Population Pharmacokinetics in Oncology and Its Clinical Applications.

Most traditional cytotoxic drugs are characterized by steep dose-response relationships and narrow therapeutic windows [...].

Managing the COVID-19 health crisis: a survey of Swiss hospital pharmacies.

BACKGROUND: The COVID-19 pandemic strained healthcare systems immensely as of 2020. Switzerland's hospital pharmacies' responses during the first wave were surveyed with a view to improving the quality of pharmaceutical management in future health crises. METHODS: An online survey was sent to the heads of all of Switzerland's hospital pharmacies. The questionnaire was organised into eleven sections of questions covering many topics regarding the management of COVID-19's first wave. Data collection occurred from May to June 2020. RESULTS: Analyses were performed using the 43 questionnaires (66%), with at least one answer per questionnaire, out of 65 distributed. Seventeen of 41 pharmacies responding (41%) had existing standard operating procedures or pandemic plans and 95% of these (39/41) set up crisis management steering committees. Twenty-nine of 43 pharmacies responding (67%) created new activities to respond to the pandemic's specific needs. Twenty-six of 39 pharmacies responding (67%) created new drug lists for: COVID-19-specific treatments (85%; 22/26), sedatives (81%; 21/26), anaesthetics (77%; 20/26) and antibiotics (73%; 19/26). Drug availability in designated COVID-19 wards was managed by increasing existing stocks (54%; 22/41 pharmacies) and creating extra storage space (51%; 21/41). Two drugs generated the greatest concern about shortages: propofol (49%; 19/39 pharmacies) and midazolam (44%; 17/39). Remdesivir stocks ran out in 26% of pharmacies (10/39). Twelve of 43 pharmacies (28%) drafted specific new documents to respond to medical needs regarding drug administration, 12 (28%) did so for drug preparation and 10 (23%) did so for treatment choices. CONCLUSIONS: Switzerland's hospital pharmacies encountered many challenges related to the COVID-19 crisis and had to find solutions quickly, effectively and safely. The survey highlighted the key role that hospital pharmacies played in many aspects of the pandemic by providing logistical and clinical support to medical and nursing care teams. The lessons and experiences outlined could be used to improve the quality of hospital pharmacies' readiness for similar future events.

From Personalized to Precision Medicine in Oncology: A Model-Based Dosing Approach to Optimize Achievement of Imatinib Target Exposure.

Imatinib is a targeted cancer therapy that has significantly improved the care of patients with chronic myeloid leukemia (CML) and gastrointestinal stromal tumor (GIST). However, it has been shown that the recommended dosages of imatinib are associated with trough plasma concentration (Cmin) lower than the target value in many patients. The aims of this study were to design a novel model-based dosing approach for imatinib and to compare the performance of this method with that of other dosing methods. Three target interval dosing (TID) methods were developed based on a previously published PK model to optimize the achievement of a target Cmin interval or minimize underexposure. We compared the performance of those methods to that of traditional model-based target concentration dosing (TCD) as well as fixed-dose regimen using simulated patients (n = 800) as well as real patients' data (n = 85). Both TID and TCD model-based approaches were effective with about 65% of Cmin achieving the target imatinib Cmin interval of 1000-2000 ng/mL in 800 simulated patients and more than 75% using real data. The TID approach could also minimize underexposure. The standard 400 mg/24 h dosage of imatinib was associated with only 29% and 16.5% of target attainment in simulated and real conditions, respectively. Some other fixed-dose regimens performed better but could not minimize over- or underexposure. Model-based, goal-oriented methods can improve initial dosing of imatinib. Combined with subsequent TDM, these approaches are a rational basis for precision dosing of imatinib and other drugs with exposure-response relationships in oncology.

Precision Oncology by Point-of-Care Therapeutic Drug Monitoring and Dosage Adjustment of Conventional Cytotoxic Chemotherapies: A Perspective.

Therapeutic drug monitoring (TDM) of conventional cytotoxic chemotherapies is strongly supported yet poorly implemented in daily practice in hospitals. Analytical methods for the quantification of cytotoxic drugs are instead widely presented in the scientific literature, while the use of these therapeutics is expected to keep going for longer. There are two main issues hindering the implementation of TDM: turnaround time, which is incompatible with the dosage profiles of these drugs, and exposure surrogate marker, namely total area under the curve (AUC). Therefore, this perspective article aims to define the adjustment needed from current to efficient TDM practice for cytotoxics, namely point-of-care (POC) TDM. For real-time dose adjustment, which is required for chemotherapies, such POC TDM is only achievable with analytical methods that match the sensitivity and selectivity of current methods, such as chromatography, as well as model-informed precision dosing platforms to assist the oncologist with dose fine-tuning based on quantification results and targeted intervals.

Full-scale simulations to improve disaster preparedness in hospital pharmacies.

PURPOSE: Assess whether full-scale simulation exercises improved hospital pharmacies' disaster preparedness. METHODS: Swiss hospital pharmacies performed successive full-scale simulation exercises at least four months apart. An interprofessional team created two scenarios, each representing credible regional-scale disasters involving approximately fifty casualties (a major road accident and a terrorist attack). Four exercise assessors used appraisal forms to evaluate participants' actions and responses during the simulation (rating them using five-point Likert scales). RESULTS: Four hospital pharmacies performed two full-scale simulation exercises each. Differences between exercises one and two were observed. On average, the four hospitals accomplished 69% ± 6% of the actions expected of them during exercise one. The mean rate of expected actions accomplished increased to 84% ± 7% (p < 0.005) during exercise two. Moreover, the average quality of actions improved from 3.0/5 to 3.6/5 (p = 0.01), and the time required to gather a crisis management team drastically decreased between simulations (from 23 to 5 min). The main challenges were communication (reformulation) and crisis management. Simulation exercise number one resulted in three hospital pharmacies creating disaster action plans and the fourth improving its already existing plan. CONCLUSION: This study highlighted the value of carrying out full-scale disaster simulations for hospital pharmacies as they improved overall institutional preparedness and increased staff awareness. The number of expected actions accomplished increased significantly. In the future, large-scale studies and concept dissemination are warranted.

Dosing strategies of imipenem in neonates based on pharmacometric modelling and simulation.

OBJECTIVES: Imipenem is a broad-spectrum antibacterial agent used in critically ill neonates after failure of first-line treatments. Few studies have described imipenem disposition in this population. The objectives of our study were: (i) to characterize imipenem population pharmacokinetics (PK) in a cohort of neonates; and (ii) to conduct model-based simulations to evaluate the performance of six different dosing regimens aiming at optimizing PK target attainment. METHODS: A total of 173 plasma samples from 82 neonates were collected over 15 years at the Lausanne University Hospital, Switzerland. The majority of study subjects were preterm neonates with a median gestational age (GA) of 27 weeks (range: 24-41), a postnatal age (PNA) of 21 days (2-153) and a body weight (BW) of 1.16 kg (0.5-4.1). PK data were analysed using non-linear mixed-effect modelling (NONMEM). RESULTS: A one-compartment model best characterized imipenem disposition. Population PK parameters estimates of CL and volume of distribution were 0.21 L/h and 0.73 L, with an interpatient variability (CV%) of 20.1% on CL in a representative neonate (GA 27 weeks, PNA 21 days, BW 1.16 kg, serum creatinine, SCr 46.6 µmol/L). GA and PNA exhibited the greatest impact on PK parameters, followed by SCr. These covariates explained 36% and 15% of interindividual variability in CL, respectively.Simulated regimens using a dose of 20-25 mg/kg every 6-12 h according to postnatal age led to the highest PTA (T>MIC over 100% of time). CONCLUSIONS: Dosing adjustment according to BW, GA and PNA optimizes imipenem exposure in neonates.

Pharmaceutical Interventions on Hospital Discharge Prescriptions: Prospective Observational Study Highlighting Challenges for Community Pharmacists.

BACKGROUND: Transition between hospital and ambulatory care is a delicate step involving several healthcare professionals and presenting a considerable risk of drug-related problems. OBJECTIVE: To investigate pharmaceutical interventions made on hospital discharge prescriptions by community pharmacists. METHOD: This observational, prospective study took place in 14 community pharmacies around a Swiss acute care hospital. We recruited patients with discharge prescriptions (minimum three drugs) from the internal medicine ward of the hospital. The main outcome measures were: number and type of pharmaceutical interventions made by community pharmacists, time spent on discharge prescriptions, number of medication changes during the transition of care. RESULTS: The study included 64 patients discharged from the hospital. Community pharmacists made a total of 439 interventions; a mean of 6.9 ± 3.5 (range 1-16) interventions per patient. All of the discharge prescriptions required pharmaceutical intervention, and 61 (95%) necessitated a telephone call to the patients' hospital physician for clarifications. The most frequent interventions were: confirming voluntary omission of a drug (31.7%), treatment substitution (20.5%), dose adjustment (16.9%), and substitution for reimbursement issues (8.8%). Roughly half (52%) of all discharge prescriptions required 10-20 min for pharmaceutical validation. The mean number of medication changes per patient was 16.4: 9.6 changes between hospital admission and discharge, 2.6 between hospital discharge and community pharmacy, and 4.2 between community pharmacy and a general practitioner's appointment. CONCLUSION: Hospital discharge prescriptions are complex and present a significant risk of medication errors. Community pharmacists play a key role in preventing and identifying drug-related problems.

Elevated acute phase proteins affect pharmacokinetics in COVID-19 trials: Lessons from the CounterCOVID - imatinib study.

This study aimed to determine whether published pharmacokinetic (PK) models can adequately predict the PK profile of imatinib in a new indication, such as coronavirus disease 2019 (COVID-19). Total (bound + unbound) and unbound imatinib plasma concentrations obtained from 134 patients with COVID-19 participating in the CounterCovid study and from an historical dataset of 20 patients with gastrointestinal stromal tumor (GIST) and 85 patients with chronic myeloid leukemia (CML) were compared. Total imatinib area under the concentration time curve (AUC), maximum concentration (Cmax ) and trough concentration (Ctrough ) were 2.32-fold (95% confidence interval [CI] 1.34-3.29), 2.31-fold (95% CI 1.33-3.29), and 2.32-fold (95% CI 1.11-3.53) lower, respectively, for patients with CML/GIST compared with patients with COVID-19, whereas unbound concentrations were comparable among groups. Inclusion of alpha1-acid glycoprotein (AAG) concentrations measured in patients with COVID-19 into a previously published model developed to predict free imatinib concentrations in patients with GIST using total imatinib and plasma AAG concentration measurements (AAG-PK-Model) gave an estimated mean (SD) prediction error (PE) of -20% (31%) for total and -7.0% (56%) for unbound concentrations. Further covariate modeling with this combined dataset showed that in addition to AAG; age, bodyweight, albumin, CRP, and intensive care unit admission were predictive of total imatinib oral clearance. In conclusion, high total and unaltered unbound concentrations of imatinib in COVID-19 compared to CML/GIST were a result of variability in acute phase proteins. This is a textbook example of how failure to take into account differences in plasma protein binding and the unbound fraction when interpreting PK of highly protein bound drugs, such as imatinib, could lead to selection of a dose with suboptimal efficacy in patients with COVID-19.

Optimizing Oral Targeted Anticancer Therapies Study for Patients With Solid Cancer: Protocol for a Randomized Controlled Medication Adherence Program Along With Systematic Collection and Modeling of Pharmacokinetic and Pharmacodynamic Data.

BACKGROUND: The strengthening or substitution of intravenous cytotoxic chemotherapy cycles by oral targeted anticancer therapies, such as protein kinase inhibitors (PKIs), has provided impressive clinical benefits and autonomy as well as a better quality of life for patients with cancer. Despite these advances, adverse event management at home and medication adherence remain challenging. In addition, PKI plasma concentrations vary significantly among patients with cancer receiving the same dosage, which could explain part of the observed variability in the therapeutic response. OBJECTIVE: The aim of this optimizing oral targeted anticancer therapies (OpTAT) study is to optimize and individualize targeted anticancer treatments to improve patient care and self-monitoring through an interprofessional medication adherence program (IMAP) combined with measurement PKI plasma concentrations. METHODS: The OpTAT study has two parts: (1) a 1:1 randomized medication adherence program, in which the intervention consists of regular motivational interviewing sessions between the patient and the pharmacist, along with the delivery of PKIs in electronic monitors, and (2) a systematic collection of blood samples and clinical and biological data for combined pharmacokinetic and pharmacodynamic analysis. On the basis of the electronic monitor data, medication adherence will be compared between groups following the three operational definitions: implementation of treatment during the persistent period, persistence with treatment and longitudinal adherence. The implementation will be described using generalized estimating equation models. The persistence of PKI use will be represented using a Kaplan-Meier survival curve. Longitudinal adherence is defined as the product of persistence and implementation. PKI pharmacokinetics will be studied using a population approach. The relationship between drug exposure and efficacy outcomes will be explored using Cox regression analysis of progression-free survival. The relationship between drug exposure and toxicity will be analyzed using a pharmacokinetic-pharmacodynamic model and by logistic regression analysis. Receiver operating characteristic analyses will be applied to evaluate the best exposure threshold associated with clinical benefits. RESULTS: The first patient was included in May 2015. As of June 2021, 262 patients had participated in at least one part of the study: 250 patients gave at least one blood sample, and 130 participated in the adherence study. Data collection is in process, and the final data analysis is planned to be performed in 2022. CONCLUSIONS: The OpTAT study will inform us about the effectiveness of the IMAP program in patients with solid cancers treated with PKIs. It will also shed light on PKI pharmacokinetic and pharmacodynamic properties, with the aim of learning how to adapt the PKI dosage at the individual patient level to increase PKI clinical suitability. The IMAP program will enable interprofessional teams to learn about patients' needs and to consider their concerns about their PKI self-management, considering the patient as an active partner. TRIAL REGISTRATION: ClinicalTrials.gov NCT04484064; https://clinicaltrials.gov/ct2/show/NCT04484064. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/30090.

Using risk analysis to ensure patients' medication safety during hospital relocations and evacuations.

OBJECTIVES: To ensure patient safety and the preparedness of medication processes during hospital relocations and evacuations by using Failure Modes, Effects, and Criticality Analysis (FMECA). METHODS: The relocation of six regional hospitals to a single building, resulting in 400 beds being moved, could be compared with an emergency evacuation. An FMECA was performed on the hospital group's internal medicine and intensive care units (IMU and ICU), examining how medication processes would be affected by a hospital relocation or evacuation. RESULTS: We identified 59 hospital relocation and 68 evacuation failure modes. Failure modes were ranked based on their criticality index (CI; range 1-810). The higher the CI, the greater the patient-related risk. Average initial IMU and ICU hospital relocation CI scores were 160 (range 105-294) and 201 (range 125-343), respectively, subsequently reduced to 32 (-80%) and 49 (-76%) after mitigation measures. Average initial IMU and ICU evacuation CI scores were 319 (range 245-504) and 592 (range 441-810), respectively, subsequently reduced to 194 (-39%) and 282 (-52%). Most mitigation measures (17/22), such as for example checklists, could be implemented in both situations. Due to their unpredictable nature, five measures were specific to evacuation situations. CONCLUSIONS: This study highlights the value of using an FMECA on medication processes to anticipate potential negative impacts on patient safety during hospital relocations or evacuations. Preparation for a hospital relocation can provide useful knowledge and an opportunity to test mitigation measures that might prove useful in evacuations.

Using risk analysis to anticipate and mitigate failures during a hospital pharmacy relocation.

OBJECTIVES: Documented experiences of relocating hospital pharmacies are rare, but adequate preparation is vital to ensuring smooth pharmacy operation and patient safety. In the autumn of 2019, the Pharmacy of Eastern Vaud Hospitals, composed of four units (Logistics, Manufacturing, Clinical Pharmacy, and Nursing Home Supply), was relocated to a new hospital in just a few days. In this context, a failure modes, effects and criticality analysis (FMECA) was carried out before the relocation in order to anticipate any failure modes likely to affect the pharmacy's missions or patient safety during the move. METHODS: The FMECA was performed by a multidisciplinary team (pharmacists and logisticians) which analysed the complete upcoming process of relocating the pharmacy and its implications. Criticality indices (CIs) were defined based on the matrix developed by Williams et al, which sets a maximum score of 810. Every potential failure mode identified was analysed, and mitigation measures were proposed for each one. RESULTS: The analysis identified 86 potential failures. The mean initial CI calculated for the entire pharmacy relocation was 177 (min 4-max 567), but this was estimated to be reduced to 39 (-78%) after mitigation measures were identified. Within the whole pharmacy, the failures with the highest CIs were identified in the Logistics unit. Among these, the time necessary to transfer the pharmacy's drugs from their traditional alphabetical storage location to their new location using robotic, chaotic storage principles was identified as the riskiest potential failure. Indeed, the rapid availability of emergency medicines would have to be guaranteed at all times. CONCLUSIONS: The present study highlighted the relevance of using an FMECA-type evaluation to anticipate the impact of a hospital pharmacy relocation. This tool enabled pharmacy professionals to structure their potential relocation problems and reflect on mitigation measures in order to provide concerted, realistically applicable solutions before the move.

Emergency and Disaster Preparedness of European Hospital Pharmacists: A Survey.

OBJECTIVE: This study was focused on reviewing the emergency and disaster preparedness of European hospital pharmacists. METHODS: An online survey based on International Pharmaceutical Federation (FIP) guidelines for natural disasters was sent to European hospital pharmacies, with the support of the European Association of Hospital Pharmacists. Additional questions were added about the characteristics of respondents, as well as preparedness and experience of manmade disasters. Descriptive statistics were used to analyze the results. RESULTS: Hospital pharmacists in France (20%) and Spain (19%) returned most of the 306 questionnaires completed in 27 countries. Half of the respondents had analyzed their regional disaster risk, but 65% had never practiced emergency drills. Fifteen percent of respondents had experienced at least 1 major emergency or disaster event in the last 5 years. Fifty-six percent of those respondents who experienced a disaster subsequently created and promoted internal standard operating procedures (SOPs) for future emergencies, versus 23% for those who had not experienced disasters. Among pharmacists having experienced disasters, 40% organized a post-disaster debriefing to improve their future response. CONCLUSIONS: Results highlighted that most European hospital pharmacists were not fully compliant with FIP guidelines. However, respondents who had experienced disasters were more likely to create and promote SOPs for future disasters. Further worldwide analysis and benchmarking are necessary, and FIP guidelines should be more strongly promoted.

Population Pharmacokinetics of Erlotinib in Patients With Non-small Cell Lung Cancer: Its Application for Individualized Dosing Regimens in Older Patients.

PURPOSE: Erlotinib is an oral first-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor approved for non-small cell lung cancers (NSCLC) with EGFR-activating mutations. Older patients experience more toxicities compared with younger patients at the standard recommended dose of 150 mg once daily. The aims of this study were to describe the pharmacokinetic profile of erlotinib in unselected patients with NSCLC, to quantify and explain its variability, to challenge the standard recommended dose in older patients, and to propose clinical recommendations for the therapeutic management of patients taking erlotinib. METHODS: A population pharmacokinetic model was developed using erlotinib plasma concentrations collected from patients with NSCLC participating in a routine therapeutic drug monitoring program (with the nonlinear mixed effect modeling program NONMEM). Relevant demographic characteristics, clinical factors, and co-medications were tested as potential covariates. An independent dataset was used for model validation. Simulations based on the final model allowed comparison of expected erlotinib concentrations under standard and alternative dosing regimens for smokers and for several age groups. FINDINGS: A total of 481 erlotinib plasma concentrations from 91 patients with NSCLC were used for model building and 239 plasma drug concentrations from 107 patients for model validation. A one-compartment model with first-order absorption and elimination provided the best fit. Average erlotinib CL/F with interindividual variability (%CV) was 3.8 L/h (41.5%), and V/F was 166 L (53.8%). The absorption rate constant was 1.48 h-1. The external validation showed a negligible bias of -4% (95% CI, -7 to -1) in the individual predictions, with a precision of 23%. Current smoking and use of proton pump inhibitors were associated with higher CL/F, whereas age was associated with lower CL/F. Simulations suggest that a lower dose in older patients would decrease the risk of overexposure. IMPLICATIONS: This large cohort study confirms the substantial interindividual variability in erlotinib plasma exposure and the impact of smoking and proton pump inhibitor intake. This large variability in erlotinib pharmacokinetics indicates that the standard recommended dose of 150 mg once daily is likely not appropriate to reach the expected concentrations in each patient. Concentration monitoring should be performed to individually adjust the erlotinib dosing regimen. The observed decrease in erlotinib CL/F with age suggests that a lower starting daily dose of 100 mg with concentration-guided dose adjustment would prevent overexposure and potential toxicity in older frail patients with co-morbidities.

The Steps to Therapeutic Drug Monitoring: A Structured Approach Illustrated With Imatinib.

Pharmacometric methods have hugely benefited from progress in analytical and computer sciences during the past decades, and play nowadays a central role in the clinical development of new medicinal drugs. It is time that these methods translate into patient care through therapeutic drug monitoring (TDM), due to become a mainstay of precision medicine no less than genomic approaches to control variability in drug response and improve the efficacy and safety of treatments. In this review, we make the case for structuring TDM development along five generic questions: 1) Is the concerned drug a candidate to TDM? 2) What is the normal range for the drug's concentration? 3) What is the therapeutic target for the drug's concentration? 4) How to adjust the dosage of the drug to drive concentrations close to target? 5) Does evidence support the usefulness of TDM for this drug? We exemplify this approach through an overview of our development of the TDM of imatinib, the very first targeted anticancer agent. We express our position that a similar story shall apply to other drugs in this class, as well as to a wide range of treatments critical for the control of various life-threatening conditions. Despite hurdles that still jeopardize progress in TDM, there is no doubt that upcoming technological advances will shape and foster many innovative therapeutic monitoring methods.

Therapeutic Drug Monitoring of Targeted Anticancer Protein Kinase Inhibitors in Routine Clinical Use: A Critical Review.

BACKGROUND: Therapeutic response to oral targeted anticancer protein kinase inhibitors (PKIs) varies widely between patients, with insufficient efficacy of some of them and unacceptable adverse reactions of others. There are several possible causes for this heterogeneity, such as pharmacokinetic (PK) variability affecting blood concentrations, fluctuating medication adherence, and constitutional or acquired drug resistance of cancer cells. The appropriate management of oncology patients with PKI treatments thus requires concerted efforts to optimize the utilization of these drug agents, which have probably not yet revealed their full potential. METHODS: An extensive literature review was performed on MEDLINE on the PK, pharmacodynamics, and therapeutic drug monitoring (TDM) of PKIs (up to April 2019). RESULTS: This review provides the criteria for determining PKIs suitable candidates for TDM (eg, availability of analytical methods, observational PK studies, PK-pharmacodynamics relationship analysis, and randomized controlled studies). It reviews the major characteristics and limitations of PKIs, the expected benefits of TDM for cancer patients receiving them, and the prerequisites for the appropriate utilization of TDM. Finally, it discusses various important practical aspects and pitfalls of TDM for supporting better implementation in the field of cancer treatment. CONCLUSIONS: Adaptation of PKIs dosage regimens at the individual patient level, through a rational TDM approach, could prevent oncology patients from being exposed to ineffective or unnecessarily toxic drug concentrations in the era of personalized medicine.

Comparison against current standards of a DNA aptamer for the label-free quantification of tobramycin in human sera employed for therapeutic drug monitoring.

The use of DNA aptamers in biosensors for the quantification of pharmaceuticals in the clinics would help to overcome the limitations of antibody-based detection for small molecules. The interest for such systems is proven by the ever-increasing number of aptamer-based solutions for analytics proposed in the literature as proof-of-concept demonstrators. Despite such diversity, these platforms often lack a comparative assessment of their performances against the current standard of practice in the clinics when using real samples. We employed an aptamer against tobramycin discovered in our laboratory to quantify through surface plasmon resonance the concentration of the antibiotic in clinical samples obtained from patients treated with tobramycin and undergoing therapeutic drug monitoring. We then compared the performances of our detection strategy against the current standard of practice. Our results show how, using adequate calibration and matrix complexity reduction, DNA aptamer-based direct assays can assess clinically relevant concentrations of small molecules in patient serum and with good correlation to current standards used in the clinics.

Quantification of the next-generation oral anti-tumor drugs dabrafenib, trametinib, vemurafenib, cobimetinib, pazopanib, regorafenib and two metabolites in human plasma by liquid chromatography-tandem mass spectrometry.

A sensitive and selective method of high performance liquid chromatography (HPLC) coupled to tandem mass spectrometry (MS/MS) has been developed for the simultaneous quantification of six anticancer protein kinase inhibitors (PKIs), dabrafenib, trametinib, vemurafenib, cobimetinib, pazopanib, regorafenib, and two active metabolites (regorafenib-M2 and regorafenib-M5) in human plasma. Plasma protein precipitation with methanol enables the sample extraction of 100 µL aliquot of plasma. Analytes are detected by electrospray triple-stage quadrupole mass spectrometry and quantified using the calibration curves with stable isotope-labeled internal standards. The method was validated based on FDA recommendations, including assessment of extraction yield (74-104%), matrix effects, analytical recovery (94-104%) with low variability (<15%). The method is sensitive (lower limits of quantification within 1 to 200 ng/mL), accurate (intra- and inter-assay bias: -0.3% to +12.7%, and -3.2% to +6.3%, respectively) and precise (intra- and inter-assay CVs within 0.7-7.3% and 2.5-8.0%, respectively) over the clinically relevant concentration range (upper limits of quantification 500 to 100,000 ng/mL). This method is applied in our laboratory for both clinical research programs and routine therapeutic drug monitoring service of PKIs.

Effect of Adherence on Pharmacokinetic/Pharmacodynamic Relationships of Oral Targeted Anticancer Drugs.

The emergence of oral targeted anticancer agents transformed several cancers into chronic conditions with a need for long-term oral treatment. Although cancer is a life-threatening condition, oncology medication adherence-the extent to which a patient follows the drug regimen that is intended by the prescriber-can be suboptimal in the long term, as in any other chronic disease. Poor adherence can impact negatively on clinical outcomes, notably because most of these drugs are given as a standard non-individualized dosage despite marked inter-individual variabilities that can lead to toxic or inefficacious drug concentrations. This has been especially studied with the prototypal drug imatinib. In the context of therapeutic drug monitoring (TDM), increasingly advocated for oral anticancer treatment optimization, unreported suboptimal adherence affecting drug intake history may lead to significant bias in the concentration interpretation and inappropriate dosage adjustments. In the same way, suboptimal adherence may also bias the results of pharmacokinetic modeling studies, which will affect in turn Bayesian TDM interpretation that relies on such population models. Detailed knowledge of the influence of adherence on plasma concentrations in pharmacokinetic studies or in routine TDM programs is however presently missing in the oncology field. Studies on this topic are therefore eagerly awaited to better pilot the treatment of cancer with the new targeted agents and to find their optimal dosage regimen. Hence, the development and assessment of effective medication adherence programs are warranted for these treatments.