¹ Linear regression was used to determine the slope (_z) of 4 to 7 points judged to be in the terminal linear phase of the sirolimus concentration-time profile. Because plasma sirolimus concentrations were usually near or below the limit of quantitation of the assay by 12 to 24 hours after dosing, only C_max and t_max were determined from the plasma profiles. The whole blood to plasma ratio (B/P) was determined as the average of B/P values at individual time points up to 24 hours.

Statistical Analyses
Differences between subject groups with respect to demographic characteristics, sirolimus pharmacokinetic parameters, and clinical laboratory values were evaluated using 1-way analysis of variance (ANOVA). The Tukey Studentized range test was used when ANOVA showed a significant difference. A univariate analysis (Pearson correlations) was used to investigate potential correlations between the pharmacokinetic parameters of sirolimus and selected demographic and laboratory parameters. All statistical analyses were performed using Statistical Analysis System software.¹²

	RESULTS

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Study Population
Fourteen men and 4 women were included in both the hepatic impairment and matched control groups. The hepatic-impaired subjects and healthy controls were well matched for age, weight, and height as shown in Table I (http://jcp.sagepub.com/cgi/content/full/45/12/1368/DC1/). In the hepatic impairment group, severity of liver disease was mild (Child-Pugh grade A) for 13 subjects and moderate (Child-Pugh grade B) for 5 subjects. Ascites was observed by physical examination in 7 subjects with hepatic impairment (3 with Child-Pugh grade A, 4 with grade B impairment). Administration of concomitant medications was sparse; only 5 subjects with hepatic impairment (Child-Pugh grade A) received any concomitant therapy. None of the therapies were agents known to interact with sirolimus.

Baseline laboratory values for hepatic-impaired subjects and healthy matched controls are shown online in Table I. As expected, mean values for AST/SGOT, ALT/SGPT, alkaline phosphatase, total bilirubin, and prothrombin time were significantly increased in hepatic-impaired subjects (P = .001) compared with matched controls, while the mean values for albumin were significantly decreased in hepatic-impaired subjects (P = .001) compared with controls.

Pharmacokinetics
Sirolimus pharmacokinetic parameters for hepatic-impaired subjects and healthy matched controls, based on both whole-blood and plasma sirolimus concentrations, are shown in Table II. The mean values of whole-blood sirolimus terminal half-life (t_1/2), total area under the concentration time curve (AUC_0-), and oral-dose mean residence time (MRT_po) were significantly increased (P = .001) in hepatic-impaired subjects compared with controls. The percentage increases in t_1/2, AUC_0-, and MRT_po were 24.9%, 48.3%, and 41.1%, respectively, in Child-Pugh grade A subjects and 88.5%, 95.7%, and 125%, respectively, in Child-Pugh grade B subjects. Based on pairwise comparisons, the significant differences in sirolimus t_1/2 were due to increases in Child-Pugh grade B subjects, while the significant differences in sirolimus AUC_0- and MRT_po were due to increases in both Child-Pugh grade A and B subjects.

Mean whole-blood sirolimus weight-normalized oral-dose clearance (CL/F) values were significantly decreased (P = .02) in hepatic-impaired subjects compared with matched controls. The percentage decreases in CL/F in Child-Pugh grade A and B subjects were -31.8% and -36.0%, respectively. Based on pairwise comparisons, the significant difference in sirolimus CL/F was due to a decrease in Child-Pugh grade A subjects compared with matched controls. Child-Pugh grade B subjects did not show a significant difference, which may have been due to the larger intersubject variability in these subjects (CV = 62.7%) compared with Child-Pugh grade A subjects (CV = 36.5%) and matched controls (CV = 35.4%).

The mean values for C_max, t_max, and V_ss/F of whole-blood sirolimus were not significantly different among the 3 subject groups. Close similarities among the 3 subject groups in both C_max and t_max suggested that hepatic impairment did not affect the absorption rate of sirolimus.

Mean plasma sirolimus C_max and t_max values were not significantly different among the 3 groups. Mean values of the sirolimus B/P ratio were significantly increased (P = .02) in hepatic-impaired subjects compared with matched controls. The percentage decreases in B/P were 29.7% and 93.5% in Child-Pugh grade A and B subjects, respectively. Based on pairwise comparisons, the significant difference in the sirolimus B/P ratio was due to an increase in Child-Pugh grade B subjects.

Correlation With Laboratory Parameters
Based on univariate correlation analysis, statistically significant relationships (P .05) were observed between various sirolimus pharmacokinetic parameters and prestudy laboratory values indicative of hepatic dysfunction. The P values for various univariate correlations ranged from .0369 to .001 (n = 35 to 36), but the explained variabilities (r²) did not exceed 65%, which would appear to preclude the use of clinical laboratory tests for a priori sirolimus dose adjustments in individual subjects with hepatic impairment.

Safety
Sirolimus administration was well tolerated by all subjects. Seven subjects reported adverse events. In the hepatic impairment group, the adverse events consisted of headache in 3 subjects (2 Child-Pugh grade A, 1 Child-Pugh grade B) and nausea in 1 subject (Child-Pugh grade A). In the control group, 2 subjects complained of headache and 1 subject experienced pruritis (itching on her face and hands). All adverse events were considered to be mild, and all resolved without intervention other than treatment of a headache in 1 subject. Occasional abnormal laboratory values were reversible and were not considered to be an adverse event by the investigator.

	DISCUSSION

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Sirolimus is a known substrate for both hepatic⁵ and intestinal CYP3A,⁶ and it has been shown that CYP3A concentrations decreased 75% in subjects with severe chronic liver disease (without chronic cholestasis).¹³ Thus, the significant increase in total exposure (P = .001) and concomitant decrease in weight-normalized oral-dose clearance (P = .02) among hepatically impaired subjects in the current study were not unexpected. However, no significant effect on the sirolimus absorption-related parameters C_max and t_max was observed among the hepatically impaired subjects in this study. Because the first-pass effect of sirolimus has both hepatic and intestinal components, the data suggest that the intestinal first-pass component of sirolimus may not be significantly affected by hepatic impairment.

The sirolimus whole B/P ratio was significantly increased by hepatic impairment in this study (P = .001), but the mechanism for this increase is not clear. An increased partitioning of sirolimus between whole blood and plasma could result from a reduction in the binding capacity of plasma, either due to reduced concentrations of binding proteins or to displacement by compounds that accumulate in liver disease.¹⁴ Sirolimus shows appreciable binding to both lipoproteins (about 40%) and the lipoprotein-free fraction (about 60%) of plasma.¹⁵ Overall, the binding of sirolimus to plasma proteins has been reported to range from 92%¹ to 97.5%.¹⁵ It is also known that drug binding to plasma proteins decreases as a result of hypoalbuminemia (albumin 3 g/dL)¹⁶ and hyperbilirubinemia (bilirubin 4.5 mg/dL).¹⁷ The subjects enrolled in the present study did not show either hypoalbuminemia or hyperbilirubinemia, but both albumin and total bilirubin concentrations were significantly affected by hepatic impairment (P = .001). Compared with matched controls, mean albumin concentrations showed a maximum mean decrease of only 13%, but total bilirubin concentrations showed a maximum mean increase of 167%. The increases in mean total bilirubin concentrations among the 3 subject groups were highly correlated with both their mean B/P ratios (r = 0.999) and mean plasma sirolimus C_max values (r = - 1.00). Despite an increase in the B/P ratio, the V_ss/F of sirolimus was large and unaffected by the presence of hepatic impairment (P = .93).

The mean sirolimus B/P ratios for healthy subjects in this study (B/P = 117 ± 24, n = 18) were similar to those previously reported for healthy fasting subjects receiving either a single 15-mg dose of sirolimus (B/P = 84.4 ± 35.9, n = 22)¹⁰ or single 42-mg dose of [¹⁴C]-sirolimus (B/P = 142, n = 6).¹⁸ Nevertheless, the estimates in healthy subjects were considerably larger than previously reported estimates of mean B/P ratios in stable renal transplant subjects receiving multiple-dose CsA and either concomitant single-dose¹⁹ (B/P = 34.4 ± 17.6, n = 36) or concomitant multiple-dose²⁰ (B/P = 38.8 ± 12.8, n = 30) sirolimus. The lower estimates of B/P in stable renal transplant subjects may have been due to the known hyperlipidemic effect of sirolimus.¹ Based on a 42-day study in renal allograft subjects (n = 6) receiving sirolimus at a dose of 10 mg/d,²¹ significant increases were observed not only in total plasma cholesterol (+50%) and triglycerides (+95%) but also in the apolipoproteins ApoB-100 (+28%) and ApoC-III (+92%). Because sirolimus is approximately 40% bound to the lipoprotein fraction in blood over a sirolimus concentration range of 5 to 100 ng/mL,¹⁵ increases in plasma lipoproteins may increase the sirolimus plasma concentrations, leading to a lower B/P ratio in renal allograft subjects.

Because the subjects with mild to moderate hepatic impairment in this study exhibited statistically significant decreases in oral-dose clearances, oral doses of sirolimus may need to be decreased in individual renal transplant subjects with mild to moderate hepatic impairment. The data suggest an approximate 33% decrease in the sirolimus dose for both Child-Pugh grade A and Child-Pugh grade B subjects. However, a considerable overlap in ranges of the whole-blood sirolimus pharmacokinetic parameters among subject groups was observed, and the data revealed that 8 of 18 hepatically impaired subjects (6 Child-Pugh A, 2 Child-Pugh B) showed CL/F values that overlapped with those for healthy subjects.

It is reasonable to question whether the observed difference between hepatic-impaired subjects and healthy controls in CL/F is relevant in renal transplant patients. This appears to be the case since data after sirolimus multiple-dose administration in 40 stable renal transplant patients²⁰ showed a mean ± SD sirolimus CL/F of 208 ± 95 mL/h/kg, compared with 215 ± 76 mL/h/kg in healthy matched controls for the current study.

A prudent dose-adjustment strategy would therefore include initial trough monitoring to assess whether whole-blood sirolimus trough concentrations fall within a putative safe target range. This range is assumed to be approximated by the 10th and 90th percentiles of whole-blood sirolimus concentrations in renal transplant patients who were enrolled in sirolimus pivotal clinical trials. Thus, whole-blood sirolimus concentrations would be adjusted, if necessary, to fall within ranges of either 4.5 to 14 ng/mL or 10 to 28 ng/mL during fixed-dose regimens of either 2 mg/d or 5 mg/d, respectively, and within 17 to 29 ng/mL during a cyclosporine withdrawal regimen.¹

	ACKNOWLEDGEMENTS

TOP ABSTRACT METHODS RESULTS DISCUSSION ACKNOWLEDGEMENTS REFERENCES

 
Supported by grants from Wyeth Research, Collegeville, Pennsylvania.

DOI: 10.1177/0091270005281350

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TOP ABSTRACT METHODS RESULTS DISCUSSION ACKNOWLEDGEMENTS REFERENCES

 

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				J. J. Zimmerman, A. Patat, V. Parks, R. Moirand, and K. Matschke Pharmacokinetics of Sirolimus (Rapamycin) in Subjects With Severe Hepatic Impairment J. Clin. Pharmacol., March 1, 2008; 48(3): 285 - 292. [Abstract] [Full Text] [PDF]

This Article Abstract Full Text (PDF) Supplementary Data Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Request Reprints Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (3) Citing Articles via Google Scholar Google Scholar Articles by Zimmerman, J. J. Articles by Matschke, K. Search for Related Content PubMed PubMed Citation Articles by Zimmerman, J. J. Articles by Matschke, K. Social Bookmarking                   What's this?