Dried Urine Spot Analysis for assessing cardiovascular drugs exposure applicable in spaceflight conditions.

Cardiovascular pharmacological countermeasures will be required as a preventive measure of cardiovascular deconditioning and early vascular ageing for long term space travelers. Physiological changes during spaceflight could have severe implications on drug pharmacokinetics and pharmacodynamics (PK/PD). However, limitations exist for the implementation of drug studies due to the requirements and constraints of this extreme environment. Therefore, we developed an easy sampling method on dried urine spot (DUS), for the simultaneous quantification of 5 antihypertensive drugs in human urine: irbesartan, valsartan, olmesartan, metoprolol and furosemide analyzed by liquid chromatography-tandem mass spectrometry (LC-MS/MS), considering spaceflight parameters. This assay was validated in terms of linearity, accuracy, and precision with satisfactory results. There were no relevant carry-over, matrix interferences. The targeted drugs were stable in urine collected by DUS until 6 months at +21 °C, +4°C, -20 °C (with or without desiccants) and at 30 °C during 48 h. Irbesartan, valsartan and olmesartan were not stable at 50 °C during 48 h. This method was found to be eligible for space pharmacology studies in terms of practicality, safety, robustness and energy costs. It has been successfully implemented in space tests programs led in 2022.

Pulmonary toxicity of mTOR inhibitors. Comparisons of two populations: Solid organ recipients and cancer patients.

INTRODUCTION: Mammalian target of rapamycin (mTOR) inhibitors-associated pneumonitis (mTOR-IP) has long been described in solid organ recipients (T) patients but more recently in cancer (K) patients. Its overall characteristics have never been compared between these 2 populations. The aim of this study was to compare them in terms of presentation, severity and outcome in T and in K patients. MATERIAL AND METHODS: We carried out a retrospective study in a single French tertiary center. Four databases were used to ensure the exhaustive collection of all mTOR-IP cases between 2001 and 2020. All clinical, biological, radiological, pathological and outcome data were reviewed. RESULTS: Thirty-nine patients with mTOR-IP were diagnosed during this period, 24T and 15K patients. The average dosage of everolimus and sirolimus was 2,65mg (±1,78) and 2,75mg (±0,96) in T patients, respectively, versus 8,75mg (±2,26) for everolimus in K patients. The overall prevalence of mTOR-IP was 6.4% with a median time of occurrence of 7 months [IQR 3-35 months]. mTOR-IP were significantly more frequent (P<0.001) and occurred earlier (P<0.001) in cancer patients. No clinical, functional, radiological, pathological nor outcome differences were otherwise observed between the 2 groups. Average everolimus blood levels at the time of mTOR-IP diagnosis were in the range of recommended therapeutic values. CONCLUSION: Our study shows that mTOR-IP is comparable in terms of presentation in T and in K patients but that it occurs significantly earlier after drug introduction in the latter. This raises questions as to the potential role of the higher doses used in K patients as well as that of co-treatments in the pathogeny of the disease.

Urine N-acetyl-Ser-Asp-Lys-Pro measurement as a versatile biomarker to assess adherence to angiotensin-converting enzyme inhibitors.

BACKGROUND: Poor adherence to treatment is a major health issue in hypertension. The large number of drugs to be detected limits the implementation of chemical adherence testing by liquid chromatography/mass spectrometry (LC-MS/MS). AcSDKP, a peptide accumulating in the presence of angiotensin-converting-enzyme inhibitor (ACEI) treatment, has been validated as a proven marker of adherence by enzyme-linked immunosorbent assay. Our aim was to validate urine measurements of AcSDKP compared with active metabolites of various ACEI, measured simultaneously by LC-MS/MS. METHOD: We first studied the time-dependent relationships between urinary perindoprilat and AcSDKP in a pharmacokinetic/pharmacodynamic study in healthy volunteers. We then compared the sensitivity and specificity of urinary AcSDKP vs. three ACEI active metabolites (enalaprilat, perindoprilat, ramiprilat) taken as reference to detect nonadherence in spot urine samples from a prospective cohort of hypertensive outpatients. RESULTS: The urinary excretion profiles of AcSDKP and perindoprilat were similar, exhibited a significant correlation, and showed excellent agreement in healthy volunteers. In patients, we found a similar agreement between AcSDKP and the three ACEI metabolites urinary concentrations. The sensitivity and specificity for adherence assessment of urine AcSDKP was 92.2 and 100%, respectively. We observed a difference in the evaluation of good adherence between ACEI metabolites (85.7%) and AcSDKP (79.0%) because of discrepancies in samples where AcSDKP reached undetectability quicker than ACEI metabolites. This characteristic of AcSDKP is of particular interest and could better reflect the true adherence status of patients. CONCLUSION: Overall, spot urine AcSDKP measurement by LC-MS/MS is a reliable marker of the intake of ACEI treatment and could substitute ACEI metabolites detection.

Antifungal Drugs TDM: Trends and Update.

PURPOSE: The increasing burden of invasive fungal infections results in growing challenges to antifungal (AF) therapeutic drug monitoring (TDM). This review aims to provide an overview of recent advances in AF TDM. METHODS: We conducted a PubMed search for articles during 2016-2020 using "TDM" or "pharmacokinetics" or "drug-drug-interaction" with "antifungal," consolidated for each AF. Selection was limited to English language articles with human data on drug exposure. RESULTS: More than 1000 articles matched the search terms. We selected 566 publications. The latest findings tend to confirm previous observations in real-life clinical settings. The pharmacokinetic variability related to special populations is not specific but must be considered. AF benefit-to-risk ratio, drug-drug interaction (DDI) profiles, and minimal inhibitory concentrations for pathogens must be known to manage at-risk situations and patients. Itraconazole has replaced ketoconazole in healthy volunteers DDI studies. Physiologically based pharmacokinetic modeling is widely used to assess metabolic azole DDI. AF prophylactic use was studied more for Aspergillus spp. and Mucorales in oncohematology and solid organ transplantation than for Candida (already studied). Emergence of central nervous system infection and severe infections in immunocompetent individuals both merit special attention. TDM is more challenging for azoles than amphotericin B and echinocandins. Fewer TDM requirements exist for fluconazole and isavuconazole (ISZ); however, ISZ is frequently used in clinical situations in which TDM is recommended. Voriconazole remains the most challenging of the AF, with toxicity limiting high-dose treatments. Moreover, alternative treatments (posaconazole tablets, ISZ) are now available. CONCLUSIONS: TDM seems to be crucial for curative and/or long-term maintenance treatment in highly variable patients. TDM poses fewer cost issues than the drugs themselves or subsequent treatment issues. The integration of clinical pharmacology into multidisciplinary management is now increasingly seen as a part of patient care.

Is there any Hope for Monitoring Adherence in an Efficient and Feasible Way for Resistant Hypertension Diagnosis and Follow-Up?

PURPOSE OF REVIEW: Non-adherence to antihypertensive treatment is highly prevalent and represents a major factor affecting their effectiveness in hypertensive patients, thus contributing to apparent treatment resistance. It is however often overlooked because the methods to assess non-adherence are mainly subjective, limiting their usefulness in clinical practice. Non-adherence to treatment affects daily patient management, resulting in inappropriate, costly, and potentially harmful treatments and loss of the expected benefits from antihypertensive drugs. RECENT FINDINGS: Specialized centers now use a combination of objective screening tools. Firstly, snapshots of adherence levels can be provided by analytical drug detection in various biological matrixes using liquid chromatography-tandem mass spectrometry (LC-MS/MS) and secondly electronic monitoring systems of drug delivery which provide longitudinal data on adherence. Routine utilization of those tools allows the detection of non-adherence in patients with resistant hypertension, thus enabling implementation of appropriate interventions to improve drug adherence and avoid unnecessary treatment intensification. Other complementary techniques, such as digital health feedback system with ingestible sensors, are currently evaluated. In the context of an increasing burden of uncontrolled and apparent treatment-resistant hypertension, detecting non-adherence to antihypertensive therapy is, as acknowledged by the latest guidelines, a top priority to implement in clinical practice but still faces medical conservatism and disbelief.

Belatacept-based immunosuppression: A calcineurin inhibitor-sparing regimen in heart transplant recipients.

Belatacept (BTC) is indicated for prophylaxis of graft rejection in adults receiving a renal transplant (Tx). This retrospective observational study (three centers) included all heart transplant recipients receiving BTC between January 2014 and October 2018. Forty EBV+ patients mean GFR 35 ± 20 mL/min/m2 were identified, among whom belatacept was initiated during the first 3 months after transplantation in 12 patients, and later in 28 patients. Several patients were multiorgan transplant recipients. Study outcomes were GFR, safety, and changes in immunosuppressive therapy. The main reason for switching to BTC was to preserve renal function, resulting in discontinuation of CNI and changes in immunosuppressive therapy in 76% of cases. At study closeout, 24/40 patients were still on BTC therapy. GFR was improved (+59%, P = .0002*) within 1 month, particularly in the early group. More episodes of rejection were observed among "late" patients (1 death). Sixteen treatment discontinuations were recorded: GFR recovery (n = 4), DSA no longer detectable (n = 1), compliance issues (n = 3), poor venous access (n = 2), multiple infections (n = 1), 1 death (fungal lung infection), and treatment failure (n = 4). Median follow-up was 24 months. Four patients developed de novo DSA (MFI<1500). BTC is an effective alternative immunosuppressive for postoperative transient kidney failure, stabilizing delayed renal function, with acceptable safety profile under careful monitoring.

Lack of association of Aspergillus colonization with the development of bronchiolitis obliterans syndrome in lung transplant recipients: An international cohort study.

BACKGROUND: Bronchiolitis obliterans syndrome (BOS) is a major limitation in the long-term survival of lung transplant recipients (LTRs). However, the risk factors in the development of BOS remain undetermined. We conducted an international cohort study of LTRs to assess whether Aspergillus colonization with large or small conidia is a risk factor for the development of BOS. METHODS: Consecutive LTRs from January 2005 to December 2008 were evaluated. Rates of BOS and associated risk factors were recorded at 4 years. International Society of Heart and Lung Transplantation criteria were used to define fungal and other infections. A Cox proportional-hazards-model was constructed to assess the association between Aspergillus colonization and the development of BOS controlling for confounders. RESULTS: A total of 747 LTRs were included. The cumulative incidence of BOS at 4 years after transplant was 33% (250 of 747). Additionally, 22% of LTRs experienced Aspergillus colonization after transplantation. Aspergillus colonization with either large (hazard ratio [HR] = 0.6, 95% confidence interval [CI] = 0.3-1.2, p = 0.12) or small conidia (HR = 0.9, 95% CI = 0.6-1.4, p = 0.74) was not associated with the development of BOS. Factors associated with increased risk of development of BOS were the male gender (HR = 1.4, 95% CI = 1.1-1.8, p = 0.02) and episodes of acute rejection (1-2 episodes, HR = 1.5, 95% CI = 1.1-2.1, p = 0.014; 3-4 episodes, HR = 1.6, 95% CI = 1.0-2.6, p = 0.036; >4 episodes, HR = 2.2, 95% CI = 1.1-4.3, p = 0.02), whereas tacrolimus use was associated with reduced risk of BOS (HR = 0.6, 95% CI = 0.5-0.9, p = 0.007). CONCLUSIONS: We conclude from this large multicenter cohort of lung transplant patients, that Aspergillus colonization with large or small conidia did not show an association with the development of BOS.

Clinical risk factors for invasive aspergillosis in lung transplant recipients: Results of an international cohort study.

BACKGROUND: Invasive aspergillosis (IA) is a frequent complication in lung transplant recipients (LTRs). Clinical risk factors for IA have not been fully characterized, especially in the era of extensive anti-fungal prophylaxis. The primary objective of this study was to evaluate the clinical risk factors associated with IA in LTRs. The secondary objective was to assess the mortality in LTRs who had at least 1 episode of IA compared with LTRs who never had experienced IA. METHODS: We conducted an international, multicenter, retrospective cohort study of 900 consecutive adults who received lung transplants between 2005 and 2008 with 4years of follow-up. Risk factors associated with IA were identified using univariate and multiple regression Cox proportional hazards models. RESULTS: Anti-fungal prophylaxis was administered to 61.7% (555 of 900) of patients, and 79 patients developed 115 episodes of IA. The rate to development of the first episode was 29.6 per 1,000 person-years. Aspergillus fumigatus was the most common species isolated (63% [72 of 115 episodes]). Through multivariate analysis, significant risk factors identified for IA development were single lung transplant (hazard ratio, 1.84; 95% confidence interval, 1.09-3.10; p = 0.02,) and colonization with Aspergillus at 1 year post-transplantation (hazard ratio, 2.11; 95% confidence interval, 1.28-3.49; p = 0.003,). Cystic fibrosis, pre-transplant colonization with Aspergillus spp, and use of anti-fungal prophylaxis were not significantly associated with the development of IA. Time-dependent analysis showed IA was associated with higher mortality rates. CONCLUSION: Incidence of IA remains high in LTRs. Single-lung transplant and airway colonization with Aspergillus spp. within 1 year post-transplant were significantly associated with IA.

Posaconazole Tablets in Real-Life Lung Transplantation: Impact on Exposure, Drug-Drug Interactions, and Drug Management in Lung Transplant Patients, Including Those with Cystic Fibrosis.

Appropriate exposure to posaconazole (PSZ) has been limited until the recent approval of the delayed-release oral tablet formulation. Our goal was to determine the exposure obtained by using the standard dose of 300 mg once a day in lung transplant (LT) patients, including patients with cystic fibrosis (CF). PSZ trough concentrations (C0) were determined using a liquid chromatography-tandem mass spectrometry assay. Indicative thresholds of interest were <0.7 mg/liter for prophylaxis and 1 to 3 mg/liter for cure. The tacrolimus (TRL) and everolimus (ERL) C0 measured during PSZ exposure were also collected. The interaction with proton-pump inhibitors (PPI) was evaluated. We recorded the results for 21 CF patients with LT (CFLT patients), 11 non-CF patients with LT (NCFLT patients), and 27 nontransplant (NT) patients in pneumology departments. The weights of the NCFLT, CFLT, and NT patients were 59.2 ± 8.4, 48.8 ± 8.4, and 63.7 ± 16.6 kg, respectively (P = 0.001* [asterisk means that statistical test is significant]), and the PSZ C0 exposures for these patients were 1.9 ± 1.5, 1.1 ± 0.8, and 2.4 ± 1.8 mg/liter, respectively (P < 0.00001*). More than 60% of the concentrations were in the therapeutic range. In CFLT patients, the administration of one 300-mg PSZ tablet quickly achieved an exposure similar to that achieved with the PSZ oral suspension formulation (OSF) administered 3 or 4 times a day for several months. The TRL C0/dose ratio (C0/D) was 7.4 ± 4.4 mg/liter with PSZ tablets, whereas it was 4.6 ± 0.8 mg/liter with the PSZ oral solution (P = 0.034*). The ERL C0/D was similar with both formulations. PPI had no impact on the PSZ concentration (1.49 ± 1.07 mg/liter without PPI versus 1.33 ± 1.17 mg/liter with PPI; P = 0.4134*). Despite the high levels of exposure, PSZ remained well tolerated (one case of diarrhea and one case of fatigue were reported). PSZ tablet administration allows satisfactory exposure, even in CFLT patients, with a dosage lower than that of the PSZ OSF. This once-a-day formulation was not impacted by PPI, which are extensively used in CF patients.

Clinical outcome of cystic fibrosis patients colonized by Scedosporium species following lung transplantation: A single-center 15-year experience.

BACKGROUND: Fungi of the genus Scedosporium are emerging pathogens responsible for severe infections in lung transplant recipients. These infections are associated with poor prognosis and some centers consider now Scedosporium species colonization as a contraindication to lung transplantation (LT) even though no published evidence demonstrates that Scedosporium species colonization is associated with higher morbidity or mortality after LT. METHODS: Here, we aim to describe characteristics and outcome of cystic fibrosis (CF) lung transplant recipients colonized with Scedosporium species in a single center over a 15-year period. RESULTS: During the study period, 14 patients had scedosporial colonization reported. Only one patient, colonized before transplantation by Lomentospora prolificans, developed scedosporial disease. Among the eight patients colonized before transplantation by Scedosporium apiospermum complex, the median survival was 1.92 year (range 0.21-12.5). All these patients except one became free of fungal colonization after transplantation with antifungal prophylaxis including voriconazole or posaconazole. For the five patients colonized after LT, including two with L. prolificans, the median survival was 1.75 years (range 0.1-13); three of them are still alive. CONCLUSIONS: It appears to us that scedosporial colonization may not be a contraindication for LT in CF patients, as long as S. apiospermum complex is involved and a life-long azole prophylaxis prescribed.

Therapeutic Drug Monitoring of Everolimus: A Consensus Report.

In 2014, the Immunosuppressive Drugs Scientific Committee of the International Association of Therapeutic Drug Monitoring and Clinical Toxicology called a meeting of international experts to provide recommendations to guide therapeutic drug monitoring (TDM) of everolimus (EVR) and its optimal use in clinical practice. EVR is a potent inhibitor of the mammalian target of rapamycin, approved for the prevention of organ transplant rejection and for the treatment of various types of cancer and tuberous sclerosis complex. EVR fulfills the prerequisites for TDM, having a narrow therapeutic range, high interindividual pharmacokinetic variability, and established drug exposure-response relationships. EVR trough concentrations (C0) demonstrate a good relationship with overall exposure, providing a simple and reliable index for TDM. Whole-blood samples should be used for measurement of EVR C0, and sampling times should be standardized to occur within 1 hour before the next dose, which should be taken at the same time everyday and preferably without food. In transplantation settings, EVR should be generally targeted to a C0 of 3-8 ng/mL when used in combination with other immunosuppressive drugs (calcineurin inhibitors and glucocorticoids); in calcineurin inhibitor-free regimens, the EVR target C0 range should be 6-10 ng/mL. Further studies are required to determine the clinical utility of TDM in nontransplantation settings. The choice of analytical method and differences between methods should be carefully considered when determining EVR concentrations, and when comparing and interpreting clinical trial outcomes. At present, a fully validated liquid chromatography tandem mass spectrometry assay is the preferred method for determination of EVR C0, with a lower limit of quantification close to 1 ng/mL. Use of certified commercially available whole-blood calibrators to avoid calibration bias and participation in external proficiency-testing programs to allow continuous cross-validation and proof of analytical quality are highly recommended. Development of alternative assays to facilitate on-site measurement of EVR C0 is encouraged.

Expression of calcineurin activity after lung transplantation: a 2-year follow-up.

The objective of this pharmacodynamic study was to longitudinally assess the activity of calcineurin during the first 2 years after lung transplantation. From March 2004 to October 2008, 107 patients were prospectively enrolled and their follow-up was performed until 2009. Calcineurin activity was measured in peripheral blood mononuclear cells. We report that calcineurin activity was linked to both acute and chronic rejection. An optimal activity for calcineurin with two thresholds was defined, and we found that the risk of rejection was higher when the enzyme activity was above the upper threshold of 102 pmol/mg/min or below the lower threshold of 12 pmol/mg/min. In addition, we report that the occurrence of malignancies and viral infections was significantly higher in patients displaying very low levels of calcineurin activity. Taken together, these findings suggest that the measurement of calcineurin activity may provide useful information for the management of the prevention therapy of patients receiving lung transplantation.

Validation of an ultra-high performance liquid chromatography tandem mass spectrometric method for quantifying uracil and 5,6-dihydrouracil in human plasma.

A simple, rapid, sensitive and specific ultra-high-performance liquid chromatography-tandem mass spectrometry method (Waters UPLC-MS-MS) is developed and validated for the quantification of uracil (U) and 5,6-dihydrouracil (UH2) levels in human plasma. Analytes are extracted using ethyl acetate and isopropanol after deproteination, and separated by high-performance liquid chromatography (HPLC) (Acquity UPLC BEH C18 column) in a binary mobile phase system under gradient elution conditions at a flow rate of 0.4 mL/min. 5-Bromo-uracil (UBr) is used as the internal standard. The detection is performed on a triple-quadrupole mass spectrometer via electrospray positive ionization. Multiple reaction monitoring mode using the transitions m/z 112.82 → 70.05, m/z 114.88 → 55.04 and m/z 190.83 → 117.86 is used to quantify U, UH2 and UBr, respectively. The method is linear in the concentration range of 0.625-160.0 ng/mL. The total run time is 4.5 min per injection. Nine-point calibration curve and four-points quality controls are used. Excellent linearity and precision are observed with correlation coefficient (r(2)) > 0.9999. The intra-batch and inter-batch precisions are ≤ 7.3% and ≤ 8.6%, and accuracy is ≤ 17%. The developed method is shown to be suitable for routine quantitative determination of U, UH2 and 5,6-dihydrouracil-to-uracil ratio in clinical practice.

[Level of evidence for therapeutic drug monitoring of posaconazole]. / Niveau de preuve du suivi thérapeutique pharmacologique du posaconazole.

Posaconazole, systemic antifungal marketed in France since 2006, is indicated as second line in curative treatment of invasive fungal infections (IFI) (aspergillosis...) and prophylaxis of IFI in patients receiving chemotherapy or hematopoietic stem cell transplantation. The analysis of the literature indicates a concentration-efficacy relationship, but to date, no study has been able to show a concentration-toxicity correlation due to its favourable safety profile and the difficulty to obtain high concentrations. In curative, maintenance of trough plasma concentrations between 0.5 and 1.5 mg/L seems to be associate with an efficacy. In prophylaxis, a threshold of 0.5 mg/L corresponds to a minimal exposure. However this target is not yet well defined. Saturation of absorption above the 800 mg oral dose limits the adjustment of concentrations. As such, the Therapeutic Drug Monitoring of posaconazole can be recommended.

[Level of evidence for therapeutic drug monitoring of vancomycin]. / Niveau de preuve pour le suivi thérapeutique pharmacologique de la vancomycine.

Vancomycin is an antibiotic for exclusive hospital use administrated in intravenous infusion to treat systemic infections. It is mainly eliminated by kidneys and potentially nephrotoxic. Data available show that Therapeutic Drug Monitoring (TDM) of vancomycin is highly recommended. It aims to ensure efficacy and avoid resistance by maintaining trough plasma concentrations above the MIC. Secondary, vancomycine TDM may be indicated to prevent nephrotoxicity in high risk patients. TDM is often underwent at steady state (48 to 72 h after the treatment initiation) unless in case of renal impairment (24 h). While compared with intermittent administration, continuous infusion did not result in prognosis improvement; however it resulted in lower pharmacokinetic variability and better cost-efficiency. Targeted trough concentrations for intermittent infusion are between 15 and 20 mg/L (up to 25-30 mg/L for GISA). In case of continuous infusion, targets are higher (25 to 40 mg/L).

[Not Available]. / Niveau de preuve pour le suivi thérapeutique pharmacologique de la vancomycine.

Level of Evidence for Therapeutic Drug Monitoring of Vancomycin. Vancomycin is an antibiotic for exclusive hospital use administrated in intravenous infusion to treat systemic infections. It is mainly eliminated by kidneys and potentially nephrotoxic. Data available show that Therapeutic Drug Monitoring (TDM) of vancomycin is highly recommended. It aims to ensure efficacy and avoid resistance by maintaining trough plasma concentrations above the MIC. Secondary, vancomycine TDM may be indicated to prevent nephrotoxicity in high risk patients. TDM is often underwent at steady state (48 to 72 h after the treatment initiation) unless in case of renal impairment (24 h). While compared with intermittent administration, continuous infusion did not result in prognosis improvement; however it resulted in lower pharmacokinetic variability and better cost-efficiency. Targeted trough concentrations for intermittent infusion are between 15 and 20 mg/L (up to 25-30 mg/L for GISA). In case of continuous infusion, targets are higher (25 to 40 mg/L).

[Not Available]. / Niveau de preuve du suivi thérapeutique pharmacologique du posaconazole.

Posaconazole, systemic antifungal marketed in France since 2006, is indicated as second line in curative treatment of invasive fungal infections (IFI) (aspergillosis. . . ) and prophylaxis of IFI in patients receiving chemotherapy or hematopoietic stem cell transplantation. The analysis of the literature indicates a concentration-efficacy relationship, but to date, no study has been able to show a concentration-toxicity correlation due to its favourable safety profile and the difficulty to obtain high concentrations. In curative, maintenance of trough plasma concentrations between 0.5 and 1.5 mg/L seems to be associate with an efficacy. In prophylaxis, a threshold of 0.5 mg/L corresponds to a minimal exposure. However this target is not yet well defined. Saturation of absorption above the 800 mg oral dose limits the adjustment of concentrations. As such, the Therapeutic Drug Monitoring of posaconazole can be recommended.