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Factors Affecting the Pharmacokinetics of Tacrolimus in the First Year After Renal Transplantation
MONITORING OF TACROLIMUS Factors Affecting the Pharmacokinetics of Tacrolimus in the First Year After Renal Transplantation N.A. Undre, A. Scha¨fer, and the European Tacrolimus Multicentre Renal Study Group
T
HE pharmacokinetics of tacrolimus have been characterised in healthy volunteers and liver and kidney transplant patients.1–5 The oral bioavailability of tacrolimus averages 20% to 25%; however, the inter-individual variability in this parameter is large. A strong correlation exists between AUC and trough concentrations of tacrolimus (Cmin) in whole blood. In systemic circulation, tacrolimus binds strongly to erythrocytes, resulting in a distribution ratio of 20:1 for tacrolimus whole-blood concentrations relative to plasma concentration. This ratio appears to be dependent on hematocrit levels and tacrolimus concentrations in blood.6 In plasma the drug is highly bound (. 98.8%) to plasma proteins, mainly to serum albumin and a-1-acid glycoprotein. Tacrolimus is a low-clearance drug; the extraction ratio is equivalent to about 3% of liver blood flow. For highly bound, low-extraction-ratio drugs, clearance is materially affected by changes in hematocrit and plasma protein binding. Systemically available tacrolimus is cleared by hepatic metabolism. Cytochrome P450 3A4 iso-enzyme is the principal enzyme responsible for its metabolism.7 Drugs that induce this iso-enzyme (eg, corticosteroids) may increase the metabolism of tacrolimus, thus resulting in a decrease of tacrolimus blood levels. The objectives of this evaluation were to determine the relationship among changes in hematocrit, albumin, and corticosteroid dosing on the disposition of tacrolimus during 12 months of treatment in renal transplant recipients. PATIENTS AND METHODS Patients Dosing and blood concentration data from renal allograft recipients randomised to treatment with tacrolimus in a European phase III multicentre comparative study of the efficacy and safety of tacrolimus and cyclosporine were used in this evaluation.8 A total of 303 patients were randomised to treatment with tacrolimus. Their mean age was 46.6 years (range 18 to 72 years) and their mean weight was 67.6 kg (range 33 to 130 kg); 196 of the 303 patients were male.
Fig 1. Mean (6 SEM) total daily oral dose of tacrolimus during the first year post-renal transplantation.
Dosing and Administration The initial recommended dose was 0.30 mg/kg per day administered in two divided doses; subsequent doses were adjusted to maintain the whole-blood concentration of tacrolimus within the recommended target range (10 to 20 ng/mL during first 3 months and 5 to 15 ng/mL thereafter), taking into account the patient’s clinical condition in relation to the risk of rejection and the occurrence of adverse effects.
Study Design Blood samples for the determination of trough tacrolimus concentrations were taken immediately prior to the morning dose. Samples were collected three times a week for the first 21 days after transplantation and subsequently at each follow-up visit at days 28 and 42 and then at months 3, 6, 9, and 12.
From the European Tacrolimus Multicentre Renal Study Group (see Acknowledgment section), Fujisawz GmbH, Munich, Germany. Address reprint requests to N.A. Undre, Fujisawa GmbH, Levelingstrasse 12, D-81606 Munich, Germany.
© 1998 by Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010
0041-1345/98/$19.00 PII S0041-1345(98)00234-6
Transplantation Proceedings, 30, 1261–1263 (1998)
1261
1262
UNDRE AND SCHAFER
Fig 2. Mean (6 SEM) whole-blood trough tacrolimus concentrations during the first year post-renal transplantation. Fig 3. Correlation between hematocrit and relative clearance (r 5 0.84, P 5 .017).
Analytical Methods Tacrolimus concentrations were determined by the microparticle enzyme immunoassay method based on the Abbott IMx analyser. The limit of detection for this assay was 5.0 ng/mL. For the purposes of this analysis, values for tacrolimus blood levels below the limit of detection of the assay were taken to be 2.5 ng/mL.
Pharmacokinetic Analysis Clearance was not measured directly in this clinical study. The ratio of dose (mg/kg)/Cmin(ng/mL) was considered to be proportional to the total body clearance (TBC) of tacrolimus and is referred to as relative clearance. This is a reasonable assumption because:
TBC(po) 5 dose(po) z F/AUC(po) where F is the fraction of the oral dose absorbed.9 Cmin correlates well with AUC; therefore, assuming constant bioavailability, dose/ Cmin is approximately equal to TBC. The relationships between relative clearance and changes in hematocrit and albumin during the early posttransplant period, and corticosteroid dose during months 2 to 12, were examined by linear regression.
tacrolimus dose was 0.26 mg/kg and the corresponding mean whole-blood trough concentration was 19.6 ng/mL. The mean dose fluctuated little during the first 4 weeks’ posttransplantation (0.25 to 0.27 mg/kg), but the mean trough blood concentration declined steadily to 12.9 ng/mL by week 2. The mean dose decreased gradually from 0.26 mg/kg per day at week 4 to 0.12 mg/kg per day during the final 3 months of the study, a reduction of 54%. However, the mean trough concentration declined by only 29% from 13.3 ng/mL at week 4 to 9.4 ng/mL at months 10 to 12. Levels of hematocrit and albumin over the first 12 weeks’ posttransplant and the estimated relative clearances of tacrolimus are presented in Table 1. Statistical evaluation of the data indicates a significant correlation between relative clearance and both hematocrit (r 5 0.81; P 5 .017; see Fig 3) and albumin levels (r 5 0.74, P 5 .047; see Fig 4). The mean oral doses of corticosteroids (adjusted to doses equivalent to prednisone) during months 2 to 12 and the
RESULTS Whole-Blood Concentrations and Pharmacokinetics
The mean oral daily doses and the corresponding wholeblood trough concentrations of tacrolimus over 1 year are presented graphically in Figs 1 and 2. On day 1, the mean Table 1. Mean Hematocrit and Albumin Levels and the Corresponding Estimates of Relative Clearance of Tacrolimus Time Posttransplant
Hematocrit (%)
Albumin (g/L)
Relative Clearance (L/kg)
Day 1 Week 1 Week 2 Week 3 Week 4 Week 6 Week 12
0.35 0.28 0.27 0.29 0.30 0.32 0.34
43.0 34.0 35.0 37.5 39.0 40.0 41.0
13.3 18.0 20.2 20.7 19.5 16.3 15.9
Fig 4. Correlation between albumin and relative clearance of tacrolimus (r 5 0.74, P 5 .047).
PHARMACOKINETICS OF TACROLIMUS
1263
Table 2. Mean Daily Dose of Oral Steroids and Relative Clearance of Tacrolimus Time Posttransplant
Mean (SD) Dose (mg/kg)
Relative Clearance (L/kg)
Month 2 Month 3 Months 4 – 6 Months 7–9 Months 10 –12
0.19 (0.17) 0.15 (0.19) 0.12 (0.09) 0.10 (0.06) 0.10 (0.05)
16.3 15.9 14.3 12.5 12.8
for a given dose during the early posttransplant period, and thus both should be monitored. The relationship between relative clearance and mean oral corticosteroid dose during maintenance therapy (2 to 12 months’ posttransplantation) suggests that, as the dose of corticosteroids is reduced, the dose of tacrolimus should also be lowered to maintain blood concentrations within the therapeutic range. ACKNOWLEDGMENTS
corresponding relative clearances are listed in Table 2. Relative clearance correlated with the mean oral steroid dose (r 5 0.94; P 5 .0172; see Fig 5). DISCUSSION
Results of this evaluation show that the trough whole-blood concentration of tacrolimus after renal transplantation correlates with hematocrit and albumin concentration during the first few weeks of treatment, and with corticosteroid dose from months 2 to 12 posttransplant. This is consistent with the finding that tacrolimus is strongly bound to red cells and serum albumin. This observation is of clinical significance because dose adjustment may be required to maintain blood concentrations within the therapeutic range in patients in whom hematocrit or albumin concentrations are changing. Tacrolimus has a low clearances, and a change in dose may take several days to achieve steady-state concentrations. Hematocrit and albumin concentration may therefore be potential early markers of changes in blood concentration
Participants in the European Tacrolimus Multicentre Renal Study Group included: A.D. Mayer, J. Dmitrewski (Queen Elizabeth Hospital, Birmingham, B15 2TH); J.P. Squifflet, T. Besse (Universite´ Catholique de Louvain, Cliniques Universitaires Saint-Luc, 1200 Bruxelles); B. Grabensee, B. Klein (Heinrich Heine Universita¨t Du ¨sseldorf, D-40225 Du ¨sseldorf); F.W. Eigler, U. Heemann (Universita¨tsklinik, D-45147 Essen); M. Behrend (Medizinische Hochschule Hannover, D-30625 Hannover); Y. Vanrenterghem, J. Donck (Universitaire Ziekenhuizen Gasthuisberg, 3000 Leuven); J. van Hooff, M. Christiaans (Academisch Ziekenhuis, 6201 BX Maastricht); J.M. Morales, A. Andres (Hospital Universitario “12 de Octubre,” 28041-Madrid); R.W.G. Johnson, C. Short (Manchester Royal Infirmary, Manchester, M13 9WL); B. Buchholz, N. Rehmert (Westfa¨lische Wilhelms Universita ¨t, D-48149 Mu ¨nster); W. Land (Ludwig-Maximilians-Universita¨t, Klinikum Großhadern, D-81366 Mu ¨nchen); J.L.R. Forsythe (Royal Victoria Infirmary, Newcastle-upon-Tyne, NE1 4LP); D. Talbot, Renal Transplant Unit, Freeman Hospital, High Heaton, Newcastleupon-Tyne NE7, H.-H. Neumayer, I. Hauser (Klinik Nu ¨rnberg Su ¨d, D-90471 Nu ¨rnberg); B.G. Ericzon, C. Brattstro ¨m, K. Claesson (Karolinska Institute, Huddinge Hospital, S-141 86 Huddinge/ Uppsala University Hospital, S-751 85 Uppsala); F. Mu ¨hlbacher, E. Pohanka (Allgemeines Krankenhaus, A-1090 Wien).
REFERENCES
Fig 5. Correlation between oral steroid dose and relative clearance of tacrolimus (r 5 0.94, P 5 .0172).
1. Aweeka FT, Benet LZ, Gambertoglio JG, et al: Clin Pharmacol Ther 53(2):151, 1993 2. Lee C, Jusko W, Shaefer M, et al: Clin Pharmacol Ther 53(2):181, 1993 3. Lee C, Hewitt J, Aweeka F, et al: Clin Pharmacol Ther 53(2):238, 1993 4. Mekki Q, Lee C, Aweeka F, et al: Clin Pharmacol Ther 53(2):238, 1993 5. Undre N, Mo ¨ller A, and the FK506 European Study Group: Transpl Int 7:S15, 1994 6. Beysens AJ, Wijnen RMH, Beuman GH, et al: Transplant Proc 23: 2745, 1991 7. Karanam BV, Vincent SH, Lee Chiu SH: Drug Metab Dispos 811, 1994 8. Mayer AD, Dmitrewski J, Squifflet J-P, et al: Transplantation 64:436, 1997 9. Rowlands M, Tozer TN: Clinical Pharmacokinetics: Concepts and Applications, 2nd ed. Philadelphia: Lea & Febiger, 1989, p 42
T
HE pharmacokinetics of tacrolimus have been characterised in healthy volunteers and liver and kidney transplant patients.1–5 The oral bioavailability of tacrolimus averages 20% to 25%; however, the inter-individual variability in this parameter is large. A strong correlation exists between AUC and trough concentrations of tacrolimus (Cmin) in whole blood. In systemic circulation, tacrolimus binds strongly to erythrocytes, resulting in a distribution ratio of 20:1 for tacrolimus whole-blood concentrations relative to plasma concentration. This ratio appears to be dependent on hematocrit levels and tacrolimus concentrations in blood.6 In plasma the drug is highly bound (. 98.8%) to plasma proteins, mainly to serum albumin and a-1-acid glycoprotein. Tacrolimus is a low-clearance drug; the extraction ratio is equivalent to about 3% of liver blood flow. For highly bound, low-extraction-ratio drugs, clearance is materially affected by changes in hematocrit and plasma protein binding. Systemically available tacrolimus is cleared by hepatic metabolism. Cytochrome P450 3A4 iso-enzyme is the principal enzyme responsible for its metabolism.7 Drugs that induce this iso-enzyme (eg, corticosteroids) may increase the metabolism of tacrolimus, thus resulting in a decrease of tacrolimus blood levels. The objectives of this evaluation were to determine the relationship among changes in hematocrit, albumin, and corticosteroid dosing on the disposition of tacrolimus during 12 months of treatment in renal transplant recipients. PATIENTS AND METHODS Patients Dosing and blood concentration data from renal allograft recipients randomised to treatment with tacrolimus in a European phase III multicentre comparative study of the efficacy and safety of tacrolimus and cyclosporine were used in this evaluation.8 A total of 303 patients were randomised to treatment with tacrolimus. Their mean age was 46.6 years (range 18 to 72 years) and their mean weight was 67.6 kg (range 33 to 130 kg); 196 of the 303 patients were male.
Fig 1. Mean (6 SEM) total daily oral dose of tacrolimus during the first year post-renal transplantation.
Dosing and Administration The initial recommended dose was 0.30 mg/kg per day administered in two divided doses; subsequent doses were adjusted to maintain the whole-blood concentration of tacrolimus within the recommended target range (10 to 20 ng/mL during first 3 months and 5 to 15 ng/mL thereafter), taking into account the patient’s clinical condition in relation to the risk of rejection and the occurrence of adverse effects.
Study Design Blood samples for the determination of trough tacrolimus concentrations were taken immediately prior to the morning dose. Samples were collected three times a week for the first 21 days after transplantation and subsequently at each follow-up visit at days 28 and 42 and then at months 3, 6, 9, and 12.
From the European Tacrolimus Multicentre Renal Study Group (see Acknowledgment section), Fujisawz GmbH, Munich, Germany. Address reprint requests to N.A. Undre, Fujisawa GmbH, Levelingstrasse 12, D-81606 Munich, Germany.
© 1998 by Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010
0041-1345/98/$19.00 PII S0041-1345(98)00234-6
Transplantation Proceedings, 30, 1261–1263 (1998)
1261
1262
UNDRE AND SCHAFER
Fig 2. Mean (6 SEM) whole-blood trough tacrolimus concentrations during the first year post-renal transplantation. Fig 3. Correlation between hematocrit and relative clearance (r 5 0.84, P 5 .017).
Analytical Methods Tacrolimus concentrations were determined by the microparticle enzyme immunoassay method based on the Abbott IMx analyser. The limit of detection for this assay was 5.0 ng/mL. For the purposes of this analysis, values for tacrolimus blood levels below the limit of detection of the assay were taken to be 2.5 ng/mL.
Pharmacokinetic Analysis Clearance was not measured directly in this clinical study. The ratio of dose (mg/kg)/Cmin(ng/mL) was considered to be proportional to the total body clearance (TBC) of tacrolimus and is referred to as relative clearance. This is a reasonable assumption because:
TBC(po) 5 dose(po) z F/AUC(po) where F is the fraction of the oral dose absorbed.9 Cmin correlates well with AUC; therefore, assuming constant bioavailability, dose/ Cmin is approximately equal to TBC. The relationships between relative clearance and changes in hematocrit and albumin during the early posttransplant period, and corticosteroid dose during months 2 to 12, were examined by linear regression.
tacrolimus dose was 0.26 mg/kg and the corresponding mean whole-blood trough concentration was 19.6 ng/mL. The mean dose fluctuated little during the first 4 weeks’ posttransplantation (0.25 to 0.27 mg/kg), but the mean trough blood concentration declined steadily to 12.9 ng/mL by week 2. The mean dose decreased gradually from 0.26 mg/kg per day at week 4 to 0.12 mg/kg per day during the final 3 months of the study, a reduction of 54%. However, the mean trough concentration declined by only 29% from 13.3 ng/mL at week 4 to 9.4 ng/mL at months 10 to 12. Levels of hematocrit and albumin over the first 12 weeks’ posttransplant and the estimated relative clearances of tacrolimus are presented in Table 1. Statistical evaluation of the data indicates a significant correlation between relative clearance and both hematocrit (r 5 0.81; P 5 .017; see Fig 3) and albumin levels (r 5 0.74, P 5 .047; see Fig 4). The mean oral doses of corticosteroids (adjusted to doses equivalent to prednisone) during months 2 to 12 and the
RESULTS Whole-Blood Concentrations and Pharmacokinetics
The mean oral daily doses and the corresponding wholeblood trough concentrations of tacrolimus over 1 year are presented graphically in Figs 1 and 2. On day 1, the mean Table 1. Mean Hematocrit and Albumin Levels and the Corresponding Estimates of Relative Clearance of Tacrolimus Time Posttransplant
Hematocrit (%)
Albumin (g/L)
Relative Clearance (L/kg)
Day 1 Week 1 Week 2 Week 3 Week 4 Week 6 Week 12
0.35 0.28 0.27 0.29 0.30 0.32 0.34
43.0 34.0 35.0 37.5 39.0 40.0 41.0
13.3 18.0 20.2 20.7 19.5 16.3 15.9
Fig 4. Correlation between albumin and relative clearance of tacrolimus (r 5 0.74, P 5 .047).
PHARMACOKINETICS OF TACROLIMUS
1263
Table 2. Mean Daily Dose of Oral Steroids and Relative Clearance of Tacrolimus Time Posttransplant
Mean (SD) Dose (mg/kg)
Relative Clearance (L/kg)
Month 2 Month 3 Months 4 – 6 Months 7–9 Months 10 –12
0.19 (0.17) 0.15 (0.19) 0.12 (0.09) 0.10 (0.06) 0.10 (0.05)
16.3 15.9 14.3 12.5 12.8
for a given dose during the early posttransplant period, and thus both should be monitored. The relationship between relative clearance and mean oral corticosteroid dose during maintenance therapy (2 to 12 months’ posttransplantation) suggests that, as the dose of corticosteroids is reduced, the dose of tacrolimus should also be lowered to maintain blood concentrations within the therapeutic range. ACKNOWLEDGMENTS
corresponding relative clearances are listed in Table 2. Relative clearance correlated with the mean oral steroid dose (r 5 0.94; P 5 .0172; see Fig 5). DISCUSSION
Results of this evaluation show that the trough whole-blood concentration of tacrolimus after renal transplantation correlates with hematocrit and albumin concentration during the first few weeks of treatment, and with corticosteroid dose from months 2 to 12 posttransplant. This is consistent with the finding that tacrolimus is strongly bound to red cells and serum albumin. This observation is of clinical significance because dose adjustment may be required to maintain blood concentrations within the therapeutic range in patients in whom hematocrit or albumin concentrations are changing. Tacrolimus has a low clearances, and a change in dose may take several days to achieve steady-state concentrations. Hematocrit and albumin concentration may therefore be potential early markers of changes in blood concentration
Participants in the European Tacrolimus Multicentre Renal Study Group included: A.D. Mayer, J. Dmitrewski (Queen Elizabeth Hospital, Birmingham, B15 2TH); J.P. Squifflet, T. Besse (Universite´ Catholique de Louvain, Cliniques Universitaires Saint-Luc, 1200 Bruxelles); B. Grabensee, B. Klein (Heinrich Heine Universita¨t Du ¨sseldorf, D-40225 Du ¨sseldorf); F.W. Eigler, U. Heemann (Universita¨tsklinik, D-45147 Essen); M. Behrend (Medizinische Hochschule Hannover, D-30625 Hannover); Y. Vanrenterghem, J. Donck (Universitaire Ziekenhuizen Gasthuisberg, 3000 Leuven); J. van Hooff, M. Christiaans (Academisch Ziekenhuis, 6201 BX Maastricht); J.M. Morales, A. Andres (Hospital Universitario “12 de Octubre,” 28041-Madrid); R.W.G. Johnson, C. Short (Manchester Royal Infirmary, Manchester, M13 9WL); B. Buchholz, N. Rehmert (Westfa¨lische Wilhelms Universita ¨t, D-48149 Mu ¨nster); W. Land (Ludwig-Maximilians-Universita¨t, Klinikum Großhadern, D-81366 Mu ¨nchen); J.L.R. Forsythe (Royal Victoria Infirmary, Newcastle-upon-Tyne, NE1 4LP); D. Talbot, Renal Transplant Unit, Freeman Hospital, High Heaton, Newcastleupon-Tyne NE7, H.-H. Neumayer, I. Hauser (Klinik Nu ¨rnberg Su ¨d, D-90471 Nu ¨rnberg); B.G. Ericzon, C. Brattstro ¨m, K. Claesson (Karolinska Institute, Huddinge Hospital, S-141 86 Huddinge/ Uppsala University Hospital, S-751 85 Uppsala); F. Mu ¨hlbacher, E. Pohanka (Allgemeines Krankenhaus, A-1090 Wien).
REFERENCES
Fig 5. Correlation between oral steroid dose and relative clearance of tacrolimus (r 5 0.94, P 5 .0172).
1. Aweeka FT, Benet LZ, Gambertoglio JG, et al: Clin Pharmacol Ther 53(2):151, 1993 2. Lee C, Jusko W, Shaefer M, et al: Clin Pharmacol Ther 53(2):181, 1993 3. Lee C, Hewitt J, Aweeka F, et al: Clin Pharmacol Ther 53(2):238, 1993 4. Mekki Q, Lee C, Aweeka F, et al: Clin Pharmacol Ther 53(2):238, 1993 5. Undre N, Mo ¨ller A, and the FK506 European Study Group: Transpl Int 7:S15, 1994 6. Beysens AJ, Wijnen RMH, Beuman GH, et al: Transplant Proc 23: 2745, 1991 7. Karanam BV, Vincent SH, Lee Chiu SH: Drug Metab Dispos 811, 1994 8. Mayer AD, Dmitrewski J, Squifflet J-P, et al: Transplantation 64:436, 1997 9. Rowlands M, Tozer TN: Clinical Pharmacokinetics: Concepts and Applications, 2nd ed. Philadelphia: Lea & Febiger, 1989, p 42