Development and validation of a multiplex HPLC-MS/MS assay for the monitoring of JAK inhibitors in patient plasma.

Janus kinase inhibitors (JAKi) are oral small molecules used in the treatment of a broad spectrum of autoimmune and myeloproliferative diseases. JAKi exhibit significant intra- and inter-individual pharmacokinetic variabilities, due to fluctuations in compliance with oral treatments and their metabolism essentially driven by cytochrome P450 enzymes. Intrinsically, JAKi have dose-response relationship and narrow therapeutic index: therapeutic drug monitoring (TDM) is expected to optimize and adapt their dosage regimen in order to resolve problems of efficacy and tolerance linked to dose and safety. A sensitive analytical method using multiplex high-performance liquid-chromatography coupled to tandem mass spectrometry (HPLC-MS/MS) was developed and validated for the simultaneous quantification in plasma of the 6 major currently used JAKi, namely abrocitinib, baricitinib, fedratinib, ruxolitinib, tofacitinib, and upadacitinib. Plasma samples are subjected to protein precipitation with MeOH, using stable isotopically labelled internal standards. The separation of JAKi in supernatants diluted 1:1 with ultrapure H2O was performed using a C18 column Xselect HSS T3 2.5 µm, 2.1x150 mm using a mobile phase composed of formic acid (FA) 0.2% and acetonitrile (+FA 0.1%) in gradient mode. The analytical run time for the multiplex assay was 7 min. JAKi drugs were monitored by electrospray ionization in the positive mode followed by triple-stage quadrupole MS/MS analysis. The method was validated according to SFSTP and ICH guidelines over the clinically relevant concentration ranges (0.5-200 ng/mL for abrocitinib, baricitinib and upadacitinib; 1-400 ng/mL for tofacitinib; 0.5-400 ng/mL for ruxolitinib, and 10-800 ng/mL for fedratinib). This multiplex HPLC-MS/MS assay achieved good performances in term of trueness (91.1-113.5%), repeatability (3.0-9.9%), and intermediate precision (4.5-11.3%). We developed and validated a highly sensitive method for the multiplex quantification of the JAKi abrocitinib, baricitinib, fedratinib, ruxolitinib, tofacitinib, and upadacitinib in human plasma. The method will be applied for prospective clinical pharmacokinetic studies to determine whether TDM programs for JAKi based on residual drug concentrations can be recommended using disease-specific therapeutic ranges.

Clinically relevant bidirectional drug-drug interaction between midostaurin and voriconazole.

Midostaurin is often prescribed with azole antifungals in patients with leukaemia, either for aspergillosis prophylaxis or treatment. Midostaurin is extensively metabolized by cytochrome (CYP) 3A4. In addition, it inhibits and induces various CYPs at therapeutic concentrations. Thus, midostaurin is associated with a high potential for drug-drug interactions (DDIs), both as a substrate (victim) and as a perpetrator. However, data on midostaurin as a perpetrator of DDIs are scarce, as most pharmacokinetic studies have focused on midostaurin as a victim drug. We report a clinically relevant bidirectional DDI between midostaurin and voriconazole during induction treatment. A 49-year-old woman with acute myeloid leukaemia developed invasive pulmonary aspergillosis after induction chemotherapy. She was treated with voriconazole at standard dosage. Six days after starting midostaurin, she developed visual hallucinations with a concurrent sharp increase in voriconazole blood concentration (Ctrough 10.3 mg L-1 , target Ctrough 1-5 mg L-1 ). Neurotoxicity was considered to be related to voriconazole overexposure. The concentration of midostaurin was concomitantly six-fold above the average expected level, but without safety issues. Midostaurin was stopped and the dosage of voriconazole was adjusted with therapeutic drug monitoring. The evolution was favourable, with quick resolution and no recurrence of visual hallucinations. To our knowledge, this is the first case suggesting that midostaurin and voriconazole reciprocally inhibit each other's metabolism, leading to increased exposure of both. This case highlights the knowledge gap regarding drug-drug interactions between midostaurin and azole antifungals. Close clinical and therapeutic drug monitoring is advised in such cases.

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.

Implementation and Cross-Validation of a Pharmacokinetic Model for Precision Dosing of Busulfan in Hematopoietic Stem Cell Transplanted Children.

Busulfan, a drug used in conditioning prior to hematopoietic stem cell transplantation (HSCT) in children, has a narrow therapeutic margin. The model-informed precision dosing (MIPD) of busulfan is desirable, but there is a lack of validated tools. The objective of this study was to implement and cross-validate a population pharmacokinetic (PK) model in the Tucuxi software for busulfan MIPD in HSCT children. A search of the literature was performed to identify candidate population PK models. The goodness of fit of three selected models was assessed in a dataset of 178 children by computing the mean error (ME) and root-mean-squared error of prediction (RMSE). The best model was implemented in Tucuxi. The individual predicted concentrations, the area under the concentration-time curve (AUC), and dosage requirements were compared between the Tucuxi model and a reference model available in the BestDose software in a subset of 61 children. The model from Paci et al. best fitted the data in the full dataset. In a subset of 61 patients, the predictive performance of Tucuxi and BestDose models was comparable with ME values of 6.4% and -2.5% and RMSE values of 11.4% and 13.6%, respectively. The agreement between the estimated AUC and the predicted dose was good, with 6.6% and 4.9% of the values being out of the 95% limits of agreement, respectively. To conclude, a PK model for busulfan MIPD was cross-validated and is now available in the Tucuxi software.

[Janus kinase inhibitors : new perspectives for precision medicine ?] / Inhibiteurs des Janus kinases : nouvelles perspectives pour la médecine de précision ?

Janus kinase inhibitors (JAKi), such as tofacitinib, baricitinib, upadacitinib or ruxolitinib, are small molecules active on specific intracellular targets and used orally for the treatment of autoimmune or myeloproliferative diseases. Their remarkable therapeutic efficacy is offset by a significant risk of toxicities, essentially dose-dependent and a variable pharmacokinetic profile. The JAKi represent a new therapeutic armamentarium for treating autoimmune, myeloproliferative and inflammatory diseases (incl. COVID-19), but require thorough treatment individualization and close monitoring. Therapeutic Drug Monitoring (TDM) of JAKi could allow a personalized prescription and improve the efficacy-toxicity profile.

Les inhibiteurs des Janus kinases (JAKi), tels que le tofacitinib, le baricitinib, l'upadacitinib ou le ruxolitinib, représentent une nouvelle classe de petites molécules actives sur des cibles intra-cellulaires spécifiques, utilisables par voie orale pour traiter des maladies autoimmunes ou néoplasies myéloprolifératives. Leur efficacité thérapeutique remarquable est contrebalancée par un risque significatif de toxicités essentiellement dose-dépendantes et un profil pharmacocinétique variable. Les JAKi constituent une nouvelle arme thérapeutique pour le traitement des maladies autoimmunes, myéloprolifératives et inflammatoires (Covid-19), mais nécessitent une individualisation et un suivi attentifs. Le suivi thérapeutique des médicaments des JAKi pourrait permettre de personnaliser leur prescription et améliorer leur profil efficacité-toxicité.

Quantification of serotonin and eight of its metabolites in plasma of healthy volunteers by mass spectrometry.

Serotonin is transformed into melatonin under the control of the light/dark cycle, representing a cornerstone of circadian rhythmicity. Serotonin also undergoes extensive metabolism to produce 5-hydroxyindoleacetic acid (5-HIAA), a biomarker for the diagnosis and monitoring of serotonin secreting neuroendocrine tumors (NETs). While serotonin, melatonin and their metabolites are part of an integrated comprehensive system, human observations about their respective plasma concentrations are still limited. We report here for the first time a multiplex UHPLC-MS/MS assay for the quantification of serotonin, 5-HIAA, 5-hydroxytryptophol (5-HTPL), N-acetyl-serotonin (NAS), Mel, 6-OH-Mel, 5-methoxytryptamine (5-MT), 5-methoxytryptophol (5-MTPL), and 5-methoxyindoleacetic acid (5-MIAA) in human plasma. Analytes were extracted by protein precipitation and solid phase extraction. Plasma concentrations for these analytes were determined in 102 healthy volunteers. The LLOQ of the assay ranges from 2.2 nM for serotonin to 1.0 pM for 6-OH-Mel. This sensitivity enables the quantification of circulating serotonin, 5-HIAA, NAS, Mel, and 5-MIAA, even at their lowest diurnal concentrations. This assay will enable specific, precise and accurate measurement of serotonin, Mel and their metabolites to draw a detailed picture of this complex pineal metabolism, allowing a dynamic understanding of these pathways and providing promising biomarkers and a metabolic signature for serotonin-secreting NETs.

[Medicines, sex and gender]. / Médicaments, sexe et genre.

Sex-related differences affecting pharmacokinetic and pharmacodynamic processes result mostly from sex dimorphisms in body composition, and liver and kidney function, in addition to hormonal regulation of enzymes, transporters and drug receptors. Gender biases have long compromised the identification of these differences in clinical trials. They also modulate prescription patterns and therapeutic benefits. Men and women would benefit from different standard dosages of some anti-infectives, anticancer agents and other treatments requiring precise dosage adjustment. This would alleviate the well-documented excess of adverse reactions affecting women. However, the variability of pharmacological responses within each sex exceeds the average male-female difference, highlighting the importance of other criteria for therapeutic individualisation.

Les processus pharmacocinétiques et pharmacodynamiques reflètent les dimorphismes sexuels affectant la composition corporelle, les fonctions rénale, hépatique et la régulation des enzymes, transporteurs et récepteurs de médicaments. Des biais liés au genre ont longtemps compromis l'identification de ces différences dans les essais cliniques. Ils modulent aussi la prescription et le bénéfice thérapeutique. Des posologies standard différentes entre hommes et femmes mériteraient d'être proposées pour certains anti-infectieux, anticancéreux et autres traitements requérant un ajustement posologique précis. Cela atténuerait le surcroît démontré d'effets indésirables touchant les femmes. La variabilité des réponses pharmacologiques dans chaque sexe excède la différence moyenne hommes-femmes, rappelant l'importance d'autres critères d'individualisation thérapeutique.

Fractures After Denosumab Discontinuation: A Retrospective Study of 797 Cases.

A rebound of osteoclast activity during the 2 years after a treatment or prevention of osteoporosis with denosumab (Dmab) leads to an increased risk of vertebral fractures (VFs). We attempted to identify the risk factors for these VF and to examine the protective role of bisphosphonates. For that, 22 specialists in Switzerland provided data of unselected patients, treated with denosumab for osteoporosis or breast cancer without metastases under aromatase inhibitors, who have received at least two injections of Dmab, with at least 1 year of follow-up after discontinuation. The questionnaire covered separately the periods before, during, and after Dmab treatment, and registered clinical, radiological, and lab data. For the analysis of the risk factors, the main outcomes were the time to the first VF after the treatment, the presence of multiple VFs (MVFs), and the number of VFs. The incidence of VF was 16.4% before, 2.2% during, and 10.3% after the treatment with Dmab. The risk of VF after Dmab discontinuation was associated with an increased risk of non-vertebral fractures. The pretreatment predictors of the post-treatment fracture risk were a parental hip fracture and previous VFs. Further risk factors appeared later, such as low total hip bone mineral density (BMD) during and after denosumab, increased bone resorption markers, and the loss of total hip BMD after the denosumab. Treatment with bisphosphonates, especially after Dmab, had a protective effect. Bisphosphonates given before Dmab did not further decrease the risk of VF in cases who got bisphosphonates after Dmab. This study shows that the risk of VF is poorly predictable before the prescription of denosumab. But during and after the treatment, bone resorption markers and BMD have a significant predictive value. Bisphosphonates after the treatment with denosumab are protective against VFs. © 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Ensuring Sufficient Trough Plasma Concentrations for Broad-Spectrum Beta-Lactam Antibiotics in Children With Malignancies: Beware of Augmented Renal Clearance!

Introduction: Broad-spectrum beta-lactams are commonly prescribed for empirical or selective treatment of bacterial infections in children with malignancies. In the immunocompromised, appropriate concentration exposure is crucial to ensure antimicrobial efficacy. Augmented renal clearance (ARC) is increasingly recognized in this population, and raises concern for unmet concentration targets. We conducted a retrospective evaluation of meropenem and piperacillin exposure in our hospital's pediatric hematology-oncology patients. Materials and Methods: We compared trough levels of meropenem and piperacillin in a cohort of unselected pediatric hematology-oncology patients stratified based on their estimated renal function as decreased, normal or with ARC, and on their neutrophil count. Results: Thirty-two children provided a total of 51 meropenem and 76 piperacillin samples. On standard intermittent intravenous regimen, 67% of all trough plasma concentrations were below targeted concentrations. In neutropenic children with bacterial infection, all meropenem and 60% of piperacillin levels were below target. Nearly two-thirds of total samples came from children with ARC. In these patients, antimicrobial exposure was insufficient in 85% of cases (compared to 36% in the decreased or normal renal function groups), despite a dosage sometimes exceeding the maximum recommended daily dose. Under continuous infusion of piperacillin, only 8% of plasma levels were insufficient. Discussion: Intermittent administration of meropenem and piperacillin often fails to ensure sufficient concentration exposure in children treated for malignancies, even at maximal recommended daily dosage. This can in part be attributed to ARC. We recommend thorough assessment of renal function, resolute dosage adjustment, continuous infusion whenever possible and systematic therapeutic drug monitoring.

Influence of Drug-Drug Interactions on the Pharmacokinetics of Atorvastatin and Its Major Active Metabolite ortho-OH-Atorvastatin in Aging People Living with HIV.

BACKGROUND: People living with HIV (PLWH) are aging and experience age-related physiological changes and comorbidities. Atorvastatin is a widely prescribed lipid-lowering agent metabolized by cytochrome P450 (CYP) 3A4, whose hepatocyte uptake is facilitated by organic anion transporting polypeptide (OATP) 1B1/1B3. Inhibition or induction of this enzyme and hepatic transporter can increase or decrease atorvastatin exposure, respectively. OBJECTIVE: This study aimed to describe the pharmacokinetic profile of atorvastatin and its major metabolite, and to evaluate drug-drug interactions (DDIs) with antiretrovirals (ARVs). METHODS: The atorvastatin pharmacokinetic profile was best described by a two-compartment model with first-order absorption and elimination. Metabolite concentrations were described by considering both linear metabolism from atorvastatin and presystemic metabolism. The influence of demographic and clinical covariates on drug and metabolite pharmacokinetics was assessed using NONMEM®. Model-based simulations were performed to evaluate the magnitude of DDIs with ARVs. RESULTS: Full pharmacokinetic profiles (98 atorvastatin + 62 o-OH-atorvastatin concentrations) and sparse concentrations (78 and 53 for atorvastatin and o-OH-atorvastatin, respectively) were collected in 59 PLWH. Interindividual variability was high. The coadministration of boosted ARVs decreased atorvastatin clearance by 58% and slowed down o-OH-atorvastatin formation by 88%. Atorvastatin clearance increased by 78% when coadministered with CYP3A4 inducers. Simulations revealed a 180% increase and 44% decrease in atorvastatin exposure (area under the curve) in the presence of ARVs with inhibiting and inducing properties, respectively. CONCLUSION: This study showed an important interindividual variability in atorvastatin pharmacokinetics that remains largely unexplained after the inclusion of covariates. Since boosted ARVs double atorvastatin exposure, the initial dosage might be reduced by half, and titrated based on individual clinical targets.

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.

UHPLC-MS/MS assay for simultaneous determination of amlodipine, metoprolol, pravastatin, rosuvastatin, atorvastatin with its active metabolites in human plasma, for population-scale drug-drug interactions studies in people living with HIV.

Thanks to highly active antiretroviral treatments, HIV infection is now considered as a chronic condition. Consequently, people living with HIV (PLWH) live longer and encounter more age-related chronic co-morbidities, notably cardiovascular diseases, leading to polypharmacy. As the management of drug-drug interactions (DDIs) constitutes a key aspect of the care of PLWH, the magnitude of pharmacokinetic DDIs between cardiovascular and anti-HIV drugs needs to be more thoroughly characterized. To that endeavour, an UHPLC-MS/MS bioanalytical method has been developed for the simultaneous determination in human plasma of amlodipine, metoprolol, pravastatin, rosuvastatin, atorvastatin and its active metabolites. Plasma samples were subjected to protein precipitation with methanol, followed by evaporation at room temperature under nitrogen of the supernatant, allowing to attain measurable plasma concentrations down to sub-nanogram per milliliter levels. Stable isotope-labelled analytes were used as internal standards. The five drugs and two metabolites were analyzed using a 6-min liquid chromatographic run coupled to electrospray triple quadrupole mass spectrometry detection. The method was validated over the clinically relevant concentrations ranging from 0.3 to 480 ng/mL for amlodipine, atorvastatin and p-OH-atorvastatin, and 0.4 to 480 ng/mL for pravastatin, 0.5 to 480 ng/mL for rosuvastatin and o-OH-atorvastatin, and 3 to 4800 ng/mL for metoprolol. Validation performances such as trueness (95.4-110.8%), repeatability (1.5-13.4%) and intermediate precision (3.6-14.5%) were in agreement with current international recommendations. Accuracy profiles (total error approach) were lying within the limits of ±30% accepted in bioanalysis. This rapid and robust UHPLC-MS/MS assay allows the simultaneous quantification in plasma of the major currently used cardiovascular drugs and offers an efficient analytical tool for clinical pharmacokinetics as well as DDIs studies.

Population pharmacokinetics of dolutegravir: influence of drug-drug interactions in a real-life setting.

OBJECTIVES: Dolutegravir is widely prescribed owing to its potent antiviral activity, high genetic barrier and good tolerability. The aim of this study was to characterize dolutegravir's pharmacokinetic profile and variability in a real-life setting and to identify individual factors and co-medications affecting dolutegravir disposition. METHODS: A population pharmacokinetic model was developed using NONMEM®. Relevant demographic factors, clinical factors and co-medications were tested as potential covariates. Simulations based on the final model served to compare expected dolutegravir concentrations under standard and alternative dosage regimens in the case of drug-drug interactions. RESULTS: A total of 620 dolutegravir plasma concentrations were collected from 521 HIV-infected individuals under steady-state conditions. A one-compartment model with first-order absorption and elimination best characterized dolutegravir pharmacokinetics. Typical dolutegravir apparent clearance (CL/F) was 0.93 L/h with 32% between-subject variability, the apparent volume of distribution was 20.2 L and the absorption rate constant was fixed to 2.24 h-1. Older age, higher body weight and current smoking were associated with higher CL/F. Atazanavir co-administration decreased dolutegravir CL/F by 38%, while darunavir modestly increased CL/F by 14%. Rifampicin co-administration showed the largest impact on CL/F. Simulations suggest that average dolutegravir trough concentrations are 63% lower after 50 mg/12h with rifampicin compared with a standard dosage of 50 mg/24h without rifampicin. Average trough concentrations after 100 mg/24h and 100 mg/12h with rifampicin are 92% and 25% lower than the standard dosage without rifampicin, respectively. CONCLUSIONS: Patients co-treated with dolutegravir and rifampicin might benefit from therapeutic drug monitoring and individualized dosage increase, up to 100 mg/12 h in some cases.

Complementary medicine use during cancer treatment and potential herb-drug interactions from a cross-sectional study in an academic centre.

Complementary medicine (CM) is used by one third to one half of cancer patients throughout the world. The objective of this study was to describe the prevalence of CM use and the potential for interactions with cancer treatments in an academic oncology centre. A cross-sectional study was conducted among patients undergoing current cancer treatment. Among 132 included patients, 56% had used CM since their cancer diagnosis and 45% were using CM during cancer treatment at the time of the survey. The main CM used were green tea (35%), herbal tea (35%), homeopathy (27%), dietary supplements (27%), and herbal medicines (27%). A small majority of patients (58%) spontaneously mentioned the use of CM to their oncologist. Of 42 identified combinations of concomitant use of biologically based CM and anticancer agents among the study patients, the potential for pharmacokinetic interactions of clinical relevance was not expected in 17 combinations (40%), hypothetical and deemed unlikely in 23 (55%), and of probable low clinical relevance in 2 (5%). Considering the high prevalence of CM use, active enquiries should be made by healthcare professionals to detect symptoms that may relate to CM tolerance and effects or that suggest interactions between CM and cancer treatments.

Imatinib Uptake into Cells is Not Mediated by Organic Cation Transporters OCT1, OCT2, or OCT3, But is Influenced by Extracellular pH.

BACKGROUND: Cancer cells undergo genetic and environmental changes that can alter cellular disposition of drugs, notably by alterations of transmembrane drug transporters expression. Whether the influx organic cation transporter 1 (OCT1) encoded by the gene SLC221A1 is implicated in the cellular uptake of imatinib is still controversial. Besides, imatinib ionization state may be modulated by the hypoxic acidic surrounding extracellular microenvironment. OBJECTIVE: To determine the functional contribution of OCTs and extracellular pH on imatinib cellular disposition. METHODS: We measured imatinib uptake in two different models of selective OCTs drug transporter expression (transfected Xenopus laevis oocytes and OCT-expressing HEK293 human cells), incubated at pH 7.4 and 6, using specific mass spectrometry analysis. RESULTS: Imatinib cellular uptake occurred independently of OCT1- OCT2- or OCT3-mediated drug transport at pH 7.4. Uptake of the OCTs substrate tetraethylammonium in oocytes remained intact at pH 6, while the accumulation of imatinib in oocytes was 10-fold lower than at pH 7.4, irrespectively of OCTs expressions. In OCT1- and OCT2-HEK cells at pH 6, imatinib accumulation was reduced by 2- 3-fold regardless of OCTs expressions. Since 99.5% of imatinib at pH6 is under the cationic form, the reduced cellular accumulation of imatinib at such pH may be explained by the lower amount of uncharged imatinib remaining for passive diffusion across cellular membrane. CONCLUSION: Imatinib is not a substrate of OCTs 1-3 while the environmental pH modulates cellular disposition of imatinib. The observation that a slightly acidic extracellular pH influences imatinib cellular accumulation is important, considering the low extracellular pH reported in the hematopoietic leukemia/ cancer cell microenvironment.

Polypharmacy, Drug-Drug Interactions, and Inappropriate Drugs: New Challenges in the Aging Population With HIV.

BACKGROUND: Antiretroviral therapy has transformed HIV infection from a deadly into a chronic condition. Aging people with HIV (PWH) are at higher risk of polypharmacy, potential drug-drug interactions (DDIs), and potentially inappropriate medications (PIMs). This study aims to compare prescribed drugs, polypharmacy, and potential DDIs between young (<65 years old) and elderly (≥65 years old) PWH. The prevalence of PIMs was assessed in elderly. METHODS: PWH from 2 centers within the Swiss HIV Cohort Study were asked to fill in a form with all their current medications. Polypharmacy was defined as being on ≥5 non-HIV drugs. PIMs were evaluated using Beers criteria. Potential DDIs for the most prescribed therapeutic classes were screened with the Liverpool interaction database. RESULTS: Among the 996 PWH included, 122 were ≥65 years old. Polypharmacy was more frequent in the elderly group (44% vs 12%). Medications and potential DDIs differed according to the age group: cardiovascular drugs and related potential DDIs were more common in the elderly group (73% of forms included ≥1 cardiovascular drug; 11% of cardiovascular drugs involved potential DDIs), whereas central nervous system drugs were more prescribed and involved in potential DDIs in younger PWH (26%, 11%). Potential DDIs were mostly managed through dosage adjustments. PIMs were found in 31% of the elderly group. CONCLUSIONS: Potential DDIs remain common, and PIMs constitute an additional burden for the elderly. It is important that prescribers develop and maintain a proactive approach for the recognition and management of DDIs and other prescribing issues frequently encountered in geriatric medicine.

Sensitive quantification of the somatostatin analog AP102 in plasma by ultra-high pressure liquid chromatography-tandem mass spectrometry and application to a pharmacokinetic study in rats.

AP102 is a di-iodinated octapeptide somatostatin agonist (SSA) designed to treat acromegaly and neuroendocrine tumors. A sensitive and selective method was validated for the quantification of AP102 in plasma following the European Medicines Agency (EMA) and Food and Drug Administration (FDA) guidelines. Sample preparation was performed using solid-phase extraction microplates. Chromatographic separation was achieved on an ultra-high pressure liquid chromatography (UHPLC) C18 column in 6.0 minutes. The compounds were quantified using multiple reaction monitoring on a tandem quadrupole mass spectrometer with 13 C,15 N-labeled AP102 as internal standard. Calibration ranged from 50 to 10000 pg/mL. The lower limit of quantification (LLOQ) was measured at 20 pg/mL, and robust analytical performances were obtained with trueness at 99.2%-100.0%, intra-assay imprecision at 2.5%-4.4%, and inter-assay imprecision at 8.9%-9.7%. The accuracy profiles (total error) built on the 3 concentrations levels showed accuracy within the 70%-130% range. AP102 is remarkably stable since no proteolytic fragments were detected on plasma samples analyzed by Orbitrap-MS. Pharmacokinetic studies were conducted in rats, after single dose (1, 3, and 10 µg/kg, sc) and continuous subcutaneous administration (osmotic minipumps for 28 days, 3.0 or 10.0 µg/kg/h). AP102 showed a rapid absorption by the subcutaneous route (Tmax : 15-30 minutes) and a fast elimination (t1/2 : 33-86 minutes). The PK profile of AP102 exhibited a mean clearance of 1.67 L/h and a mean distribution volume at steady state of 7.16 L/kg, about 10-fold higher than those observed with other SSA or non- and mono-iodinated AP102. LogD7.4 determination confirmed the lipophilic properties of AP102 that might influence its distribution in tissues.