Standard pentostatin dose reductions in renal insufficiency are not adequate: Selected patients with steroid-refractory acute graft-versus-host disease

Ming J. Poi, Craig C. Hofmeister, Jeffrey S. Johnston, Ryan B. Edwards, Buffy S. Jansak, David M. Lucas, Sherif Farag, James T. Dalton, Steven M. Devine, Michael R. Grever, Mitch A. Phelps

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

Background and Objective: Pentostatin is an irreversible inhibitor of adenosine deaminase and has been used to prevent graft-versus-host disease (GVHD) and to treat both acute and chronic GVHD. Dose reduction equations for patients with renal insufficiency are based on few patients with limited pharmacokinetic and clinical results. This phase II study (NCT00201786) was conducted to assess pentostatin efficacy and infectious complications seen from our previous phase I study in steroid-refractory acute GVHD (aGVHD). Patients and Methods: Hospitalized patients with steroid-refractory aGVHD were given pentostatin 1.5 mg/m2/day intravenously on days 1-3 of each 14-day cycle. Prior to each dose, dose modifications were based on Cockcroft-Gault estimated creatinine clearance (eCrCL) with 30-50 mL/min/1.73 m 2 leading to a 50 % dose reduction and eCrCL less than 30 mL/min/1.73 m2 leading to study removal. Plasma pentostatin area under the concentration-time curve (AUC) and incidence of infectious complications were evaluated. Results: Two of the eight patients treated demonstrated excessive pentostatin exposure as determined by measurement of AUC. One of these patients had renal impairment, whereas the other patient demonstrated borderline renal function. Despite dose reduction to 0.75 mg/m 2, AUCs were significantly increased compared to the other patients in this study. Seven of eight patients treated with pentostatin had cytomegalovirus (CMV) viremia after pentostatin treatment; however none developed proven CMV disease. Conclusion: A 50 % dose reduction in patients with eCrCL 30-50 mL/min/1.73 m2 seems reasonable. However, the eCrCL should be interpreted with extreme caution in patients who are critically ill and/or with poor performance status. Renal function assessment based on the Cockcroft-Gault method could be significantly overestimated thus risking pentostatin overdosing. These results imply a need to closely monitor pentostatin exposure in patients with renal insufficiency.

Original languageEnglish
Pages (from-to)705-712
Number of pages8
JournalClinical Pharmacokinetics
Volume52
Issue number8
DOIs
StatePublished - Aug 2013

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Pentostatin
Graft vs Host Disease
Renal Insufficiency
Steroids
Creatinine
Cytomegalovirus
Kidney
Adenosine Deaminase Inhibitors
Viremia
Critical Illness
Area Under Curve

ASJC Scopus subject areas

  • Pharmacology (medical)
  • Pharmacology

Cite this

Standard pentostatin dose reductions in renal insufficiency are not adequate : Selected patients with steroid-refractory acute graft-versus-host disease. / Poi, Ming J.; Hofmeister, Craig C.; Johnston, Jeffrey S.; Edwards, Ryan B.; Jansak, Buffy S.; Lucas, David M.; Farag, Sherif; Dalton, James T.; Devine, Steven M.; Grever, Michael R.; Phelps, Mitch A.

In: Clinical Pharmacokinetics, Vol. 52, No. 8, 08.2013, p. 705-712.

Research output: Contribution to journalArticle

Poi, MJ, Hofmeister, CC, Johnston, JS, Edwards, RB, Jansak, BS, Lucas, DM, Farag, S, Dalton, JT, Devine, SM, Grever, MR & Phelps, MA 2013, 'Standard pentostatin dose reductions in renal insufficiency are not adequate: Selected patients with steroid-refractory acute graft-versus-host disease', Clinical Pharmacokinetics, vol. 52, no. 8, pp. 705-712. https://doi.org/10.1007/s40262-013-0064-7
Poi, Ming J. ; Hofmeister, Craig C. ; Johnston, Jeffrey S. ; Edwards, Ryan B. ; Jansak, Buffy S. ; Lucas, David M. ; Farag, Sherif ; Dalton, James T. ; Devine, Steven M. ; Grever, Michael R. ; Phelps, Mitch A. / Standard pentostatin dose reductions in renal insufficiency are not adequate : Selected patients with steroid-refractory acute graft-versus-host disease. In: Clinical Pharmacokinetics. 2013 ; Vol. 52, No. 8. pp. 705-712.
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abstract = "Background and Objective: Pentostatin is an irreversible inhibitor of adenosine deaminase and has been used to prevent graft-versus-host disease (GVHD) and to treat both acute and chronic GVHD. Dose reduction equations for patients with renal insufficiency are based on few patients with limited pharmacokinetic and clinical results. This phase II study (NCT00201786) was conducted to assess pentostatin efficacy and infectious complications seen from our previous phase I study in steroid-refractory acute GVHD (aGVHD). Patients and Methods: Hospitalized patients with steroid-refractory aGVHD were given pentostatin 1.5 mg/m2/day intravenously on days 1-3 of each 14-day cycle. Prior to each dose, dose modifications were based on Cockcroft-Gault estimated creatinine clearance (eCrCL) with 30-50 mL/min/1.73 m 2 leading to a 50 {\%} dose reduction and eCrCL less than 30 mL/min/1.73 m2 leading to study removal. Plasma pentostatin area under the concentration-time curve (AUC) and incidence of infectious complications were evaluated. Results: Two of the eight patients treated demonstrated excessive pentostatin exposure as determined by measurement of AUC. One of these patients had renal impairment, whereas the other patient demonstrated borderline renal function. Despite dose reduction to 0.75 mg/m 2, AUCs were significantly increased compared to the other patients in this study. Seven of eight patients treated with pentostatin had cytomegalovirus (CMV) viremia after pentostatin treatment; however none developed proven CMV disease. Conclusion: A 50 {\%} dose reduction in patients with eCrCL 30-50 mL/min/1.73 m2 seems reasonable. However, the eCrCL should be interpreted with extreme caution in patients who are critically ill and/or with poor performance status. Renal function assessment based on the Cockcroft-Gault method could be significantly overestimated thus risking pentostatin overdosing. These results imply a need to closely monitor pentostatin exposure in patients with renal insufficiency.",
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T2 - Selected patients with steroid-refractory acute graft-versus-host disease

AU - Poi, Ming J.

AU - Hofmeister, Craig C.

AU - Johnston, Jeffrey S.

AU - Edwards, Ryan B.

AU - Jansak, Buffy S.

AU - Lucas, David M.

AU - Farag, Sherif

AU - Dalton, James T.

AU - Devine, Steven M.

AU - Grever, Michael R.

AU - Phelps, Mitch A.

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