Despite the fact that pharmacokinetic exposure of kinase inhibitors (KIs) is highly variable and clear relationships exist between exposure and treatment outcomes, fixed dosing is still standard practice. This review aims to summarize the available clinical pharmacokinetic and pharmacodynamic data into practical guidelines for individualized dosing of KIs through therapeutic drug monitoring (TDM). Additionally, we provide an overview of prospective TDM trials and discuss the future steps needed for further implementation of TDM of KIs.

The large-scale genetic profiling of tumours can identify potentially actionable molecular variants for which approved anticancer drugs are available 1-3 . However, when patients with such variants are treated with drugs outside of their approved label, successes and failures of targeted therapy are not systematically collected or shared. We therefore initiated the Drug Rediscovery protocol, an adaptive, precision-oncology trial that aims to identify signals of activity in cohorts of patients, with defined tumour types and molecular variants, who are being treated with anticancer drugs outside of their approved label. To be eligible for the trial, patients have to have exhausted or declined standard therapies, and have malignancies with potentially actionable variants for which no approved anticancer drugs are available. Here we show an overall rate of clinical benefit-defined as complete or partial response, or as stable disease beyond 16 weeks-of 34% in 215 treated patients, comprising 136 patients who received targeted therapies and 79 patients who received immunotherapy. The overall median duration of clinical benefit was 9 months (95% confidence interval of 8-11 months), including 26 patients who were experiencing ongoing clinical benefit at data cut-off. The potential of the Drug Rediscovery protocol is illustrated by the identification of a successful cohort of patients with microsatellite instable tumours who received nivolumab (clinical benefit rate of 63%), and a cohort of patients with colorectal cancer with relatively low mutational load who experienced only limited clinical benefit from immunotherapy. The Drug Rediscovery protocol facilitates the defined use of approved drugs beyond their labels in rare subgroups of cancer, identifies early signals of activity in these subgroups, accelerates the clinical translation of new insights into the use of anticancer drugs outside of their approved label, and creates a publicly available repository of knowledge for future decision-making.The precision treatment of cancer holds great promise for patients in terms of life extension and quality of life 1,2,4-7 . However, early studies and experiences with genetically and molecularly informed decisions regarding treatment have also identified considerable hurdles, which may jeopardize the way in which we capitalize on precision medicine [8][9][10][11] . First, populations of patients who are eligible for specific treatments or trials become smaller and trials accrue slower, owing to pre-selection by targeted sequencing of candidate variants and to slow implementation of pre-selection tests. Second, these candidate variants can, in general, be appreciated only when their tissue context Online contentAny methods, additional references, Nature Research reporting summaries, source data, extended data, supplementary information, acknowledgements, peer review information; details of author contributions and competing interests; and statements of data and code availability are available at

Purpose: Nasopharyngeal carcinoma (NPC) is causally linked to Epstein-Barr virus (EBV) infection. Because all tumor cells carry EBV, the virus itself is a potential target for therapy. In these tumor cells, EBV hides in a latent state and expresses only a few non-immunogenic proteins for EBV maintenance and contributes to tumor growth. We developed a cytolytic virus activation (CLVA) therapy for NPC treatment, reactivating latent EBV, triggering immune recognition, and inducing susceptibility to antiviral therapy.Experimental Design: CLVA therapy combines gemcitabine (GCb) and valproic acid (VPA) for virus activation and tumor clearance with (val)ganciclovir (GCV) as the antiviral drug to block virus replication and kill proliferating virus-infected cells. CLVA treatment was optimized and validated in NPC cell lines and subsequently tested in 3 Dutch patients with NPC that was refractory to conventional treatment.Results: In NPC cell lines, both GCb and VPA can induce the lytic cycle of EBV. Their combination resulted in a strong synergistic effect. The addition of GCV resulted in higher cytotoxicity compared with chemotherapy alone, which was not observed in EBV-negative cells. CLVA therapy was analyzed in 3 patients with end-stage NPC. Patients developed increased levels of viral DNA in the circulation originating from apoptotic tumor cells, had disease stabilization, and experienced improved quality of life.Conclusions: Our results in the initial CLVA-treated patients indicate that the therapy had a biological effect and was well tolerated with only moderate transient toxicity. This new virus-specific therapy could open a generic approach for treatment of multiple EBV-associated malignancies.

The pharmacokinetics of miltefosine in leishmaniasis patients are, to a great extent, unknown. We examined and characterized the pharmacokinetics of miltefosine in a group of patients with Old World (Leishmania major) cutaneous leishmaniasis. Miltefosine plasma concentrations were determined in samples taken during and up to 5 months after the end of treatment from 31 Dutch military personnel who contracted cutaneous leishmaniasis in Afghanistan and were treated with 150 mg miltefosine/day for 28 days. Samples were analyzed with a validated liquid chromatography-tandem mass spectrometry assay with a lower limit of quantification (LLOQ) of 4 ng/ml. Population pharmacokinetic modeling was performed with nonlinear mixed-effect modeling, using NONMEM. The pharmacokinetics of miltefosine could best be described by an open two-compartment disposition model, with a first elimination half-life of 7.05 days and a terminal elimination half-life of 30.9 days. The median concentration in the last week of treatment (days 22 to 28) was 30,800 ng/ml. The maximum duration of follow-up was 202 days after the start of treatment. All analyzed samples contained a concentration above the LLOQ. Miltefosine is eliminated from the body much slower than previously thought and is therefore still detectable in human plasma samples taken 5 to 6 months after the end of treatment. The presence of subtherapeutic miltefosine concentrations in the blood beyond 5 months after treatment might contribute to the selection of resistant parasites, and moreover, the measures for preventing the teratogenic risks of miltefosine treatment should be reconsidered.

Background:The aim of this study was to quantitatively assess the effect of anthropometric and biochemical variables and third-space effusions on paclitaxel pharmacokinetics in solid tumor patients. Materials and Methods: Plasma concentration-time data of paclitaxel were collected in patients with non^small cell lung cancer (n = 84), ovarian cancer (n = 40), and various solid tumors (n = 44), totaling 168 patients. Paclitaxel was given as a 3-hour infusion (n = 163) at doses ranging from 100 to 250 mg/m 2 , or as a 24-hour infusion (n = 5) at a dose of 135 or 175 mg/m 2 . Data were analyzed using nonlinear mixed-effect modeling. Results: A three-compartment model with saturable elimination and distribution was used to describe concentration-time data. Male gender and body surface area were positively correlated with maximal elimination capacity of paclitaxel (VM EL ); patient age and total bilirubin were negatively correlated withVM EL (P < 0.005 for all correlations).Typically, male patients had a 20% higher VM EL ; a 0.2 m 2 increase of body surface area led to a 9% increase of VM EL ; a 10-year increase of patient age led to a 5% decrease of VM EL ; and a 10-Amol increase of total bilirubin led to a 14% decrease of VM EL . Third-space effusions were not correlated with paclitaxel pharmacokinetics. Conclusions: This extended retrospective population analysis showed patient gender to significantly and independently affect paclitaxel distribution and elimination. Body surface area, total bilirubin, and patient age were confirmed to affect paclitaxel elimination. This pharmacokinetic model allowed quantification of the covariate effects on the elimination of paclitaxel and may be used for covariate-adapted paclitaxel dosing.Paclitaxel formulated in Cremophor EL is regularly administered to patients with non -small cell lung cancer (NSCLC), ovarian cancer, and breast cancer. The pharmacokinetics of paclitaxel were initially believed to be linear, but Sonnichsen and Gianni reported that paclitaxel pharmacokinetics were best described with a two-and three-compartment model, respectively, with saturable elimination and saturable distribution to the tissues (1, 2). Later, the formulation vehicle of paclitaxel, Cremophor EL, was reported to be the cause of the (apparent) nonlinear plasma behavior of paclitaxel, probably by entrapment of paclitaxel into micelles (3 -7). Generally, substantial interpatient variability of paclitaxel pharmacokinetic variables has been noted (8).Hepatic metabolism and biliary excretion are the most important elimination routes of paclitaxel and its metabolites (9). Paclitaxel has been shown to bind extensively to plasma proteins (from 95% to < 97%), with high central (mean = 13.8 L/m 2 ) and steady-state (mean = 182 L/m 2 ) volumes of distribution (10-13). However, data on specific tissue and compartment distribution of paclitaxel in humans following i.v. administration are limited. Paclitaxel concentrations in ascites have been analyzed in single patients, where the concentration ...

Purpose: Paclitaxel and carboplatin are frequently used in advanced ovarian cancer following cytoreductive surgery. Threshold models have been used to predict paclitaxel pharmacokineticpharmacodynamics, whereas the time above paclitaxel plasma concentration of 0.05 to 0.2 Amol/L (t C > 0.05-0.2 ) predicts neutropenia.The objective of this study was to build a population pharmacokinetic-pharmacodynamic model of paclitaxel/carboplatin in ovarian cancer patients. Experimental Design: One hundred thirty-nine ovarian cancer patients received paclitaxel (175 mg/m 2 ) over 3 h followed by carboplatin area under the concentration-time curve 5 mg/mL*min over 30 min. Plasma concentration-time data were measured, and data were processed using nonlinear mixed-effect modeling. Semiphysiologic models with linear or sigmoidal maximum response and threshold models were adapted to the data. Results: One hundred five patients had complete pharmacokinetic and toxicity data. In 34 patients with measurable disease, objective response rate was 76%. Neutrophil and thrombocyte counts were adequately described by an inhibitory linear response model. Paclitaxel t C > 0.05 was significantly higher in patients with a complete (91.8 h) or partial (76.3 h) response compared with patients with progressive disease (31.5 h; P = 0.02 and 0.05, respectively).Patients with paclitaxel t C > 0.05 > 61.4 h (mean value) had a longer time to disease progression compared with patients with paclitaxel t C > 0.05 < 61.4 h (89.0 versus 61.9 weeks; P = 0.05).Paclitaxel t C > 0.05 was a good predictor for severe neutropenia (P = 0.01), whereas carboplatin exposure (C max and area under the concentration-time curve) was the best predictor for thrombocytopenia (P < 10 -4 ). Conclusions: In this group of patients, paclitaxel t C > 0.05 is a good predictive marker for severe neutropenia and clinical outcome, whereas carboplatin exposure is a good predictive marker for thrombocytopenia.

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.

Purpose: Despite the extensive clinical experience with docetaxel, unpredictable interindividual variability in efficacy and toxicity remain important limitations associated with the use of this anticancer drug. Large interindividual pharmacokinetic variability has been associated with variation in toxicity profiles. Genetic polymorphisms in drug-metabolizing enzymes and drug transporters could possibly explain the observed pharmacokinetic variability. The aim of this study was therefore to investigate the influence of polymorphisms in the CYP3A and ABCB1 genes on the population pharmacokinetics of docetaxel. Experimental Design: Whole blood samples were obtained from patients with solid tumors and treated with docetaxel to quantify the exposure to docetaxel. DNA was collected to determine polymorphisms in the CYP3A and ABCB1 genes with DNA sequencing. A population pharmacokinetic analysis of docetaxel was done using nonlinear mixed-effect modeling. Results: In total, 92 patients were assessable for pharmacokinetic analysis of docetaxel. A threecompartmental model adequately described the pharmacokinetics of docetaxel. Several polymorphisms in the CYP3A and ABCB1 genes were found, with allele frequencies of 0.54% to 48.4%. The homozygous C1236T polymorphism in the ABCB1 gene (ABCB1*8) was significantly correlated with a decreased docetaxel clearance (À25%; P = 0.0039). No other relationships between polymorphisms and pharmacokinetic variables reached statistical significance. Furthermore, no relationship between haplotypes of CYP3A and ABCB1and the pharmacokinetics could be identified. Conclusions: The polymorphism C1236T in the ABCB1 gene was significantly related to docetaxel clearance. Our current finding may provide a meaningful tool to explain interindividual differences in docetaxel treatment in daily practice.The anticancer drug docetaxel (Taxotere) is approved for the treatment of patients with early-stage, locally advanced and/or metastatic breast cancer, non -small-cell lung cancer, and androgen-independent metastatic prostate cancer. The recommended dose ranges from 75 to 100 mg/m 2 given as a 1-hour infusion once every 3 weeks. An important limitation associated with docetaxel use is the unpredictable interindividual variability in efficacy and toxicity. Potential causes for such variability in drug effects include the pathogenesis and severity of the disease being treated, the occurrence of unintended drug interactions, and impairment of hepatic and renal function (1). Despite the potential importance of these clinical variables in determining drug effects, it is recognized that inherited differences in metabolism and excretion can have an even greater effect on the efficacy and toxicity of drugs (1).The metabolism of docetaxel consists of a CYP3A-mediated oxidation of the tert-butylpropionate side chain, which results in the formation of four metabolites with reduced cytotoxic activity (2). The elimination pathway is mediated by the membrane-localized, energy-dependent drug efflux ABC tran...