Renal Function and Its Impact on the Concentration of Ceftazidime-Avibactam: A cross-sectional study.

OBJECTIVES: This study measured the effect of renal function on the plasma concentrations of ceftazidime and avibactam in critically ill patients. We also sought to measure the concentration ratio of ceftazidime to avibactam. METHODS: This was a cohort study at a tertiary referral centre in Italy, on patients treated with continuous infusion of ceftazidime-avibactam (CAZ-AVI) between November 2019 and December 2023. The association between creatine clearance (CrCl) and free plasma ceftazidime and avibactam concentration, as well as CAZ-AVI ratio was explored to assess correlation and potential risk to fail to achieve target therapeutic concentration. RESULTS: 52 patients, predominantly male (75%), with a median age of 68.5 years were included. Our analyses provided strong evidence for inverse correlation between CrCl and both free-CAZ (r=-0.627; R2=0.3936; P<0.001) and free-AVI plasma concentration (r=-0.619; R2=0.3832; P<0.001). Overall CrCl alone could explain about 40% of overall variation of either free-CAZ and free-AVI. Linear models suggest that free-CAZ and free-AVI concentration drop of about 7.31% and 9.23% for each 10 point increase of CrCl, respectively. . Assessment of the CAZ-AVI ratio supports a direct linear association with CrCl suggesting that free-AVI concetration is more affected by CrCl variation than free-CAZ concentration. Patients with CrCl ≥130 mL/min showed a significantly higher risk of suboptimal drug exposure (i.e. less than 4 times the MIC) both to CAZ and AVI. CONCLUSION: The findings emphasize the need for individualized dosing strategies of CAZ-AVI based on renal function, for antibiotics used in critically ill patients. The study suggests that underdosing in patients with high CrCl is likely to be common and as such could affect drug effectiveness.

Revolutionizing Daptomycin Dosing: A Single 7-11-Hour Sample for Pragmatic Application.

Precision daptomycin dosing faces clinical implementation barriers despite known exposure-safety concerns with the use of twice the regulatory-approved doses. We propose achieving a single 7-11-hour post-dose plasma target concentration of 30 mg/L to 43 mg/L to be a practical starting point to facilitate precision daptomycin dosing.

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.

Meropenem PK/PD Variability and Renal Function: "We Go Together".

BACKGROUND: Meropenem is a carbapenem antibiotic widely employed for serious bacterial infections. Therapeutic drug monitoring (TDM) is a strategy to optimize dosing, especially in critically ill patients. This study aims to show how TDM influences the management of meropenem in a real-life setting, not limited to intensive care units. METHODS: From December 2021 to February 2022, we retrospectively analyzed 195 meropenem serum concentrations (Css). We characterized patients according to meropenem exposure, focusing on the renal function impact. RESULTS: A total of 36% (n = 51) of the overall observed patients (n = 144) were in the therapeutic range (8-16 mg/L), whereas 64% (n = 93) required a meropenem dose modification (37 patients (26%) underexposed; 53 (38%) overexposed). We found a strong relationship between renal function and meropenem concentrations (correlation coefficient = -0.7; p-value < 0.001). We observed different dose-normalized meropenem exposure (Css/D) among renal-impaired (severe and moderate), normal, and hyperfiltrating patients, with a median (interquartile range) of 13.1 (10.9-20.2), 7.9 (6.1-9.5), 3.8 (2.6-6.0), and 2.4 (1.6-2.7), respectively (p-value < 0.001). CONCLUSIONS: Meropenem TDM in clinical practice allows modification of dosing in patients inadequately exposed to meropenem to maximize antibiotic efficacy and minimize the risk of antibiotic resistance, especially in renal alterations despite standard dose adaptations.

Clinical impact of body mass index on palbociclib treatment outcomes and effect on exposure.

The impact of body mass index (BMI) on treatment outcomes in patients with cancer is gaining increasing attention given the limited data available. The aim of this study was to investigate the contribution of BMI on the safety and efficacy profile of palbociclib in 134 patients with metastatic luminal-like breast cancer treated with palbociclib and endocrine therapy (ET). Normal-weight and underweight patients (BMI<25) were compared with overweight and obese (BMI≥25). Detailed clinical and demographic data were collected. Patients with a BMI<25 had a higher incidence of relevant-hematologic toxicities (p = 0.001), dose reduction events (p = 0.003), and tolerated lower dose intensities (p = 0.023) compared to patients with a BMI≥25. In addition, patients with a BMI<25 had significantly shorter progression-free survival (log-rank p = 0.0332). A significant difference was observed in the subgroup of patients for whom systemic palbociclib concentrations were available: patients with a BMI<25 had a 25% higher median minimum plasma concentrations (Cmin) compared to BMI≥25. This study provides compelling evidence for a clinically relevant contribution of BMI in discriminating a group of patients who experienced multiple toxicities that appeared to affect treatment adherence and lead to poorer survival. BMI could become a valuable tool for personalizing the starting dose of palbociclib to improve its safety and efficacy.

Ampicillin and Ceftobiprole Combination for the Treatment of Enterococcus faecalis Invasive Infections: "The Times They Are A-Changin".

BACKGROUND: Enterococcus faecalis is responsible for a large variety of severe infections. This study is a case series reporting our experience in the treatment of E. faecalis invasive infections with ampicillin in combination with ceftobiprole (ABPR). METHODS: We retrospectively analyzed all the medical records of patients admitted to the University Hospital of Udine from January to December 2020 with a diagnosis of infective endocarditis or primary or non-primary complicated or uncomplicated bacteremia caused by E. faecalis. RESULTS: Twenty-one patients were included in the final analysis. The clinical success rate was very high, accounting for 81% of patients, and microbiological cure was obtained in 86% of patients. One relapse was recorded in one patient who did not adhere to the partial oral treatment prescribed. Therapeutic drug monitoring (TDM) was always performed for ampicillin and ceftobiprole, and serum concentrations of both drugs were compared to the MICs of the different enterococcal isolates. CONCLUSIONS: ABPR is a well-tolerated antimicrobial regimen with anti-E. faecalis activity. TDM can help clinicians optimize medical treatments to achieve the best possible efficacy with fewer side effects. ABPR might be a reasonable option for the treatment of severe invasive infections caused by E. faecalis due to the high level of enterococcal penicillin-binding protein (PBP) saturation.

Therapeutic Drug Monitoring of Mycophenolic Acid as a Precision Medicine Tool for Heart Transplant Patients: Results of an Observational Pharmacokinetic Pilot Study.

In the clinical practice management of heart transplant (HTx), the impact of calcineurin inhibitors co-administration on pharmacokinetics (PKs) of mycophenolic acid (MPA), mycophenolate mofetil (MMF) active drug, is not adequately considered. This retrospective study investigated full MPA-PK profiles by therapeutic drug monitoring (TDM) in 21 HTx recipients treated with MMF combined with cyclosporine (CsA) or tacrolimus (TAC) at a median time of 2.6 months post-transplant. The two treatment groups were compared. We described the main MPA-PK parameters in patients developing acute cellular rejection (ACR) and those who did not. Median dose-adjusted MPA-trough levels and MPA-AUC0-12h were higher in patients co-treated with TAC than with CsA (p = 0.0001 and p = 0.006, respectively). MPA-Cmax and Tmax were similar between the two groups, whereas the enterohepatic recirculation biomarker of MPA (MPA-AUC4-12h) was higher in the MMF and TAC group (p = 0.004). Consistently, MPA clearance was higher in the MMF and CsA group (p = 0.006). In total, 87.5% of ACR patients were treated with MMF and CsA, presenting a lower MPA-AUC0-12h (p = 0.02). This real-world study suggested the CsA interference on MPA-PK in HTx, evidencing the pivotal role of MPA TDM as a precision medicine tool in the early phase after HTx. A prospective study is mandatory to investigate this approach to HTx clinical outcomes.

Population pharmacokinetics of continuous infusion of piperacillin/tazobactam in very elderly hospitalized patients and considerations for target attainment against Enterobacterales and Pseudomonas aeruginosa.

Continuous infusion (CI) piperacillin/tazobactam is frequently used to treat infections in very elderly patients. This study aimed to conduct a population pharmacokinetic analysis of CI piperacillin/tazobactam, and to identify optimal dosages for safe and effective probability of target attainment (PTA) against Enterobacterales and Pseudomonas aeruginosa. Non-linear mixed-effects modelling was performed with Pmetrics. Monte Carlo simulations assessed the steady-state concentration (Css) of increasing piperacillin/tazobactam regimens (from 2.25 to 18 g daily by continuous infusion). Permissible doses were defined as those associated with <10% probability of Css >157.2 mg/L. PTA at the pharmacodynamic targets of free plasma steady-state concentration (fCss)/minimum inhibitory concentration (MIC) ≥1 and ≥4 and cumulative fraction of response (CFR) against EUCAST MIC distribution were also calculated. A total of 141 patients (median age 85 years) provided 217 plasma piperacillin Css. Most patients (55.2%) had hospital-acquired pneumonia and intra-abdominal infections. A one-compartment pharmacokinetic model with parallel linear and Michaelis-Menten elimination best described piperacillin data. Creatinine clearance (CLCR) was the covariate retained by the model. Pharmacokinetic estimates were 6.05 L/h for clearance and 3.39 mg/L for the Michaelis-Menten constant. Permissible doses were up to 4.5, 9, 11.25 and 13.5 g daily by continuous infusion for patients with CLCR of 0-19, 20-39, 40-59 and 60-79 mL/min/1.73 m2, respectively. At the clinical breakpoint of 8 mg/L, the permissible doses only achieved optimal PTA for fCss/MIC ≥1 in patients with CLCR 20-79 mL/min/1.73 m2. Optimal CFRs with the permissible doses were only attained against Escherichia coli and Proteus mirabilis. Permissible dosages and CLCR should be considered for prescribing CI piperacillin/tazobactam in very elderly patients.

Area-under-the-Curve-Based Mycophenolate Mofetil Dosage May Contribute to Decrease the Incidence of Graft-versus-Host Disease after Allogeneic Hematopoietic Cell Transplantation in Pediatric Patients.

Acute graft-versus-host disease (GvHD) remains the second leading cause of death, after disease relapse, in patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT). The medical records of 112 pediatric patients who underwent allo-HSCT from matched unrelated and haploidentical donors were analyzed. Patients were divided into two groups, according to the GvHD prophylactic regimen used. In the control group, GvHD prophylaxis consisted of cyclosporine A (CsA) and methotrexate (MTX) or CsA and mycophenolate mofetil (MMF) at a standard daily dose of 30 mg/kg. All subjects in the study group received tacrolimus (FK506) and MMF. In this group, MMF was subjected to therapeutic drug monitoring (TDM) through mycophenolic acid (MPA) area under the curve AUC0-12. We found a statistically significant difference in both overall acute GvHD (p < 0.0001) and overall chronic GvHD (p < 0.05) incidence between the study and the control group. The initial daily MMF dose and the age at transplant in the study group proved to be inversely correlated (r = -0.523, p < 0.0001). The children under six years of age required a significantly higher daily MMF dose (p < 0.008). This study showed that pharmacological monitoring of MPA AUC0-12 concentration allowed a reduction in the incidence of acute and chronic GvHD. MMF showed age-dependent pharmacokinetics due to greater drug clearance in younger children.

Comparison of clinical effects, trough and peak levels between branded and generic formulation of Cyclosporine in stable psoriatic patients.

BACKGROUND: Cyclosporine A (CyA) is a drug for moderate-to-severe psoriasis. Recently, a generic formulation has been approved as bioequivalent to the branded one. The guidelines for the bioequivalence for critical-dose drugs with a narrow therapeutic range, such as CyA, are questionable. Therefore, it is important to assess the clinical outcome and the pharmacokinetics of different formulations in various patient groups. The current literature lacks of this information in dermatology. The primary objective of this prospective study is to investigate the clinical equivalence (in terms of maintenance of clinical effect) between the generic formulation of CyA and its branded one in patients with psoriasis. A secondary objective is to analyze their trough (C0) and peak levels (C2). METHODS: Twenty patients with stable psoriasis under treatment with the branded CyA were monitored in terms of clinical efficacy (psoriasis area severity index, PASI), safety (laboratory values), and their pharmacokinetics utilizing trough (C0) and peak plasma concentration (C2). The same patients were subsequently shifted to the generic formulation for comparison. RESULTS: In our sample the efficacy of the two formulations was equal in most cases (P=0.863). A non-significant difference between the C0 and C2 of the branded CyA compared to the generic one emerged (respectively P=0.738 and P=0.695). CONCLUSIONS: The branded and the generic formulations of CyA seem to be not only bioequivalent, but also comparable in terms of clinical efficacy in patients with psoriasis. However, larger samples are required to confirm these findings.

MeltDose Technology vs Once-Daily Prolonged Release Tacrolimus in De Novo Liver Transplant Recipients.

BACKGROUND: An extended-release formulation of tacrolimus designed for once-daily administration (LCP-TAC) is a new prolonged-release tacrolimus (TAC-PR) formulation using a drug delivery technology designed to enhance the bioavailability of drugs compared with TAC-PR. The aim of this study was to retrospectively compare de novo administration of LCP-TAC and TAC-PR for therapeutic trough levels and daily dosage during the first 30 days after first liver transplant (LT). METHODS: A total of 35 patients submitted to first LT between 2016 and 2018 were retrospectively enrolled: 16 received LCP-TAC, while 19 received TAC-PR as de novo immunosuppression. Patients were analyzed for daily dosage and trough levels at postoperative days (PODs) 3, 7, 15, and 30. RESULTS: The initial dose of tacrolimus did not differ between LCP-TAC and TAC-PR (mean, 5.19 [SD, 1.72] mg/d vs mean, 5.26 [SD, 1.91] mg/d, P = .90). On PODs 7, 15, and 30 the daily dosage was statistically lower for LCP-TAC compared with TAC-PR (mean, 5.44 [SD, 2.06] mg/d vs mean, 7.68 [SD, 2.91] mg/d, P = .01; mean, 5.33 [SD, 2.23] mg/d vs mean, 8.82 [SD, 2.35] mg/d, P < .001; and mean, 5.38 [SD, 2.50] mg/d vs mean, 9.81 [SD, 3.78] mg/d, P < .001, respectively). The therapeutic trough levels were significantly higher for LCP-TAC on POD 3 (mean, 5.05 [SD, 3.58] ng/mL vs mean, 2.42 [SD, 2.75] ng/mL, P = .03) and POD 5 (mean, 7.35 [SD, 5.12] ng/mL vs mean, 4.17 [SD, 2.05] ng/mL, P = .04), while no differences were found on PODs 7, 15, and 30.The percentage of patients on POD 3 achieving a trough level higher than 6 ng/mL was higher for LCP-TAC than TAC-PR (40% vs 13%, P = .05). CONCLUSIONS: LCP-TAC after LT is safe and might enhance bioavailability, reducing the amount of drug necessary to achieve therapeutic trough levels compared with TAC-PR.

Exercise performance increase in smokeless tobacco-user athletes after overnight nicotine abstinence.

The use of nicotine administered through smokeless tobacco (snus) has increased among athletes. The purpose of this study was to investigate the ergogenic effects of snus on aerobic performance during exercise until exhaustion in athletes after abstinence or satiety nicotine conditions. The study utilized a randomized, controlled, within-subject design experiment. Sixteen male snus-user athletes completed an exercise until exhaustion at a constant load of their 80% of V ˙ O 2 max (calculated by a maximal incremental test) in two separate sessions, corresponding to nicotine conditions: 12-hour overnight abstinence and satiety. A portion of 1 g of snus (~8 mg/g of nicotine) was administered 25 minutes before each experimental test. In each session, time to exhaustion (TTE), global rating of perceived exertion, cardiovascular and metabolic responses, and muscle and cerebral oxygenation were measured. Nicotine and cotinine analysis confirmed session conditions (abstinence or satiety). Snus induced a significant increase (+13.1%) of TTE following abstinence (24.1 ± 10.7 minutes) compared to satiety condition (20.9 ± 8.0 minutes; P = 0.0131). The baseline values revealed that abstinence of snus induced significant increase in the oxygenation of the muscular tissues (+4%), in metabolic values and in cardiovascular parameters, when compared to satiety condition. Our results indicate an increase of exercise performance (+13.1% TTE) due to snus administration in an abstinence condition. Considering that twelve hours of abstinence from snus-contained nicotine affected metabolic, cardiovascular and muscular tissue oxygenation, we suggest that snus administration at test time might relieve these withdrawal changes and yield an increase in time to exhaustion.

The effects of oral smokeless tobacco administration on endurance performance.

BACKGROUND: Smokeless tobacco is widely used by athletes to enhance performance. Nicotine is a central nervous system stimulant and acts on cardiocirculatory and metabolic systems, involving tissue blood flow and circulatory vasoreactivity. The aim of this study was to investigate the effects of the oral smokeless tobacco (Swedish snus (SS)) on the perception of fatigue and time to exhaustion (TTE) during moderate-intensity aerobic exercise. METHODS: Fourteen healthy non-tobacco male users were recruited for a double-blind, controlled crossover design (SS vs. snus placebo (SP)). Subjects were tested for 3 sessions: experimental session 1 (Exp1) consisted of an incremental test to determine the maximal aerobic power output (Wmax), whereas Exp2 and Exp3 consisted of exercising at 65%Wmax until exhaustion in SS or SP conditions. During Exp2 and Exp3, muscle and cerebral oxygenation was assessed by means of near-infrared spectroscopy, and the rating of perceived exertion (RPE) was recorded. RESULTS: Comparing SS with SP tests, significant differences (p < 0.05) were found in the values of cerebral (~3%) and muscular tissues oxygenation (~4%) in the first 30 min of exercise. The RPE values were not significantly different between the 2 conditions (SS vs. SP). No significant difference was found in TTE (SS: 54.25 ± 21.84 min; SP: 50.01 ± 17.03 min). CONCLUSION: This study showed that muscular and cerebral oxygenation increased significantly with snus administration during an endurance exercise until exhaustion, but this did not affect fatigue perception and TTE. The results showed that snus could not be considered an ergogenic substance in non-tobacco users.

A 10-Year Experience of Therapeutic Drug Monitoring (TDM) of Linezolid in a Hospital-wide Population of Patients Receiving Conventional Dosing: Is there Enough Evidence for Suggesting TDM in the Majority of Patients?

A retrospective study was conducted to assess our 10-year experience of therapeutic drug monitoring (TDM) of linezolid in a large patient population to establish whether conventional dosing may result in adequate drug exposure in the majority of patients. Patients included in this study underwent TDM of linezolid trough concentration (Cmin ) during treatment with conventional doses of 600 mg every 12 hr in the period between January 2007 and June 2016. The desired range of Cmin was set between 2 and 7 mg/L (underexposure, Cmin  < 2 mg/L; overexposure, Cmin  > 7 mg/L). Multivariate logistic regression analysis investigated variables potentially correlated with linezolid Cmin . One thousand and forty-nine patients had 2484 linezolid Cmin assessed during treatment with conventional doses. Median (IQR) linezolid Cmin was 5.08 mg/L (2.78-8.52 mg/L). Linezolid Cmin was within the desired range in 50.8% of cases (1262/2484). Overexposure (n = 821; 33%) occurred much more frequently than underexposure (n = 401; 16.2%) and was severe (>20 mg/L) in 3.9% of cases (98/2484). Linezolid overexposure was significantly associated with CrCLC-G estimates ≤40 mL/min. (OR 1.463; 95% CI 1.124-1.904, p = 0.005). Linezolid underexposure was significantly associated with CrCLC-G estimates >100 mL/min. (OR 3.046; 95% CI 2.234-4.152, p < 0.001). Linezolid Cmin was not correlated linearly with CrCLC-G (R2  = 0.061). Variability in renal function explained only partially the very wide interindividual linezolid Cmin variability. Our study suggests that TDM could represent a valuable approach in optimizing linezolid exposure in the majority of patients.

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.

Might isoniazid plasma exposure be a valuable predictor of drug-related hepatotoxicity risk among adult patients with TB?

OBJECTIVES: To investigate the relationship between isoniazid plasma exposure and the likelihood of elevation of ALT (≥51 IU/L) among adult patients with TB. METHODS: A retrospective observational study was conducted in patients who underwent periodic monitoring of hepatic function and in whom pharmacokinetic data were collected. Monte Carlo simulation was performed with the intent of identifying the probability of achieving an AUC24 greater than the identified threshold of hepatotoxicity with different dosing regimens (2.5, 5.0 and 7.5 mg/kg/day). RESULTS: Forty-one out of 185 evaluable patients (22.2%) had an ALT elevation. A mild correlation between isoniazid AUC0-24 and ALT increase was observed (Spearman's ρ = 0.34, P < 0.001). Patients with ALT ≥51 IU/L showed significantly higher isoniazid exposure than those with ALT <51 IU/L (mean AUC24 of 58.33 versus 31.28 mg·h/L, P < 0.001). The probabilities of ALT elevation were 0.82 and 0.12 for isoniazid AUC24 ≥55.0 and <55.0 mg·h/L, respectively. Use of a logistic regression model estimated a likelihood of developing hepatotoxicity of 0.5 and 0.9 when in the presence of an isoniazid AUC24 of 53.7 and 70.0 mg·h/L, respectively. Simulation showed that the standard isoniazid 5 mg/kg daily dose gave a probability of ALT increase of 0.46 for slow acetylators and 0.03 for rapid acetylators. CONCLUSIONS: Plasma isoniazid exposure might be a valuable predictor of drug-related hepatotoxicity. Early assessment of isoniazid exposure at the beginning of treatment might allow prompt dosage reduction among those patients who are experiencing drug overexposure, thus containing the risk of hepatotoxicity occurrence.

A 1 year retrospective audit of quality indicators of clinical pharmacological advice for personalized linezolid dosing: one stone for two birds?

AIM: This study explored the clinical and economic impact of clinical pharmacological advice (CPA) (based on therapeutic drug monitoring [TDM] results, and on patients' characteristics and co-medications) on personalized linezolid therapy in a tertiary care hospital. METHODS: A 1 year retrospective analysis of quality indicators of CPA (clinicians' adherence rate to CPA, pre-post rate of linezolid trough concentrations within the desired range and cost balance analysis) was conducted. RESULTS: Five hundred and forty-four CPAs were provided to clinicians during 2014 for personalizing linezolid therapy in 168 patients. Clinicians' adherence to CPAs was very high (94.7%). The pre-post rate of linezolid Cmin distribution showed a favourable impact of CPA on patient care (pre-post ratio of Cmin within the desired range + 23.4%, pre, 51.2% vs. post, 74.6%). Overall, linezolid dosage was mainly reduced (56.9% of cases), whereas dose augmentation was needed only in a minority of cases (7.7%). Cost balance analysis showed that overall 1258 standard doses of linezolid (unitary dose 600 mg) were spared for treating 168 patients with a personalized dosage for a median duration of 11 days (range 3-128 days) with a cost saving of 60038.05 €. CONCLUSION: Active computerized advice elaborated by the clinical pharmacologist on the basis of TDM results and of patient's pathophysiological data and co-medications may be cost-effective for personalizing linezolid treatment.

[Pharmacogenetics of immunosuppressants]. / Farmacogenetica degli immunosoppressori.

Individualized drug therapy with immunosuppressants is an hot topic in transplantation. Therapeutic drug monitoring (TDM) is currently utilized to guide therapy, but toxic or subtherapeutic concentrations can only be identified after the drug is administered. Pharmacogenetics, by studying the relationship between a human genetic difference and drug response, holds great promises in optimizing immunosuppressive drug prescribing for solid organ transplantation.Nevertheless, a complete translation in the clinic has lagged behind,due to the overall complexity of the genetic approach, and the lack of sound evidence of identified genetic polymorphisms in ultimately explaining drug exposure. However, for tacrolimus it is likely that a genotype-based drug dosage can benefit patient outcome, while for cyclosporine data appear less convincing. Mycophenolic acid undergoes a complex metabolic pathway and various genes affecting drug disposition are under investigations, with promising results for some of them of being of value in aiding clinicians in decision making. Finally, for sirolimus and everolimus the lack of data and the absence of large prospective studies do not allow to draw any conclusion.

Knowledge about health effects of cigarette smoking and quitting among Italian university students: the importance of teaching nicotine dependence and treatment in the medical curriculum.

Aims of the study were to compare medical students (MS) to non-MS with respect to their knowledge of smoking and to investigate the effect of a short educational intervention on MS knowledge. MS (n = 962) and students of architecture and law (n = 229) were asked to complete a 60-item questionnaire addressing knowledge of smoking epidemiology and health effects ("Score 1"), and effectiveness of cessation treatments ("Score 2"). Upon completion of questionnaire, fourth year MS received a lecture on tobacco dependence. These students were asked to complete the same questionnaire one and two years later. Mean values for Score 1 were 48.9 ± 11.5% in MS and 40.5 ± 11.4% in non-MS (P < 0.001; d = 0.69). Respective values for Score 2 were 48.1 ± 10.8% and 42.6 ± 10.6% (P < 0.001; d = 0.50). Fifth year students who had attended the lecture in year 4 scored higher than students who had not attended the lecture. Significant differences were noted one but not two years after the educational intervention. In conclusion, MS know slightly more about smoking-related diseases and methods to achieve cessation than nonmedical students; a short educational intervention was associated with better knowledge one year later, but the effect was moderate and short-lived.