Diversity of dose-individualization and therapeutic drug monitoring practices of platinum compounds: a review

ABSTRACT

Introduction: Platinum-derived drugs are commonly used for the treatment of solid tumors. The differences in chemical structures of these molecules lead to different pharmacological properties, in terms of indication, efficacy, and toxicity. Their pharmacokinetics (PK) differ according to their respective renal elimination and have led to many studies investigating their dose optimization.

Area covered: This review attempts to summarize and compare PK and pharmacodynamics of cisplatin, carboplatin, and oxaliplatin, with an emphasis on differences of dose calculations and opportunities for therapeutic drug monitoring (TDM) in various patient populations.

Expert opinion: Although cisplatin and carboplatin can be considered as analogs since they share the same DNA interacting properties, the slower hydrolysis of the latter results in a better safety profile. Carboplatin is the only drug in oncology to be administrated according to a target area under the curve of concentration versus time, considering that its PK variability is almost fully explained by renal function, not by body size. This enables individual dosing based on predicted carboplatin clearance (along with patients renal characteristics) or on actual clearance with TDM, especially in a high-dose protocol.

KEYWORDS:

• Cytotoxic drugs
• dose individualization
• interindividual variability
• pharmacokinetics-pharmacodynamics relationships
• population pharmacokinetics
• platinum compounds
• therapeutic drug monitoring

Article highlights

• Platinum agents (i.e. cisplatin, carboplatin, oxaliplatin) are still the cornerstone of treatment for several solid tumors. Despite the common structure of cisplatin and carboplatin, only a unique physicochemical characteristic (i.e. their stability to hydrolysis in plasma) endows them with different pharmacological properties and diversified therapeutic and side-effects spectra.

• Renal elimination and irreversible binding to plasma proteins contribute in different proportions to the platinum epuration process that strongly depends on the nature of the platinum compound.

• For cisplatin and oxaliplatin, dosing according the patient’s body-surface area (i.e. doses in mg/m²) is still relevant. However, for carboplatin, for which renal glomerular filtration elimination is predominant, dose adaptation is based on target drug exposure, characterized by the area under the concentration-time curve (AUC) and predicted carboplatin clearance based on the glomerular filtration rate (GFR).

• Therapeutic drug monitoring (TDM) practices may be set up for both cisplatin and carboplatin in specific clinical situations such as high-dose regimens or pediatric patients. This review presents the main pharmacokinetics/pharmacodynamics relationships that have led implementing TDM for platinum compounds along with the specific situations where TDM is relevant.

This box summarizes key points contained in the article.

Acknowledgments

The authors would like to acknowledge Dr. Gail Taillefer, native English speaking medical writer (Professor emeritus of English) for her language and editorial support.

Declaration of interest

The authors have no 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.