Sanofi-aventis - A high throughput assay for oxaliplatin in clinical samples

Importance of the topic

Accurate quantification of oxaliplatin-derived platinum in biological fluids is essential for understanding the pharmacokinetics, pharmacodynamics and toxicity of this anticancer agent. High-throughput, reliable assays support large-scale clinical studies and help optimize dosing regimes for improved patient outcomes.

Objectives and study overview

The Global Metabolism and Pharmacokinetics department at sanofi-aventis tested a new ICP-MS system to overcome limitations of their existing instrument. The aims were to develop fast, simple and robust analytical methods for determining platinum levels in plasma ultrafiltrate (PUF), plasma and urine, validate performance against the previous ICP-MS, and extend assays to other platinum-based drugs.

Methodology and instrumentation

Sample preparation protocols were streamlined by replacing a one-hour heated acid digestion with a dilution step using 1 % tetramethylammonium hydroxide (TMAH) and 30 minutes mixing for plasma and urine. The Agilent 7500a ICP-MS was selected for its superior matrix tolerance, lower background, wide dynamic range and compact footprint. Analysis conditions enabled a run time of approximately 4–4.5 minutes per sample, compared to 8–8.5 minutes on the former instrument.

Instrumentation

• Agilent 7500a ICP-MS in standard (non-collision) mode
• Off-axis ion lens system for reduced background
• Dual-mode detector for extended dynamic range
• Compact benchtop design to save laboratory space

Key results and discussion

The transition to the Agilent 7500a led to a more than threefold increase in daily sample throughput (from ~70 to ~240 samples for PUF and plasma). Validation across nominal concentrations (1.0–25 000 ng/mL) showed accuracy within ±12 % and tight confidence intervals. The robust matrix tolerance eliminated lengthy digestions and maintained detection limits in the sub-ng/L range. Over five years, annual platinum analyses rose sharply after the instrument installation, confirming its reliability and productivity.

Benefits and practical applications

• Significant reduction in sample preparation time and overall analysis cycle
• Enhanced throughput to support large clinical pharmacokinetic studies
• Improved method robustness with minimal maintenance downtime
• Scalable assays for other platinum compounds (cisplatin, carboplatin) using identical workflows

Future trends and applications

Further integration of high-resolution mass spectrometry or hyphenated techniques (e.g., LC-ICP-MS) could enable simultaneous speciation of platinum metabolites. Automation of sample handling and on-line dilution will drive throughput even higher. Emerging therapies combining multiple metal-based drugs will benefit from adaptable ICP-MS platforms. Real-time monitoring of platinum in microdialysis or cell culture matrices presents another frontier.

Conclusion

The Agilent 7500a ICP-MS met the department’s requirements for fast, reliable platinum assays in clinical samples. The investment was rapidly recouped through increased throughput and consistent analytical performance. The ease of extending methods to other platinum agents underscores the instrument’s versatility for pharmacokinetic and toxicology studies.

References

• Agilent Technologies. A high throughput assay for oxaliplatin in clinical samples. Publication Number 5989-7077EN, September 1, 2007.