Therapeutic drug monitoring of oral anticancer drugs - preliminary results of a prospective study

Abstract

Background: Oral anticancer drugs show a high interpatient variability in pharmacokinetics (PK). Even though exposure has been linked to efficacy and toxicity for many of these drugs, they are still dosed using a one-size-fits-all approach. Consequently, individual patients (pts) have a high probability to be either underdosed or overdosed, potentially leading to decreased antitumor efficacy or increased toxicity. Therapeutic drug monitoring (TDM), which is personalised dosing based on measured drug levels, can be used to address these problems and thereby optimize treatment outcomes. Methods: This prospective clinical study (www.trialregister.nl, NL6695) evaluates the feasibility, tolerability and efficacy of TDM of oral anticancer drugs. In total, 600 pts will be included for 23 different drugs. Pts starting regular treatment with one of these drugs at the approved dose are included. PK sampling is performed 4, 8, and 12 weeks after start of treatment and every 12 weeks thereafter. Drug concentrations are measured and trough concentrations (Cmin) are estimated. In case of Cmin below the predefined target and acceptable toxicity, a PK-guided intervention is recommended. This may include emphasizing compliance, adaptations in concomitant medication (due to drug-drug interactions), concomitant intake with food, splitting intake moments or dose increments. Results: In total, 274 pts were included (trametinib (n=43), abiraterone (n=38), enzalutamide (n=35), imatinib (n=33), pazopanib (n=23), other (n=102)), of whom 246 pts had available PK data. 83 pts (34%) were underdosed and had ≥1PK samples below the predefined target. In 48 of 246 pts (20%) a PK-guided intervention was performed, which was successful (i.e. target attainment without additional toxicities) in 39 pts (81%). In 35 pts, a PK-guided intervention could not be performed, due to toxicity (17 pts), logistical reasons (13 pts) or lack of physician adherence (5 pts). Conclusions: This prospective study shows that PK-guided dose optimization of oral anticancer drugs is feasible in clinical practice. A PK-guided intervention was recommended in 20% of the patients and resulted in target attainment without additional toxicities in 81% of these patients.