Renal impairment and DPD testing: Watch out for false-positive results!

Measuring uracil (U) levels in plasma is a convenient surrogate to establish dihydropyrimidine dehydrogenase (DPD) status in patients scheduled with 5-fluorouracil (5-FU) or capecitabine. To what extent renal impairment could impact on U levels and thus be a confounding factor is a rising concern. Here, we report the case of a cancer patient with severe renal impairment scheduled for 5-FU-based regimen. Determination of his DPD status was complicated because of his condition and the influence of intermittent haemodialysis when monitoring U levels. The patient was initially identified as markedly DPD-deficient upon U measurement (i.e., U = 40 ng/mL), but further monitoring between and immediately after dialysis showed mild deficiency only (i.e., U = 34 and U = 19 ng/mL, respectively). Despite this discrepancy, a starting dose of 5-FU was cut by 50% upon treatment initiation. Tolerance was good and 5-FU dosing was next shifted to 25% reduction, then further shifted to normal dosing at the 5th course, with still no sign for drug-related toxicities. Further DPYD genotyping showed none of the four allelic variants usually associated with loss of DPD activity. Of note, the excellent tolerance upon standard dosing strongly suggests that this patient was actually not DPD-deficient, despite U values always above normal concentrations. This case report highlights how critical is the information regarding the renal function of patients with cancer when phenotyping DPD using U plasma as a surrogate, and that U accumulation in patients with such condition is likely to yield false-positive results.

Machine-Learning Exploration of Exposure-Effect Relationships of Cisplatin in Head and Neck Cancer Patients.

BACKGROUND: Cisplatin is a pivotal drug in the treatment of head and neck cancer, and personalized dosage should help the preservation of an optimal toxicity-efficacy ratio. METHODS: We analyzed the exposure-effect relationships of 80 adult patients with head and neck cancers and treated with standard Cisplatin-based regimen administered as three-hour infusion. Individual pharmacokinetics (PK) parameters of Cisplatin were identified using a Bayesian approach. Nephrotoxicity and ototoxicity were considered as typical Cisplatin-related toxicities according to Common Terminology Criteria for Adverse Events (CTCAE) standards. Efficacy was evaluated based upon Response Evaluation Criteria in Solid Tumors (RECIST) criteria. Up to nine different machine-learning algorithms were tested to decipher the exposure-effect relationships with Cisplatin. RESULTS: The generalized linear model was the best algorithm with an accuracy of 0.71, a recall of 0.55 and a precision of 0.75. Among the various metrics for exposure (i.e., maximal concentration (Cmax), area-under-the-curve (AUC), trough levels), Cmax, comprising a range between 2.4 and 4.1 µg/mL, was the best one to be considered. When comparing a consequent, model-informed dosage with the standard dosage in 20 new patients, our strategy would have led to a reduced dosage in patients who would eventually prove to have severe toxicities while increasing dosage in patients with progressive disease. CONCLUSION: Determining a target Cmax could pave the way for PK-guided precision dosage with Cisplatin given as three-hour infusion.