Development of a Pharmacokinetic Model of Mitotane: Toward Personalized Dosing in Adrenocortical Carcinoma

T.M.A. Kerkhofs, L.J.J. Derijks, H. Ettaieb, J. den Hartigh, K. Neef, H. Gelderblom, H.J. Guchelaar, H.R. Haak

Research output: Contribution to journalArticleAcademicpeer-review

5 Citations (Scopus)

Abstract

Background: Mitotane is the drug of choice in medical treatment of adrenocortical carcinoma. The antineoplastic effect seems to be correlated with a minimum plasma level of 14 mg/L, but plasma concentration build-up is in general slow due to the long elimination half-life. Consequently, the therapeutic effect sets in after weeks or even months. The objective of this study was to develop a pharmacokinetic model that enables clinicians to adjust dosing based on a target drug exposure, which facilitates personalized therapy.

Methods: Data on dosing and plasma level measurements performed throughout mitotane therapy were retrospectively collected in a population of 29 patients from 2 hospitals. A population pharmacokinetic model was constructed based on data from 20 patients using iterative 2-stage Bayesian fitting (MWPharm). The model was validated in an independent sample of 9 patients.

Results: The concentration-time data were best described by a 3-compartment model. The model estimated mitotane clearance at 0.94 +/- 0.37 L/h and a volume of distribution in the steady state at 161 +/- 68 L/kg of lean body mass. The mean prediction error was 14% +/- 13%.

Conclusions: A pharmacokinetic model was developed, which characterized mitotane by slow clearance and large volume of distribution. The model seems to be able to predict mitotane levels in individual patients with an error margin of 14%. The model enables one to adapt dosing based on individual plasma level measurements in prospective setting, which improves the accuracy of the prediction. We expect that individualization of mitotane dosing leads to anticipated and more rapid attainment of the therapeutic levels and potentially to improved clinical management of mitotane treatment.

Original languageEnglish
Pages (from-to)58-65
Number of pages8
JournalTherapeutic Drug Monitoring
Volume37
Issue number1
DOIs
Publication statusPublished - Feb 2015

Keywords

  • adrenocortical carcinoma
  • mitotane
  • pharmacokinetics
  • 2-STAGE BAYESIAN-TECHNIQUE
  • FOLLOW-UP
  • O,P'DDD
  • CANCER

Cite this

Kerkhofs, T.M.A. ; Derijks, L.J.J. ; Ettaieb, H. ; den Hartigh, J. ; Neef, K. ; Gelderblom, H. ; Guchelaar, H.J. ; Haak, H.R. / Development of a Pharmacokinetic Model of Mitotane: Toward Personalized Dosing in Adrenocortical Carcinoma. In: Therapeutic Drug Monitoring. 2015 ; Vol. 37, No. 1. pp. 58-65.
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title = "Development of a Pharmacokinetic Model of Mitotane: Toward Personalized Dosing in Adrenocortical Carcinoma",
abstract = "Background: Mitotane is the drug of choice in medical treatment of adrenocortical carcinoma. The antineoplastic effect seems to be correlated with a minimum plasma level of 14 mg/L, but plasma concentration build-up is in general slow due to the long elimination half-life. Consequently, the therapeutic effect sets in after weeks or even months. The objective of this study was to develop a pharmacokinetic model that enables clinicians to adjust dosing based on a target drug exposure, which facilitates personalized therapy.Methods: Data on dosing and plasma level measurements performed throughout mitotane therapy were retrospectively collected in a population of 29 patients from 2 hospitals. A population pharmacokinetic model was constructed based on data from 20 patients using iterative 2-stage Bayesian fitting (MWPharm). The model was validated in an independent sample of 9 patients.Results: The concentration-time data were best described by a 3-compartment model. The model estimated mitotane clearance at 0.94 +/- 0.37 L/h and a volume of distribution in the steady state at 161 +/- 68 L/kg of lean body mass. The mean prediction error was 14{\%} +/- 13{\%}.Conclusions: A pharmacokinetic model was developed, which characterized mitotane by slow clearance and large volume of distribution. The model seems to be able to predict mitotane levels in individual patients with an error margin of 14{\%}. The model enables one to adapt dosing based on individual plasma level measurements in prospective setting, which improves the accuracy of the prediction. We expect that individualization of mitotane dosing leads to anticipated and more rapid attainment of the therapeutic levels and potentially to improved clinical management of mitotane treatment.",
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author = "T.M.A. Kerkhofs and L.J.J. Derijks and H. Ettaieb and {den Hartigh}, J. and K. Neef and H. Gelderblom and H.J. Guchelaar and H.R. Haak",
year = "2015",
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Development of a Pharmacokinetic Model of Mitotane: Toward Personalized Dosing in Adrenocortical Carcinoma. / Kerkhofs, T.M.A.; Derijks, L.J.J.; Ettaieb, H.; den Hartigh, J.; Neef, K.; Gelderblom, H.; Guchelaar, H.J.; Haak, H.R.

In: Therapeutic Drug Monitoring, Vol. 37, No. 1, 02.2015, p. 58-65.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - Development of a Pharmacokinetic Model of Mitotane: Toward Personalized Dosing in Adrenocortical Carcinoma

AU - Kerkhofs, T.M.A.

AU - Derijks, L.J.J.

AU - Ettaieb, H.

AU - den Hartigh, J.

AU - Neef, K.

AU - Gelderblom, H.

AU - Guchelaar, H.J.

AU - Haak, H.R.

PY - 2015/2

Y1 - 2015/2

N2 - Background: Mitotane is the drug of choice in medical treatment of adrenocortical carcinoma. The antineoplastic effect seems to be correlated with a minimum plasma level of 14 mg/L, but plasma concentration build-up is in general slow due to the long elimination half-life. Consequently, the therapeutic effect sets in after weeks or even months. The objective of this study was to develop a pharmacokinetic model that enables clinicians to adjust dosing based on a target drug exposure, which facilitates personalized therapy.Methods: Data on dosing and plasma level measurements performed throughout mitotane therapy were retrospectively collected in a population of 29 patients from 2 hospitals. A population pharmacokinetic model was constructed based on data from 20 patients using iterative 2-stage Bayesian fitting (MWPharm). The model was validated in an independent sample of 9 patients.Results: The concentration-time data were best described by a 3-compartment model. The model estimated mitotane clearance at 0.94 +/- 0.37 L/h and a volume of distribution in the steady state at 161 +/- 68 L/kg of lean body mass. The mean prediction error was 14% +/- 13%.Conclusions: A pharmacokinetic model was developed, which characterized mitotane by slow clearance and large volume of distribution. The model seems to be able to predict mitotane levels in individual patients with an error margin of 14%. The model enables one to adapt dosing based on individual plasma level measurements in prospective setting, which improves the accuracy of the prediction. We expect that individualization of mitotane dosing leads to anticipated and more rapid attainment of the therapeutic levels and potentially to improved clinical management of mitotane treatment.

AB - Background: Mitotane is the drug of choice in medical treatment of adrenocortical carcinoma. The antineoplastic effect seems to be correlated with a minimum plasma level of 14 mg/L, but plasma concentration build-up is in general slow due to the long elimination half-life. Consequently, the therapeutic effect sets in after weeks or even months. The objective of this study was to develop a pharmacokinetic model that enables clinicians to adjust dosing based on a target drug exposure, which facilitates personalized therapy.Methods: Data on dosing and plasma level measurements performed throughout mitotane therapy were retrospectively collected in a population of 29 patients from 2 hospitals. A population pharmacokinetic model was constructed based on data from 20 patients using iterative 2-stage Bayesian fitting (MWPharm). The model was validated in an independent sample of 9 patients.Results: The concentration-time data were best described by a 3-compartment model. The model estimated mitotane clearance at 0.94 +/- 0.37 L/h and a volume of distribution in the steady state at 161 +/- 68 L/kg of lean body mass. The mean prediction error was 14% +/- 13%.Conclusions: A pharmacokinetic model was developed, which characterized mitotane by slow clearance and large volume of distribution. The model seems to be able to predict mitotane levels in individual patients with an error margin of 14%. The model enables one to adapt dosing based on individual plasma level measurements in prospective setting, which improves the accuracy of the prediction. We expect that individualization of mitotane dosing leads to anticipated and more rapid attainment of the therapeutic levels and potentially to improved clinical management of mitotane treatment.

KW - adrenocortical carcinoma

KW - mitotane

KW - pharmacokinetics

KW - 2-STAGE BAYESIAN-TECHNIQUE

KW - FOLLOW-UP

KW - O,P'DDD

KW - CANCER

U2 - 10.1097/FTD.0000000000000102

DO - 10.1097/FTD.0000000000000102

M3 - Article

VL - 37

SP - 58

EP - 65

JO - Therapeutic Drug Monitoring

JF - Therapeutic Drug Monitoring

SN - 0163-4356

IS - 1

ER -