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PurposeThis review provides an overview of the current challenges in oral targeted antineoplastic drug (OAD) dosing and outlines the unexploited value of therapeutic drug monitoring (TDM). Factors influencing the pharmacokinetic exposure in OAD therapy are depicted together with an overview of different TDM approaches. Finally, current evidence for TDM for all approved OADs is reviewed.MethodsA comprehensive literature search (covering literature published until April 2020), including primary and secondary scientific literature on pharmacokinetics and dose individualisation strategies for OADs, together with US FDA Clinical Pharmacology and Biopharmaceutics Reviews and the Committee for Medicinal Products for Human Use European Public Assessment Reports was conducted.ResultsOADs are highly potent drugs, which have substantially changed treatment options for cancer patients. Nevertheless, high pharmacokinetic variability and low treatment adherence are risk factors for treatment failure. TDM is a powerful tool to individualise drug dosing, ensure drug concentrations within the therapeutic window and increase treatment success rates. After reviewing the literature for 71 approved OADs, we show that exposure-response and/or exposure-toxicity relationships have been established for the majority. Moreover, TDM has been proven to be feasible for individualised dosing of abiraterone, everolimus, imatinib, pazopanib, sunitinib and tamoxifen in prospective studies. There is a lack of experience in how to best implement TDM as part of clinical routine in OAD cancer therapy.ConclusionSub-therapeutic concentrations and severe adverse events are current challenges in OAD treatment, which can both be addressed by the application of TDM-guided dosing, ensuring concentrations within the therapeutic window.

Purpose While in the era of precision medicine, the right drug for each patient is selected based on molecular tumor characteristics, most novel oral targeted anticancer agents are still being administered using a one-size-fits-all fixed dosing approach. In this review, we discuss the scientific evidence for dose individualization of oral targeted therapies in oncology, based on therapeutic drug monitoring (TDM). Methods Based on literature search and our own experiences, seven criteria for drugs to be suitable candidates for TDM will be addressed: (1) absence of an easily measurable biomarker for drug effect; (2) long-term therapy; (3) availability of a validated sensitive bioanalytical method; (4) significant variability in pharmacokinetic exposure; (5) narrow therapeutic range; (6) defined and consistent exposure-response relationships; (7) feasible dose-adaptation strategies. Results All of these requirements are met for most oral targeted therapies in oncology. Also, prospective studies have already shown TDM to be feasible for imatinib, pazopanib, sunitinib, everolimus, and endoxifen. Conclusions In order to realize the full potential of personalized medicine in oncology, patients should not only be treated with the right drug, but also at the right dose. TDM could be a suitable tool to achieve this.

Background Osimertinib, an irreversible inhibitor of the epidermal growth factor receptor (EGFR) is an important drug in the treatment of EGFR-mutation positive non-small cell lung cancer (NSCLC). Clinical trials with osimertinib could not demonstrate an exposure-efficacy relationship, while a relationship between exposure and toxicity has been found. In this study, we report the exposure–response relationships of osimertinib in a real-life setting. Methods A retrospective observational cohort study was performed, including patients receiving 40 - 80 mg osimertinib as ≥ 2 line therapy and from whom pharmacokinetic samples were collected during routine care. Trough plasma concentrations (C min,pred ) were estimated and used as a measure of osimertinib exposure. A previously defined exploratory pharmacokinetic threshold of 166 µg/L was taken to explore the exposure-efficacy relationship. Results A total of 145 patients and 513 osimertinib plasma concentration samples were included. Median progression free survival (PFS) was 13.3 (95% confidence interval (CI):10.3 – 19.1) months and 9.3 (95% CI: 7.2 – 11.1) months for patients with C min,pred  < 166 µg/L and C min,pred  ≥ 166 µg/L, respectively ( p  = 0.03). In the multivariate analysis, a C min,pred  < 166 µg/L resulted in a non-statistically significant hazard ratio of 1.10 (95% CI: 0.60 – 2.01;  p  = 77). Presence of a EGFR driver-mutation other than the exon 19 del or L858R mutations, led to a shorter PFS with a hazard ratio of 2.89 (95% CI: 1.18 – 7.08;  p  = 0.02). No relationship between exposure and toxicity was observed ( p  = 0.91). Conclusion In our real-life cohort, no exposure–response relationship was observed for osimertinib in the current dosing scheme. The feasibility of a standard lower fixed dosing of osimertinib in clinical practice should be studied prospectively.

Aim In the registration trial, cabozantinib exposure ≥ 750 ng/mL correlated to improved tumor size reduction, response rate and progression free survival (PFS) in patients with metastatic renal cell cancer (mRCC). Because patients in routine care often differ from patients in clinical trials, we explored the cabozantinib exposure–response relationship in patients with mRCC treated in routine care. Methods Cabozantinib trough concentrations (C min ) were collected and average exposure was calculated per individual. Exposure–response analyses were performed using the earlier identified target of C min  > 750 ng/mL and median C min . In addition, the effect of dose reductions on response was explored. PFS was used as measure of response. Results In total, 59 patients were included:10% were classified as favourable, 61% as intermediate and 29% as poor IMDC risk group, respectively. Median number of prior treatment lines was 2 (0–5). Starting dose was 60 mg in 46%, 40 mg in 42% and 20 mg in 12% of patients. Dose reductions were needed in 58% of patients. Median C min was 572 ng/mL (IQR: 496–701). Only 17% of patients had an average C min  ≥ 750 ng/mL. Median PFS was 52 weeks (95% CI: 40–64). No improved PFS was observed for patients with C min  ≥ 750 ng/mL or ≥ 572 ng/ml. A longer PFS was observed for patients with a dose reduction vs. those without (65 vs. 31 weeks, p  = .001). After incorporating known covariates (IMDC risk group and prior treatment lines (< 2 vs. ≥ 2)) in the multivariable analysis, the need for dose reduction remained significantly associated with improved PFS (HR 0.32, 95% CI:0.14–0.70, p  = .004). Conclusion In these explorative analyses, no clear relationship between increased cabozantinib exposure and improved PFS was observed. Average cabozantinib exposure was below the previously proposed target in 83% of patients. Future studies should focus on validating the cabozantinib exposure required for long term efficacy.

Background Pazopanib is a tyrosine kinase inhibitor indicated for the treatment of renal cell carcinoma and soft tissue sarcoma. Despite the high inter-patient variability in pharmacokinetic exposure, pazopanib is administered at a fixed dose of 800 mg once daily (QD). Pharmacokinetic exposure is linked to both efficacy and toxicity. In this case report, we illustrate the value of therapeutic drug monitoring by describing two patients with adequate pazopanib trough concentrations (C min ) at an eight times lower than standard dose. Case presentation Patient A is a 69-year-old woman with metastatic leiomyosarcoma who had significant toxicities and a high C min on the standard dose. While dose reductions to 200 mg QD and later 200 mg every other day were made, pazopanib C min remained above the efficacy threshold. Patient B is a 50-year-old male with metastatic angiosarcoma and a history of Gilbert syndrome. Pazopanib treatment was initiated at the standard dose of 800 mg QD, but was reduced to 200 mg QD 1-week-on - 1-week-off due to total bilirubin elevation. Pazopanib C min was adequate in this patient as well. Conclusion It could be valuable to measure pazopanib levels in case of dose reductions due to toxicity, as exposure could still be adequate at considerably lower than standard doses.

Palbociclib, ribociclib, and abemaciclib are inhibitors of the cyclin-dependent kinases 4 and 6 approved for the treatment of locally advanced or metastatic breast cancer. In this review, we provide an overview of the available clinical pharmacokinetic and pharmacodynamic characteristics of these novel drugs, summarize the results of food–effect and drug–drug interaction studies, and highlight exposure–response and exposure–toxicity relationships. All three drugs exhibit a large inter-individual variability in exposure (coefficient of variation range 40–95% for minimum plasma concentration), are extensively metabolized by cytochrome P450 3A4, and have their brain penetration limited by efflux transporters. Abemaciclib has three active metabolites with similar potency that are clinically relevant (i.e., M2, M20, M18), whereas the metabolites of palbociclib and ribociclib are not of clinical significance. Pharmacokinetic exposure increases in a dose-proportional manner for palbociclib, whereas exposure increases under- and over-proportionally with an increasing dose for abemaciclib and ribociclib, respectively. High exposure is associated with an increased risk of neutropenia, and for ribociclib also to corrected QT prolongation. For abemaciclib, a clear exposure–efficacy relationship has been described, while for palbociclib and ribociclib exposure–response analyses remain inconclusive. Future studies are needed to address exposure–efficacy relationships to further improve dosing.

Background In ANCA-associated vasculitis the acute phase of the disease is often preceded by prodromal symptoms. The aim of the present study was to analyze the relation between the duration of the prodromal phase and renal damage. Methods Patients with ANCA-associated vasculitis and renal involvement from a retrospective single-center cohort were divided into two equal groups based on the duration of the prodromal phase. The prodromal phase was defined as the time between first vasculitis related symptoms and the date of diagnosis. Clinical characteristics at diagnosis and renal items on the vasculitis damage index at 6 months were compared between the two groups. In addition, the relation between a long prodromal phase and 3-year end-stage renal disease and mortality as a composite outcome was studied. Results A total of 72 patients were included (age 64 ± 12 years; 74% male; 96% Caucasian). At diagnosis, in patients with a prodromal phase ≤22 weeks versus >22 weeks estimated glomerular filtration rate and proteinuria did not differ significantly (35 (interquartile range 50) versus 30 (50) ml/min p  = 0.84; 75% versus 87%, p  = 0.21 respectively). Furthermore, Birmingham Vasculitis Activity Scores were comparable (7 (3), p  = 0.71). At 6 months, a long prodromal phase was associated with proteinuria (odds ratio 5.38, 95% confidence interval (CI) 1.47–19.62), but not with an estimated glomerular filtration rate ≤ 50 ml/min (odds ratio 0.89, 95% CI 0.33–2.37) in multivariable analyses. In addition, a long prodromal phase was associated with end-stage renal disease/mortality (hazard ratio 5.22, 95% CI 1.13–24.20). Conclusions A long prodromal phase was associated with proteinuria and 3-year end-stage renal disease/mortality, but not with a reduced renal function at 6 months. These results underline the importance of an early diagnosis in ANCA-associated vasculitis patients in order to improve renal outcomes.

Previous studies demonstrated better outcomes for mCRPC (metastatic castration resistant prostate cancer) patients with higher abiraterone exposure (minimal plasma concentration (C ) > 8.4 ng/mL), but around 40% of patients experience exposure below this target. Pharmacokinetic (PK)-guided interventions following Therapeutic Drug Monitoring (TDM) could optimise exposure and outcomes. We aimed to evaluate the feasibility and effect on treatment outcomes of abiraterone TDM. Patients with low exposure levels (Low-group, C  < 8.4 ng/mL) got a PK-guided intervention. We compared exposure, adverse event (AE) incidence, time on treatment (ToT) and Prostate-Specific Antigen response rate (PSArr) between the Low-group and Adequate-group. We included 167 mCRPC patients, with 56 in the Adequate-group and 111 in the Low-group. Interventions were successful 86% of the time. Exposure between groups became corresponding (Low-group: 7.95 to 20.5 ng/mL, Adequate-group: 20.8 ng/mL, p = 0.72) with comparable AE incidence (17% vs. 23%, p = 0.4). Median ToT and PSArr were similar (351 vs. 379 days, p = 0.35; 61.3% vs. 67.9%, p = 0.51). PK-guided interventions improved above target exposure from 33.5% to 81.4% of patients without additional AEs. While historically, low exposure patients had significantly shorter survival, PK-guided interventions eliminated this disparity. As interventions are effective, low-cost and safe, TDM for abiraterone should be considered to enhance treatment outcomes.

Oral anti-hormonal drugs are essential in the treatment of breast and prostate cancer. It is well known that the interpatient variability in pharmacokinetic exposure is high for these agents and exposure–response relationships exist for many oral anti-hormonal drugs. Yet, they are still administered at fixed doses. This could lead to underdosing and thus suboptimal efficacy in some patients, while other patients could be overdosed resulting in unnecessary side effects. Therapeutic drug monitoring (TDM), individualized dosing based on measured blood concentrations of the drug, could therefore be a valid option to further optimize treatment. In this review, we provide an overview of relevant clinical pharmacokinetic and pharmacodynamic characteristics of oral anti-hormonal drugs in oncology and translate these into practical guidelines for TDM. For some agents, TDM targets are not well established yet and as a reference the median pharmacokinetic exposure could be targeted (exemestane: minimum plasma concentration ( C min ) 4.1 ng/mL and enzalutamide: C min 11.4 mg/L). However, for most drugs, exposure–efficacy analyses could be translated into specific targets (abiraterone: C min 8.4 ng/mL, anastrozole: C min 34.2 ng/mL, and letrozole: C min 85.6 ng/mL). Moreover, prospective clinical trials have shown TDM to be feasible for tamoxifen, for which the exposure–efficacy threshold of its active metabolite endoxifen is 5.97 ng/mL. Based on the available data, we therefore conclude that individualized dosing based on drug concentrations is feasible and promising for oral anti-hormonal drugs and should be developed further and implemented into clinical practice.

Although kinase inhibitors (KIs) are generally effective, their use has a large impact on the current health care budget. Dosing strategies to reduce treatment costs are warranted. Boosting pharmacokinetic exposure of KIs metabolized by cytochrome P450 (CYP)3A4 with ritonavir might result in lower doses needed and subsequently reduces treatment costs. This study is a proof-of-concept study to evaluate if the dose of erlotinib can be reduced by co-administration with ritonavir. In this open-label, cross-over study, we compared the pharmacokinetics of monotherapy erlotinib 150 mg once daily (QD) (control arm) with erlotinib 75 mg QD plus ritonavir 200 mg QD (intervention arm). Complete pharmacokinetic profiles at steady-state were taken up to 24 h after erlotinib intake for both dosing strategies. Nine patients were evaluable in this study. For the control arm, the systemic exposure over 24 h, maximum plasma concentration and minimal plasma concentration of erlotinib were 29.3 μg*h/mL (coefficient of variation (CV):58%), 1.84 μg/mL (CV:60%) and 1.00 μg/mL (CV:62%), respectively, compared with 28.9 μg*h/mL (CV:116%, p = 0.545), 1.68 μg/mL (CV:68%, p = 0.500) and 1.06 μg/mL (CV:165%, p = 0.150) for the intervention arm. Exposure to the metabolites of erlotinib (OSI-413 and OSI-420) was statistically significant lower following erlotinib plus ritonavir dosing. Similar results regarding safety in both dosing strategies were observed, no grade 3 or higher adverse event was reported. Pharmacokinetic exposure at a dose of 75 mg erlotinib when combined with the strong CYP3A4 inhibitor ritonavir is similar to 150 mg erlotinib. Ritonavir-boosting is a promising strategy to reduce erlotinib treatment costs and provides a rationale for other expensive therapies metabolized by CYP3A4.