Early Exposure of Kidney Transplant Recipients with Chronic Antibody-Mediated Rejection to Tocilizumab-A Preliminary Study.

Tocilizumab prevents clinical worsening of chronic antibody-mediated rejection (CAMR) of kidney transplant recipients. Optimization of this treatment is necessary. We identified the determinants of early tocilizumab exposure (within the first three months) and investigated the relationship between early plasma tocilizumab exposure and graft function. Patients with CAMR who started treatment with tocilizumab were retrospectively included. Demographic, clinical, and biological determinants of the tocilizumab trough concentration (Cmin) were studied using a linear mixed effect model, and the association between early exposure to tocilizumab (expressed as the sum of Cmin over the three first months (M) of treatment (ΣCmin)) and the urinary albumin-to-creatinine ratio (ACR) determined at M3 and M6 were investigated. Urinary tocilizumab was also measured in seven additional patients. Seventeen patients with 51 tocilizumab Cmin determinations were included. In the multivariate analysis, the ACR and time after tocilizumab initiation were independently associated with the tocilizumab Cmin. The ΣCmin was significantly lower (p = 0.014) for patients with an ACR > 30 mg/mmol at M3 and M6 than for patients with an ACR < 30 mg/mmol. Tocilizumab was detected in urine in only 1/7 patients. This study is the first to suggest that early exposure to tocilizumab may be associated with macroalbuminuria within the first six months in CAMR patients.

Discrepancies between dihydropyrimidine dehydrogenase phenotyping and genotyping: What are the explanatory factors?

AIM: Dihydropyrimidine dehydrogenase (DPD) deficiency can be detected by phenotyping (measurement of plasma uracil [U], with U ≥ 16 µg/L defining a partial deficiency) and/or by genotyping (screening for the four most frequent DPYD variants). We aimed to determine the proportion of discrepancies between phenotypic and genotypic approaches and to identify possible explanatory factors. METHODS: Data from patients who underwent both phenotyping and genotyping were retrospectively collected. Complementary genetic analyses (genotyping of the variant c.557A>G and DPYD sequencing) were performed for patients with U ≥ 16 µg/L without any common variants. The characteristics of patients classified according to the congruence of the phenotyping and genotyping approaches were compared (Kruskal-Wallis test), and determinants of U levels were studied in the whole cohort (linear model). RESULTS: Among the 712 included patients, phenotyping and genotyping were discordant for 12.5%, with 63 (8.8%) having U ≥ 16 µg/L in the absence of a common variant. Complementary genetic investigations marginally reduced the percentage of discrepancies to 12.1%: Among the nine additional identified variants, only the c.557A>G variant, carried by three patients, had been previously reported to be associated with DPD deficiency. Liver dysfunction could explain certain discordances, as ASAT, ALP, GGT and bilirubin levels were significantly elevated, with more frequent liver metastases in patients with U ≥ 16 µg/L and the absence of a DPYD variant. The impact of cytolysis was confirmed, as ASAT levels were independently associated with increased U (p < 0.001). CONCLUSION: The frequent discordances between DPD phenotyping and genotyping approaches highlight the need to perform these two approaches to screen for all DPD deficiencies.

Quantitative impact of pre-analytical process on plasma uracil when testing for dihydropyrimidine dehydrogenase deficiency.

AIMS: Determining dihydropyrimidine dehydrogenase (DPD) activity by measuring patient's uracil (U) plasma concentration is mandatory before fluoropyrimidine (FP) administration in France. In this study, we aimed to refine the pre-analytical recommendations for determining U and dihydrouracil (UH2 ) concentrations, as they are essential in reliable DPD-deficiency testing. METHODS: U and UH2 concentrations were collected from 14 hospital laboratories. Stability in whole blood and plasma after centrifugation, the type of anticoagulant and long-term plasma storage were evaluated. The variation induced by time and temperature was calculated and compared to an acceptability range of ±20%. Inter-occasion variability (IOV) of U and UH2 was assessed in 573 patients double sampled for DPD-deficiency testing. RESULTS: Storage of blood samples before centrifugation at room temperature (RT) should not exceed 1 h, whereas cold (+4°C) storage maintains the stability of uracil after 5 hours. For patients correctly double sampled, IOV of U reached 22.4% for U (SD = 17.9%, range = 0-99%). Notably, 17% of them were assigned with a different phenotype (normal or DPD-deficient) based on the analysis of their two samples. For those having at least one non-compliant sample, this percentage increased up to 33.8%. The moment of blood collection did not affect the DPD phenotyping result. CONCLUSION: Caution should be taken when interpreting U concentrations if the time before centrifugation exceeds 1 hour at RT, since it rises significantly afterwards. Not respecting the pre-analytical conditions for DPD phenotyping increases the risk of DPD status misclassification.

Variability of Isavuconazole Trough Concentrations during Longitudinal Therapeutic Drug Monitoring.

Isavuconazole (ISA), a triazole antifungal agent, is licensed for the treatment of invasive aspergillosis and mucormycosis. Therapeutic drug monitoring (TDM) is a cornerstone of treatment efficacy for triazole antifungals due to their pharmacokinetic variability, except for ISA, for which the utility of TDM is still uncertain. We performed a retrospective study that aimed to assess the inter- and intra-individual variability of ISA trough concentrations (Cmin) and to identify the determinants involved in such variability. ISA Cmin measured in adult patients at the Grenoble Alpes University Hospital between January 2018 and August 2020 were retrospectively analyzed. In total, 304 ISA Cmin for 33 patients were analyzed. The median ISA Cmin was 2.8 [25th−75th percentiles: 2.0−3.7] mg/L. The inter- and intra-individual variability was 41.5% and 30.7%, respectively. Multivariate analysis showed independent covariate effects of dose (ß = 0.004 ± 3.56 × 10−4, p < 0.001), Aspartate aminotransférase (ASAT) (ß = 0.002 ± 5.41 × 10−4, p = 0.002), and protein levels (ß = 0.022 ± 0.004, p < 0.001) on ISA Cmin, whereas C reactive protein levels did not show any association. This study, conducted on a large number of ISA Cmin, shows that ISA exposure exhibits variability, explained in part by the ISA dose, and ASAT and protein levels.

Implementation of a Vancomycin Dose-Optimization Protocol in Neonates: Impact on Vancomycin Exposure, Biological Parameters, and Clinical Outcomes.

Vancomycin dosing used in neonates results frequently in insufficient concentrations. A vancomycin dose-optimization protocol consisting of an individualization of loading and maintenance doses (administered during continuous infusion) through a previously validated pharmacokinetic model was implemented in our center. This monocenter retrospective study aimed to compare vancomycin average concentration (Cavg) in the therapeutic range (15 to 25 mg/L) and biological and clinical parameters before and after implementation of this protocol. A total of 60 and 59 courses of vancomycin treatment in 45 and 49 patients were analyzed in groups before and after implementation, respectively. Initial vancomycin Cavg were more frequently in the therapeutic range in the group after implementation (74.6% versus 28.3%, P < 0.001), with 1.6-fold higher Cavg (20.3 [17.0-22.2] mg/L versus 12.9 [11.3-17.0] mg/L, P < 0.001). Considering all Cavg during longitudinal therapeutic drug monitoring (TDM), the frequency of therapeutic Cavg was higher in the group after implementation (74.8% [n = 103] versus 31% [n = 116], P < 0.001). The dose optimization protocol was also associated with a reduced time to obtain a negative blood culture (P < 0.001) and fewer antibiotic switches (P = 0.025), without increasing the frequency of nephrotoxicity. Clinical outcomes also appeared to be improved, with less periventricular leukomalacia (P = 0.021), trended toward less respiratory instability (P = 0.15) and a shorter duration of vasoactive drug use (P = 0.18) for neonates receiving personalized doses of vancomycin. This personalized vancomycin dose protocol improves vancomycin exposure in neonates, with good safety, and suggests an improvement in biological and clinical outcomes.

Variability of Tacrolimus Trough Concentration in Liver Transplant Patients: Which Role of Inflammation?

Tacrolimus presents high intra and inter-individual variability in its blood trough concentration (Cmin). Knowledge of the factors that are involved in tacrolimus Cmin variability is thus clinically important to prevent or limit it. Inflammation can affect the pharmacokinetic properties of drugs. We evaluated the contribution of acute inflammation in the pharmacokinetic variability of tacrolimus blood Cmin in a large cohort of liver transplant patients. Demographic, biological, and clinical data from 248 liver transplant patients treated with tacrolimus from January 2010 to December 2016 were retrospectively collected from medical records. In total, 1573 Cmin/dose and concomitant C-reactive protein (CRP) measurements were analysed. In multivariate analysis, the log Cmin/dose of tacrolimus was significantly and positively associated with the hematocrit, ALAT, and CRP concentrations. CRP concentrations were higher (p = 0.003) for patients with tacrolimus overexposure (i.e., tacrolimus Cmin > 15 µg/L) (median CRP (10th-90th percentiles): 27 mg/L (3-149 mg/L), n = 91) than they were for patients with a tacrolimus Cmin ≤ 15 µg/L (13 mg/mL (3-95 mg/L), n = 1482)). CRP in the fourth quartile (49 to 334 mg/L) was associated with a 2.6-fold increased risk of tacrolimus Cmin overexposure. Our study provides evidence that inflammation contributes to tacrolimus Cmin variability and suggests that inflammation should be considered for the correct interpretation of tacrolimus blood concentration.

Combined Impact of Inflammation and Pharmacogenomic Variants on Voriconazole Trough Concentrations: A Meta-Analysis of Individual Data.

Few studies have simultaneously investigated the impact of inflammation and genetic polymorphisms of cytochromes P450 2C19 and 3A4 on voriconazole trough concentrations. We aimed to define the respective impact of inflammation and genetic polymorphisms on voriconazole exposure by performing individual data meta-analyses. A systematic literature review was conducted using PubMed to identify studies focusing on voriconazole therapeutic drug monitoring with data of both inflammation (assessed by C-reactive protein level) and the pharmacogenomics of cytochromes P450. Individual patient data were collected and analyzed in a mixed-effect model. In total, 203 patients and 754 voriconazole trough concentrations from six studies were included. Voriconazole trough concentrations were independently influenced by age, dose, C-reactive protein level, and both cytochrome P450 2C19 and 3A4 genotype, considered individually or through a combined genetic score. An increase in the C-reactive protein of 10, 50, or 100 mg/L was associated with an increased voriconazole trough concentration of 6, 35, or 82%, respectively. The inhibitory effect of inflammation appeared to be less important for patients with loss-of-function polymorphisms for cytochrome P450 2C19. Voriconazole exposure is influenced by age, inflammatory status, and the genotypes of both cytochromes P450 2C19 and 3A4, suggesting that all these determinants need to be considered in approaches of personalization of voriconazole treatment.

Modeling Approach to Predict the Impact of Inflammation on the Pharmacokinetics of CYP2C19 and CYP3A4 Substrates.

PURPOSE: For decades, inflammation has been considered a cause of pharmacokinetic variability, mainly in relation to the inhibitory effect of pro-inflammatory cytokines on the expression level and activity of cytochrome P450 (CYP). In vitro and clinical studies have shown that two major CYPs, CYP2C19 and CYP3A4, are both impaired. The objective of the present study was to quantify the impact of the inflammatory response on the activity of both CYPs in order to predict the pharmacokinetic profile of their substrates according to systemic C-reactive protein (CRP). METHODS: The relationships between CRP concentration and both CYPs activities were estimated and validated using clinical data first on midazolam then on voriconazole. Finally, clinical data on omeprazole were used to validate the findings. For each substrate, a physiologically based pharmacokinetics model was built using a bottom-up approach, and the relationships between CRP level and CYP activities were estimated by a top-down approach. After incorporating the respective relationships, we compared the predictions and observed drug concentrations. RESULTS: Changes in pharmacokinetic profiles and parameters induced by inflammation seem to be captured accurately by the models. CONCLUSIONS: These findings suggest that the pharmacokinetics of CYP2C19 and CYP3A4 substrates can be predicted depending on the CRP concentration.

Variability of rituximab and tocilizumab trough concentrations in patients with rheumatoid arthritis.

Patients with rheumatoid arthritis (RA) are eligible for treatment with therapeutic monoclonal antibodies (mAbs) that target tumor necrosis factor α (TNFα), as well as others, such as rituximab (RTX) and tocilizumab (TCZ). Although pharmacokinetic variability and the link between concentration-clinical response of anti-TNFα mAbs have been well-described, little is known about RTX and TCZ. We aimed to evaluate the variability of RTX and TCZ serum concentrations in RA patients treated in second-line and the relationship between RTX/TCZ concentrations and the clinical response. Serum mAb trough concentrations of RA patients treated with RTX (n = 35) or TCZ (n = 46) were determined at week 24 by liquid chromatography-tandem mass spectrometry. The clinical response was assessed at week 24 by the change in the disease activity score in the 28 joints-erythrocyte sedimentation rate from baseline (ΔDAS28-Erythrocyte Sedimentation Rate) and according to the European League Against Rheumatism (EULAR) recommendations. RTX and TCZ trough concentrations were highly variable, with a coefficient of variation of 171.3% for RTX (median [10th-90th percentiles]: <1.0 µg/mL [<1.0-5.1]) and 132.6% for TCZ (median [10th-90th percentiles]: 5.4 µg/mL [<1.0-27.8]). Univariate analysis did not identify any determinants of such variability, except cotreatment with methotrexate, which was associated with lower RTX concentrations (P = 0.03). The response to treatment was not related to the RTX or TCZ trough concentration. RTX and TCZ trough concentrations at 24 weeks were highly variable in RA patients treated in the second line, without any link concentration-clinical response having been demonstrated.

Neglecting Plasma Protein Binding in COVID-19 Patients Leads to a Wrong Interpretation of Lopinavir Overexposure.

Boffito et al. recalled the critical importance to correctly interpret protein binding. Changes of lopinavir pharmacokinetics in coronavirus disease 2019 (COVID-19) are a perfect illustration. Indeed, several studies described that total lopinavir plasma concentrations were considerably higher in patients with severe COVID-19 than those reported in patients with HIV. These findings have led to a reduction of the dose of lopinavir in some patients, hypothesizing an inhibitory effect of inflammation on lopinavir metabolism. Unfortunately, changes in plasma protein binding were never investigated. We performed a retrospective cohort study. Data were collected from the medical records of patients hospitalized for COVID-19 treated with lopinavir/ritonavir in intensive care units or infectious disease departments of Toulouse University Hospital (France). Total and unbound concentrations of lopinavir, C reactive protein, albumin, and alpha-1-acid glycoprotein (AAG) levels were measured during routine care on the same samples. In patients with COVID-19, increased total lopinavir concentration is the result of an increased AAG-bound lopinavir concentration, whereas the unbound concentration remains constant, and insufficient to reduce the severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) viral load. Although international guidelines have recently recommended against using lopinavir/ritonavir to treat severe COVID-19, the description of lopinavir pharmacokinetics changes in COVID-19 is a textbook case of the high risk of misinterpretation of a total drug exposure when changes in protein binding are not taken into consideration.

Tocilizumab Trough Levels Variability in Kidney-Transplant Candidates Undergoing Desensitization.

The presence of anti-HLA antibodies is an increasing challenge in kidney transplantation. Tocilizumab (TCZ), a monoclonal antibody targeting the interleukin-6 receptor (IL-6R), has been proposed to complement conventional desensitization therapy. We aimed to describe TCZ plasma trough concentrations and their variability and to investigate the link between TCZ concentration and the evolution of anti-HLA antibodies. Sensitized kidney-transplant candidates treated monthly with TCZ (8 mg/kg) for desensitization were retrospectively included. TCZ concentrations were determined by liquid chromatography-tandem mass spectrometry. Seventy-four TCZ concentrations from 10 patients were analyzed. The TCZ trough concentration ranged from <1.0 to 52.5 mg·L-1, with a median of 25.6 mg·L-1 [25th-75th percentiles: 13.2-35.3 mg·L-1). The inter- and intra-individual coefficients of variation were 55.0% and 33.0%, respectively. The TCZ trough concentration was not related to IL-6 (rho = -0.46, p = 0.792), soluble IL-6R (rho = -0.81, p = 0.65) concentrations or reduction of anti-HLA antibodies (mixed-effects model adjusting, effect of TCZ trough concentration: rho = -0.004, p = 0.26). The individual median TCZ concentration tended to be associated with the number of antibodies, with an initial MFI > 3000 that dropped to <3000 after TCZ treatment (rho = 0.397, p = 0.083). TCZ trough concentrations in kidney-transplant candidates treated for desensitization were highly variable. Further studies on larger cohorts are needed to study the possible link between TCZ concentrations and the reduction of anti-HLA antibodies.

Simultaneous quantification of rituximab and eculizumab in human plasma by liquid chromatography-tandem mass spectrometry and comparison with rituximab ELISA kits.

OBJECTIVES: Specific and sensitive analytical techniques to quantify therapeutic monoclonal antibodies (mAbs) are required for therapeutic drug monitoring. The quantification of mAbs has been historically performed using enzyme-linked immunosorbent assays (ELISAs), for which the limitations in terms of specificity have led to the development of alternative analytical strategies. METHODS: Here, we describe the validation of a liquid chromatography tandem mass-spectrometry (LC-MS/MS) method for the simultaneous quantification of rituximab (RTX - anti-CD20) and eculizumab (ECU - anti-C5). Sample preparation was based on our previously published method, using protein G purification and trypsin digestion. A new specific peptide for RTX, containing an N-terminal pyroglutamine and a trypsin miss-cleavage, enables better sensitivity, while peptide of ECU was chosen thanks to an in silico trypsin digestion and the Skyline® software. Full-length stable-isotope-labeled adalimumab was added to plasma samples as an internal standard. RTX in 50 human serum samples was quantified by LC-MS/MS and the concentrations obtained compared to those obtained with two commercial ELISA kits (Lisa Tracker® and Promonitor®). RESULTS: Calibration curves were linear from 1 to 200 µg.mL-1 for RTX and 5 to 200 µg.mL-1 for ECU, and within-day and between-day accuracy and precision fulfilled Food and Drug Administration validation criteria. Comparison of the LC-MS/MS method with ELISA showed a negligible bias with the Lisa Tracker® kit (4%), but significant bias with the Promonitor® assay (mean underestimation of 69% for the Promonitor® assay). CONCLUSIONS: This new LC-MS/MS method allows the simultaneous quantification of RTX and ECU in human samples and could be used for therapeutic drug monitoring.

[Pharmacokinetic changes related to acute infection. Examples from the SARS-CoV-2 pandemic]. / Modifications pharmacocinétiques liées à une infection aiguë. Exemples issus de la pandémie de SARS-CoV-2.

The knowledge of factors of pharmacokinetic variability is important in order to personalize pharmacological treatment, particularly for drugs with a narrow therapeutic range for which pharmacological therapeutic monitoring is recommended. Inflammation is a protective response against acute infections and injuries that contributes to intra- and inter-individual variability in drug exposure by modulating the activity of enzymes involved in drug metabolism, and by altering the binding of drugs to plasma proteins. The understanding of the impact of inflammation on drug metabolism and the related clinical consequences allow to better take into consideration the effect of inflammation on the variability of drug exposure. We first summarized the molecular mechanisms by which inflammation contributes to the inhibition of drug metabolism enzymes. We then presented an updated overview of the consequences of the outcome of acute infectious event on pharmacokinetic exposure of drugs with a narrow therapeutic range and that are substrates of cytochrome P450, and the related clinical consequences. Finally, in the context of the COVID-19 pandemic, we reported examples of drug overexposures in COVID- 19 infected patients.

Tablets or oral suspension for posaconazole in lung transplant recipients? Consequences for trough concentrations of tacrolimus and everolimus.

AIMS: A new formulation of posaconazole (PCZ), delayed-release tablets (PCZ-tab), increases PCZ bioavailability and plasma trough concentrations (Cmin ) over those achieved with an oral suspension (PCZ-susp). PCZ is an inhibitor of cytochrome P450 3A4 and P-glycoprotein. We therefore investigated the impact of PCZ-tab treatment on blood Cmin and doses of tacrolimus (TAC) and everolimus (EVR). METHODS: Eighteen lung transplant patients receiving TAC (n = 13) or TAC + EVR (n = 5) between June 2015 and March 2016 were retrospectively included. Ten of these patients received both PCZ-tab and PCZ-susp (i.e. switched patients); the other 8 received only PCZ-tab. Plasma Cmin of PCZ (n = 64), blood Cmin of TAC (n = 299) and EVR (n = 80) were determined during routine therapeutic drug monitoring by liquid chromatography-tandem mass spectrometry. RESULTS: PCZ Cmin on PCZ-tab treatment (n = 48) was 2.5 times higher than that on PCZ-susp therapy (n = 16), for both PCZ patients (P < .0001) and for switched patients (P = .003). PCZ initiation, regardless of galenic form, increased TAC and EVR Cmin adjusted for dose (D), 3-fold and 3.5-fold, respectively (P < .0001 for both). PCZ-tab treatment was associated with a higher TAC Cmin /D (PCZ-tab vs PCZ-susp: 0.004 ± 0.004 L-1 vs 0.009 ± 0.006 L-1 , P < .0001) and lower TAC daily dose than PCZ-susp (PCZ-tab vs PCZ-susp: 1.08 ± 0.92 vs 2.32 ± 1.62 mg d-1 , P < .0001). EVR Cmin /D was higher and EVR dose tended to be lower on PCZ-tab than on PCZ-susp. CONCLUSION: The greater PCZ exposure achieved during PCZ-tab treatment increased drug-drug interactions with TAC and EVR, resulting in greater exposure, potentially exposing patients to higher risks of adverse effects.

Optimization of voriconazole therapy for treatment of invasive aspergillosis: Pharmacogenomics and inflammatory status need to be evaluated.

AIMS: Cytochrome 2C19 genotype-directed dosing of voriconazole (VRC) reduces the incidence of insufficient VRC trough concentrations (Cmin ) but does not account for CYP3A polymorphisms, also involved in VRC metabolism. This prospective observational study aimed to evaluate the utility of a genetic score combining CYP2C19 and CYP3A genotypes to predict insufficient initial VRC Cmin (<1 mg/L). METHODS: The genetic score was determined in hematological patients treated with VRC. The higher the genetic score, the faster the metabolism of the patient. The impact of the genetic score was evaluated considering initial VRC Cmin and all VRC Cmin (n = 159) determined during longitudinal therapeutic drug monitoring. RESULTS: Forty-three patients were included, of whom 41 received VRC for curative indication. Thirty-six patients had a genetic score ≥2, of whom 11 had an initial insufficient VRC Cmin . A genetic score ≥2 had a positive predictive value of 0.31 for having an initial insufficient VRC Cmin and initial VRC Cmin was not associated with the genetic score. The lack of association between the genetic score and VRC Cmin may be related to the inflammatory status of the patients (C-reactive protein [CRP] levels: median [Q1-Q3]: 43.0 [11.0-110.0] mg/L), as multivariate analysis performed on all VRC Cmin identified CRP as an independent determinant of the VRC Cmin adjusted for dose (P < .0001). CONCLUSION: The combined genetic score did not predict low VRC exposure in patients with inflammation, which is frequent in patients with invasive fungal infections. Strategies for the individualization of VRC dose should integrate the inflammatory status of patients in addition to pharmacogenetic variants.

Impact of Loading Dose of Caspofungin in Pharmacokinetic-Pharmacodynamic Target Attainment for Severe Candidiasis Infections in Patients in Intensive Care Units: the CASPOLOAD Study.

This study evaluated the impact of a high loading dose of caspofungin (CAS) on the pharmacokinetics of CAS and the pharmacokinetic-pharmacodynamic (PK-PD) target attainment in patients in intensive care units (ICU). ICU patients requiring CAS treatment were prospectively included to receive a 140-mg loading dose of CAS. Plasma CAS concentrations (0, 2, 3, 5, 7, and 24 h postinfusion) were determined to develop a two-compartmental population PK model. A Monte Carlo simulation was performed and the probabilities of target attainment (PTAs) were computed using previously published MICs. PK-PD targets were ratios of area under the concentration-time curve from 0 to 24 h (AUC0-24h) divided by the MIC (AUC0-24h/MIC) of 250, 450, and 865 and maximal concentration (Cmax) divided by the MIC (Cmax/MIC) of 5, 10, 15, and 20. Among 13 included patients, CAS clearance was 0.98 ± 0.13 liters/h and distribution volumes were V1 = 9.0 ± 1.2 liters and V2 = 11.9 ± 2.9 liters. Observed and simulated CAS AUC0-24h were 79.1 (IQR 55.2; 108.4) and 81.3 (IQR 63.8; 102.3) mg · h/liter during the first 24 h of therapy, which is comparable to values usually observed in ICU patients at day 3 or later. PTAs were >90% for MICs of 0.19 and 0.5 mg/liter, considering AUC/MIC = 250 and Cmax/MIC = 10 as PK-PD targets, respectively. Thus, a high loading dose of CAS (140 mg) increased CAS exposure in the first 24 h of therapy, allowing early achievement of PK-PD targets for most Candida strains. Such a strategy seems to improve treatment efficacy, though further studies are needed to assess the impact on clinical outcomes. (This study has been registered at ClinicalTrials.gov under identifier NCT02413892.).

Inflammation is a major regulator of drug metabolizing enzymes and transporters: Consequences for the personalization of drug treatment.

Inflammation is an evolutionary process that allows survival against acute infection or injury. Inflammation is also a pathophysiological condition shared by numerous chronic diseases. In addition, inflammation modulates important drug-metabolizing enzymes and transporters (DMETs), thus contributing to intra- and interindividual variability of drug exposure. A better knowledge of the impact of inflammation on drug metabolism and its related clinical consequences would help to personalize drug treatment. Here, we summarize the kinetics of inflammatory mediators and the underlying transcriptional and post-transcriptional mechanisms by which they contribute to the inhibition of important DMETs. We also present an updated overview of the effect of inflammation on the pharmacokinetic parameters of most of the drugs that are DMET substrates, for which therapeutic drug monitoring is recommended. Furthermore, we provide opinions on how to integrate the inflammatory status into pharmacogenetics, therapeutic drug monitoring, and population pharmacokinetic strategies to improve the personalization of drug treatment for each patient.

Unexpected overdose blood concentration of tacrolimus: Keep in mind the role of inflammation.

Tacrolimus is the cornerstone of the therapeutic immunosuppressive strategy in liver transplantation. The inter-individual and intra-individual variability of its trough blood concentrations is a surrogated biomarker of allograft rejection. Here we described two cases of patients with liver transplant who exhibited increases of tacrolimus blood trough concentration adjusted on the dose while experiencing acute inflammatory episodes. These case reports highlight the inhibitory effect of acute inflammation on tacrolimus metabolism and show that it accounts for the longitudinal intra-individual variability of tacrolimus blood concentrations, beyond drug-drug interaction and observance.

Pharmacokinetic herb-drug interaction between ginger and crizotinib.

The use of complementary and alternative medicine at least once during or after cancer treatment has increased over the past years from an estimated 25% in the 1970s and 1980s to more than 32% in the 1990s and to 49% after 2000. The risk of herb-drug interaction is therefore increasingly recognized as a public health problem. To the best of our knowledge, we report here the first case of interaction between ginger and anticancer drug, with serious consequences for the patient. There is an urgent need regarding complementary and alternative medicine: Both clinicians and patients should be aware of the potential interactions between herbs and prescribed drugs.