Proactive therapeutic monitoring of dalbavancin concentrations in the long-term management of chronic osteoarticular/periprosthetic joint infections.

Here, we describe the use of proactive therapeutic drug monitoring (TDM) to individualize the optimal timing of drug injections in 16 adult patients with chronic osteoarticular infections receiving a median of 7 injections of dalbavancin (up to 12 injections in 15 months). Dalbavancin injections were repeated at medians of 39-47 days, with infusion intervals ranging from 26 to 69 days. TDM can facilitates a precise, targeted use of dalbavancin for infections requiring prolonged treatments.

Therapeutic Drug Monitoring of Dalbavancin in Real Life: A Two-Year Experience.

Dalbavancin is a long-acting lipoglycopeptide that is registered for the treatment of acute bacterial skin and skin structure infections, and it is also increasingly used for infections that require prolonged antibiotic treatment. Here, we present the results from the first 2 years of a service set up in December 2021 for the therapeutic drug monitoring (TDM) of dalbavancin in clinical settings. In particular, we compared the trough concentration (Cmin) to maximum concentration (Cmax) in patients with osteoarticular infections receiving prolonged treatment with dalbavancin. Log-linear regression models were used to estimate the timing of dalbavancin administration with the goal of maintaining Cmin concentrations of >8 mg/L in the two TDM-based strategies. From December 2021 to November 2023, 366 TDMs of dalbavancin from 81 patients were performed. The Cmin and Cmax concentrations of dalbavancin ranged from 4.1 to 70.5 mg/L and from 74.9 to 995.6 mg/L, respectively. With log-linear regression models, we estimated that each injection should be administered every 42-48 days to maintain the Cmin concentrations. Out of the 81 patients, 37 received at least three doses of dalbavancin for the treatment of osteoarticular infections. Despite there being no significant differences in the days of dalbavancin treatment (130 ± 97 versus 106 ± 102 days), the patients in the Cmax-based TDM group received a significantly lower number of dalbavancin injections (5.2 ± 1.8 versus 7.3 ± 2.6 injections, p = 0.005), and they were administered over a longer period of time (40 ± 10 versus 29 ± 14 days, p = 0.013) than in the Cmin-based TDM group. In conclusion, Cmax-based TDM was associated with a significant reduction in the inter-individual variability of dalbavancin concentrations and lower drug dosing frequency than those of Cmin-based TDM. This approach could, therefore, favor a more rational and targeted use of dalbavancin in patients requiring prolonged treatment.

Effects of the androgen receptor inhibitor enzalutamide on the pharmacokinetics of dolutegravir and tenofovir: a case report.

ABSTRACT: Enzalutamide is an androgen receptor inhibitor used for the treatment of prostate cancer. Although enzalutamide causes a favorable adverse effect profile, it might cause drug-drug interactions with some antiretrovirals. No major differences on the main dolutegravir and tenofovir pharmokinetocs were observed in this case report when comparing baseline assessments with those following the introduction of enzalutamide, also when given at higher doses, in a 63-year-old male living with HIV and prostate cancer.

In linezolid underexposure, pharmacogenetics matters: The role of CYP3A5.

The exposure to linezolid is characterized by a large inter-individual variability; age, renal dysfunction and body weight explain this variability only to a limited extent and a considerable portion of it remains unexplained; therefore, we decided to investigate the role of individual genetic background focusing in particular on the risk of linezolid underexposure. 191 patients in therapy with linezolid at the standard dose of 600 mg twice daily were considered. Linezolid plasma concentration was determined at the steady state and classified as "below", "within" or "above" reference range. Genetic polymorphisms for ATP Binding Cassette Subfamily B Member 1 (ABCB1), Cytochrome P450 (CYP) enzymes CYP3A4 and CYP3A5, and Cytochrome P450 Oxidoreductase (POR) were investigated. Age significantly correlated with drug exposure, and patients CYP3A5 expressers (GA and AA) were found at high risk to be underexposed to the drug when treated at standard dose. This association was confirmed even after correction with age. No association was found with ABCB1 polymorphism. Our data suggest that CYP3A5 polymorphisms might significantly affect linezolid disposition, putting patients at higher risk to be underexposed, while P-glycoprotein polymorphism seem not to play any role.

ABCC4 single-nucleotide polymorphisms as markers of tenofovir disoproxil fumarate-induced kidney impairment.

Recently, the use of antiretroviral drug tenofovir disoproxil fumarate (TDF) is increased, thanks to the new co-formulation with doravirine, the availability of booster-free regimens, and its advantageous lipid-lowering effect. The aim of our study was to identify genetic markers that contribute to assess the risk of TDF-related renal toxicity. We have retrospectively investigated, in 179 HIV positive patients treated with TDF, the association between the main variants in ABCC2, ABCC4, and ABCC10 genes and four safety endpoints, three clinically relevant as renal outcomes and a higher tenofovir plasma concentration. In patients with an annual eGFR decline >5 mL/min/1.73 m2 a difference in genotype frequencies was observed for ABCC10 c.1875 + 526 G>A (3 subjects AA vs. 44 GG + GA, p = 0.045). In patients with an eGFR decrement >25%, plus a decline in GFR category and TDF discontinuation, a difference was observed for ABCC4 c.*38T>G (35 subjects TG + GG vs. 18 TT, p = 0.052). At univariate analysis OR was 1.39 [(95% CI 1.00-1.96) p = 0.054] and at multivariate analysis OR was 1.49 [(95% CI 1.00-2.22) p = 0.049]. The stronger associations were found between the tenofovir accumulation and ABCC4 c.*38T>G and c.3348G>A: the percentage of these patients was higher in the TG + GG (p = 0.011) and in the AA (p = 0.004) genotype, respectively. The logistic regression analysis confirmed these significant relationships. No significant association was observed in patients with eGFR < 60 mL/min/1.73m2 and with the studied ABCC2 polymorphisms. Our results show a major role for a combined determination of ABCC4/ABCC10 variants as an indicator of tenofovir toxicity in the clinical practice.

Supra-therapeutic Linezolid Trough Concentrations in Elderly Patients: A Call for Action?

BACKGROUND AND OBJECTIVE: According to the drug label, linezolid dosage adjustments are not needed in geriatric patients. Nevertheless, clinical evidence suggests that elderly patients may benefit from the use of reduced linezolid doses to limit drug overexposure. Here, we aimed to describe the results of the last 5 years of therapeutic drug monitoring of linezolid in our institution with a special focus on elderly patients. METHODS: Linezolid therapeutic drug monitoring requests collected between January 2016 and June 2020 were considered. Linezolid trough concentrations were considered both as a continuous variable and as a categorical variable, clustering data according to the therapeutic range proposed by available literature (< 2, 2-8, and > 8 mg/L, respectively). Patients' age and sex were considered as categorical variables. Comparisons of linezolid trough concentrations between groups of patients stratified according to age were performed using an analysis of variance; comparisons in the frequency distributions were performed using the chi-squared test. RESULTS: From 2016 to 2020, we collected 3250 linezolid TDM requests. A highly significant, progressive increment in the linezolid trough concentrations was observed moving from patients aged < 50 years (5.8 ± 5.6 mg/L) to those aged > 90 years (16.6 ± 10.0 mg/L), with an overall increment of 30% per decade of age. Nearly 30%, 50%, and 65% of patients aged < 65 years, 65-80 years, and > 80 years, respectively, had supra-therapeutic linezolid trough concentrations at the first therapeutic drug monitoring assessment. This trend did not change significantly moving from 2016 to 2020. CONCLUSIONS: Elderly patients given linezolid at the conventional 600-mg twice-daily dose might be at a high risk of being overexposed to treatment, eventually increasing their risk to experience drug-related hematological toxicity. Reduced linezolid dosing schemes should be potentially considered in elderly patients at a low risk of treatment failure, ideally guided by therapeutic drug monitoring.

A Comparison of Tenofovir Predose Concentrations in Generic Pre-exposure Prophylaxis Formulations: A Short Communication.

BACKGROUND: There is extensive evidence to show that pre-exposure prophylaxis (PrEP) using tenofovir disoproxil fumarate (TDF)-based formulations dramatically reduces the risk of HIV acquisition among individuals without HIV infection. Here, the authors aim to compare tenofovir plasma predose concentrations in subjects taking PrEP daily versus on demand and using different TDF-based generic formulations. METHODS: Subjects providing informed signed consent for the measurement of tenofovir plasma levels were included in the study. Predose drug concentrations were stratified according to PrEP administration and the type of TDF-based formulation. The control group consisted of patients with HIV infection who were matched for renal function and were administered branded TDF that was not combined with boosted-antiretroviral drugs. RESULTS: The study consisted of 100 subjects (mean age, 39 ± 10 years; body weight, 77 ± 11 kg). A wide distribution in tenofovir predose concentrations was observed, with values ranging from 17 to 297 ng/mL (coefficient of variation 77%). No significant differences were noted in tenofovir predose concentrations between subjects who were administered PrEP daily (n = 75) or on demand (n = 25) [94 (35-255) versus 104 (37-287) ng/mL; P = 0.476]. Comparable tenofovir predose concentrations were found between patients with HIV infection (n = 220) who were administered branded TDF and those without HIV infection who were treated with 5 different generic TDF-based formulations with generics-to-branded ratios. These were always within the range of 80%-125% and were used to define bioequivalence. CONCLUSIONS: The marketed generic formulations of TDF delivered tenofovir plasma predose concentrations comparable with those delivered by branded formulations.

Dolutegravir-Based Antiretroviral Regimens for HIV Liver Transplant Patients in Real-Life Settings.

BACKGROUND AND OBJECTIVES: Liver transplantation is now considered a safe procedure in patients with HIV because of the advent of potent antiretroviral therapies (ART). OBJECTIVE: We aimed to describe the use of dolutegravir-based maintenance ART in patients with HIV and liver transplant regularly followed in our hospital. METHODS: We searched the database of our Department of Infectious Diseases for liver transplant recipients receiving calcineurin inhibitor-based maintenance immunosuppression concomitantly treated with dolutegravir for at least 1 month. RESULTS: Ten HIV-positive liver transplant recipients were identified. At 4.6 ± 3.5 years post-transplant, all the patients were switched to dolutegravir-based therapies for treatment simplification. However, at 1 year after the switch, five of the ten patients returned to their previous ART regimens because of increased serum transaminases (n = 1), reversible increased serum creatinine (n = 4), repeated episodes of nausea/vomiting (n = 1) and variable out-of-range concentrations of tacrolimus or cyclosporine (n = 2). However, it should be recognized that these events cannot be unequivocally ascribed to dolutegravir and, in the case of increased serum creatinine, are predictable. CONCLUSIONS: The management of HIV-positive liver transplant recipients in clinical practice is a complex task, where possibility of simplifying antiretroviral regimens must be balanced with the need to guarantee optimal immunosuppression and the finest treatment tolerability. A multidisciplinary approach involving physicians and clinical pharmacologists/pharmacists could help achieve this goal.

Drug-Drug Interactions Between Antiretrovirals and Carbamazepine/Oxcarbazepine: A Real-Life Investigation.

BACKGROUND: Carbamazepine and oxcarbazepine are potent modulators of metabolic enzymes. Hence, potential drug-drug interactions (DDIs) may occur between these 2 drugs and antiretrovirals. Here, we aimed to assess the relevance of these drug-drug interactions in real-life clinical settings. METHODS: Patients treated concomitantly with carbamazepine or oxcarbazepine and antiretrovirals for at least 3 months were considered. Data on therapeutic drug monitoring (TDM) of both antiepileptic and antiretrovirals as trough concentrations were collected. HIV-infected patients not concomitantly treated with antiepileptic drugs and who underwent TDM for antiretrovirals in the previous 2 years were considered as controls. RESULTS: Eleven HIV-positive patients prescribed carbamazepine or oxcarbazepine were identified. All the TDM evaluations for carbamazepine and oxcarbazepine that resulted were within the therapeutic ranges. TDM results of darunavir measured in these patients were comparable with values usually measured in the control group. Conversely, the trough concentrations for atazanavir and dolutegravir demonstrated significantly lower values when compared with values usually measured in HIV-infected patients not treated with antiepileptic drugs (190 ± 91 versus 546 ± 380 ng/mL; -65%, P < 0.001; 191 ± 78 versus 1096 ± 510 ng/mL; -83%, P < 0.001, respectively). CONCLUSIONS: Co-administration of carbamazepine or oxcarbazepine with atazanavir or dolutegravir should be avoided owing to the potential risk of virological failure; in case of these 2 drugs, the adoption of TDM is strongly advisable, eventually combining with increased antiretroviral doses.

Assessment of Antiepileptic Drug Concentrations in HIV-Infected versus HIV-Negative Patients: A Retrospective Analysis.

INTRODUCTION: A higher rate of subtherapeutic psychotropic drug concentrations was recently found in HIV-infected versus HIV-negative patients. In this study, we sought to investigate if this trend could also apply to antiepileptic drugs. METHODS: Overall, 700 HIV-infected patients were screened during the first 2 years after the introduction of our outpatient polytherapy management service (Gestione Ambulatoriale Politerapie [GAP]) in the search for subjects with antiepileptic drug trough concentration assessments. The distribution of such concentrations was compared with that in HIV-negative patients monitored over the same period. RESULTS: The search identified 97 HIV-infected patients concomitantly receiving antiretroviral and antiepileptic drugs, for a total of 310 drug measurements. Overall, 30%, 64% and 6%, versus 28%, 65% and 7%, of the antiepileptic concentrations measured in HIV-infected versus HIV-negative patients (1090 patients, for a total of 3488 antiepileptic concentrations measured) were below, within, or above the therapeutic targets, respectively. The antiepileptic drug valproate was associated with the highest risk of subtherapeutic drug concentrations, with 57% and 46% of determinations below the therapeutic range in HIV-positive and HIV-negative patients, respectively. Remarkably, the concentrations of valproate were significantly lower in HIV-infected versus HIV-negative patients (47.9 ± 21.2 versus 53.9 ± 21.6 mg/L; p < 0.05). CONCLUSION: In our retrospective study, most HIV-infected patients had antiepileptic drug concentrations falling within the therapeutic targets, with the exception of valproate, which was associated with a higher rate of subtherapeutic concentrations compared with other antiepileptic drugs.