Pharmacokinetic parameters of artesunate and dihydroartemisinin in rats infected with Fasciola hepatica

Objectives The pharmacokinetic (PK) parameters of artesunate, recently discovered to possess promising trematocidal activity, and its main metabolite dihydroartemisinin (DHA) were determined in rats infected with hepatic and biliary stages of Fasciola hepatica and compared with uninfected rats after single intragastric and intravenous (iv) doses. Methods Rats infected with F. hepatica for 25 and 83 days and uninfected rats were cannulated in the right jugular vein and blood samples were withdrawn at selected timepoints following 10 mg/kg of iv and a single 100 mg/kg oral dose of artesunate. Plasma was analysed for artesunate and DHA by liquid chromatography coupled to tandem mass spectrometry. Results Rats harbouring juvenile and adult F. hepatica infections revealed considerable changes in PK parameters of artesunate and DHA. Following oral administration, maximum plasma concentrations (Cmax) of artesunate and DHA were 1.8-2.3-fold higher in infected rats [artesunate: 1334 ± 1404 ng/mL (no infection) versus 2454 ± 1494 ng/mL (acute infection) and 2768 ± 538 ng/mL (chronic infection); DHA: 3802 ± 2149 ng/mL (no infection) versus 6507 ± 3283 ng/mL (acute infection) and 9093 ± 884 ng/mL (chronic infection)]. The AUCs of artesunate and DHA were 2.1-4.4-fold greater in infected rats. An opposite trend was observed after iv injection. Cmax and AUC of artesunate and DHA following iv dosing were 5784 ± 3718 and 140 938 ± 128 783 ng·min/mL and 3849 ± 3060 and 86 107 ± 41 863 ng·min/mL, respectively, in uninfected rats versus 2623 ± 1554 and 21 617 ± 12 230 ng·min/mL and 2835 ± 980 and 64 290 ± 29 057 ng·min/mL, respectively, in rats harbouring a chronic infection. The elimination half-lives (t1/2) of artesunate and DHA were considerably altered in infected rats following oral and iv administration of artesunate. Conclusions F. hepatica infections strongly influence the disposition kinetics of artesunate and its metabolite in rats. The clinical implications of this finding need to be carefully studie

Variable viral clearance despite adequate ganciclovir plasma levels during valganciclovir treatment for cytomegalovirus disease in D+/R- transplant recipients

ABSTRACT: BACKGROUND: Valganciclovir, the oral prodrug of ganciclovir, has been demonstrated equivalent to iv ganciclovir for CMV disease treatment in solid organ transplant recipients. Variability in ganciclovir exposure achieved with valganciclovir could be implicated as a contributing factor for explaining variations in the therapeutic response. This prospective observational study aimed to correlate clinical and cytomegalovirus (CMV) viral load response (DNAemia) with ganciclovir plasma concentrations in patients treated with valganciclovir for CMV infection/disease. METHODS: Seven CMV D+/R- transplant recipients (4 kidney, 2 liver and 1 heart) were treated with valganciclovir (initial dose was 900-1800 mg/day for 3-6.5 weeks, followed by 450-900 mg/day for 2-9 weeks). DNAemia was monitored by real time quantitative PCR and ganciclovir plasma concentration was measured at trough (Ctrough) and 3 h after drug administration (C3h) by HPLC. RESULTS: Four patients presented with CMV syndrome, two had CMV tissue-invasive disease after prophylaxis discontinuation, and one liver recipient was treated pre-emptively for asymptomatic rising CMV viral load 5 weeks post-transplantation in the absence of prophylaxis. CMV DNAemia decreased during the first week of treatment in all recipients except in one patient (median decrease: -1.2 log copies/mL, range: -1.8 to 0) despite satisfactory ganciclovir exposure (AUC0-12 = 48 mg.h/L, range for the 7 patients: 40-118 mg.h/L). Viral clearance was obtained in five patients after a median of time of 34 days (range: 28-82 days). Two patients had recurrent CMV disease despite adequate ganciclovir exposure (65 mg.h/L, range: 44-118 mg.h/L). CONCLUSIONS: Valganciclovir treatment for CMV infection/disease in D+/R- transplant recipients can thus result in variable viral clearance despite adequate ganciclovir plasma concentrations, probably correlating inversely with anti-CMV immune responses after primary infection

Infectious complications and graft outcome following treatment of acute antibody-mediated rejection after kidney transplantation: A nationwide cohort study.

Acute antibody-mediated rejection (AMR) remains a challenge after kidney transplantation (KT). As there is no clear-cut treatment recommendation, accurate information on current therapeutic strategies in real-life practice is needed. KT recipients from the multicenter Swiss Transplant Cohort Study treated for acute AMR during the first post-transplant year were included retrospectively. We aimed at describing the anti-rejection protocols used routinely, as well as patient and graft outcomes, with focus on infectious complications. Overall, 65/1669 (3.9%) KT recipients were treated for 75 episodes of acute AMR. In addition to corticosteroid boluses, most common therapies included plasmapheresis (56.0%), intravenous immunoglobulins (IVIg) (38.7%), rituximab (25.3%), and antithymocyte globulin (22.7%). At least one infectious complication occurred within 6 months from AMR treatment in 63.6% of patients. Plasmapheresis increased the risk of overall (hazard ratio [HR]: 2.89; P-value = 0.002) and opportunistic infection (HR: 5.32; P-value = 0.033). IVIg exerted a protective effect for bacterial infection (HR: 0.29; P-value = 0.053). The recovery of renal function was complete at 3 months after AMR treatment in 67% of episodes. One-year death-censored graft survival was 90.9%. Four patients (6.2%) died during the first year (two due to severe infection). In this nationwide cohort we found significant heterogeneity in therapeutic approaches for acute AMR. Infectious complications were common, particularly among KT recipients receiving plasmapheresis

Pharmacie clinique au sein de quatre CHU de la francophonie, intégration et encadrement des pharmaciens cliniciens : une étude exploratoire

CONTEXTE : L’exercice de la pharmacie continue d’évoluer à travers le monde. On reconnaît de plus en plus le rôle clinique du pharmacien et son intégration au sein des équipes de soins est irréversible. En dépit de ces progrès, il existe encore de grandes disparités entre la couverture de soins offertes par les pharmaciens hospitaliers à travers le monde. Cette disparité peut être attribuable à différents facteurs. OBJECTIFS : L’objectif principal est de décrire l’organisation de la pharmacie clinique au sein de quatre centres hospitaliers universitaires de quatre pays de la francophonie. L’objectif secondaire est d’identifier les similitudes et différences et d’identifier des pistes d’avenir. MÉTHODES : Il s’agit d’une étude descriptive transversale exploratoire. L’étude cible un centre hospitalier universitaire (CHU) de France, de Belgique, de Suisse et du Canada (Québec). Un pharmacien expert impliqué dans la gestion de la pharmacie clinique de chaque CHU a été approché à l’initiative d’un membre de l’équipe. Un groupe de travail de cinq pharmaciens a été formé. RÉSULTATS : Durant l’année 2021, le groupe s’est réuni à dix occasions de façon virtuelle. Bien que tous dotés d’une mission universitaire, les établissements comportent un nombre de lits et des volumes d’activités très différents. La dotation en pharmaciens est également très différente (0,83 ETP pharmacien/1000 admissions en Belgique, 0,22 en France, 0,59 en Suisse et 2,39 au Québec). Au Canada, en France et en Belgique, des pharmaciens exercent de la pharmacie clinique auprès de patients de façon centralisée ou décentralisée, incluant de manière plus ou moins exhaustive, de l’analyse d’ordonnance, de la conciliation médicamenteuse, des entretiens pharmaceutiques et des plans de soins lors de la sortie d’hospitalisation. CONCLUSIONS : L’exercice de la pharmacie clinique est très hétérogène dans une sélection de quatre hôpitaux universitaires de la francophonie. Une identification de similitudes et différences peut inspirer des améliorations à apporter à l’organisation de l’activité en pharmacie clinique. Ces travaux ont contribué à la mise en place d’une communauté de pratique sur la pharmacie clinique dans la francophonie.[Clinical pharmacy in four French-speaking university hospitals, integration and supervision of clinical pharmacists: An exploratory study] BACKGROUND: Pharmacy practice continues to evolve worldwide. The clinical role of the pharmacists is increasingly recognized and their integration into the health care team is irreversible. Despite this progress, there are still a wide disparity in the scope of practice provided by hospital pharmacists around the world. This disparity can be attributed to a variety of factors. OBJECTIVES: The primary objective is to describe the organization of clinical pharmacy in four university hospitals in four French-speaking countries. The secondary objective is to identify similarities and differences and to identify perspectives for the future. METHODS: This is an exploratory cross-sectional descriptive study. The study targeted a university hospital (CHU) in France, Belgium, Switzerland and Canada (Quebec). A volunteer expert pharmacist involved in the management of clinical pharmacy at each hospital was approached at the initiative of a team member. A working group of five pharmacists was set up. RESULTS: During the year 2021, the group met virtually on ten occasions. Although all institutions have an academic mission, they have very different numbers of beds and volumes of activity. The number of pharmacists is also very different (0.83 FTE pharmacist/1000 admissions in Belgium, 0.22 in France, 0.59 in Switzerland and 2.39 in Quebec). In all countries, pharmacists provide clinical pharmacy services to patients in a centralised or decentralised manner, including, to various extent, prescription analysis, medication reconciliation, pharmaceutical interviews and discharge plans. CONCLUSIONS: Clinical pharmacy practice is very heterogeneous in a selection of four French-speaking teaching hospitals. Identification of similarities and differences may inspire improvements in the organization of clinical pharmacy activity. This work has contributed to the establishment of a community of practice on clinical pharmacy in the French-speaking world

Ganciclovir Exposure under a 450 mg Daily Dosage of Valganciclovir for the Prevention of Cytomegalovirus Disease in Kidney Transplant Recipients.

Background: It is suggested that a low dose of valganciclovir can be equally effective than a standard dose for cytomegalovirus (CMV) prophylaxis after kidney transplantation. The aim of our study was to determine the ganciclovir exposure observed under a routine daily dosage of 450 mg valganciclovir in kidney transplant recipients with a wide range of renal function. Methods: In this prospective study, kidney transplant recipients with a GFR MDRD above 25 mL/min at risk for CMV (donor or recipient seropositive for CMV) received a dose of valganciclovir (450 mg daily) prophylaxis for 3 months. Ganciclovir levels at trough (Ctrough) and at peak (C3h) were measured monthly. Ganciclovir exposure (AUC0-24) was estimated using Bayesian non-linear mixed-effect modelling (NONMEM) and compared between 3 groups of patients according to their kidney function: GFRMDRD 26-39 mL/min (Group 1), GFRMDRD 40-59 mL/min (Group 2) and GFRMDRD 60-90 mL/min (Group 3). CMV DNAemia was assessed during and after prophylaxis using PCR. Results: Thirty-six patients received 450 mg daily of valganciclovir for 3 months. Median ganciclovir C3h was 3.9 mg/L (range: 1.3-7.1) and Ctrough was 0.4 mg/L (range 0.1-2.7). Median (range) AUC0-24 of ganciclovir was 59.3 mg.h/L (39.0-85.3) in Group 1 patients, 35.8 mg.h/L (24.9-55.8) in Group 2 patients and 29.6 mg.h/L (22.0- 43.2) in Group 3 patients (p<0.001). Anemia was more common in Group 1 patients compared to patients on the other groups (p=0.01). No differences in other adverse events according to ganciclovir exposure were observed. CMV DNAemia was not detected during prophylaxis. After discontinuing prophylaxis, CMV DNAemia was seen in 8/34 patients (23.5%) and 4/36 patients (11%) developed CMV disease. Conclusion: A routine dosage of valganciclovir achieved plasma levels of ganciclovir in patients with GFR>60 mL/min similar to those previously reported using oral ganciclovir. A daily dose of 450 mg valganciclovir appears to be acceptable for CMV prophylaxis in most kidney transplant recipients

Infectious complications and graft outcome following treatment of acute antibody-mediated rejection after kidney transplantation: A nationwide cohort study

Acute antibody-mediated rejection (AMR) remains a challenge after kidney transplantation (KT). As there is no clear-cut treatment recommendation, accurate information on current therapeutic strategies in real-life practice is needed. KT recipients from the multicenter Swiss Transplant Cohort Study treated for acute AMR during the first post-transplant year were included retrospectively. We aimed at describing the anti-rejection protocols used routinely, as well as patient and graft outcomes, with focus on infectious complications. Overall, 65/1669 (3.9%) KT recipients were treated for 75 episodes of acute AMR. In addition to corticosteroid boluses, most common therapies included plasmapheresis (56.0%), intravenous immunoglobulins (IVIg) (38.7%), rituximab (25.3%), and antithymocyte globulin (22.7%). At least one infectious complication occurred within 6 months from AMR treatment in 63.6% of patients. Plasmapheresis increased the risk of overall (hazard ratio [HR]: 2.89; P-value = 0.002) and opportunistic infection (HR: 5.32; P-value = 0.033). IVIg exerted a protective effect for bacterial infection (HR: 0.29; P-value = 0.053). The recovery of renal function was complete at 3 months after AMR treatment in 67% of episodes. One-year death-censored graft survival was 90.9%. Four patients (6.2%) died during the first year (two due to severe infection). In this nationwide cohort we found significant heterogeneity in therapeutic approaches for acute AMR. Infectious complications were common, particularly among KT recipients receiving plasmapheresis

Low-dose valganciclovir is efficacious and safe for prophylaxis of cytomegalovirus infection in kidney transplantation

Background: Optimal valganciclovir (VGC) dosage and duration for cytomegalovirus (CMV) prophylaxis in kidney transplant recipients remains controversial. This study aimed to determine GCV blood levels and efficacy/safety observed under low-dose oral VGC in kidney transplant recipients. Secondly, to quantify the variability of GCV blood levels, and its potential clinical impact. Methods: In this prospective study, each patient at risk for CMV undergoing kidney transplantation received low-dose VGC (450 mg qd) prophylaxis for 3 months, unless GFR was below 40 mL/min, in which case the dose was adapted to 450 mg every other day. GCV levels, at trough (Ctrough) and at peak (C3h) were measured monthly and CMV viremia was assessed during and after prophylaxis using real time quantitative Polymerase Chain Reaction. Adverse effects were recorded on each GCV sampling. Patients were followed up to one year after transplantation. Results: 38 kidney recipients (19 D+/R+, 11 D+/R-, 8 D-/R+) received 3-month VGC prophylaxis. Most patients (mean GFR of 59 mL/min) received 450 mg qd but the dose was reduced to 450 mg every other day in 6 patients with mean GFR of 22 mL/min. Average GCV C3h and Ctrough (regressed at 24h or 48h) were 3.9 mg/L (CV 33%, range: 1.3-8.2) and 0.4 mg/L (CV 111%, range 0.1-3.3). Population pharmacokinetic analysis showed a fair dispersion of the parameters mainly influenced by renal function. Despite this variability, patients remained aviremic during VGC prophylaxis. Neutropenia and thrombocytopenia (grade 2-4) were reported in 4% and 3% of patients respectively. During follow-up, asymptomatic CMV viremia was reported in 25% patients. One year after transplantation, 12% patients (all D+/R-) had developed a CMV disease, which was treated with a therapeutic 6-week course of oral VGC. Conclusion: Average GCV blood levels after oral administration of low-dose VGC in kidney transplant recipients were comparable to those previously reported with oral GCV prophylaxis, efficacious and well tolerated. Thus, a 3-month course of low-dose VGC is appropriate for the renal function of most kidney transplant recipients

Disposition of oral valganciclovir during continuous renal replacement therapy in two lung transplant recipients

Background: Oral valganciclovir (VGC) is hydrolysed into active ganciclovir (GCV) which is eliminated in the kidney by filtration and secretion. VGC dosage has to be adapted in renal failure with continuous renal replacement therapy (CRRT), a condition sometimes encountered early after solid organ transplantation. This investigation aimed to determine whether VGC 450 mg every 48 hours provides appropriate GCV exposure for cytomegalovirus (CMV) prophylaxis during CRRT. Methods: GCV pharmacokinetics were extensively studied during CRRT in two lung transplant recipients with acute renal failure receiving VGC 450 mg every 48 hours trough a nasogastric tube. In vitro experiments using blank whole blood spiked with GCV further investigated exchanges between plasma and erythrocytes. Results: GCV disposition was characterised by an area under the curve (AUC) of 98.0 and 55.4 mg h/L, resulting in trough concentrations of 0.7 and 0.2 mg/L, an apparent total body clearance of 3.3 and 5.8 L/h, a terminal half-life of 16.9 and 14.1 h, and an apparent volume of distribution of 60.3 and 104.9 L. The observed sieving coefficient (filtrate/plasma) was 1.05 and 0.96, and the hemofiltration clearance 3.3 and 3.1 L/h, respectively. High sieving values could be explained by an efflux of GCV from erythrocytes. In vitro experiments confirmed that erythrocytes are loaded with significant GCV amount and release it quickly into plasma, thus contributing to the apparent efficacy of hemofiltration. Conclusion: These results indicate that a VGC dosage of 450 mg every 48 hours was adequate for CMV prophylaxis during CRRT, providing GCV levels similar to those reported using 900 mg qd in transplant recipients with normal renal function

Valganciclovir to prevent or treat cytomegalovirus disease in organ transplantation.

Cytomegalovirus (CMV) is generally considered the most significant pathogen to infect patients following organ transplantation. Significant improvements have been achieved in the management of CMV disease over recent years, especially since the introduction of oral drugs such as oral ganciclovir followed by valganciclovir (VGC), a prodrug of ganciclovir with enhanced bioavailability. Several randomized controlled trials have shown that VGC is an efficacious and convenient oral drug to prevent or treat CMV disease in solid-organ transplant recipients. In this article, we discuss the clinical and pharmacological experience with the use of VGC for the management of CMV in solid-organ transplant recipients. Finally, novel strategies to further reduce the incidence of CMV disease after transplantation are also reviewed