Level of evidence for therapeutic drug monitoring of taxanes

Abstract

Taxanes are anticancer drugs on the market for more than 10 years that are thought to be interesting for therapeutic drug monitoring (TDM): high inter- and intra-patient variability, relationship between exposure and efficacy and especially toxicity. Nevertheless, the paclitaxel and docetaxel characteristics result in different conclusions for these two molecules with respect to their TDM. For paclitaxel, the nonlinear pharmacokinetics makes that the parameter which seems the more reliable to toxicity or outcome is the time during which the plasma concentration exceeds 0.05 μm. Concentration controlled studies using Bayesian adaptation showed that the TDM of paclitaxel is feasible in routine. However, this target needs to be prospectively validated with new weekly schedules of administration, leading to a balance between 'recommended' and 'potentially useful'. For docetaxel, the 3-weekly administration, which is the more effective scheme, is also the more toxic. However, neutropenia can be individually modeled and efficiently predicted without using plasma drug concentrations. The docetaxel TDM using this docetaxel-related neutropenia modeling however needs to be prospectively validated in routine. The level of evidence of TDM thus 'needs to be assessed'.

CETSA-based target engagement of taxanes as biomarkers for efficacy and resistance

“…During therapy the pharmacokinetic (PK) profile in the individual patient will also affect TE by determining the amount of taxanes reaching the tumour environment. To optimize PK, drug monitoring is sometimes used during taxane therapy to demonstrate appropriate serum concentrations of the drug 18 .…”

A new high-performance liquid chromatography-tandem mass spectrometry method for the determination of paclitaxel and 6α-hydroxy-paclitaxel in human plasma: Development, validation and application in a clinical pharmacokinetic study

“…Less common cancers, such as endometrial, unknown primary, testes, esophageal and Kaposi’s sarcoma, also have meaningful response rates to PTX either alone or in combination with other agents [ 5 – 7 ]. High inter- and intra-patient variability in PTX pharmacokinetics and the relationship between haematological toxicity and plasma exposure make Therapeutic Drug Monitoring (TDM) necessary in order to treat patients with the correct dose [ 8 ]. In fact, the longer the period that PTX plasma concentration is over 0.05 μM (about 43 ng/mL), the higher the risk for severe neutropenia [ 8 ].…”

“…High inter- and intra-patient variability in PTX pharmacokinetics and the relationship between haematological toxicity and plasma exposure make Therapeutic Drug Monitoring (TDM) necessary in order to treat patients with the correct dose [ 8 ]. In fact, the longer the period that PTX plasma concentration is over 0.05 μM (about 43 ng/mL), the higher the risk for severe neutropenia [ 8 ]. Moreover, PTX is used in a wide range of doses (80–225 mg/m 2 ) and it showed a disproportionate increase in plasma C max (maximum concentration) and AUC (area under the plasma concentration-vs time curve) as the dose increased, suggesting saturation of elimination at higher concentrations of the drug [ 9 , 10 ].…”

Validated RP-HPLC Method for Quantification of Paclitaxel in Human Plasma – Eliminates Negative Influence of Cremophor El

“…Currently body surface area (BSA) is used in the dosing of paclitaxel, leading to significant inter individual differences in plasma concentrations and risk of severe and treatment limiting adverse effects (5,6). Quantification of paclitaxel in the blood or plasma samples is necessary to establish pharmacokinetic parameters that can assess inter and intra individual variability, thereby making necessary dose adjustments to improve therapeutic efficacy and minimizing the adverse effects (7).…”