Therapeutic drug monitoring-based precision dosing of oral targeted therapies in oncology: a prospective multicenter study.

BACKGROUND: Oral targeted therapies show a high pharmacokinetic (PK) interpatient variability. Even though exposure has been positively correlated with efficacy for many of these drugs, these are still dosed using a one-size-fits-all approach. Consequently, individuals have a high probability to be either underexposed or overexposed, potentially leading to suboptimal outcomes. Therapeutic drug monitoring, which is personalized dosing based on measured systemic drug concentrations, could address these problems. PATIENTS AND METHODS: Patients were enrolled in this prospective multicenter study (www.trialregister.nl; NL6695) if they started treatment with one of the 24 participating oral targeted therapies. Primary outcome was to halve the proportion of underexposed patients, compared with historical data. PK sampling was carried out after 4, 8 and 12 weeks, and every 12 weeks thereafter. In case of Cmin below the predefined target and manageable toxicity, a pharmacokinetically guided intervention was proposed (i.e. checking compliance and drug-drug interactions, concomitant intake with food, splitting intake moments or dose increments). RESULTS: In total, 600 patients were included of whom 426 patients are assessable for the primary outcome and 552 patients had ≥1 PK sample(s) available and were therefore assessable for the overall analyses. Pharmacokinetically guided dosing reduced the proportion of underexposed patients at the third PK measurement by 39.0% (95% confidence interval 28.0% to 49.0%) compared with historical data. At the third PK measurement, 110 out of 426 patients (25.8%) had a low exposure. In total, 294 patients (53.3%) had ≥1 PK sample(s) below the preset target at a certain time point during treatment. In 166 of these patients (56.5%), pharmacokinetically guided interventions were carried out, which were successful in 113 out of 152 assessable patients (74.3%). CONCLUSIONS: Pharmacokinetically guided dose optimization of oral targeted therapies was feasible in clinical practice and reduced the proportion of underexposed patients considerably.

Exposure-response analyses of abiraterone and its metabolites in real-world patients with metastatic castration-resistant prostate cancer.

BACKGROUND: Abiraterone acetate is an oral 17α-hydroxylase/C17,20-lyase (CYP17) inhibitor approved for the treatment of metastatic castration-resistant prostate cancer (mCPRC) patients. Previously, a prospective observational trial demonstrated a relationship between abiraterone trough concentrations (Cmin) in plasma and treatment efficacy. The aim of our study was to investigate the exposure-response relationship of abiraterone and its metabolites, and to study if the proposed target for abiraterone of 8.4 ng/mL is feasible in a "real-world" patient cohort. PATIENTS AND METHODS: mCRPC patients who had at least one abiraterone plasma concentration at steady-state were included in this study. Plasma abiraterone and its metabolites levels were analyzed using a validated liquid chromatography-mass spectrometry method. Using calculated Cmin values of abiraterone and its active metabolite Δ(4)-abiraterone (D4A), univariate, and multivariable Cox regression analyses were performed. RESULTS: Sixty-two patients were included in this retrospective analysis, of which 42% were underexposed (mean abiraterone Cmin ≤ 8.4 ng/mL). In multivariable analysis, Cmin ≥ 8.4 ng/mL was associated with longer prostate-specific antigen (PSA) independent progression-free survival (16.9 vs 6.1 months; p = 0.033), which resulted in a hazard ratio of 0.44 (95% confidence interval: 0.23-0.82, p = 0.01). D4A Cmin did not show a relationship with treatment efficacy. CONCLUSION: Our study shows that mCRPC patients with an abiraterone Cmin ≥ 8.4 ng/mL have a better prognosis compared with patients with low Cmin. Monitoring Cmin of abiraterone can help to identify those patients at risk of suboptimal treatment for whom treatment optimization may be appropriate.