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PHARMACOKINETICS/SPECIAL POPULATIONS |
From Clinical Pharmacology, Wyeth Research, Collegeville, Pennsylvania (Dr Zimmerman, Mr Matschke); Clinical Research and Development, Wyeth Research, Paris, France (Dr Patat, Ms Parks); and Biotrial, rue Jean-Louis Bertrand, Technopole Atalante Villejean, Rennes, France (Dr Patat, Dr Moirand).
Address for correspondence: Joan Korth-Bradley, Clinical Pharmacology, Wyeth Research, 500 Arcola Road, Collegeville, PA 19426; e-mail: korthbj{at}wyeth.com.
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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.002) in mean whole-blood sirolimus t
(168%), AUC0-
(210%), and MRToral (261%), together with a decrease (P = .001) in CL/F (-67%), were observed in subjects with severe hepatic impairment compared with healthy matched controls. Sirolimus pharmacokinetic data in Child-Pugh grade A (n = 13, mild) and B (n = 5, moderate) subjects from a previous identically designed study were available for an inter-study comparison. Overall, mean t, weight-normalized AUC, and MRToral increased steadily, whereas mean CL/F decreased steadily, with increasing degrees of hepatic impairment. CL/F showed large intersubject variabilities within subject types and extensive overlap among the subject types. The results of this study suggest that an initial sirolimus dose reduction of approximately 60% is appropriate in patients with acute severe hepatic impairment; this should be followed by further dose adjustment, based on therapeutic drug monitoring, until the trough concentrations have stabilized at sirolimus levels existing prior to the onset of acute liver failure.
Key Words: Sirolimus • hepatic impairment • Child-Pugh grade • pharmacokinetics • immunosuppressive agents
Sirolimus is absorbed rapidly (median time to peak concentration [tmax] = 1 hour) when administered orally as a nonaqueous solution to stable renaltrans plant subjects by either single-dose5 or multiple-dose6 regimens. The systemic availability of sirolimus in stable renal transplant subjects is approximately 14%.7 Sirolimus is concentrated in formed elements of the blood8; the whole blood-to-plasma (B/P) ratio of sirolimus in renal allograft subjects is approximately 36, which is independent of concentration over a wide range.5,6,9 Sirolimus is administered once daily in renal allograft subjects because of its terminal half-life in whole blood of approximately 62 hours.6
Sirolimus is a known substrate for the hepatic10 and intestinal11 cytochrome P450 (CYP) CYP3A4 enzymes in vitro, and it has been shown that CYP3A concentrations were decreased by 75% in livers from subjects with severe chronic liver disease (without chronic cholestasis).12 Furthermore, the results of a previous sirolimus pharmacokinetic study in adult subjects with mild (Child-Pugh grade A, n = 13) to moderate (Child-Pugh grade B, n = 5) hepatic impairment showed decreases in whole-blood sirolimus weight-normalized oral dose clearance (CL/F) of -31.8% and -36.0%, respectively.13 This study was therefore conducted to determine the effect of severe hepatic impairment (Child-Pugh grade C) on the pharmacokinetics of sirolimus in adult subjects.
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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The subjects recruited for this study included 9 adults with Child-Pugh grade C14 hepatic impairment without encephalopathy and 9 healthy adults who were matched by sex, age (±5 years), weight (±10% of subject's dry weight), and smoking habit to the subjects with severe hepatic impairment. All subjects were 18 to 70 years of age, had a dry body weight greater than 50 kg (excluding the estimated weight of ascites and edema), and had a body mass index (BMI) less than 30 kg/m2 based on dry body weight.15
The weights associated with edema and ascites were based on the following: clinically detectable edema (
2 kg), ascites detectable by ultrasound ( 1 kg), clinically detectable ascites ( 2 kg), distended ascites for a subject of small frame ( 5 kg), and distended ascites for a subject of large frame ( 10 kg).
In addition, each subject abstained from caffeine-containing products, alcoholic beverages, and grapefruit-containing products for 24 hours before sirolimus administration until the end of the inpatient stay (day 7 for subjects with hepatic impairment and day 3 for matched healthy controls). Women of childbearing potential had a negative serum pregnancy test (β-HCG) result before administration of sirolimus and used a medically acceptable birth control method from the screening visit through the end of the study (day 14).
Subjects with severe hepatic impairment had chronic liver disease that was consistent with Child-Pugh classification (eg, measurements for ascites, bilirubin, albumin, and prothrombin time). The subjects were medically stable for at least 2 weeks before sirolimus administration and had no laboratory test values that were outside the normal limits, with the exception of those related to hepatic functional impairment. Medications necessary for the management of the subject's liver disease and associated conditions were permitted if the regimen was stable for at least 2 weeks before sirolimus administration. Low-dose estrogen, progestin, or estrogen-progestin combination therapy was also permitted for hormone replacement provided that the regimen was stable for at least 2 weeks before sirolimus administration. Subjects in the control group had no clinically significant medical history or physical or laboratory findings at screening. The use of any recreational or investigational drug or treatment with any known substrates, inducers, or inhibitors of CYP3A4 was not allowed within 30 days before sirolimus administration.
Clinical Study
Each subject received a 15-mg dose of sirolimus after fasting overnight for a minimum of 10 hours. The dose of sirolimus was prepared by transferring 3 mL of a nonaqueous oral solution (Rapamune 5 mg/mL) to a glass containing 120 mL of water and mixing. After study drug administration, the subjects with severe hepatic impairment remained at the unit for 144 hours and returned for blood sample collections and safety evaluations at 216 and 312 hours. Matched control subjects remained at the unit for 48 hours and returned for blood sample collections and safety evaluations at 72, 96, 120, 144, 216, and 312 hours.
Venous blood samples (3 mL) were collected at each of the following time points relative to dose administration: 0 (predose), 0.33, 0.67, 1, 2, 3, 5, 8, 12, 24, 48, 72, 96, 120, 144, 216, and 312 hours (13 days). A duplicate set of blood samples was collected for preparation of plasma (3 mL) on the same time schedule through 24 hours after dosing. All samples were maintained at 37°C immediately after blood draws. Blood samples for plasma assay were centrifuged at 1500g for 10 minutes at 37°C. All samples were then stored frozen at -70°C to -80°C until analyzed for blood or plasma concentrations of sirolimus.
Bioanalysis
Whole blood and plasma samples were analyzed for sirolimus concentrations using validated high-performance liquid chromatographic tandem mass spectrometry (LC/MS/MS) methods by Taylor Technology, Inc (Princeton, New Jersey). Following addition of 5 ng of internal standard (IS, 32-desmethoxyrapamyin) to a 1-mL blood or plasma sample, sirolimus and IS were extracted into 1-chlorobutane. The reconstituted samples were chromatographed under reverse-phase conditions on a Keystone BetaBasic C4 column at 50°C using a Hewlett-Packard Series II 1090L HPLC system (Hewlett-Packard Co, Rockville, Maryland). The mobile phase was a gradient system of methanolic and aqueous solutions containing 20 mM ammonium acetate. The mass spectrometer (Finnigan MAT TSQ-700 or TSQ-700, Finnigan Corp, San Jose, California) was operated in atmospheric pressure chemical ionization mode with argon as the collision gas. Sirolimus and IS were detected in the column effluent at m/e ratios of 864.5 and 834.5. The linear ranges of the assay in blood and plasma were 0.1 to 100 ng/mL (sensitivity was 0.1 ng/mL) and 0.25 to 100 ng/mL (sensitivity was 0.25 ng/mL), respectively. The in-process quality control (QC) samples in whole blood showed a mean interday bias ranging from -5.1% to -0.7%, and the mean interday imprecision, expressed as a percentage coefficient of variation (%CV), ranged from 3.9% to 4.8%. The corresponding values for inter-day bias and imprecision for QC samples in plasma ranged from -7.3% to 4.0% and from 2.4% to 6.3%, respectively.
Pharmacokinetic Analyses
The values of peak concentration (Cmax) and time of peak concentration (tmax) were read directly from the blood or plasma concentration-time profiles. Other pharmacokinetic parameters were calculated using standard noncompartmental equations.16 Log-linear regression was used to determine the terminal disposition slope (
z) based on the last 5 time points of the concentration-time curve. Because plasma sirolimus concentrations were usually near or below the limit of quantitation of the assay by 8 hours after dosing, only Cmax and tmax were determined from the plasma profiles. The whole B/P was determined as the average of B/P values at individual time points up to 12 hours.
Statistical Analyses
The differences between Child-Pugh grade C subjects and matched controls with respect to demographic characteristics, sirolimus pharmacokinetic parameters, and clinical laboratory values were evaluated using 1-way analysis of variance (ANOVA). A 2-sided 
value 0.05 was considered statistically significant. A univariate analysis (Pearson correlations) was used to investigate potential correlations between the pharmacokinetic parameters of sirolimus and clinical laboratory parameters that were significantly different in subjects with severe hepatic cirrhosis compared with healthy subjects. All statistical analyses were performed using Statistical Analysis System (SAS, Cary, North Carolina) statistical software.17
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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.014) were observed in the mean values for AST/SGOT (aspartate aminotransferase/serum glutamic oxaloacetic transaminase, +159%), alkaline phosphatase (+173%), total bilirubin (+462%), and prothrombin time (+62.2%), but significant decreases (P = .047) were observed for albumin (-46.1%), total protein (-9.1%), creatinine (-32.6%), and hematocrit (-28.0%), and no significant change was observed in ALT/SGPT (alanine aminotransferase/serum glutamic pyruvate transaminase).
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The administration of concomitant medications was sparse, and only 4 subjects with Child-Pugh grade C hepatic impairment received intermittent concomitant therapy. None of the therapies included agents known to interact with sirolimus.
Pharmacokinetics
Mean concentration-time profiles of sirolimus in whole blood over a 13-day time course for Child-Pugh grade C and healthy control subjects are shown in Figure 1. The mean profiles for the 2 groups closely overlapped during the first few hours after dosing (Figure 1, inset), reflecting very similar rates of absorption. Mean concentrations of sirolimus in whole blood did not differ significantly between the groups at any time point through 12 hours (P .099). At all time points from 24 hours onward, however, mean whole-blood concentrations of sirolimus were significantly higher in subjects with hepatic impairment (P .028) than in the control group (Figure 1).
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), total area under the concentration-time curve (AUC0-), and oral dose mean residence time (MRToral) were significantly increased (P .002) in Child-Pugh grade C subjects compared with matched controls. Mean whole-blood sirolimus weight-normalized oral dose clearance (CL/F) was significantly decreased (P = .001) in Child-Pugh grade C subjects compared with matched controls. The mean values for Cmax, tmax, and Vss/F of whole-blood sirolimus were not significantly different between the 2 subject groups.
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Neither the mean plasma sirolimus Cmax and tmax values nor the sirolimus B/P ratios were significantly different between the 2 subject groups. However, it should be pointed out that the estimates of Cmax, tmax, and B/P ratios were based on very sparse plasma data. None of the subjects showed a complete profile over 12 hours. Only 1 subject in the Child-Pugh grade C group and 1 subject in the healthy group showed complete profiles over the time course of 0.33 to 8 hours. Overall, the number of available estimates of the B/P ratio in individual subjects over time ranged from 3 to 7 in the Child-Pugh grade C group (n = 9) and 2 to 7 in the healthy group (n = 9). Based on the available data, there were no increasing or decreasing trends in B/P ratios over time.
Correlation With Laboratory Parameters
Significant correlations (P .05) were generally observed between the whole-blood sirolimus pharmacokinetic parameters and the clinical laboratory values. However, the explained variabilities (R2) about the regression lines for whole-blood sirolimus CL/F versus individual laboratory tests were no greater than 71.4% (CL/F vs creatinine), which would limit the usefulness of estimating CL/F in individual subjects with hepatic impairment based on such clinical data.
Safety
Single 15-mg oral doses of sirolimus were generally well tolerated in subjects with severe hepatic impairment (Child-Pugh grade C) and in healthy subjects. Out of a total of 17 treatment-emergent adverse events (TEAEs) reported, 4 events occurred in 3 healthy subjects and 13 events occurred in 6 subjects with severe hepatic impairment. Most of the TEAEs were mild and not related to sirolimus. All of the TEAEs resolved. The most common TEAE in healthy subjects was headache (2, 22%), whereas the most common TEAEs in subjects with severe hepatic impairment were fever (2, 22%), diarrhea (2, 22%), and muscle cramps (2, 22%). Two serious adverse events were reported in the severe hepatic impairment group. One subject, a 36-year-old man, experienced hydrochole-cystitis in the poststudy period; he recovered after a short period of hospitalization. Another subject, a 55-year-old woman who had been on a waiting list to receive a liver transplant, died in the poststudy period because of renal insufficiency/hepatorenal syndrome. Neither of these serious adverse events was considered related to the single-dose administration of sirolimus.
There were no clinically relevant changes in vital signs, electrocardiograms, or laboratory values in the healthy subjects during the study. In subjects with severe hepatic impairment, the QTc interval, which is commonly associated with the underlying disease state, was often potentially clinically important.
Comparison With Subjects Showing Mild or Moderate Hepatic Impairment
Pharmacokinetic data from a similar previous study13 in subjects with mild (Child-Pugh grade A) and moderate (Child-Pugh grade B) hepatic impairment were available for comparison with those from the current study. The 2 studies were conducted at different investigational sites, but the study designs were essentially identical. Table III provides a tabulation of the mean data for sirolimus parameters (t, AUC, CL/F, and MRToral and B/P ratio) that were significantly affected by hepatic impairment in the 2 studies.
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The data for healthy matched controls from the current and previous studies were combined, even though a two 1-sided t test comparison of the 2 populations showed inequivalence based on the least squares percentage geometric mean ratios ([current study]/[previous study]) and (95% confidence interval [CI]) of 86% (70%-106%) for AUC and 143% (117%-176%) for CL/F. A combined data set appeared justified because sirolimus is a substrate for both CYP3A and P-glycoprotein (P-gp), and the expressions of these proteins exhibit large intersubject variability.19 Furthermore, the range in geometric means for CL/F in the previous Child-Pugh grade A/B study and the current Child-Pugh grade C study (204 vs 292 mL/h/kg, respectively) is consistent with the range in CL/F geometric means observed in other populations of healthy subjects receiving sirolimus by oral solution (17920 vs 29421 mL/h/kg). The AUC values in Table III were weight normalized because the body weights of subjects in the previous (79.9 ± 12.6 kg) and current (64.3 ± 9.8 kg) studies were significantly different (P = .0033).
The data in Table III show that whole-blood sirolimus t, AUC (weight normalized), and MRToral increased steadily, and CL/F (weight normalized) decreased steadily with increasing degrees of hepatic impairment. The sirolimus whole B/P ratio was significantly affected by hepatic impairment only in Child-Pugh grade B subjects.13 Figure 2 presents frequency plots of whole-blood sirolimus CL/F values. Large intersubject variability was observed within and among subject types.
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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.002) in sirolimus whole-blood t (168%), AUC0- (210%), and MRToral (261%), together with a significant decrease (P = .001) in CL/F (-67%), were observed in subjects with severe hepatic impairment compared with healthy matched controls. No statistically significant differences between the 2 groups were observed for Cmax and tmax in either whole blood or plasma, which suggest that hepatic impairment did not affect the absorption rate of sirolimus.13 Furthermore, orally administered sirolimus has a first-pass effect that involves both hepatic and intestinal components. The lack of a significant difference between subjects with hepatic impairment and matched controls in Cmax and tmax suggests that the intestinal first-pass component of sirolimus may not be significantly affected by hepatic impairment. However, this may also be attributable to a decrease in sirolimus absorption and a comparable decrease in the intestinal first-pass component leading to no net change in the fraction of drug reaching the hepatic portal circulation.
The results of the current study were also compared with those from a similar, previous clinical trial13 in subjects with mild (Child-Pugh grade A) and moderate (Child-Pugh grade B) hepatic impairment. Based on the data in Table III, geometric mean ratios of hepatic-impaired to healthy subjects showed that whole-blood sirolimus t values of subjects with Child-Pugh grade A, B, or C hepatic impairment were increased approximately 22%, 78%, and 159%, respectively; whole-blood sirolimus AUC values were increased approximately 43%, 94%, and 189%, respectively. The corresponding decreases in whole-blood sirolimus CL/F among subjects with Child-Pugh grade A, B, or C impairment were approximately -40%, -48%, and -60%, respectively, compared with healthy controls. Large intersubject variabilities in AUC and CL/F were observed within subject types. The data in Figure 2 illustrate the overlap in whole-blood sirolimus CL/F among subject types: 10 of 27 subjects with hepatic impairment (Child-Pugh grades A [n = 6], B [n = 2], and C [n = 2]) overlapped those in healthy controls (n = 27).
Although the mean B/P ratios in subjects with Child-Pugh grade A and B hepatic impairment showed large increases compared with healthy subjects, the B/P ratios in grade C subjects were more similar to those in healthy subjects than to those in grade A or B subjects. Factors that could potentially have affected the B/P ratio include plasma protein/lipoprotein binding, hematocrit, the temperature for plasma processing, and sirolimus concentrations.
Based on a review of the clinical laboratory data, mean values for albumin, triglycerides, and hematocrit were decreased in grade C subjects compared with healthy controls (combined data set) by approximately -53% (19.3 vs 40.7 g/L), -62% (0.80 vs 2.1 µMol/L), and -27% (30.9% vs 42.2%), respectively. In grade A subjects, changes in mean values of albumin, triglycerides, and hematocrit were +4.4%, -14%, and -3.3%, respectively; in grade B subjects, changes in mean values were -7.6%, -48%, and -6.9%, respectively.
A priori, the observed decreases in albumin (decreased plasma protein binding) and triglyceride (decreased plasma lipoprotein binding) concentrations would lower plasma sirolimus concentrations and could be expected to increase the B/P ratio, but the decrease in hematocrit (decreased partitioning into red blood cells) would lower blood concentrations and could be expected to decrease the B/P ratio. Furthermore, although an increase in temperature, from 20°C to 37°C during plasma processing, has been shown to increase the B/P ratio of tacrolimus,22 the partitioning of sirolimus between formed blood elements and plasma has been shown to be temperature independent over a range of 4°C to 37°C.8 The influence of sirolimus concentrations on the B/P ratio could potentially be manifested by a saturation of the blood cell uptake, but this does not appear to be a factor in the current study because there were no increasing or decreasing trends in B/P during the first 8 hours after sirolimus administration. Thus, the mechanism for the decrease in B/P in grade C subjects remains unclear.
The decrease in whole-blood sirolimus CL/F with increasing hepatic impairment suggests that oral doses of sirolimus need to be decreased in some individual renal transplant subjects with mild to severe hepatic impairment. However, the extensive overlap among the subject types (Figure 2) would tend to preclude the prediction of a dose regimen in individual patients based solely on mean CL/F values. Instead, a strategy that incorporates a reduction in the initial maintenance dose, followed by whole-blood concentration monitoring, is recommended.
It is important to review the conditions under which the results from the current study in Child-Pugh grade C subjects transfer directly to renal transplant patients. Renal allograft recipients with previously healthy livers generally do not develop chronic liver disease unless a separate, unrelated disease process is present (eg, chronic alcoholism23) or unless the underlying cause of chronic renal disease is also associated with progressive liver injury (eg, autosomal recessive or, rarely, autosomal dominant polycystic kidney disease24-26). Chronic liver disease generally progresses slowly over many years in the presence of such diseases, and any increases in sirolimus trough levels resulting from the loss of hepatic function could most likely be adjusted through routine therapeutic drug monitoring (TDM). On the other hand, acute hepatic functional deterioration can occur rapidly following severe acute insults, such as the ingestion of a sufficiently large acetaminophen overdose27 or fulminant acute hepatitis B viral infection.28 These patients are often acutely ill and are hospitalized after presenting to the doctor's office or emergency department. Results from this study suggest that, in such patients, a sirolimus dose reduction of approximately 60% is appropriate, followed by further dose adjustment based on TDM until sirolimus concentrations stabilize at levels existing prior to acute liver failure. Based on previous guidelines,1 sirolimus TDM and dose adjustments should occur at intervals no shorter than 7 to 14 days.
Trough monitoring provides a means of assessing whether whole-blood sirolimus trough concentrations fall within a putative safe and effective 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/day or 5 mg/day, respectively, and within 17 to 29 ng/mL during a CsA withdrawal regimen.1
In conclusion, subjects with acute severe hepatic impairment may exhibit a significant increase in sirolimus whole-blood exposure. The results of this study suggest a sirolimus dose reduction of approximately 60% in such patients, which should be followed by concentration monitoring and dose adjustments until sirolimus concentrations stabilize at levels existing prior to development of acute liver failure.
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ACKNOWLEDGEMENTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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Financial disclosure: Supported by grants from Wyeth Research, Collegeville, Pennsylvania.
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REFERENCES |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONACKNOWLEDGEMENTSREFERENCES |
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5. Johnson EM, Zimmerman J, Duderstadt K, et al. A randomized, double-blind, placebo-controlled study of the safety, tolerance, and preliminary pharmacokinetics of ascending single doses of orally administered sirolimus (rapamycin) in stable renal transplant recipients [abstract]. Transplant Proc. 1996;28: 987.[Web of Science][Medline] [Order article via Infotrieve]
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