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Estimation of minimum whole-blood tacrolimus concentration for therapeutic drug monitoring with plasma prednisolone concentration: A retrospective cohort study in Japanese kidney transplant recipients
VOLUME 67, NUMBER 2, MARCH/APRIL 2006
Estimation of Minimum Whole-Blood Tacrolimus Concentration for Therapeutic Drug Monitoring with Plasma Prednisolone Concentration: A Retrospective Cohort Study in Japanese Kidney Transplant Recipients Nobuyuki Sugioka, PhD1,2; Akiko Matsushita, MS1; Takatoshi Kokuhu, BPharm2; Masahiko Okamoto, MD, PhD3; Norio Yoshimura, MD, PhD3; Yukako Ito, PhD1; Nobuhito Shibata, PhD4; and Kanji Takada, PhD 1
7Department of Pharmacokinetics, Kyoto Pharmaceutical University, Kyoto, Japan; 2Department of Hospital Pharmacy, Kyoto Prefectural University of Medicine, Kyoto, Japan; 3Department of Transplantation and Regenerative Surgery, Kyoto Prefectural University of Medicine, Kyoto, Japan; and 4Department of Biopharmaceutics, Faculty of Pharmaceutical Science, Doshisha Women's College of Liberal Arts, Kyoto, Japan
ABSTRACT Background: In immunosuppressive therapy administered after organ transplantation, therapeutic drug monitoring (TDM) of tacrolimus must be performed frequently because of the large variation in its pharmacokinetic properties and a progressive decrease in dose requirements. An indicator for estimating the target minimum whole-blood tacrolimus concentration (Cm~n TAC)would be useful to minimize the number of blood samplings required for tacrolimus TDM. Objectives: The primary objective of this study was to investigate whether plasma prednisolone concentration, postoperative days (POD) and AUC 0 to 9 hours before transplantation (AUC0_9~,,) are useful indicators of tacrolimus TDM. The secondary objective was to determine the usefulness of blood tacrolimus concentration as an indicator of the development of nontraumatic, glucocorticoid-induced necrosis of the femoral head, an adverse event that has been associated with the use of prednisolone in vivo. Methods: This open-label, nonrandomized, retrospective study was conducted at the Department of Transplantation and Regenerative Surgery, Kyoto Prefectural University of Medicine, Kyoto, Japan. Data from 43 male and 22 female patients (mean age, 38 years [range, 9-64 years]) who received a living-related kidney transplant from 2001 to 2004 were included. Multiple blood samplings were performed to determine AUC0_9int, AUC 0 to 9 hours after drug administration and after transplantation (AUC0_9), Cm~n TAC'Cm~x' and Tm~x after transplantation. The correlations between each parameter were determined. The correlation between POD and the changes in tacrolimus bioavailability was investigated
Acceptedfor publicationFebruary20, 2006.
Reproduction in whole or part is not permitted.
Copyright © 2006 Excerpta Medica, Inc.
doi:l 0.1016/j.curtheres.2006.04.005 0011-393X/06/$19.00
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using the indicator, defined as the tacrolimus dose required to maintain the target (10-15 ng/mL) Cmin TAC (d°se/C10-15)" Correlations between dose/C10_15 and AUC0_9int (3 AUC0_9int groups, defined as follows: low, medium, and high [<93, ___93-<152, and ___152 ng • h/mL, respectively]) were determined. Correlations between mean Cm~n values of prednisolone at a dose of 40 mg on PODs 4 to 11 (Cmin PSL40) and Cmin TAC' or AUC0_9int were determined. A subanalysis was used to determine the relationship between dose/C10_15 and the prevalence of nontraumatic, glucocorticoid-induced necrosis of the femoral head. Results: Cm~n TACwas found to be significantly correlated with AUC0_9int (r = 0.554; P < 0.001) and Cmh~PSL40 (r = 0.336; P < 0.001). In the low-AUCo_9h~t group, dose/C10_15 was higher than that of the other groups (P< 0.01). AUCo_9intwas significantly correlated with Cmin PSL40 (r = 0.445; P < 0.001). Dose/C10_15 in the patient group that had necrosis of the femoral head was lower than that of the group without necrosis (n = 6; P < 0.01). Conclusions: The results of this small, r e t r o s p e c t i v e s t u d y s u g g e s t t h a t Cmin PSL40, AUC0-9int, and POD were significant predictors of Cm~n TAC" These p a r a m e t e r s were found to be a useful indicator of tacrolimus TDM in these Japanese transplant recipients. Our results also suggest that dose/C10_15 and AUC0_9int might be useful indicators for estimating the risk for nontraumatic, steroid-induced necrosis of the femoral head. (Curr Ther Res Clin Exp. 2006;67: 103-117) Copyright © 2006 Excerpta Medica, Inc. Key words: tacrolimus, prednisolone, blood concentration, therapeutic drug monitoring.
INTRODUCTION Tacrolimus, a macrolide lactone, is an immunosuppressive agent that inhibits the signal-transduction pathway that leads to T-lymphocyte activation. 1-3 Tacrolimus has been used for preventing or treating graft rejection after organ transplantation. 4~ Therapeutic drug monitoring (TDM) is essential to minimizing toxicity while maintaining the efficacy of immunosuppressants such as tacrolimus, which has high variability in its pharmacokinetic (PK) properties. 7-9 In the TDM of tacrolimus, the most widely used indicator is minimum whole-blood tacrolimus concentration (Cmin TAC).1° TO maintain target Cmin TAC' TDM must be performed frequently, every day until 14 postoperative days (PODs) in our institution. 11 To minimize the number of blood samplings required for tacrolimus TDM, an indicator for estimating Cm~n TACwould be useful. In general, AUC is a useful indicator for TDM because systemic exposure is measured as AUC. Therefore, to establish the possible usefulness of a method for estimating Cm~n TAC'we investigated the PK properties of tacrolimus in kidney transplant recipients, including AUC 0 to 9 hours after drug administration before transplantation (AUC0_9~nt) and 0 to 9 hours after drug administration and after transplantation (AUC0_9). Previous s t u d i e s have r e p o r t e d a progressive d e c r e a s e in t a c r o l i m u s d o s e requirements as time after adult organ t r a n s p l a n t recipients elapsed. 12,13 How-
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ever, in J apanes e kidney t r a n s p l a n t recipients, t i m e - d e p e n d e n t increases in the bioavailability of tacrolimus within 4 weeks of transplantation were not found in a MEDLINE search of the literature (key terms: tacrolimus, kidney [renal], pharmacokmetics, bioavailability [AUC], and time after transplantation [time-dependent]; years: 1974-2006). If time dependent increase of blood clearance was observed in Japanese kidney transplant patients, POD might be another useful parameter for estimating Cm~n TAC" Prednisolone, a synthetic glucocorticoid, is commonly used in the treatment of a variety of inflammatory diseases such as rheumatism, hepatitis, and nephritis. After kidney transplantation, prednisolone is used concomitantly with tacrolimus or cyclosporin A in immunosuppressive t herapy in all cases of kidney transplantation in our institution. 14 Adverse events (AEs) associated with the use of prednisolone include nontraumatic, glucocorticoid-induced necrosis of the femoral head. About 6% of kidney transplant recipient's nontraumatic, glucocorticoid-induced necrosis of the femoral head was developed in our institution. 15 Despite using the same protocol for prednisolone administration, studies in adult kidney transplant recipients have found different clinical courses of this disorder, indicating individual differences in steroid sensitivity. 16 Prednisolone and tacrolimus are metabolized by the same i s o e n z y m e - cy to chr om e P450 (CYP) 3A4.17,18 Competitive inhibition has been report ed with combination t r e a t m e n t with t hese 2 drugs. 18 Both drugs are a s u b s t r a t e of P-glycoprotein, a t r a ns por t e r that plays an important role in drug absorption and distribution. Therefore, it is hypothesized that tacrolimus and prednisolone have a similar absorption and clearance rate in the body. In addition, the bioavailability of prednisolone is almost 100%, 19-21 with the result that plasma prednisolone concentrations per dose reflect prednisolone clearance. Prednisolone is typically administered as a fixed-dose regimen in transplant recipients in our institution. 14 For this reason, and because tacrolimus has the same elimination pathway and large variations in bioavailability, we hypothesized that plasma prednisolone concentrations might serve as an indicator of tacrolimus TDM in patients receiving immunosuppressive regimens after transplantation, and that the risks for AEs associated with prednisolone use can be estimated using tacrolimus TDM. The primary objective of this st udy was to investigate w het her plasma prednisolone concentration is a useful indicator of tacrolimus TDM. The s e c o n d a r y objective was to determine w h e t h e r Cm~n TAC is useful as an indicator of the development of nontraumatic, glucocorticoid-induced necrosis of the femoral head.
PATIENTS A N D METHODS This open-label, nonrandomized, retrospective cohort st udy was conducted at the Department of Transplantation and Regenerative Surgery, Kyoto Prefectural University of Medicine, Kyoto, Japan. The study protocol was approved by the
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ethics committee at the university, and informed consent was obtained from all patients or their legal guardians (for patients aged <18 years).
Study Population Data from the medical records of Japanese patients (43 male and 22 female; mean age, 38 years [range, 9-64 years]) who had received a living-related kidney transplant at the university from 2001 to 2004 were included. All patients who had been administered tacrolimus treatment as described earlier were retrospectively enrolled in the study. To investigate the relationship between the PK properties of tacrolimus and plasma prednisolone concentration, the patients for whom these data were available were included in this subanalysis.
Immunosuppressive Regimen The following immunosuppressive regimen, developed by the Department of Transplantation and Regenerative Surgery for use after living-related kidney transplantation, was used in the patients. The initial dose of tacrolimus (0.3 mg. kg -1 • d -1) was administered orally for 2 days before transplantation. Tacrolimus (0.1 mg • kg -1 • d-1) was administered by continuous IV infusion on the day of transplantation before surgery, followed by oral tacrolimus (0.3 mg/kg BID) for 3 weeks. The dose of tacrolimus was adjusted based on the results of Cm~n TACmonitoring empirically. Target Cm~n TACwas 10 to 15 ng/mL. Methylprednisolone 500 mg was administered by continuous IV infusion on the day of transplantation before surgery, followed by prednisolone 50 mg/d on PODs 0 to 3 and prednisolone 40 mg/d on PODs 4 to 11. On PODs 12 to 19, the dose of prednisolone was decreased to 30 mg/d, and subsequently reduced by 5 mg each week until a dose of 10 mg/d was reached. On POD 21, azathioprine (0.50-0.75 mg/kg PO BID) or mycophenolate mofetil (10.0-12.5 mg/kg PO BID) was added to the regimen. This was continued until the patient was discharged from the hospital. Pharmacokinetic Assessment of Tacrolimus For PK studies of tacrolimus, blood samples were obtained 2 days before transplantation and at 0, 1, 2, 3, 4, 6, and 9 hours after drug administration on PODs 14, 21, and 28. PK parameters (eg, AUC0_9, Cm~, Tm~) were determined from those data. To determine Cmin TAC' blood samples were obtained before drug administration each day through POD 14. After POD 14, blood samples were obtained before drug administration every other day until POD 28. Blood tacrolimus concentration was measured using microparticle enzyme immunoassay (IMx system, Abbott Laboratories, Abbott Park, Illinois). 22 AUC0_9 and AUC0_9int were calculated using the trapezoidal rule. Plasma Prednisolone Concentration Plasma prednisolone concentration was measured using the high-performance liquid chromatography (HPLC) method described by Rose and Jusko, 23 of which
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internal standard, the mobile phase, and organic s o r b e n t for liquid-liquid extraction were modified by us. Plasma samples for the determination of prednisolone concentration were collected before oral administration of prednisolone 40 mg/d on PODs 4 to 11. More than 3 blood samples (2 mL) were obtained between PODs 4 to 11 from each patient, and the mean prednisolone concentration was calculated and considered as an indicator of prednisolone clearance at an early stage of prednisolone treatment (Cm~" values of prednisolone at dose of 40 mg on PODs 4-11 [Cmi" PSL40])"The prednisolone and carbamazepine used as internal standards were purchased from Nacalai Tesque, Kyoto, Japan. Acetonitrile and methanol were HPLC grade; all other reagents were reagent grade. The preparation of plasma samples was based on liquid-liquid extraction with dichloromethane. The com pounds were separated on a cyanopropyl column using acetonitrile-methanol-water (66:17:17, v/v) as the mobile phase. UV detection was used at a wavelength of 254 nm. The HPLC system (Shimadzu Corporation, Kyoto, Japan) consisted of an LC-10A liquid delivery module, an SPD-10A UV detector, a CTO-10A column oven, and a Simpac CLC-CN column (150 mm × 6 mm; interior diameter, 5 1Jm). Samples were injected using an SIL-10A automatic injector. The system was controlled with an SCL-10A system controller. The area under each objective peaks in chromatograph were calibrated with a Shimadzu CR-8A data processor. The standard curves of prednisolone ranging from 0.01 to 500 1Jg/mL were considered linear. CV values (%) of inter- and intra-assay reproducibility were <10%. Tacrolimus Concentration as an Indicator of Prednisolone Adverse Events To investigate whether blood tacrolimus concentration might be useful as an indicator of the development of AEs associated with prednisolone use, the relationship between tacrolimus bioavailability in patients with and without nontraumatic, glucocorticoid-induced necrosis of the femoral head was investigated using the tacrolimus dose required to maintain the target (10-15 ng/mL) Cmi. TAC (d°se/C10-15) as the indicator of bioavailability. This subanalysis used data from patients diagnosed with nontraumatic, steroid-induced necrosis of the femoral head (diagnosed according to the criteria of the Research Committee of the Ministry of Health and Welfare of Japan24); data from the remaining patients were used as references. Statistical Analysis The correlations between Cm~"TAC or AUC0_9 and tacrolimus dose, Cm~, or Tm~ were determined. After POD 14, dose/C10_l 5 was considered an indicator of bioavailability. The relationship between POD and dose/C10_l 5 was investigated. The correlations between dose/C10_15, POD, and AUC0_9int were determined using the following method. Study patients were assigned to 1 of 3 AUC0_9int groups: low, medium, and high (<93, ___93--<152, and ___152 n g • h/mL, respectively). On days 6 to 10, 11 to 15, 16 to 20, 21 to 25, 26 to 30, 31 to 35, and 36 to 40, differences in mean dose/C10_l 5 in each period between the 3 AUC0_9int
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groups were examined using 1-way analysis of variance. To investigate w h e t h e r POD, AUC0_9int, a n d / o r plasma prednisolone c o n c e n t r a t i o n s are useful as an indicator of tacrolimus TDM, the correlations b e t w e e n Cmh~ TAC' POD, tacrolimus dose, p r e d n i s o l o n e dose, AUC0_9int , and Cm~n PSL40were d e t e r m i n e d using Pearson correlation. To assess the relative effects of each p a r a m e t e r on Cm~n TAC' stepwise multiple linear regressions were p e r f o r m e d using POD, tacrolimus dose, p r e d n i s o l o n e dose, Cm~n PSL40' and AUC0_9int as i n d e p e n d e n t variables. Differences in dose/C10_15 b e t w e e n the groups with and w i t h o u t n o n t r a u matic, s t e r o i d - i n d u c e d necrosis of the femoral h e a d for 5 p e r i o d s of time (PODs 16-20, 21-25, 26-30, 31-35, and 36-40) were d e t e r m i n e d using the S t u d e n t t test. Analyses in this s t u d y were c o n d u c t e d using the StatView software package version 5.0 (SAS Institute Inc., Cary, North Carolina).
RESULTS Pharmacokinetic Properties of Tacrolimus The PK analysis of tacrolimus included 13 patients from w h o m these data were available (7 males, 6 females; range, 9-62 years). Figure 1 shows AUC0_9 of tacrolimus at various doses on PODs 14, 21, and 28. Although there was a large variation in the dose of tacrolimus (0.150.30 mg/kg), no significant differences in mean AUC0_9 were found between the 3 time points. Similarly, no significant differences in mean AUC0_9 were found between mean doses (0.30, 0.25, 0.20, and 0.15 mg/kg) on PODs 14, 21, and 28. Table I shows the correlations between the values of AUC0_9 and Cm~n TACfor Cm~, Tm~, amount (mg), and dose (mg/kg) on PODs 14, 21, and 28. At all time points, AUC0_9 was significantly correlated with Cm~ (r = 0.829, 0.925, and 0.904, respectively; all, P ~ 0.001), and Cm~n TACwas significantly correlated with AUC0_9 (r = 0.881, 0.822, and 0.886, respectively; all, P < 0.001) and Cm~ (r = 0.636, 0.621, and 0.797, respectively; P ~ 0.01, P ~ 0.01, and P ~ 0.001, respectively). Neither AUC0_9 nor Cm~nTACwas significantly associated with values of Tm~, amount, or dose. The relationship between POD and dose/C10_15 as an indicator of bioavailability on POD 14 to 40 is shown in Figure 2. As time after transplantation increased, the dose/C10_15 decreased gradually (r = -0.830; P < 0.001). Figure 3 s h o w s the relationship b e t w e e n m e a n dose/C10_15 and AUC0_9int. In all p e r i o d s (PODs 16-20, 21-25, 26-30, 31-35, and 36-40), in the lowAUC0_9int group, mean dose/C10_15 was higher (___0.253 m g . kg -1 • d -1) than that in the other groups (___0.155 m g . kg -1 • d-l), and in the middle-AUC0_9int group, mean dose/C10_15 was higher (___0.199 mg • kg -1 • d -1) than that in the high-AUC0_9int group (___0.155 m g . kg -1 • d-l). Statistically significant differences in t a c r o l i m u s dose/C10_15 b e t w e e n all 3 groups in all p e r i o d s were o b s e r v e d (all, P < 0.01). In each group, m e a n dose/C10_15 gradually d e c r e a s e d with POD (low [r = -0.927; P < 0.01]; middle [r = -0.960; P < 0.005]; high [r = -0.903; P < 0.05]).
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[] • • [] 350 -
0.15 0.20 0.25 0.30
m g • kg mg ° kg m g • kg mg • kg
1° d 1° d 1. d 1. d
1 (n 1 (n 1 (n 1 (n
= 6 and 6 on PODs 21 and 28, respectively) = 8, 14, and 6 on PODs 14, 21, and 28, respectively) = 4 , 6, and 9 on PODs 14, 21, and 28, respectively) = 4 , 6, and 5 on PODs 14, 21, and 28, respectively)
300 -
250 -
E e-
200 -
e-
150 -
100 -
50-
0
I
14
I
21
m l
28
PODs Figure 1. M e a n (SD) A U C 0 t o 9 h o u r s (AUC0_9) a f t e r a d m i n i s t r a t i o n o f v a r i o u s d o s e s o f t a c r o l i m u s o n p o s t o p e r a t i v e d a y s (PODs) 14, 21, a n d 28 in J a p a n e s e kidn e y t r a n s p l a n t r e c i p i e n t s (N = 65). N o s i g n i f i c a n t b e t w e e n - g r o u p d i f f e r e n c e s w e r e f o u n d . D a t a w e r e u n a v a i l a b l e f o r t h e 0 . 1 5 - m g • kg -1 • d -1 d o s e at POD 14.
Relationship Between Plasma Prednisolone Concentration and Tacrolimus Pharmacokinetic Properties Cmin PSL40o b t a i n e d from the 13 patients from w h o m data were available varied from 19.5 to 161.4 ng/mL (mean [SD], 56.1 [42.3] ng/mL). T h e c o r r e l a t i o n s b e t w e e n Cmin TAC and POD; t a c r o l i m u s dose, p r e d n i s o l o n e dose, AUC0_9int, and Cmin PSL40; and b e t w e e n Cmin PSL40 and AUC0_gint are s h o w n in T a b l e II. Cmin TAC was significantly negatively c o r r e l a t e d with POD (r = -0.327; P < 0.001) and significantly positively c o r r e l a t e d with AUC0_gint (r = 0.554) and Cmin PSL40 (r = 0.336) (both, P < 0.001). Cm~n TACwas not significantly a s s o c i a t e d with the tacrolimus or p r e d n i s o l o n e dose. Cmin PSL40was significantly c o r r e l a t e d with AUC0_9int (r = 0.445; P < 0.001). Cmin TAC was used as a d e p e n d e n t variable in stepwise multiple linear regressions that were performed. Four variables (POD, prednisolone dose, Cmin PSL40' and AUC0_9int) were s e l e c t e d and e n t e r e d into the regression e q u a t i o n (Table llI).
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Table I.
Relationships between the pharmacokinetic properties of tacrolimus in Japanese kidney transplant recipients. Values are correlation coefficients. AUCo_ 9
Cmax
Tmax
Amount
Dose
AUC0_ 9
-
0.829*
0.053
0.107
-0.281
Cmin TAC
0.881"
0.636 t
0.304
0.072
-0.151
AUCo_9
-
0.925*
0.100
0.068
-0.006
Cmin TAC
0.822*
0.621 t
-0.049
0.091
-0.251
AUCo_9
-
0.904*
0.320
0.122
-0.139
Cmin TAC
0.886*
0.797*
--0.104
0.196
--0.204
Time Point POD 1 4 ( n = 1 6 )
POD 21 (n = 32)
POD 28 (n = 26)
AUC0 9 = AUC 0 to 9 hours after drug administration and after transplantation; POD = postoperative day; Cmin TAC = minimum whole-blood tacrolimus concentration. *P < 0.001. tp < 0.01.
Relationship Between Dose/Clo_l 5 and N o n t r a u m a t i c , Steroid-Induced Necrosis of the Femoral Head The subanalysis of necrosis included 6 patients (4 males, 2 females; mean age, 33 y e a r s [range, 21-47 y e a r s ] ) with a diagnosis of n o n t r a u m a t i c , steroidinduced necrosis of the femoral head; data from the remaining 59 patients were used as references. F i g u r e 4 s h o w s the c o m p a r i s o n of mean dose/C10_l 5 b e t w e e n the groups with and w i t h o u t n o n t r a u m a t i c , steroid-induced necrosis of the femoral head on PODs 16 to 20, 21 to 25, 26 to 30, 31 to 35, and 36 to 40. In each period, the mean dose/C10_15 of the group that had steroid-induced necrosis of the femoral head was higher (___0.189 mg • kg -1 • d -1) than that of the group that did not have one (-0.122 m g . kg-1. d-l). Statistically significant differences were o b s e r v e d between the 2 groups in each period (all, P < 0.01). In b o t h groups, mean dose/C10_15 gradually d e c r e a s e d with POD.
DISCUSSION Tacrolimus t r e a t m e n t requires regular TDM b e c a u s e of its n a r r o w t h e r a p e u t i c range of blood c o n c e n t r a t i o n and large variability in PK properties. A strong correlation b e t w e e n s y s t e m i c exposure, AUC, and Cm~"TAChas been r e p o r t e d in patients who have u n d e r g o n e liver, kidney, and b o n e m a r r o w transplantation. 25 Cm~. TACwas significantly c o r r e l a t e d with AUC0_9 (r = 0.822-0.886) in this study, suggesting that Cm~"TAC was a good indicator for tacrolimus TDM, reflecting a p h a r m a c o l o g i c efficacy. On the o t h e r hand, AUC0_9 was not found to be signifi-
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N. Sugioka et al.
[ ] D ° s e / C l o 15 Cmi n TAC
0
0.30
- 50
0.25 - 40
"7 0.20
30
_3.
20
3r'-
E 0.15 O
r~ E °m
0.10
2 10
0.05
I
16-20
I
21-25
I
26-30
I
31-35
I
36-40
I
PODs Figure 2. Changes in tacrolimus dose required to maintain target (10-15 ng/mL) minimum whole-blood tacrolimus concentration (Cmi n TAC) (d°se/C10-1s) as an indicator of bioavailability after postoperative day (POD) 14 in Japanese kidney transplant recipients (N = 65).
cantly c o r r e l a t e d with a m o u n t or dose. Consequently, a patient's weight might not be a useful indicator of d o s e requirements. The bioavailability of tacrolimus has large inter- and intravariability (20%809/o).25,26Nonlinear blood binding and a variable blood/plasma ratio have been rep o r t e d to be major sources of interindividual variations in the PK properties of tacrolimus. 25 Also, tacrolimus is a s u b s t r a t e of P-glycoprotein and CYP 3A4. In b o t h proteins, the induction or inhibition and the change in activation caused b y drug interactions are well known. Relationships between the polymorphisms of the CYP 3A4/5 or multidrug resistance-1 gene and the tacrolimus required dose to achieve adequate blood concentration have also been found. 27 In this study, although the tacrolimus dose varied substantially (0.15-0.30 mg/kg), no significant changes in mean AUC0_9 were associated with the level of Cm~. TAC"Subsequently, tacrolimus TDM must be performed frequently. 28 In this study, to o b t a i n useful i n f o r m a t i o n for revising t h e d o s i n g r e g i m e n after k i d n e y t r a n s p l a n t a t i o n , we i n v e s t i g a t e d t h e c h a n g e in the bioavailabil-
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CURRENTTHERAPEUTICRESEARCH
• • • O 0.40 -
D°se/Clo 15in Iow-AUC09intgroup* D°se/Clo 15in medium-AUC 09int gr°up t D°se/Clo 15 in high-AUC 09int gr°up ~ CminTAC - 50
0.35 - 40
0.30 0.25
-
-30
E 0.20
_3.
-
~D
a
I=
- 20
0.15 -
3
2 O.lO
-
10 -
0.05
0
I
I
16-20
I
21-25
I
26-30
I
31-35
I
36-40
PODs Figure 3. Mean (SD) changes in tacrolimus dose required to maintain target (1015 n g / m L ) m i n i m u m w h o l e - b l o o d t a c r o l i m u s c o n c e n t r a t i o n (Cmi n TAC) (dose/Cl0_lS) as an indicator of bioavailability after postoperative day (POD) 14 in Japanese k i d n e y t r a n s p l a n t recipients (N = 65), by p r e o p e r a t i v e AUC (AUC0_9int). P < 0.01 between all groups at all t i m e points. *AUC0_9int <93 n g • h/mL; tAUC0_9int->93-<152 ng • h/mL; SAUC0_9int->152 n g • h / m E Table II. Relationships b e t w e e n m i n i m u m w h o l e - b l o o d tacrolimus c o n c e n t r a t i o n (Cmin TAC) o r m i n i m u m plasma c o n c e n t r a t i o n w i t h p r e d n i s o l o n e 40 mg (Cmin PSL40)on p o s t o p e r a t i v e days (PODs) 4 to 11 and o t h e r p h a r m a c o k i n e t i c parameters in Japanese kidney t r a n s p l a n t recipients (N = 65 f o r Cmi n TAC and N = 13 f o r Cmi n PSL40). Values are correlation coefficients.
Parameter
Cmin TAC Cmin PSL40
POD
Tacrolimus Dose
Prednisolone Dose
AUC0-9int
Cmin PSL40
-0.327*
0.042
0.21 2
0.554*
0.336*
-
-
-
0.445*
-
AUC0 9int = AUC 0 to 9 hours before transplantation. *P < 0.001.
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N. Sugioka et aL
Table III. M u l t i p l e linear regression model f o r m i n i m u m w h o l e - b l o o d tacrolimus concentration ( C m i n TAC) in Japanese kidney t r a n s p l a n t recipients.* Dependent Variable
C m i n TAC
Independent Variables
Correlation Coefficient
POD Prednisolone dose
-0.352 -0.226
Cmin PSL40 AUCo_gint Intercept
0.102 0.048 20.408
POD = postoperative day; Cmi n PSL40 = minimum plasma concentration with prednisolone 40 mg (days 4-11); AUC0 9int = AUC 0 to 9 hours before transplantation. *Multiple regression coefficient: r = 0.676; P < 0.001 (F test).
• D°se/C1015(with nontraumatic necrosis of the femoral head, n = 6) • D°se/C1015(without nontraumatic necrosis of the femoral head, n = 57) O Cil/in TAC
0.30
- 50
0.25 - 40
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PODs Figure 4. Mean (SD) changes in tacrolimus dose required to maintain target (10-15 n g / mL) m i n i m u m whole-blood tacrolimus c o n c e n t r a t i o n ( C m i n TAC) (dose/Cl0_lS) as an indicator of bioavailability after postoperative day (POD) 14 in Japanese kidney transplant patients w i t h (n = 6) or w i t h o u t (n = 59) nontraumatic, steroid-induced necrosis of the femoral head. *P < 0.01 between groups.
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ity of t a c r o l i m u s in the c o u r s e of i m m u n o s u p p r e s s i v e t h e r a p y . After transplantation, m e a n dose/C10_15 d e c r e a s e d (ie, bioavailability i n c r e a s e d ) . Moreover, a significant n e g a t i v e c o r r e l a t i o n b e t w e e n Cm~n TAC and POD (r = -0.327; P ~ 0.001) was found. T h e s e results s u g g e s t t h a t POD is a g o o d i n d i c a t o r for e s t i m a t i n g Cm~n TAC" T h e r e a s o n s h y p o t h e s i z e d for i n c r e a s e d bioavailability w e r e as follows: (1) t a c r o l i m u s a b s o r p t i o n i n c r e a s e d with t h e r e c o v e r y of gastrointestinal function; (2) bile secretion increased with increased food intake; and (3) c l e a r a n c e of t a c r o l i m u s d e c r e a s e d with increasing s e r u m proteinbinding ratio b e c a u s e of i n c r e a s i n g s e r u m albumin c o n c e n t r a t i o n with the r e c o v e r y of k i d n e y function. AUC0_9int is useful for individualizing dosing regimens before transplantation. In the low-AUC0_9int group, mean dose/C10_15 was higher than that in the o t h e r groups in all periods after transplantation, suggesting that patients with low AUC0_9int n e e d e d higher d o s e s of tacrolimus c o m p a r e d with patients in the highor middle-AUC0_9~nt group. In addition, Cmh~ TAC was positively c o r r e l a t e d with AUC0_9int @ = 0.554; P ~ 0.001), suggesting that the i m p o r t a n t factors for estimating Cmin TACwere POD and AUC0_9int. On the o t h e r hand, it is possible that tacrolimus has PK p r o p e r t i e s similar to t h o s e of p r e d n i s o l o n e in vivo, as previously h y p o t h e s i z e d . Values of AUC0_9int and Cmh~TACwere significantly c o r r e l a t e d with Cm~n PSL40in this particular s t u d y (r = 0.445 and 0.336, respectively; both, P < 0.001). At Kyoto Prefectural University of Medicine, p r e d n i s o l o n e is a d m i n i s t e r e d as a fixed regimen at a relatively high d o s e (40 mg/d) until 11 days after transplantation. We h y p o t h e sized that Cm~n PSL40would reflect p r e d n i s o l o n e c l e a r a n c e and would be a useful indicator of tacrolimus TDM. The results of multiple linear regressions also suggest that the m o s t i m p o r t a n t factors for estimating Cm~n TACwere POD, AUC0_9int , and Cmh~PSL40"TDM of p r e d n i s o l o n e using plasma c o n c e n t r a t i o n as an indicator was not found to be useful, p e r h a p s b e c a u s e of the unclear relationship b e t w e e n p l a s m a p r e d n i s o l o n e c o n c e n t r a t i o n and its t h e r a p e u t i c effects. Therefore, plasma p r e d n i s o l o n e c o n c e n t r a t i o n is not c o m m o n l y d e t e r m i n e d . However, our results suggest that the a s s e s s m e n t of plasma p r e d n i s o l o n e conc e n t r a t i o n might be a useful indicator of tacrolimus TDM. However, s t a n d a r d s n e e d to be established for measuring tacrolimus AUC before t r a n s p l a n t a t i o n and determining plasma p r e d n i s o l o n e c o n c e n t r a t i o n at an early stage after transplantation. T y p e s of n o n t r a u m a t i c n e c r o s i s of the femoral h e a d include aseptic and ischemic necrosis. The m e c h a n i s m b y which n e c r o s i s d e v e l o p s is unknown, but a c c u m u l a t e d statistical d a t a have identified t r e a t m e n t with glucocorticoid, s u c h as p r e d n i s o l o n e , as a relevant risk factor. It is n o t a b l e t h a t the n o n t r a u matic, s t e r o i d - i n d u c e d t y p e of n e c r o s i s of the femoral h e a d a c c o u n t s for a large p e r c e n t a g e of c a s e s of this disease. It has b e e n r e p o r t e d t h a t a b o u t 60% of n o n t r a u m a t i c n e c r o s i s of the femoral h e a d was g l u c o c o r t i c o i d - i n d u c e d . 29 Mean dose/Clo_l 5 in the group with n e c r o s i s was lower t h a n t h a t in the group w i t h o u t necrosis. It is c o n s i d e r e d that the bioavailability of t a c r o l i m u s was
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high in the g r o u p with n e c r o s i s , s u g g e s t i n g p r e d n i s o l o n e c l e a r a n c e m i g h t be low after t r a n s p l a n t a t i o n . T h e r e f o r e , t a c r o l i m u s TDM m i g h t b e useful for estim a t i n g t h e risk for n o n t r a u m a t i c n e c r o s i s of t h e f e m o r a l h e a d . In addition, p r e d n i s o l o n e w a s a d m i n i s t e r e d as a fixed-dose regimen, a l t h o u g h Cm~n PSL40 v a r i e d s u b s t a n t i a l l y (19.5-161.4 ng/mL). T h e r e f o r e , in d e t e r m i n i n g t h e risk for n o n t r a u m a t i c n e c r o s i s of t h e f e m o r a l h e a d , dose/C10_15 of t a c r o l i m u s w a s f o u n d to be useful as an i n d i c a t o r of p r e d n i s o l o n e c l e a r a n c e . On the o t h e r h a n d , from t h e b e g i n n i n g of g l u c o c o r t i c o i d t r e a t m e n t , n o n t r a u m a t i c n e c r o s i s of t h e f e m o r a l h e a d s h o u l d b e p r e v e n t e d . 3° In this study, AUC0_9intwas found to be significantly c o r r e l a t e d with Cmh~PSL40 (r = 0.445; P < 0.001), reflecting p r e d n i s o l o n e c l e a r a n c e in t h e e a r l y p o s t t r a n s p l a n t a t i o n s t a g e and s u g g e s t i n g t h a t AUC0_9int m i g h t be a useful i n d i c a t o r for e s t i m a t i n g the risk for s t e r o i d - i n d u c e d n e c r o s i s of the f e m o r a l head, a l t h o u g h the u s e f u l n e s s of this p a r a m e t e r is limited b y t h e n e e d for a m e a s u r e m e n t of t a c r o l i m u s AUC b e f o r e t r a n s p l a n t a t i o n . A n o t h e r limitation of this s t u d y w a s its small s a m p l e size. Additional r e s e a r c h in a larger p o p u l a t i o n is n e e d e d .
CONCLUSIONS The results of this small, r e t r o s p e c t i v e s t u d y s u g g e s t t h a t Cm~n PSL40' AUC0-9int, and POD w e r e significant p r e d i c t o r s of Cm~n TAC"T h e s e p a r a m e t e r s w e r e found to be a useful indicator of t a c r o l i m u s TDM in t h e s e J a p a n e s e kidney t r a n s p l a n t recipients. Our results also s u g g e s t t h a t dose/C10_15 and AUC0_9int might be useful i n d i c a t o r s for e s t i m a t i n g the risk for n o n t r a u m a t i c , s t e r o i d - i n d u c e d n e c r o s i s of the femoral head.
REFERENCES 1. Kino T, Hatanaka H, Hashimoto M, et al. FK-506, a novel immunosuppressant isolated from a Streptomyces. I. Fermentation, isolation, and physico-chemical and biological characteristics. J Antibiot (Tokyo). 1987;40:1249-1255. 2. Kino T, Hatanaka H, Miyata S, et al. FK-506, a novel immunosuppressant isolated from a Streptomyces. II. Immunosuppressive effect of FK506 in vitro. J Antibiot (Tokyo). 1987;40:1256-1265. 3. Sigal NH, Dumont FJ. Cyclosporin A FK-506, and rapamycin: Pharmacologic probes of lymphocyte signal transduction. Annu Rev Immunol. 1992;10:519-560. 4. Starzl TE, Todo S, Fung J, et al. FK-506 for liver, kidney, and pancreas transplantation. Lancet. 1989;2:1000-1004. 5. Uemoto S, Tanaka K, Honda K, et al. Experience with FK506 in living-related liver transplantation. Transplantation. 1993;55:288-292. 6. Plosker GL, Foster RH. Tacrolimus. A further update of its pharmacology and therapeutic use in the management of organ transplantation. Drugs. 2000;59:323-389. 7. Kershner RP, Fitzsimmons WE. Relationship of FK506 whole blood concentrations and efficacy and toxicity after liver and kidney transplantation. Transplantation. 1996;62:920-926.
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8. McMaster P, Mirza DF, Ismail T, et al. Therapeutic drug monitoring of tacrolimus in clinical transplantation. Ther Drug Monit. 1995; 17:602-605. 9. Jusko WJ, Thomson AW, Fung J, et al. Consensus document: Therapeutic monitoring of tacrolimus (FK-506). Ther Drug Monit. 1995;17:606-614. 10. Ihara H, Shinkurma D, Ichikawa Y, et al. Intra- and interindividual variation in the pharmacokinetics of tacrolimus (FK506) in the kidney transplant recipients-importance of trough level as a practical indicator. Int J Urol. 1995;2:151-155. 11. Okamoto M, Omori Y, Kadotani Y, et al. Tacrolimus-based immunosuppression in renal transplantation: 78 Experiences in a single Japanese center. Transplant Prec. 2002;34:1666. 12. Staatz CE, Willis C, Taylor PJ, et al. Population pharmacokinetics of tacrolimus in adult kidney transplant recipients. Clin Pharmacol Ther. 2002;72:660-669. 13. Okamoto M, Yoshimura N, Nakai I, et al. Beneficial effect of multiple drug therapy including tacrolimus in clinical renal transplantation. Transplant Prec. 2000;32:17161717.
14. Yasumura T, Oka T, Nakane Y. Long-term results of living related kidney transplantation: A retrospective study on 114 recipients followed over 10 years. Jpn J Surg. 1991;21:138-144. 15. Inoue S, Horii M, Asano T, et al. Risk factors for nontraumatic osteonecrosis of the femoral head after renal transplantation. Orthop Sci. 2003;8:751-756. 16. Kubo T, Fujioka M, Yamazoe S, et al. Relationship between steroid dosage and osteonecrosis of the femoral head after renal transplantation as measured by magnetic resonance imaging. Transplant Proc. 1998;30:3039-3040. 17. Lebrun-Vignes B, Archer VC, Diquet B, et al. Effect of itraconazole on the pharmacokinetics of prednisolone and methylprednisolone and cortisol secretion in healthy subjects. Br J Clin Pharmacol. 2001;51:443--450. 18. Iwasaki K, Matsuda H, Nagase K, et al. Effects of twenty-three drugs on the metabolism of FK506 by human liver microsomes. Res Cemmun Chem PatholPharmacol. 1993; 82:209-216. 19. Frey BM, Frey FJ. Clinical pharmacokinetics of prednisone and prednisolone. Clin Pharmacokinet. 1990;19:126-146. 20. Barth J, Damoiseaux M, Mollmann H, et al. Pharmacokinetics and pharmacodynamics of prednisolone after intravenous and oral administration. Int J Clin Pharmacol Ther Toxicol. 1992;30:317-324. 21. Gambertoglio JG, Amend WJ Jr, Benet LZ. Pharmacokinetics and bioavailability of prednisone and prednisolone in healthy volunteers and patients: A review. J Pharmacokinet Biopharm. 1980;8:1-52. 22. Grenier FC, Luczkiw J, Bergmann M, et al. A whole blood FK 506 assay for the IMx analyzer. Transplant Proc. 1991;23:2748-2749. 23. Rose JQ, Jusko WJ. Corticosteroid analysis in biological fluids by high-performance liquid chromatography. J Chromatogr. 1979; 162:273-280. 24. Ono K. Diagnostic criteria, typing, and staging of avascular necrosis of the femoral head. Annual Report of the Idiopathic Avascular Necrosis of the Femoral Head Ministry of Health and Welfare of Japan. 1986:330-336. 25. Jusko WJ, Piekoszewski W, Klintmalm GB, et al. Pharmacokinetics of tacrolimus in liver transplant patients. Clin Pharmacol Ther. 1995;57:281-290. 26. Boswell GW, Bekersky I, Fay J, et al. Tacrolimus pharmacokinetics in BMT patients. Bone Marrow Transplant. 1998;21:23-28.
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27. Anglicheau D, Legendre C, Thervet E. Pharmacogenetics in solid organ transplantation: Present knowledge and future perspectives. Transplantation. 2004;78:311-315. 28. Venkataramanan R, Swaminathan A, Prasad T, eta]. Clinical pharmacokinetics of tacrolimus. Clin Pharmacokinet. 1995;29:404-430. 29. Ohzono K, Saito M, Takaoka K, et al. Natural history of nontraumatic avascular necrosis of the femoral head. J Bone Joint Surg Br. 1991;73:68-72. 30. Fujioka M, Kubo T, Nakamura F, et a]. Initial changes of non-traumatic osteonecrosis of femoral head in fat suppression images: Bone marrow edema was not found before the appearance of band patterns. Magn Reson Imaging. 2001;19:985-991.
Address correspondence to: N o b u y u k i Sugioka, PhD, D e p a r t m e n t of Pharmacokinetics, Kyoto P h a r m a c e u t i c a l University, Yamashina-ku, Kyoto 6078414, Japan. E-mail: [email protected]
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Estimation of Minimum Whole-Blood Tacrolimus Concentration for Therapeutic Drug Monitoring with Plasma Prednisolone Concentration: A Retrospective Cohort Study in Japanese Kidney Transplant Recipients Nobuyuki Sugioka, PhD1,2; Akiko Matsushita, MS1; Takatoshi Kokuhu, BPharm2; Masahiko Okamoto, MD, PhD3; Norio Yoshimura, MD, PhD3; Yukako Ito, PhD1; Nobuhito Shibata, PhD4; and Kanji Takada, PhD 1
7Department of Pharmacokinetics, Kyoto Pharmaceutical University, Kyoto, Japan; 2Department of Hospital Pharmacy, Kyoto Prefectural University of Medicine, Kyoto, Japan; 3Department of Transplantation and Regenerative Surgery, Kyoto Prefectural University of Medicine, Kyoto, Japan; and 4Department of Biopharmaceutics, Faculty of Pharmaceutical Science, Doshisha Women's College of Liberal Arts, Kyoto, Japan
ABSTRACT Background: In immunosuppressive therapy administered after organ transplantation, therapeutic drug monitoring (TDM) of tacrolimus must be performed frequently because of the large variation in its pharmacokinetic properties and a progressive decrease in dose requirements. An indicator for estimating the target minimum whole-blood tacrolimus concentration (Cm~n TAC)would be useful to minimize the number of blood samplings required for tacrolimus TDM. Objectives: The primary objective of this study was to investigate whether plasma prednisolone concentration, postoperative days (POD) and AUC 0 to 9 hours before transplantation (AUC0_9~,,) are useful indicators of tacrolimus TDM. The secondary objective was to determine the usefulness of blood tacrolimus concentration as an indicator of the development of nontraumatic, glucocorticoid-induced necrosis of the femoral head, an adverse event that has been associated with the use of prednisolone in vivo. Methods: This open-label, nonrandomized, retrospective study was conducted at the Department of Transplantation and Regenerative Surgery, Kyoto Prefectural University of Medicine, Kyoto, Japan. Data from 43 male and 22 female patients (mean age, 38 years [range, 9-64 years]) who received a living-related kidney transplant from 2001 to 2004 were included. Multiple blood samplings were performed to determine AUC0_9int, AUC 0 to 9 hours after drug administration and after transplantation (AUC0_9), Cm~n TAC'Cm~x' and Tm~x after transplantation. The correlations between each parameter were determined. The correlation between POD and the changes in tacrolimus bioavailability was investigated
Acceptedfor publicationFebruary20, 2006.
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Copyright © 2006 Excerpta Medica, Inc.
doi:l 0.1016/j.curtheres.2006.04.005 0011-393X/06/$19.00
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using the indicator, defined as the tacrolimus dose required to maintain the target (10-15 ng/mL) Cmin TAC (d°se/C10-15)" Correlations between dose/C10_15 and AUC0_9int (3 AUC0_9int groups, defined as follows: low, medium, and high [<93, ___93-<152, and ___152 ng • h/mL, respectively]) were determined. Correlations between mean Cm~n values of prednisolone at a dose of 40 mg on PODs 4 to 11 (Cmin PSL40) and Cmin TAC' or AUC0_9int were determined. A subanalysis was used to determine the relationship between dose/C10_15 and the prevalence of nontraumatic, glucocorticoid-induced necrosis of the femoral head. Results: Cm~n TACwas found to be significantly correlated with AUC0_9int (r = 0.554; P < 0.001) and Cmh~PSL40 (r = 0.336; P < 0.001). In the low-AUCo_9h~t group, dose/C10_15 was higher than that of the other groups (P< 0.01). AUCo_9intwas significantly correlated with Cmin PSL40 (r = 0.445; P < 0.001). Dose/C10_15 in the patient group that had necrosis of the femoral head was lower than that of the group without necrosis (n = 6; P < 0.01). Conclusions: The results of this small, r e t r o s p e c t i v e s t u d y s u g g e s t t h a t Cmin PSL40, AUC0-9int, and POD were significant predictors of Cm~n TAC" These p a r a m e t e r s were found to be a useful indicator of tacrolimus TDM in these Japanese transplant recipients. Our results also suggest that dose/C10_15 and AUC0_9int might be useful indicators for estimating the risk for nontraumatic, steroid-induced necrosis of the femoral head. (Curr Ther Res Clin Exp. 2006;67: 103-117) Copyright © 2006 Excerpta Medica, Inc. Key words: tacrolimus, prednisolone, blood concentration, therapeutic drug monitoring.
INTRODUCTION Tacrolimus, a macrolide lactone, is an immunosuppressive agent that inhibits the signal-transduction pathway that leads to T-lymphocyte activation. 1-3 Tacrolimus has been used for preventing or treating graft rejection after organ transplantation. 4~ Therapeutic drug monitoring (TDM) is essential to minimizing toxicity while maintaining the efficacy of immunosuppressants such as tacrolimus, which has high variability in its pharmacokinetic (PK) properties. 7-9 In the TDM of tacrolimus, the most widely used indicator is minimum whole-blood tacrolimus concentration (Cmin TAC).1° TO maintain target Cmin TAC' TDM must be performed frequently, every day until 14 postoperative days (PODs) in our institution. 11 To minimize the number of blood samplings required for tacrolimus TDM, an indicator for estimating Cm~n TACwould be useful. In general, AUC is a useful indicator for TDM because systemic exposure is measured as AUC. Therefore, to establish the possible usefulness of a method for estimating Cm~n TAC'we investigated the PK properties of tacrolimus in kidney transplant recipients, including AUC 0 to 9 hours after drug administration before transplantation (AUC0_9~nt) and 0 to 9 hours after drug administration and after transplantation (AUC0_9). Previous s t u d i e s have r e p o r t e d a progressive d e c r e a s e in t a c r o l i m u s d o s e requirements as time after adult organ t r a n s p l a n t recipients elapsed. 12,13 How-
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ever, in J apanes e kidney t r a n s p l a n t recipients, t i m e - d e p e n d e n t increases in the bioavailability of tacrolimus within 4 weeks of transplantation were not found in a MEDLINE search of the literature (key terms: tacrolimus, kidney [renal], pharmacokmetics, bioavailability [AUC], and time after transplantation [time-dependent]; years: 1974-2006). If time dependent increase of blood clearance was observed in Japanese kidney transplant patients, POD might be another useful parameter for estimating Cm~n TAC" Prednisolone, a synthetic glucocorticoid, is commonly used in the treatment of a variety of inflammatory diseases such as rheumatism, hepatitis, and nephritis. After kidney transplantation, prednisolone is used concomitantly with tacrolimus or cyclosporin A in immunosuppressive t herapy in all cases of kidney transplantation in our institution. 14 Adverse events (AEs) associated with the use of prednisolone include nontraumatic, glucocorticoid-induced necrosis of the femoral head. About 6% of kidney transplant recipient's nontraumatic, glucocorticoid-induced necrosis of the femoral head was developed in our institution. 15 Despite using the same protocol for prednisolone administration, studies in adult kidney transplant recipients have found different clinical courses of this disorder, indicating individual differences in steroid sensitivity. 16 Prednisolone and tacrolimus are metabolized by the same i s o e n z y m e - cy to chr om e P450 (CYP) 3A4.17,18 Competitive inhibition has been report ed with combination t r e a t m e n t with t hese 2 drugs. 18 Both drugs are a s u b s t r a t e of P-glycoprotein, a t r a ns por t e r that plays an important role in drug absorption and distribution. Therefore, it is hypothesized that tacrolimus and prednisolone have a similar absorption and clearance rate in the body. In addition, the bioavailability of prednisolone is almost 100%, 19-21 with the result that plasma prednisolone concentrations per dose reflect prednisolone clearance. Prednisolone is typically administered as a fixed-dose regimen in transplant recipients in our institution. 14 For this reason, and because tacrolimus has the same elimination pathway and large variations in bioavailability, we hypothesized that plasma prednisolone concentrations might serve as an indicator of tacrolimus TDM in patients receiving immunosuppressive regimens after transplantation, and that the risks for AEs associated with prednisolone use can be estimated using tacrolimus TDM. The primary objective of this st udy was to investigate w het her plasma prednisolone concentration is a useful indicator of tacrolimus TDM. The s e c o n d a r y objective was to determine w h e t h e r Cm~n TAC is useful as an indicator of the development of nontraumatic, glucocorticoid-induced necrosis of the femoral head.
PATIENTS A N D METHODS This open-label, nonrandomized, retrospective cohort st udy was conducted at the Department of Transplantation and Regenerative Surgery, Kyoto Prefectural University of Medicine, Kyoto, Japan. The study protocol was approved by the
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ethics committee at the university, and informed consent was obtained from all patients or their legal guardians (for patients aged <18 years).
Study Population Data from the medical records of Japanese patients (43 male and 22 female; mean age, 38 years [range, 9-64 years]) who had received a living-related kidney transplant at the university from 2001 to 2004 were included. All patients who had been administered tacrolimus treatment as described earlier were retrospectively enrolled in the study. To investigate the relationship between the PK properties of tacrolimus and plasma prednisolone concentration, the patients for whom these data were available were included in this subanalysis.
Immunosuppressive Regimen The following immunosuppressive regimen, developed by the Department of Transplantation and Regenerative Surgery for use after living-related kidney transplantation, was used in the patients. The initial dose of tacrolimus (0.3 mg. kg -1 • d -1) was administered orally for 2 days before transplantation. Tacrolimus (0.1 mg • kg -1 • d-1) was administered by continuous IV infusion on the day of transplantation before surgery, followed by oral tacrolimus (0.3 mg/kg BID) for 3 weeks. The dose of tacrolimus was adjusted based on the results of Cm~n TACmonitoring empirically. Target Cm~n TACwas 10 to 15 ng/mL. Methylprednisolone 500 mg was administered by continuous IV infusion on the day of transplantation before surgery, followed by prednisolone 50 mg/d on PODs 0 to 3 and prednisolone 40 mg/d on PODs 4 to 11. On PODs 12 to 19, the dose of prednisolone was decreased to 30 mg/d, and subsequently reduced by 5 mg each week until a dose of 10 mg/d was reached. On POD 21, azathioprine (0.50-0.75 mg/kg PO BID) or mycophenolate mofetil (10.0-12.5 mg/kg PO BID) was added to the regimen. This was continued until the patient was discharged from the hospital. Pharmacokinetic Assessment of Tacrolimus For PK studies of tacrolimus, blood samples were obtained 2 days before transplantation and at 0, 1, 2, 3, 4, 6, and 9 hours after drug administration on PODs 14, 21, and 28. PK parameters (eg, AUC0_9, Cm~, Tm~) were determined from those data. To determine Cmin TAC' blood samples were obtained before drug administration each day through POD 14. After POD 14, blood samples were obtained before drug administration every other day until POD 28. Blood tacrolimus concentration was measured using microparticle enzyme immunoassay (IMx system, Abbott Laboratories, Abbott Park, Illinois). 22 AUC0_9 and AUC0_9int were calculated using the trapezoidal rule. Plasma Prednisolone Concentration Plasma prednisolone concentration was measured using the high-performance liquid chromatography (HPLC) method described by Rose and Jusko, 23 of which
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internal standard, the mobile phase, and organic s o r b e n t for liquid-liquid extraction were modified by us. Plasma samples for the determination of prednisolone concentration were collected before oral administration of prednisolone 40 mg/d on PODs 4 to 11. More than 3 blood samples (2 mL) were obtained between PODs 4 to 11 from each patient, and the mean prednisolone concentration was calculated and considered as an indicator of prednisolone clearance at an early stage of prednisolone treatment (Cm~" values of prednisolone at dose of 40 mg on PODs 4-11 [Cmi" PSL40])"The prednisolone and carbamazepine used as internal standards were purchased from Nacalai Tesque, Kyoto, Japan. Acetonitrile and methanol were HPLC grade; all other reagents were reagent grade. The preparation of plasma samples was based on liquid-liquid extraction with dichloromethane. The com pounds were separated on a cyanopropyl column using acetonitrile-methanol-water (66:17:17, v/v) as the mobile phase. UV detection was used at a wavelength of 254 nm. The HPLC system (Shimadzu Corporation, Kyoto, Japan) consisted of an LC-10A liquid delivery module, an SPD-10A UV detector, a CTO-10A column oven, and a Simpac CLC-CN column (150 mm × 6 mm; interior diameter, 5 1Jm). Samples were injected using an SIL-10A automatic injector. The system was controlled with an SCL-10A system controller. The area under each objective peaks in chromatograph were calibrated with a Shimadzu CR-8A data processor. The standard curves of prednisolone ranging from 0.01 to 500 1Jg/mL were considered linear. CV values (%) of inter- and intra-assay reproducibility were <10%. Tacrolimus Concentration as an Indicator of Prednisolone Adverse Events To investigate whether blood tacrolimus concentration might be useful as an indicator of the development of AEs associated with prednisolone use, the relationship between tacrolimus bioavailability in patients with and without nontraumatic, glucocorticoid-induced necrosis of the femoral head was investigated using the tacrolimus dose required to maintain the target (10-15 ng/mL) Cmi. TAC (d°se/C10-15) as the indicator of bioavailability. This subanalysis used data from patients diagnosed with nontraumatic, steroid-induced necrosis of the femoral head (diagnosed according to the criteria of the Research Committee of the Ministry of Health and Welfare of Japan24); data from the remaining patients were used as references. Statistical Analysis The correlations between Cm~"TAC or AUC0_9 and tacrolimus dose, Cm~, or Tm~ were determined. After POD 14, dose/C10_l 5 was considered an indicator of bioavailability. The relationship between POD and dose/C10_l 5 was investigated. The correlations between dose/C10_15, POD, and AUC0_9int were determined using the following method. Study patients were assigned to 1 of 3 AUC0_9int groups: low, medium, and high (<93, ___93--<152, and ___152 n g • h/mL, respectively). On days 6 to 10, 11 to 15, 16 to 20, 21 to 25, 26 to 30, 31 to 35, and 36 to 40, differences in mean dose/C10_l 5 in each period between the 3 AUC0_9int
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groups were examined using 1-way analysis of variance. To investigate w h e t h e r POD, AUC0_9int, a n d / o r plasma prednisolone c o n c e n t r a t i o n s are useful as an indicator of tacrolimus TDM, the correlations b e t w e e n Cmh~ TAC' POD, tacrolimus dose, p r e d n i s o l o n e dose, AUC0_9int , and Cm~n PSL40were d e t e r m i n e d using Pearson correlation. To assess the relative effects of each p a r a m e t e r on Cm~n TAC' stepwise multiple linear regressions were p e r f o r m e d using POD, tacrolimus dose, p r e d n i s o l o n e dose, Cm~n PSL40' and AUC0_9int as i n d e p e n d e n t variables. Differences in dose/C10_15 b e t w e e n the groups with and w i t h o u t n o n t r a u matic, s t e r o i d - i n d u c e d necrosis of the femoral h e a d for 5 p e r i o d s of time (PODs 16-20, 21-25, 26-30, 31-35, and 36-40) were d e t e r m i n e d using the S t u d e n t t test. Analyses in this s t u d y were c o n d u c t e d using the StatView software package version 5.0 (SAS Institute Inc., Cary, North Carolina).
RESULTS Pharmacokinetic Properties of Tacrolimus The PK analysis of tacrolimus included 13 patients from w h o m these data were available (7 males, 6 females; range, 9-62 years). Figure 1 shows AUC0_9 of tacrolimus at various doses on PODs 14, 21, and 28. Although there was a large variation in the dose of tacrolimus (0.150.30 mg/kg), no significant differences in mean AUC0_9 were found between the 3 time points. Similarly, no significant differences in mean AUC0_9 were found between mean doses (0.30, 0.25, 0.20, and 0.15 mg/kg) on PODs 14, 21, and 28. Table I shows the correlations between the values of AUC0_9 and Cm~n TACfor Cm~, Tm~, amount (mg), and dose (mg/kg) on PODs 14, 21, and 28. At all time points, AUC0_9 was significantly correlated with Cm~ (r = 0.829, 0.925, and 0.904, respectively; all, P ~ 0.001), and Cm~n TACwas significantly correlated with AUC0_9 (r = 0.881, 0.822, and 0.886, respectively; all, P < 0.001) and Cm~ (r = 0.636, 0.621, and 0.797, respectively; P ~ 0.01, P ~ 0.01, and P ~ 0.001, respectively). Neither AUC0_9 nor Cm~nTACwas significantly associated with values of Tm~, amount, or dose. The relationship between POD and dose/C10_15 as an indicator of bioavailability on POD 14 to 40 is shown in Figure 2. As time after transplantation increased, the dose/C10_15 decreased gradually (r = -0.830; P < 0.001). Figure 3 s h o w s the relationship b e t w e e n m e a n dose/C10_15 and AUC0_9int. In all p e r i o d s (PODs 16-20, 21-25, 26-30, 31-35, and 36-40), in the lowAUC0_9int group, mean dose/C10_15 was higher (___0.253 m g . kg -1 • d -1) than that in the other groups (___0.155 m g . kg -1 • d-l), and in the middle-AUC0_9int group, mean dose/C10_15 was higher (___0.199 mg • kg -1 • d -1) than that in the high-AUC0_9int group (___0.155 m g . kg -1 • d-l). Statistically significant differences in t a c r o l i m u s dose/C10_15 b e t w e e n all 3 groups in all p e r i o d s were o b s e r v e d (all, P < 0.01). In each group, m e a n dose/C10_15 gradually d e c r e a s e d with POD (low [r = -0.927; P < 0.01]; middle [r = -0.960; P < 0.005]; high [r = -0.903; P < 0.05]).
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[] • • [] 350 -
0.15 0.20 0.25 0.30
m g • kg mg ° kg m g • kg mg • kg
1° d 1° d 1. d 1. d
1 (n 1 (n 1 (n 1 (n
= 6 and 6 on PODs 21 and 28, respectively) = 8, 14, and 6 on PODs 14, 21, and 28, respectively) = 4 , 6, and 9 on PODs 14, 21, and 28, respectively) = 4 , 6, and 5 on PODs 14, 21, and 28, respectively)
300 -
250 -
E e-
200 -
e-
150 -
100 -
50-
0
I
14
I
21
m l
28
PODs Figure 1. M e a n (SD) A U C 0 t o 9 h o u r s (AUC0_9) a f t e r a d m i n i s t r a t i o n o f v a r i o u s d o s e s o f t a c r o l i m u s o n p o s t o p e r a t i v e d a y s (PODs) 14, 21, a n d 28 in J a p a n e s e kidn e y t r a n s p l a n t r e c i p i e n t s (N = 65). N o s i g n i f i c a n t b e t w e e n - g r o u p d i f f e r e n c e s w e r e f o u n d . D a t a w e r e u n a v a i l a b l e f o r t h e 0 . 1 5 - m g • kg -1 • d -1 d o s e at POD 14.
Relationship Between Plasma Prednisolone Concentration and Tacrolimus Pharmacokinetic Properties Cmin PSL40o b t a i n e d from the 13 patients from w h o m data were available varied from 19.5 to 161.4 ng/mL (mean [SD], 56.1 [42.3] ng/mL). T h e c o r r e l a t i o n s b e t w e e n Cmin TAC and POD; t a c r o l i m u s dose, p r e d n i s o l o n e dose, AUC0_9int, and Cmin PSL40; and b e t w e e n Cmin PSL40 and AUC0_gint are s h o w n in T a b l e II. Cmin TAC was significantly negatively c o r r e l a t e d with POD (r = -0.327; P < 0.001) and significantly positively c o r r e l a t e d with AUC0_gint (r = 0.554) and Cmin PSL40 (r = 0.336) (both, P < 0.001). Cm~n TACwas not significantly a s s o c i a t e d with the tacrolimus or p r e d n i s o l o n e dose. Cmin PSL40was significantly c o r r e l a t e d with AUC0_9int (r = 0.445; P < 0.001). Cmin TAC was used as a d e p e n d e n t variable in stepwise multiple linear regressions that were performed. Four variables (POD, prednisolone dose, Cmin PSL40' and AUC0_9int) were s e l e c t e d and e n t e r e d into the regression e q u a t i o n (Table llI).
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Table I.
Relationships between the pharmacokinetic properties of tacrolimus in Japanese kidney transplant recipients. Values are correlation coefficients. AUCo_ 9
Cmax
Tmax
Amount
Dose
AUC0_ 9
-
0.829*
0.053
0.107
-0.281
Cmin TAC
0.881"
0.636 t
0.304
0.072
-0.151
AUCo_9
-
0.925*
0.100
0.068
-0.006
Cmin TAC
0.822*
0.621 t
-0.049
0.091
-0.251
AUCo_9
-
0.904*
0.320
0.122
-0.139
Cmin TAC
0.886*
0.797*
--0.104
0.196
--0.204
Time Point POD 1 4 ( n = 1 6 )
POD 21 (n = 32)
POD 28 (n = 26)
AUC0 9 = AUC 0 to 9 hours after drug administration and after transplantation; POD = postoperative day; Cmin TAC = minimum whole-blood tacrolimus concentration. *P < 0.001. tp < 0.01.
Relationship Between Dose/Clo_l 5 and N o n t r a u m a t i c , Steroid-Induced Necrosis of the Femoral Head The subanalysis of necrosis included 6 patients (4 males, 2 females; mean age, 33 y e a r s [range, 21-47 y e a r s ] ) with a diagnosis of n o n t r a u m a t i c , steroidinduced necrosis of the femoral head; data from the remaining 59 patients were used as references. F i g u r e 4 s h o w s the c o m p a r i s o n of mean dose/C10_l 5 b e t w e e n the groups with and w i t h o u t n o n t r a u m a t i c , steroid-induced necrosis of the femoral head on PODs 16 to 20, 21 to 25, 26 to 30, 31 to 35, and 36 to 40. In each period, the mean dose/C10_15 of the group that had steroid-induced necrosis of the femoral head was higher (___0.189 mg • kg -1 • d -1) than that of the group that did not have one (-0.122 m g . kg-1. d-l). Statistically significant differences were o b s e r v e d between the 2 groups in each period (all, P < 0.01). In b o t h groups, mean dose/C10_15 gradually d e c r e a s e d with POD.
DISCUSSION Tacrolimus t r e a t m e n t requires regular TDM b e c a u s e of its n a r r o w t h e r a p e u t i c range of blood c o n c e n t r a t i o n and large variability in PK properties. A strong correlation b e t w e e n s y s t e m i c exposure, AUC, and Cm~"TAChas been r e p o r t e d in patients who have u n d e r g o n e liver, kidney, and b o n e m a r r o w transplantation. 25 Cm~. TACwas significantly c o r r e l a t e d with AUC0_9 (r = 0.822-0.886) in this study, suggesting that Cm~"TAC was a good indicator for tacrolimus TDM, reflecting a p h a r m a c o l o g i c efficacy. On the o t h e r hand, AUC0_9 was not found to be signifi-
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[ ] D ° s e / C l o 15 Cmi n TAC
0
0.30
- 50
0.25 - 40
"7 0.20
30
_3.
20
3r'-
E 0.15 O
r~ E °m
0.10
2 10
0.05
I
16-20
I
21-25
I
26-30
I
31-35
I
36-40
I
PODs Figure 2. Changes in tacrolimus dose required to maintain target (10-15 ng/mL) minimum whole-blood tacrolimus concentration (Cmi n TAC) (d°se/C10-1s) as an indicator of bioavailability after postoperative day (POD) 14 in Japanese kidney transplant recipients (N = 65).
cantly c o r r e l a t e d with a m o u n t or dose. Consequently, a patient's weight might not be a useful indicator of d o s e requirements. The bioavailability of tacrolimus has large inter- and intravariability (20%809/o).25,26Nonlinear blood binding and a variable blood/plasma ratio have been rep o r t e d to be major sources of interindividual variations in the PK properties of tacrolimus. 25 Also, tacrolimus is a s u b s t r a t e of P-glycoprotein and CYP 3A4. In b o t h proteins, the induction or inhibition and the change in activation caused b y drug interactions are well known. Relationships between the polymorphisms of the CYP 3A4/5 or multidrug resistance-1 gene and the tacrolimus required dose to achieve adequate blood concentration have also been found. 27 In this study, although the tacrolimus dose varied substantially (0.15-0.30 mg/kg), no significant changes in mean AUC0_9 were associated with the level of Cm~. TAC"Subsequently, tacrolimus TDM must be performed frequently. 28 In this study, to o b t a i n useful i n f o r m a t i o n for revising t h e d o s i n g r e g i m e n after k i d n e y t r a n s p l a n t a t i o n , we i n v e s t i g a t e d t h e c h a n g e in the bioavailabil-
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• • • O 0.40 -
D°se/Clo 15in Iow-AUC09intgroup* D°se/Clo 15in medium-AUC 09int gr°up t D°se/Clo 15 in high-AUC 09int gr°up ~ CminTAC - 50
0.35 - 40
0.30 0.25
-
-30
E 0.20
_3.
-
~D
a
I=
- 20
0.15 -
3
2 O.lO
-
10 -
0.05
0
I
I
16-20
I
21-25
I
26-30
I
31-35
I
36-40
PODs Figure 3. Mean (SD) changes in tacrolimus dose required to maintain target (1015 n g / m L ) m i n i m u m w h o l e - b l o o d t a c r o l i m u s c o n c e n t r a t i o n (Cmi n TAC) (dose/Cl0_lS) as an indicator of bioavailability after postoperative day (POD) 14 in Japanese k i d n e y t r a n s p l a n t recipients (N = 65), by p r e o p e r a t i v e AUC (AUC0_9int). P < 0.01 between all groups at all t i m e points. *AUC0_9int <93 n g • h/mL; tAUC0_9int->93-<152 ng • h/mL; SAUC0_9int->152 n g • h / m E Table II. Relationships b e t w e e n m i n i m u m w h o l e - b l o o d tacrolimus c o n c e n t r a t i o n (Cmin TAC) o r m i n i m u m plasma c o n c e n t r a t i o n w i t h p r e d n i s o l o n e 40 mg (Cmin PSL40)on p o s t o p e r a t i v e days (PODs) 4 to 11 and o t h e r p h a r m a c o k i n e t i c parameters in Japanese kidney t r a n s p l a n t recipients (N = 65 f o r Cmi n TAC and N = 13 f o r Cmi n PSL40). Values are correlation coefficients.
Parameter
Cmin TAC Cmin PSL40
POD
Tacrolimus Dose
Prednisolone Dose
AUC0-9int
Cmin PSL40
-0.327*
0.042
0.21 2
0.554*
0.336*
-
-
-
0.445*
-
AUC0 9int = AUC 0 to 9 hours before transplantation. *P < 0.001.
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N. Sugioka et aL
Table III. M u l t i p l e linear regression model f o r m i n i m u m w h o l e - b l o o d tacrolimus concentration ( C m i n TAC) in Japanese kidney t r a n s p l a n t recipients.* Dependent Variable
C m i n TAC
Independent Variables
Correlation Coefficient
POD Prednisolone dose
-0.352 -0.226
Cmin PSL40 AUCo_gint Intercept
0.102 0.048 20.408
POD = postoperative day; Cmi n PSL40 = minimum plasma concentration with prednisolone 40 mg (days 4-11); AUC0 9int = AUC 0 to 9 hours before transplantation. *Multiple regression coefficient: r = 0.676; P < 0.001 (F test).
• D°se/C1015(with nontraumatic necrosis of the femoral head, n = 6) • D°se/C1015(without nontraumatic necrosis of the femoral head, n = 57) O Cil/in TAC
0.30
- 50
0.25 - 40
0.20 -
30
E
0.15
5"
~D
O
r~ - 20 E
3
0.10
o
0.05
I
I
16-20
I
21-25
I
26-30
I
31-35
I
36-40
PODs Figure 4. Mean (SD) changes in tacrolimus dose required to maintain target (10-15 n g / mL) m i n i m u m whole-blood tacrolimus c o n c e n t r a t i o n ( C m i n TAC) (dose/Cl0_lS) as an indicator of bioavailability after postoperative day (POD) 14 in Japanese kidney transplant patients w i t h (n = 6) or w i t h o u t (n = 59) nontraumatic, steroid-induced necrosis of the femoral head. *P < 0.01 between groups.
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ity of t a c r o l i m u s in the c o u r s e of i m m u n o s u p p r e s s i v e t h e r a p y . After transplantation, m e a n dose/C10_15 d e c r e a s e d (ie, bioavailability i n c r e a s e d ) . Moreover, a significant n e g a t i v e c o r r e l a t i o n b e t w e e n Cm~n TAC and POD (r = -0.327; P ~ 0.001) was found. T h e s e results s u g g e s t t h a t POD is a g o o d i n d i c a t o r for e s t i m a t i n g Cm~n TAC" T h e r e a s o n s h y p o t h e s i z e d for i n c r e a s e d bioavailability w e r e as follows: (1) t a c r o l i m u s a b s o r p t i o n i n c r e a s e d with t h e r e c o v e r y of gastrointestinal function; (2) bile secretion increased with increased food intake; and (3) c l e a r a n c e of t a c r o l i m u s d e c r e a s e d with increasing s e r u m proteinbinding ratio b e c a u s e of i n c r e a s i n g s e r u m albumin c o n c e n t r a t i o n with the r e c o v e r y of k i d n e y function. AUC0_9int is useful for individualizing dosing regimens before transplantation. In the low-AUC0_9int group, mean dose/C10_15 was higher than that in the o t h e r groups in all periods after transplantation, suggesting that patients with low AUC0_9int n e e d e d higher d o s e s of tacrolimus c o m p a r e d with patients in the highor middle-AUC0_9~nt group. In addition, Cmh~ TAC was positively c o r r e l a t e d with AUC0_9int @ = 0.554; P ~ 0.001), suggesting that the i m p o r t a n t factors for estimating Cmin TACwere POD and AUC0_9int. On the o t h e r hand, it is possible that tacrolimus has PK p r o p e r t i e s similar to t h o s e of p r e d n i s o l o n e in vivo, as previously h y p o t h e s i z e d . Values of AUC0_9int and Cmh~TACwere significantly c o r r e l a t e d with Cm~n PSL40in this particular s t u d y (r = 0.445 and 0.336, respectively; both, P < 0.001). At Kyoto Prefectural University of Medicine, p r e d n i s o l o n e is a d m i n i s t e r e d as a fixed regimen at a relatively high d o s e (40 mg/d) until 11 days after transplantation. We h y p o t h e sized that Cm~n PSL40would reflect p r e d n i s o l o n e c l e a r a n c e and would be a useful indicator of tacrolimus TDM. The results of multiple linear regressions also suggest that the m o s t i m p o r t a n t factors for estimating Cm~n TACwere POD, AUC0_9int , and Cmh~PSL40"TDM of p r e d n i s o l o n e using plasma c o n c e n t r a t i o n as an indicator was not found to be useful, p e r h a p s b e c a u s e of the unclear relationship b e t w e e n p l a s m a p r e d n i s o l o n e c o n c e n t r a t i o n and its t h e r a p e u t i c effects. Therefore, plasma p r e d n i s o l o n e c o n c e n t r a t i o n is not c o m m o n l y d e t e r m i n e d . However, our results suggest that the a s s e s s m e n t of plasma p r e d n i s o l o n e conc e n t r a t i o n might be a useful indicator of tacrolimus TDM. However, s t a n d a r d s n e e d to be established for measuring tacrolimus AUC before t r a n s p l a n t a t i o n and determining plasma p r e d n i s o l o n e c o n c e n t r a t i o n at an early stage after transplantation. T y p e s of n o n t r a u m a t i c n e c r o s i s of the femoral h e a d include aseptic and ischemic necrosis. The m e c h a n i s m b y which n e c r o s i s d e v e l o p s is unknown, but a c c u m u l a t e d statistical d a t a have identified t r e a t m e n t with glucocorticoid, s u c h as p r e d n i s o l o n e , as a relevant risk factor. It is n o t a b l e t h a t the n o n t r a u matic, s t e r o i d - i n d u c e d t y p e of n e c r o s i s of the femoral h e a d a c c o u n t s for a large p e r c e n t a g e of c a s e s of this disease. It has b e e n r e p o r t e d t h a t a b o u t 60% of n o n t r a u m a t i c n e c r o s i s of the femoral h e a d was g l u c o c o r t i c o i d - i n d u c e d . 29 Mean dose/Clo_l 5 in the group with n e c r o s i s was lower t h a n t h a t in the group w i t h o u t necrosis. It is c o n s i d e r e d that the bioavailability of t a c r o l i m u s was
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high in the g r o u p with n e c r o s i s , s u g g e s t i n g p r e d n i s o l o n e c l e a r a n c e m i g h t be low after t r a n s p l a n t a t i o n . T h e r e f o r e , t a c r o l i m u s TDM m i g h t b e useful for estim a t i n g t h e risk for n o n t r a u m a t i c n e c r o s i s of t h e f e m o r a l h e a d . In addition, p r e d n i s o l o n e w a s a d m i n i s t e r e d as a fixed-dose regimen, a l t h o u g h Cm~n PSL40 v a r i e d s u b s t a n t i a l l y (19.5-161.4 ng/mL). T h e r e f o r e , in d e t e r m i n i n g t h e risk for n o n t r a u m a t i c n e c r o s i s of t h e f e m o r a l h e a d , dose/C10_15 of t a c r o l i m u s w a s f o u n d to be useful as an i n d i c a t o r of p r e d n i s o l o n e c l e a r a n c e . On the o t h e r h a n d , from t h e b e g i n n i n g of g l u c o c o r t i c o i d t r e a t m e n t , n o n t r a u m a t i c n e c r o s i s of t h e f e m o r a l h e a d s h o u l d b e p r e v e n t e d . 3° In this study, AUC0_9intwas found to be significantly c o r r e l a t e d with Cmh~PSL40 (r = 0.445; P < 0.001), reflecting p r e d n i s o l o n e c l e a r a n c e in t h e e a r l y p o s t t r a n s p l a n t a t i o n s t a g e and s u g g e s t i n g t h a t AUC0_9int m i g h t be a useful i n d i c a t o r for e s t i m a t i n g the risk for s t e r o i d - i n d u c e d n e c r o s i s of the f e m o r a l head, a l t h o u g h the u s e f u l n e s s of this p a r a m e t e r is limited b y t h e n e e d for a m e a s u r e m e n t of t a c r o l i m u s AUC b e f o r e t r a n s p l a n t a t i o n . A n o t h e r limitation of this s t u d y w a s its small s a m p l e size. Additional r e s e a r c h in a larger p o p u l a t i o n is n e e d e d .
CONCLUSIONS The results of this small, r e t r o s p e c t i v e s t u d y s u g g e s t t h a t Cm~n PSL40' AUC0-9int, and POD w e r e significant p r e d i c t o r s of Cm~n TAC"T h e s e p a r a m e t e r s w e r e found to be a useful indicator of t a c r o l i m u s TDM in t h e s e J a p a n e s e kidney t r a n s p l a n t recipients. Our results also s u g g e s t t h a t dose/C10_15 and AUC0_9int might be useful i n d i c a t o r s for e s t i m a t i n g the risk for n o n t r a u m a t i c , s t e r o i d - i n d u c e d n e c r o s i s of the femoral head.
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Address correspondence to: N o b u y u k i Sugioka, PhD, D e p a r t m e n t of Pharmacokinetics, Kyoto P h a r m a c e u t i c a l University, Yamashina-ku, Kyoto 6078414, Japan. E-mail: [email protected]
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