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Pharmacokinetic characteristics of methylprednisolone in korean renal transplant recipients
Pharmacokinetic Characteristics of Methylprednisolone in Korean Renal Transplant Recipients C.M. Kang, J.H. Ahn, K.W. Kahng, J.S. Kang, I.C. Shin, and J.Y. Kwak
C
OMBINED immunosuppressive therapy has improved the success rate of renal transplantation.1 Glucocorticoids have long been part of the immunosuppressive protocol for most renal transplant recipients. Glucocorticoids are usually given according to a standard dosing protocol regardless of individual differences. But considerable interpatient and racial differences in the pharmacokinetics of glucocorticoids have been reported.2– 4 There are few studies on the glucocorticoid pharmacokinetics of Korean renal transplant recipients and few prospective studies on the influence of the differences in the pharmacokinetics of methylprednisolone (m-PDS) on the occurrence of steroid-related phenomena. We evaluated the pharmacokinetic characteristics of m-PDS and the degree of interpatient variation in relatively stable Korean renal transplant recipients during the early postoperative period. We then followed up these patients to analyze the association of pharmacokinetic characteristics of m-PDS with the occurrence of steroid-related phenomena. We also studied racial differences of the pharmacokinetics of m-PDS compared with previous reports.3,4 PATIENTS AND METHODS This study included 23 renal transplant recipients, 13 males and 10 females, who received kidneys from living donors, had stable graft function continuously without an episode of acute rejection, and in
whom 15 to 21 days had elapsed since the time of transplantation. They had received triple immunosuppressive therapy consisting of cyclosporine (CyA), azathioprine, and prednisolone. Prednisolone was given at 90 mg on the first day after transplantation, tapered by 10 mg/d to 20 mg at day 8, then 20 mg/d for 3 weeks. When we performed the pharmacokinetic studies, the patients had already been taking 20 mg of oral prednisolone daily for at least 7 days. On the study day at 8 AM, 16 mg of m-PDS sodium succinate (IV) was administered to each patient instead of the usual dose (20 mg) of prednisolone (orally) after sampling 7 mL of baseline blood. Additional blood samples were drawn at 0.5, 1, 2, 3, 4, 6, 10, 14, 16, and 24 hours after the start of infusion. Plasma was separated and analyzed for m-PDS levels using high-performance liquid chromatography (HPLC) assay. Parameters for pharmacokinetics were then calculated. We followed these patients prospectively and evaluated the occurrence of probable steroid-related phenomena. We compared indirectly the pharmacokinetic data of our patients with the data of studies done in black and white renal transplant recipients.
From the Departments of Internal Medicine Pharmacology (J.S.K., I.C.S.), Department of Surgery (J.Y.K.), Hanyang University Hospital, Seoul, Korea. Address reprint requests to Dr Chong Myung Kang, Department of Internal Medicine, Hanyang University Hospital, PO Box 93, SungDong-Ku, Seoul, 133-600, Korea.
Table 1. Pharmacokinetic Parameters in Patients with Probable Steroid-Related Effects
Total Cushingoid appearance Newly onset DM Hypercholesterolemia Cataract Herpes zoster Leukocytosis† Increased ratio of BUN/sCr† Hypertension
No.
AUC (ng/h/mL)
Vd/TBW (L/kg)
23 7
1487 ⫾ 107 1652 ⫾ 242
1.28 ⫾ 0.08 1.24 ⫾ 0.16
4 12 4 4 5 3
1520 ⫾ 333 1477 ⫾ 159 1740 ⫾ 386 1785 ⫾ 127 1258 ⫾ 167 1510 ⫾ 438
17
1543 ⫾ 140
Cmax (ng/mL)
Tmax (h)
t1/2 (h)
Clp/TBW (ml/hr/Kg)
MRT (h)
366 ⫾ 27 374 ⫾ 29
0.65 ⫾ 0.07 0.79 ⫾ 0.21*
4.08 ⫾ 0.16 3.62 ⫾ 0.27
224 ⫾ 14 243 ⫾ 34
5.88 ⫾ 0.27 5.30 ⫾ 0.41
1.36 ⫾ 0.20 1.30 ⫾ 0.11 1.21 ⫾ 0.11 1.01 ⫾ 0.67 1.37 ⫾ 0.15 1.08 ⫾ 0.17
308 ⫾ 39 372 ⫾ 47 344 ⫾ 50 437 ⫾ 108 361 ⫾ 55 309 ⫾ 37
0.63 ⫾ 0.13 0.67 ⫾ 0.13 0.75 ⫾ 0.14 0.50 ⫾ 0 0.50 ⫾ 0 0.67 ⫾ 0.17
4.43 ⫾ 0.51 4.11 ⫾ 0.21 4.73 ⫾ 0.23 4.31 ⫾ 0.26 4.29 ⫾ 0.42 4.31 ⫾ 0.65
213 ⫾ 35 223 ⫾ 18 188 ⫾ 28 161 ⫾ 13* 234 ⫾ 25 189 ⫾ 31
6.67 ⫾ 0.97 5.86 ⫾ 0.27 6.59 ⫾ 0.42 6.36 ⫾ 0.47 5.97 ⫾ 0.54 5.86 ⫾ 0.84
1.22 ⫾ 0.09
375 ⫾ 33
0.68 ⫾ 0.10
4.18 ⫾ 0.20
208 ⫾ 14
5.99 ⫾ 0.36
Note: The data represent mean ⫾ SEM. Abbreviations: AUC, area under time concentration curve; Vd/TBW, volume of distribution per total body weight; Cmax, maximal concentration; Tmax, time for Cmax; t1/2, elimination half-life; Clp/TBW, clearance per total body weight; MRT, mean residence time. *P ⬍ .05 in Mann-Whitney U test. † Sustained for at least 3 months with no appropriate cause except glucocorticoid effect.
© 1999 by Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010
0041-1345/99/$–see front matter PII S0041-1345(99)00556-4
Transplantation Proceedings, 31, 2759–2760 (1999)
2759
2760
KANG, AHN, KAHNG ET AL Table 2. Racial Differences in m-PDS Pharmacokinetics
Clp/TBW (mL/h/kg) Vd/TBW (L/kg) t1/2 (h)
Koreans
Blacks(I)
Blacks(II)
Whites(I)
Whites(II)
224 ⫾ 69* 1.28 ⫾ 0.39† 4.08 ⫾ 0.76‡
206 ⫾ 70 0.95 ⫾ 0.32 3.07 ⫾ 0.44
234 ⫾ 124 1.10 ⫾ 0.60 3.40 ⫾ 1.40
327 ⫾ 129 1.33 ⫾ 0.27* 2.93 ⫾ 0.81
472 ⫾ 180 1.50 ⫾ 0.40 2.10 ⫾ 0.30
The data represent mean ⫾ SD; *P ⬍ .05 Koreans vs whites; †P ⬍ .05 Koreans vs blacks; ‡P ⬍ .05 Koreans vs both blacks and whites.
RESULTS
The mean age of these patients was 40.2 ⫾ 12.1 years and the mean serum creatinine level (sCr) was 1.50 ⫾ 0.39 mg/dL. Mean body weight (BW) was 53.9 ⫾ 9.8 kg. Mean follow-up time was 73.6 ⫾ 13.7 weeks. There was significant interpatient variation in the pharmacokinetics of m-PDS in our group of patients. The area under the curve (AUC; ng/h/mL) was significantly related to the BW (⫺22.4 ⫻ BW [kg] ⫹ 2695; r ⫽ .427; P ⬍ .05) or body surface area (BSA) of each patient (⫺1424 ⫻ BSA [m2] ⫹ 3690; r ⫽ .453; P ⬍ .05). The percent coefficient of variation in AUC was 34.6%. During the follow-up period, newly onset diabetes mellitus (DM) occurred in 4 patients; hypertension, 17; hypercholesterolemia, 12; cushingoid appearance, 7; cataract, 4; sustained leukocytosis from unknown origin, 5; and sustained increased ratio of blood urea nitrogen/sCr from unknown origin, 3. Cushingoid patients had higher Tmax than noncushingoid patients and patients with Herpes zoster had lower clearance statistically. In general, we did not find a significant influence of the pharmacokinetic parameters on the occurrence of probable steroid-related phenomena (Table 1). Korean renal transplant recipients had a larger volume of distribution than black renal transplant recipients; lower clearance than white renal transplant recipients; and a longer t1/2 than both black and white renal transplant recipients (Table 2). CONCLUSIONS
We found significant interpatient variation in the pharmacokinetics of m-PDS in Korean renal transplant recipients who had relatively stable allograft function during the early posttransplantation period. There are significant relations
between AUC and BW or BSA. However, the values of correlation coefficient were low and there was a large difference between estimated AUC and actual AUC in some patients. Therefore, it may be undesirable to give m-PDS solely based on BW or BSA of each patient. It is most desirable to give m-PDS on an individual basis after measuring its pharmacokinetics. Individualization may be more important in m-PDS pulse therapy for the treatment of acute cellular rejection. We could not find any statistically significant effect of pharmacokinetic differences on the occurrence of steroid-related phenomena. We must consider the difference between bioavailability of oral prednisolone and IV m-PDS, in addition to the differences in the pharmacodynamics of m-PDS. We found differences in the pharmacokinetics in Korean renal transplant recipients, compared with black or white renal transplant recipients. Our patients differed from black or white renal transplants on the points of posttransplantation period, types of donors, immunosuppressive regimen, glucocorticoid type, glucocorticoid dosage, and others. It is necessary to perform further large direct studies on racial differences in the pharmacokinetics and pharmacodynamics of glucocorticoids in renal transplant recipients.
REFERENCES 1. Strom TB: Kidney Int 26:353, 1983 2. Gambertoglio JG, Vincenti F, Feduska NJ, et al: J Clin Endocrinol Metab 51:561, 1980 3. Tornatore KM, Reed KA, Venuto RC: Pharmacotherapy 13:481, 1993 4. Tornatore KM, Biocevich DM, Reed K, et al: Transplantation 59:729, 1995
C
OMBINED immunosuppressive therapy has improved the success rate of renal transplantation.1 Glucocorticoids have long been part of the immunosuppressive protocol for most renal transplant recipients. Glucocorticoids are usually given according to a standard dosing protocol regardless of individual differences. But considerable interpatient and racial differences in the pharmacokinetics of glucocorticoids have been reported.2– 4 There are few studies on the glucocorticoid pharmacokinetics of Korean renal transplant recipients and few prospective studies on the influence of the differences in the pharmacokinetics of methylprednisolone (m-PDS) on the occurrence of steroid-related phenomena. We evaluated the pharmacokinetic characteristics of m-PDS and the degree of interpatient variation in relatively stable Korean renal transplant recipients during the early postoperative period. We then followed up these patients to analyze the association of pharmacokinetic characteristics of m-PDS with the occurrence of steroid-related phenomena. We also studied racial differences of the pharmacokinetics of m-PDS compared with previous reports.3,4 PATIENTS AND METHODS This study included 23 renal transplant recipients, 13 males and 10 females, who received kidneys from living donors, had stable graft function continuously without an episode of acute rejection, and in
whom 15 to 21 days had elapsed since the time of transplantation. They had received triple immunosuppressive therapy consisting of cyclosporine (CyA), azathioprine, and prednisolone. Prednisolone was given at 90 mg on the first day after transplantation, tapered by 10 mg/d to 20 mg at day 8, then 20 mg/d for 3 weeks. When we performed the pharmacokinetic studies, the patients had already been taking 20 mg of oral prednisolone daily for at least 7 days. On the study day at 8 AM, 16 mg of m-PDS sodium succinate (IV) was administered to each patient instead of the usual dose (20 mg) of prednisolone (orally) after sampling 7 mL of baseline blood. Additional blood samples were drawn at 0.5, 1, 2, 3, 4, 6, 10, 14, 16, and 24 hours after the start of infusion. Plasma was separated and analyzed for m-PDS levels using high-performance liquid chromatography (HPLC) assay. Parameters for pharmacokinetics were then calculated. We followed these patients prospectively and evaluated the occurrence of probable steroid-related phenomena. We compared indirectly the pharmacokinetic data of our patients with the data of studies done in black and white renal transplant recipients.
From the Departments of Internal Medicine Pharmacology (J.S.K., I.C.S.), Department of Surgery (J.Y.K.), Hanyang University Hospital, Seoul, Korea. Address reprint requests to Dr Chong Myung Kang, Department of Internal Medicine, Hanyang University Hospital, PO Box 93, SungDong-Ku, Seoul, 133-600, Korea.
Table 1. Pharmacokinetic Parameters in Patients with Probable Steroid-Related Effects
Total Cushingoid appearance Newly onset DM Hypercholesterolemia Cataract Herpes zoster Leukocytosis† Increased ratio of BUN/sCr† Hypertension
No.
AUC (ng/h/mL)
Vd/TBW (L/kg)
23 7
1487 ⫾ 107 1652 ⫾ 242
1.28 ⫾ 0.08 1.24 ⫾ 0.16
4 12 4 4 5 3
1520 ⫾ 333 1477 ⫾ 159 1740 ⫾ 386 1785 ⫾ 127 1258 ⫾ 167 1510 ⫾ 438
17
1543 ⫾ 140
Cmax (ng/mL)
Tmax (h)
t1/2 (h)
Clp/TBW (ml/hr/Kg)
MRT (h)
366 ⫾ 27 374 ⫾ 29
0.65 ⫾ 0.07 0.79 ⫾ 0.21*
4.08 ⫾ 0.16 3.62 ⫾ 0.27
224 ⫾ 14 243 ⫾ 34
5.88 ⫾ 0.27 5.30 ⫾ 0.41
1.36 ⫾ 0.20 1.30 ⫾ 0.11 1.21 ⫾ 0.11 1.01 ⫾ 0.67 1.37 ⫾ 0.15 1.08 ⫾ 0.17
308 ⫾ 39 372 ⫾ 47 344 ⫾ 50 437 ⫾ 108 361 ⫾ 55 309 ⫾ 37
0.63 ⫾ 0.13 0.67 ⫾ 0.13 0.75 ⫾ 0.14 0.50 ⫾ 0 0.50 ⫾ 0 0.67 ⫾ 0.17
4.43 ⫾ 0.51 4.11 ⫾ 0.21 4.73 ⫾ 0.23 4.31 ⫾ 0.26 4.29 ⫾ 0.42 4.31 ⫾ 0.65
213 ⫾ 35 223 ⫾ 18 188 ⫾ 28 161 ⫾ 13* 234 ⫾ 25 189 ⫾ 31
6.67 ⫾ 0.97 5.86 ⫾ 0.27 6.59 ⫾ 0.42 6.36 ⫾ 0.47 5.97 ⫾ 0.54 5.86 ⫾ 0.84
1.22 ⫾ 0.09
375 ⫾ 33
0.68 ⫾ 0.10
4.18 ⫾ 0.20
208 ⫾ 14
5.99 ⫾ 0.36
Note: The data represent mean ⫾ SEM. Abbreviations: AUC, area under time concentration curve; Vd/TBW, volume of distribution per total body weight; Cmax, maximal concentration; Tmax, time for Cmax; t1/2, elimination half-life; Clp/TBW, clearance per total body weight; MRT, mean residence time. *P ⬍ .05 in Mann-Whitney U test. † Sustained for at least 3 months with no appropriate cause except glucocorticoid effect.
© 1999 by Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010
0041-1345/99/$–see front matter PII S0041-1345(99)00556-4
Transplantation Proceedings, 31, 2759–2760 (1999)
2759
2760
KANG, AHN, KAHNG ET AL Table 2. Racial Differences in m-PDS Pharmacokinetics
Clp/TBW (mL/h/kg) Vd/TBW (L/kg) t1/2 (h)
Koreans
Blacks(I)
Blacks(II)
Whites(I)
Whites(II)
224 ⫾ 69* 1.28 ⫾ 0.39† 4.08 ⫾ 0.76‡
206 ⫾ 70 0.95 ⫾ 0.32 3.07 ⫾ 0.44
234 ⫾ 124 1.10 ⫾ 0.60 3.40 ⫾ 1.40
327 ⫾ 129 1.33 ⫾ 0.27* 2.93 ⫾ 0.81
472 ⫾ 180 1.50 ⫾ 0.40 2.10 ⫾ 0.30
The data represent mean ⫾ SD; *P ⬍ .05 Koreans vs whites; †P ⬍ .05 Koreans vs blacks; ‡P ⬍ .05 Koreans vs both blacks and whites.
RESULTS
The mean age of these patients was 40.2 ⫾ 12.1 years and the mean serum creatinine level (sCr) was 1.50 ⫾ 0.39 mg/dL. Mean body weight (BW) was 53.9 ⫾ 9.8 kg. Mean follow-up time was 73.6 ⫾ 13.7 weeks. There was significant interpatient variation in the pharmacokinetics of m-PDS in our group of patients. The area under the curve (AUC; ng/h/mL) was significantly related to the BW (⫺22.4 ⫻ BW [kg] ⫹ 2695; r ⫽ .427; P ⬍ .05) or body surface area (BSA) of each patient (⫺1424 ⫻ BSA [m2] ⫹ 3690; r ⫽ .453; P ⬍ .05). The percent coefficient of variation in AUC was 34.6%. During the follow-up period, newly onset diabetes mellitus (DM) occurred in 4 patients; hypertension, 17; hypercholesterolemia, 12; cushingoid appearance, 7; cataract, 4; sustained leukocytosis from unknown origin, 5; and sustained increased ratio of blood urea nitrogen/sCr from unknown origin, 3. Cushingoid patients had higher Tmax than noncushingoid patients and patients with Herpes zoster had lower clearance statistically. In general, we did not find a significant influence of the pharmacokinetic parameters on the occurrence of probable steroid-related phenomena (Table 1). Korean renal transplant recipients had a larger volume of distribution than black renal transplant recipients; lower clearance than white renal transplant recipients; and a longer t1/2 than both black and white renal transplant recipients (Table 2). CONCLUSIONS
We found significant interpatient variation in the pharmacokinetics of m-PDS in Korean renal transplant recipients who had relatively stable allograft function during the early posttransplantation period. There are significant relations
between AUC and BW or BSA. However, the values of correlation coefficient were low and there was a large difference between estimated AUC and actual AUC in some patients. Therefore, it may be undesirable to give m-PDS solely based on BW or BSA of each patient. It is most desirable to give m-PDS on an individual basis after measuring its pharmacokinetics. Individualization may be more important in m-PDS pulse therapy for the treatment of acute cellular rejection. We could not find any statistically significant effect of pharmacokinetic differences on the occurrence of steroid-related phenomena. We must consider the difference between bioavailability of oral prednisolone and IV m-PDS, in addition to the differences in the pharmacodynamics of m-PDS. We found differences in the pharmacokinetics in Korean renal transplant recipients, compared with black or white renal transplant recipients. Our patients differed from black or white renal transplants on the points of posttransplantation period, types of donors, immunosuppressive regimen, glucocorticoid type, glucocorticoid dosage, and others. It is necessary to perform further large direct studies on racial differences in the pharmacokinetics and pharmacodynamics of glucocorticoids in renal transplant recipients.
REFERENCES 1. Strom TB: Kidney Int 26:353, 1983 2. Gambertoglio JG, Vincenti F, Feduska NJ, et al: J Clin Endocrinol Metab 51:561, 1980 3. Tornatore KM, Reed KA, Venuto RC: Pharmacotherapy 13:481, 1993 4. Tornatore KM, Biocevich DM, Reed K, et al: Transplantation 59:729, 1995