Meltdose Tacrolimus Pharmacokinetics

Background Nonadherence to immunosuppressive therapy contributes to the loss of grafts. One of the problem is the fractioning of immunosuppressive dose. In fact, it was demonstrated that a single daily dose (QD) is associated with an increased adherence to therapy compared with twice daily dosing (BID). Tacrolimus (TAC), calcineurin inhibitor, is one of immunosuppression pillar in organ transplantation and its action is strongly correlated with blood concentration and therefore the therapeutic drug monitoring is recommended in the guidelines. However, one of the critical points of TAC is the poor and variable bioavailability that influences immunosuppression, and is also responsible for adverse effects. Methods MeltDose\uae Technology is a new technology to improve efficacy and/or reduce side effects. This new technology applied to TAC (Envarsus\uae or LCP-TAC) has achieved 4 main objectives: (1) improved bioavailability, (2) reduced dose fractioning to one tablet per day, (3) limited variability concentrations of TAC, and (4) lower doses of TAC will be administered. Results We analyzed the pharmacokinetic profile, efficacy, and security of Envarsus\uae

Therapeutic Drug Monitoring of Micophenolate Mofetil in Cardiac Transplant Patients by Limited Sampling Strategy: An Update

In the last few years, much progress in avoiding acute and chronic rejection in transplanted patients has been made by introducing new and more effective drugs with different formulations and combinations, and fewer side effects. Standardized protocols have been proposed for different organs, but individualized therapy based on immunosuppressive therapy blood monitoring is necessary because of pharmacological interaction, new generic drug introductions, and different absorptions and biodistributions. In specific mycophenolate mofetil dosing through mycophenolic acid (MPA), therapeutic drug monitoring has demonstrated minimal risk of organ transplant rejection. Even if the MPA area under the 12 h concentration–time curve is more accurate than MPA levels, it appears to be resource consuming and clinically impractical because of the need for numerous blood samples. Limited sampling strategy (LLS) has been proposed to overcome this problem. In heart-transplanted patients, MPA LSS is useful in guiding clinical management and dosing. The purpose of this chapter is to describe the state of the art of MPA LSS employment in heart transplantation and to perform an update of the scientific literature

Steroid-free and steroid withdrawal protocols in heart transplantation: the review of literature.

Abstract Corticosteroids (CSs) are still the mainstay of induction, rescue, and maintenance in heart transplantation (HTx). However, their use is associated with significant and well-documented side effects usually related to the dose administered and the duration of therapy. Moreover, CSs interfere with the recipient's quality of life and with the active process of graft tolerance. Physicians have been exploring ways to avoid or reduce CSs in association with other immunosuppressive drugs, minimizing side effects and costs. The regimens are classified as steroid-free or steroid withdrawal protocols. The studies analyzed in this review come to similar conclusions as benefits and adverse consequences: steroid-free protocols should be advisable and mandatory in pediatric patients, insulin-dependent diabetes mellitus (IDDM), presence of infection, familial metabolic disorders/obesity, severe osteoporosis, and in the elderly. On the other hand, steroid withdrawal can be successfully achieved in 50-80%, with late better than early withdrawal, no increase in rejection-related mortality, no adverse impact on survival, and probably a better quality of live. Safety and efficacy can certainly be improved by an individualized approach to the transplant recipient

Il trattamento integrato del paziente fumatore

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Limited Sampling Strategies to Monitoring Mycophenolic Acid Exposure in a Heterogeneous Population of Heart Transplant Recipients: A Pilot Study

Mycophenolate mofetil (MMF) represents a cornerstone in heart transplant (HTx) treatment. The area under the 12-hour concentration-time curve (AUC0-12h) of mycophenolic acid (MPA) -MMF’s active drug- is associated with treatment outcome. Nonetheless, therapeutic drug monitoring (TDM) of MPA AUC0-12h is impractical to assess in clinical practice and Limited Sampling Strategies (LSSs) represent a consolidated tool to estimate AUC0-12h. Two LSSs were previously generated in a selected cohort of HTx recipients treated with MMF and cyclosporine (CsA). This pilot study aimed to test these LSSs in a cohort of non-selected HTx recipients treated with MMF combined with CsA or tacrolimus (TAC). Complete PK profile was performed in 40 adults HTx recipients. MPA-AUC0-12h was estimated by two algorithms, LSS3 and LSS4, based on 3 and 4 time-points. The evaluation was made through linear regression and Bland-Altman analyses. Both LSS3 and LSS4 tended to underestimate the value of MPA-AUC0-12h (mean percentage prediction error, MPE%: −6.0%; and −4.8%, respectively). Nonetheless, high correlations (r: 0.92 and 0.94, respectively) and goodness of fit of linear regression models (R2: 0.84 and 0.88, respectively) emerged for both LSSs. A study with a wider and more homogenous sample size should be performed to support these results

Population Pharmacokinetics and Pharmacodynamics of Levofloxacin in Acutely Hospitalized Older Patients with Various Degrees of Renal Function

A retrospective study was conducted in a large sample of acutely hospitalized older patients who underwent therapeutic drug monitoring during levofloxacin treatment. The aim was to assess the population pharmacokinetics (popPK) and pharmacodynamics of levofloxacin among older patients. PopPK and Monte Carlo simulation were performed to define the permissible doses in older patients according to various degrees of renal function. Classification and regression tree (CART) analysis was used to detect the cutoff 24-hour area under the concentration-time curve (AUC24)/MIC ratio that best correlated with the clinical outcome. The probability of target attainment (PTA) of this value was calculated against different pathogens. A total of 168 patients were included, and 330 trough and 239 peak concentrations were used for the popPK analysis. Creatinine clearance (CrCL) was the only covariate that improved the model fit (levofloxacin CL = 0.399 + 0.051 × CrCLCKD-EPI [creatinine clearance estimated by means of the chronic kidney disease epidemiology]). Drug doses ranged between 500 mg every 48 h and 500 mg every 12 h in relation to different renal functions. The identified cutoff AUC24/MIC ratio (≥95.7) was the only covariate that correlated with a favorable clinical outcome in multivariate regression analysis (odds ratio [OR], 20.85; 95% confidence interval [CI], 1.56 to 186.73). PTAs were optimal (>80%) against Escherichia coli and Haemophilus influenzae, borderline against Staphylococcus aureus, and suboptimal against Pseudomonas aeruginosa The levofloxacin doses defined in our study may be effective for the treatment of infections due to bacterial pathogens, with an MIC of ≤0.5 mg/liter in older patients with various degrees of renal function, while minimizing the toxicity risk. Conversely, the addition of another active antimicrobial should be considered whenever treating infections caused by less susceptible pathogens

Association of ADME gene polymorphisms on toxicity to CDK4/6 inhibitors in patients with HR+ HER2- metastatic breast cancer

: A wide interindividual variability in therapeutic response to cyclin-dependent kinases 4 and 6 inhibitors (CDKis) palbociclib, ribociclib and abemaciclib, among patients with HR+/HER2- metastatic breast cancer has been reported. This study explored the impact of genetic polymorphisms in ADME genes (responsible for drug absorption, distribution, metabolism, and elimination) on CDKis safety profiles in 230 patients. Selected endpoints include grade 3/4 neutropenia at day 14 of the first treatment cycle, early dose-limiting toxicities (DLTs), and dose reductions within the initial three cycles. Our analysis revealed associations between these endpoints and polymorphisms in CYP3A4, CYP3A5, ABCB1, and ABCG2 genes. Their impact on CDKis plasma concentrations (Ctrough) was also examined. Specifically, ABCB1 c.1236C>T and c.2677C>T polymorphisms correlated significantly with grade 3/4 neutropenia at day 14 (OR 3.94, 95% CI 1.32-11.75; p = 0.014 and OR 3.32, 95% CI 1.12-9.85; p = 0.030). Additionally, ABCB1 c.3435C>T was associated with an elevated risk of early DLTs and dose reductions (OR 3.28, 95% CI 1.22-8.84, p = 0.019; OR 2.60, 95% CI 1.20-5.60, p = 0.015). Carriers of the CYP3A4*22 allele also demonstrated in univariate a higher risk of early DLTs (OR 3.10, 95% CI 1.01-9.56, p = 0.049). Furthermore, individuals with the ABCB1 1236T-3435T-2677T(A) variant haplotype exhibited significant associations with grade 3/4 neutropenia at day 14 (OR 3.36, 95% CI 1.20-9.41; p = 0.021) and early DLTs in univariate (OR 3.08, 95% CI 1.19-7.95; p = 0.020). Homozygous carriers of the ABCB1 T-T-T(A) haplotype tended to have a higher mean ribociclib Ctrough (934.0 ng/mL vs. 752.0 ng/mL and 668.0 ng/mL). Regardless preliminary, these findings offer promising insights into the role of pharmacogenetic markers in CDKis safety profiles, potentially contributing to address the interindividual variability in CDKis responses

Expression of the Atypical Chemokine Receptor D6 in Human Alveolar Macrophages in COPD

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