Population pharmacokinetics and exposure-response relationships for basiliximab in kidney transplantation

John M. Kovarik, Barry D. Kahan, P. R. Rajagopalan, William Bennett, Laura L Mulloy, Christophe Gerbeau, Michael L. Hall

Research output: Contribution to journalArticle

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Abstract

Background. Basiliximab is an interleukin-2 receptor (CD25) chimeric monoclonal antibody used for acute rejection prophylaxis in renal transplants. In the context of a randomized, double-blind efficacy trial, its population pharmacokinetics and potential exposure-response relationships were explored in de novo kidney allograft recipients receiving 40 mg basiliximab (20 mg on days 0 and 4) in addition to baseline immunosuppressive therapy with cyclosporine microemulsion and corticosteroids. Methods. Serial blood samples (8.2±1.3 per patient) were collected over 12 weeks after transplant from 169 basiliximab-treated patients, and empirical Bayes estimates of each patient's disposition parameters were derived. The duration of CD25 saturation was estimated as the time over which serum basiliximab concentrations exceeded 0.2 μg/ml. The relationships between pharmacokinetic parameters and demographic-clinical covariates were explored by regression methods and unpaired t-tests. Results. Basiliximab clearance was 36.7±15.2 ml/hr, distribution volume 8.0±2.4 L, and half life 7.4±3.0 days. Patient weight (range, 44-131 kg) and age (range, 20-69 yrs) each contributed ≤6% to the variability in clearance and volume. Gender, ethnic group, and the presence of proteinuria had no clinically relevant influences on basiliximab disposition. Receptor-saturating basiliximab concentrations were maintained for 36±14 days (range, 12-91). There was no apparent relationship between the incidence or day of onset of acute rejection episodes during CD25 saturation and basiliximab concentration (range, 0.2-5.0 μg/ml). In patients who experienced a rejection episode after basiliximab was eliminated from serum (n=33), basiliximab had not been cleared faster than in their rejection-free peers (P=0.322) nor had CD25 been saturated for a shorter period of time (33±13 days vs. 37±14 days for rejection-free patients, P=0.162). Conclusions. There were no demographic or clinical subpopulations not adequately treated with the standard basiliximab dosing regimen. Over the range of CD25 suppression durations observed in this study, extended periods of receptor blockade did not seem to confer an immunoprophylactic advantage compared with shorter periods of receptor suppression.

Original languageEnglish (US)
Pages (from-to)1288-1294
Number of pages7
JournalTransplantation
Volume68
Issue number9
DOIs
StatePublished - Nov 15 1999

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Kidney Transplantation
Pharmacokinetics
Population
basiliximab
Demography
Transplants
Kidney
Interleukin-2 Receptors
Immunosuppressive Agents
Serum
Proteinuria
Ethnic Groups
Cyclosporine
Allografts
Half-Life
Adrenal Cortex Hormones
Monoclonal Antibodies
Weights and Measures
Incidence

ASJC Scopus subject areas

  • Transplantation

Cite this

Population pharmacokinetics and exposure-response relationships for basiliximab in kidney transplantation. / Kovarik, John M.; Kahan, Barry D.; Rajagopalan, P. R.; Bennett, William; Mulloy, Laura L; Gerbeau, Christophe; Hall, Michael L.

In: Transplantation, Vol. 68, No. 9, 15.11.1999, p. 1288-1294.

Research output: Contribution to journalArticle

Kovarik, John M. ; Kahan, Barry D. ; Rajagopalan, P. R. ; Bennett, William ; Mulloy, Laura L ; Gerbeau, Christophe ; Hall, Michael L. / Population pharmacokinetics and exposure-response relationships for basiliximab in kidney transplantation. In: Transplantation. 1999 ; Vol. 68, No. 9. pp. 1288-1294.
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abstract = "Background. Basiliximab is an interleukin-2 receptor (CD25) chimeric monoclonal antibody used for acute rejection prophylaxis in renal transplants. In the context of a randomized, double-blind efficacy trial, its population pharmacokinetics and potential exposure-response relationships were explored in de novo kidney allograft recipients receiving 40 mg basiliximab (20 mg on days 0 and 4) in addition to baseline immunosuppressive therapy with cyclosporine microemulsion and corticosteroids. Methods. Serial blood samples (8.2±1.3 per patient) were collected over 12 weeks after transplant from 169 basiliximab-treated patients, and empirical Bayes estimates of each patient's disposition parameters were derived. The duration of CD25 saturation was estimated as the time over which serum basiliximab concentrations exceeded 0.2 μg/ml. The relationships between pharmacokinetic parameters and demographic-clinical covariates were explored by regression methods and unpaired t-tests. Results. Basiliximab clearance was 36.7±15.2 ml/hr, distribution volume 8.0±2.4 L, and half life 7.4±3.0 days. Patient weight (range, 44-131 kg) and age (range, 20-69 yrs) each contributed ≤6{\%} to the variability in clearance and volume. Gender, ethnic group, and the presence of proteinuria had no clinically relevant influences on basiliximab disposition. Receptor-saturating basiliximab concentrations were maintained for 36±14 days (range, 12-91). There was no apparent relationship between the incidence or day of onset of acute rejection episodes during CD25 saturation and basiliximab concentration (range, 0.2-5.0 μg/ml). In patients who experienced a rejection episode after basiliximab was eliminated from serum (n=33), basiliximab had not been cleared faster than in their rejection-free peers (P=0.322) nor had CD25 been saturated for a shorter period of time (33±13 days vs. 37±14 days for rejection-free patients, P=0.162). Conclusions. There were no demographic or clinical subpopulations not adequately treated with the standard basiliximab dosing regimen. Over the range of CD25 suppression durations observed in this study, extended periods of receptor blockade did not seem to confer an immunoprophylactic advantage compared with shorter periods of receptor suppression.",
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AU - Kovarik, John M.

AU - Kahan, Barry D.

AU - Rajagopalan, P. R.

AU - Bennett, William

AU - Mulloy, Laura L

AU - Gerbeau, Christophe

AU - Hall, Michael L.

PY - 1999/11/15

Y1 - 1999/11/15

N2 - Background. Basiliximab is an interleukin-2 receptor (CD25) chimeric monoclonal antibody used for acute rejection prophylaxis in renal transplants. In the context of a randomized, double-blind efficacy trial, its population pharmacokinetics and potential exposure-response relationships were explored in de novo kidney allograft recipients receiving 40 mg basiliximab (20 mg on days 0 and 4) in addition to baseline immunosuppressive therapy with cyclosporine microemulsion and corticosteroids. Methods. Serial blood samples (8.2±1.3 per patient) were collected over 12 weeks after transplant from 169 basiliximab-treated patients, and empirical Bayes estimates of each patient's disposition parameters were derived. The duration of CD25 saturation was estimated as the time over which serum basiliximab concentrations exceeded 0.2 μg/ml. The relationships between pharmacokinetic parameters and demographic-clinical covariates were explored by regression methods and unpaired t-tests. Results. Basiliximab clearance was 36.7±15.2 ml/hr, distribution volume 8.0±2.4 L, and half life 7.4±3.0 days. Patient weight (range, 44-131 kg) and age (range, 20-69 yrs) each contributed ≤6% to the variability in clearance and volume. Gender, ethnic group, and the presence of proteinuria had no clinically relevant influences on basiliximab disposition. Receptor-saturating basiliximab concentrations were maintained for 36±14 days (range, 12-91). There was no apparent relationship between the incidence or day of onset of acute rejection episodes during CD25 saturation and basiliximab concentration (range, 0.2-5.0 μg/ml). In patients who experienced a rejection episode after basiliximab was eliminated from serum (n=33), basiliximab had not been cleared faster than in their rejection-free peers (P=0.322) nor had CD25 been saturated for a shorter period of time (33±13 days vs. 37±14 days for rejection-free patients, P=0.162). Conclusions. There were no demographic or clinical subpopulations not adequately treated with the standard basiliximab dosing regimen. Over the range of CD25 suppression durations observed in this study, extended periods of receptor blockade did not seem to confer an immunoprophylactic advantage compared with shorter periods of receptor suppression.

AB - Background. Basiliximab is an interleukin-2 receptor (CD25) chimeric monoclonal antibody used for acute rejection prophylaxis in renal transplants. In the context of a randomized, double-blind efficacy trial, its population pharmacokinetics and potential exposure-response relationships were explored in de novo kidney allograft recipients receiving 40 mg basiliximab (20 mg on days 0 and 4) in addition to baseline immunosuppressive therapy with cyclosporine microemulsion and corticosteroids. Methods. Serial blood samples (8.2±1.3 per patient) were collected over 12 weeks after transplant from 169 basiliximab-treated patients, and empirical Bayes estimates of each patient's disposition parameters were derived. The duration of CD25 saturation was estimated as the time over which serum basiliximab concentrations exceeded 0.2 μg/ml. The relationships between pharmacokinetic parameters and demographic-clinical covariates were explored by regression methods and unpaired t-tests. Results. Basiliximab clearance was 36.7±15.2 ml/hr, distribution volume 8.0±2.4 L, and half life 7.4±3.0 days. Patient weight (range, 44-131 kg) and age (range, 20-69 yrs) each contributed ≤6% to the variability in clearance and volume. Gender, ethnic group, and the presence of proteinuria had no clinically relevant influences on basiliximab disposition. Receptor-saturating basiliximab concentrations were maintained for 36±14 days (range, 12-91). There was no apparent relationship between the incidence or day of onset of acute rejection episodes during CD25 saturation and basiliximab concentration (range, 0.2-5.0 μg/ml). In patients who experienced a rejection episode after basiliximab was eliminated from serum (n=33), basiliximab had not been cleared faster than in their rejection-free peers (P=0.322) nor had CD25 been saturated for a shorter period of time (33±13 days vs. 37±14 days for rejection-free patients, P=0.162). Conclusions. There were no demographic or clinical subpopulations not adequately treated with the standard basiliximab dosing regimen. Over the range of CD25 suppression durations observed in this study, extended periods of receptor blockade did not seem to confer an immunoprophylactic advantage compared with shorter periods of receptor suppression.

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