How close are we to personalized mitotane dosing in the treatment of adrenocortical carcinoma? State of the art and future perspectives

ABSTRACT

Introduction

Mitotane is the only drug registered specifically for adrenocortical carcinoma. Finding the optimal dose for a patient is difficult due to large differences in bioavailability, toxicity and effect. We therefore look to improve personalized dosing of mitotane.

Areas covered

We searched PubMed for studies related to mitotane dosing, pharmacokinetics, pharmacogenetics and combination therapy. Comparison of different dosing strategies have not resulted in an optimal advice. Several computerized pharmacokinetic models have been proposed to predict plasma levels. The current pharmacokinetic models do not explain the full variance in plasma levels. Pharmacogenetics have been proposed to find the unexplained variance. Studies on combination therapy have not yet led to a potential dose adjustment for mitotane.

Expert opinion

Computerized pharmacokinetics models are promising tools to predict plasma levels, further validation is needed. Pharmacogenetics are introduced in these models, but more research is required before clinical application. We believe that in the near future, personalized mitotane dosage will be aided by a validated web-based pharmacokinetic model with good predictive ability based primarily on clinical characteristics, adjustable for actual plasma levels and dosage.

KEYWORDS:

• Adrenocortical carcinoma
• mitotane
• personalized treatment
• pharmacokinetics
• pharmacogenetics

Article highlights

• Mitotane dosing is difficult due to large differences in bioavailability, toxicity and effect.

• The optimal dosing regimen is currently based on expert opinion, not empirical evidence.

• Computerized pharmacokinetic models can predict plasma levels based on clinical characteristics such as distribution, clearance and lipid levels.

• The current models explain 40% of the plasma level variance, pharmacogenetics are being investigated to find the unexplained variance.

• There are no supportive drugs yet that can lower the required mitotane dose while maintaining its adrenolytic effect.

This box summarizes key points contained in the article.

Declaration of interest

The authors have received a research grant from HRA Pharma. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.