Clinical pharmacology and therapeutic drug monitoring of voriconazole

Er wordt steeds meer aandacht besteed aan therapie op maat bij medicijngebruik. Voor sommige medicijnen kan de medicijnconcentratie in het bloed worden gemeten, om de behandeling met dit medicijn te verbeteren. Voriconazol is een medicijn dat veel gebruikt wordt bij ernstige schimmelinfecties in de longen. Voor voriconazol wordt in verschillende richtlijnen geadviseerd de voriconazol concentratie in het bloed regelmatig te controleren. Daarom is in dit proefschrift onderzocht of het meten van de voriconazol concentratie daadwerkelijk resulteert in een verbetering van de behandeling met dit medicijn. Uit de resultaten blijkt dat alleen het meten van de voriconazol bloedconcentratie niet voldoende is om de behandeling met dit medicijn te optimaliseren, maar dat het onderdeel moet uitmaken van een multidisciplinaire aanpak. Daarnaast is in dit proefschrift onderzocht welke factoren van invloed zijn op de hoeveelheid voriconazol die uiteindelijk in het bloed terecht komt. Uit deze onderzoeken bleek onder andere dat de afbraak van voriconazol is verminderd tijdens een ernstige infectie. Verder hebben wij beschreven waarom het zinnig is om naast voriconazol ook het afbraakproduct van voriconazol te meten, omdat het bijdraagt aan therapie op maat met als doel verminderen van bijwerkingen en het optimaliseren van de behandeling. Verder hebben wij praktische handvatten gegeven om de behandeling met voriconazol in de praktijk te verbeteren

Therapeutic Drug Monitoring of Posaconazole:an Update

Posaconazole is a second-generation triazole agent with a potent and broad antifungal activity. In addition to the oral suspension, a delayed-release tablet and intravenous formulation with improved pharmacokinetic properties have been introduced recently. Due to the large interindividual and intraindividual variation in bioavailability and drug-drug interactions, therapeutic drug monitoring (TDM) is advised to ensure adequate exposure and improve clinical response for posaconazole. Here, we highlight and discuss the most recent findings on pharmacokinetics and pharmacodynamics of posaconazole in the setting of prophylaxis and treatment of fungal infections and refer to the challenges associated with TDM of posaconazole

Combined Impact of Inflammation and Pharmacogenomic Variants on Voriconazole Trough Concentrations:A Meta-Analysis of Individual Data

Few studies have simultaneously investigated the impact of inflammation and genetic polymorphisms of cytochromes P450 2C19 and 3A4 on voriconazole trough concentrations. We aimed to define the respective impact of inflammation and genetic polymorphisms on voriconazole exposure by performing individual data meta-analyses. A systematic literature review was conducted using PubMed to identify studies focusing on voriconazole therapeutic drug monitoring with data of both inflammation (assessed by C-reactive protein level) and the pharmacogenomics of cytochromes P450. Individual patient data were collected and analyzed in a mixed-effect model. In total, 203 patients and 754 voriconazole trough concentrations from six studies were included. Voriconazole trough concentrations were independently influenced by age, dose, C-reactive protein level, and both cytochrome P450 2C19 and 3A4 genotype, considered individually or through a combined genetic score. An increase in the C-reactive protein of 10, 50, or 100 mg/L was associated with an increased voriconazole trough concentration of 6, 35, or 82%, respectively. The inhibitory effect of inflammation appeared to be less important for patients with loss-of-function polymorphisms for cytochrome P450 2C19. Voriconazole exposure is influenced by age, inflammatory status, and the genotypes of both cytochromes P450 2C19 and 3A4, suggesting that all these determinants need to be considered in approaches of personalization of voriconazole treatment

Caspofungin Weight-Based Dosing Supported by a Population Pharmacokinetic Model in Critically Ill Patients

The objective of this study was to develop a population pharmacokinetic model and to determine a dosing regimen for caspofungin in critically ill patients. Nine blood samples were drawn per dosing occasion. Fifteen patients with (suspected) invasive candidiasis had one dosing occasion and five had two dosing occasions, measured on day 3 (±1) of treatment. Pmetrics was used for population pharmacokinetic modeling and probability of target attainment (PTA). A target 24-h area under the concentration-time curve (AUC) value of 98 mg·h/liter was used as an efficacy parameter. Secondarily, the AUC/MIC targets of 450, 865, and 1,185 were used to calculate PTAs for Candida glabrata, C. albicans, and C. parapsilosis, respectively. The final 2-compartment model included weight as a covariate on volume of distribution (V). The mean V of the central compartment was 7.71 (standard deviation [SD], 2.70) liters/kg of body weight, the mean elimination constant (Ke) was 0.09 (SD, 0.04) h-1, the rate constant for the caspofungin distribution from the central to the peripheral compartment was 0.44 (SD, 0.39) h-1, and the rate constant for the caspofungin distribution from the peripheral to the central compartment was 0.46 (SD, 0.35) h-1. A loading dose of 2 mg/kg on the first day, followed by 1.25 mg/kg as a maintenance dose, was chosen. With this dose, 98% of the patients were expected to reach the AUC target on the first day and 100% of the patients on the third day. The registered caspofungin dose might not be suitable for critically ill patients who were all overweight (≥120 kg), over 80% of median weight (78 kg), and around 25% of lower weight (≤50 kg). A weight-based dose regimen might be appropriate for achieving adequate exposure of caspofungin in intensive care unit patients

Pharmacodynamics of Voriconazole in Children:Further Steps along the Path to True Individualized Therapy

Voriconazole is the agent of choice for the treatment of invasive aspergillosis in children at least 2 years of age. The galactomannan index is a routinely used diagnostic marker for invasive aspergillosis and can be useful for following the clinical response to antifungal treatment. The aim of this study was to develop a pharmacokinetic-pharmacodynamic (PK-PD) mathematical model that links the pharmacokinetics of voriconazole with the galactomannan readout in children. Twelve children receiving voriconazole for treatment of proven, probable, and possible invasive fungal infections were studied. A previously published population PK model was used as the Bayesian prior. The PK-PD model was used to estimate the average area under the concentration-time curve (AUC) in each patient and the resultant galactomannan-time profile. The relationship between the ratio of the AUC to the concentration of voriconazole that induced half maximal killing (AUC/EC50) and the terminal galactomannan level was determined. The voriconazole concentration-time and galactomannan-time profiles were both highly variable. Despite this variability, the fit of the PK-PD model was good, enabling both the pharmacokinetics and pharmacodynamics to be described in individual children. (AUC/EC50)/15.4 predicted terminal galactomannan (P = 0.003), and a ratio of >6 suggested a lower terminal galactomannan level (P = 0.07). The construction of linked PK-PD models is the first step in developing control software that enables not only individualized voriconazole dosages but also individualized concentration targets to achieve suppression of galactomannan levels in a timely and optimally precise manner. Controlling galactomannan levels is a first critical step to maximizing clinical response and survival

Low Caspofungin Exposure in Patients in Intensive Care Units

In critically ill patients, drug exposure may be influenced by altered drug distribution and clearance. Earlier studies showed that the variability in caspofungin exposure was high in Intensive Care Unit (ICU) patients. The primary objective of this study was to determine if the standard dose of caspofungin resulted in adequate exposure in critically ill patients. A multicenter prospective study in ICU patients with (suspected) invasive candidiasis was conducted in the Netherlands, from November 2013 to October 2015. Patients received standard caspofungin treatment and the exposure was determined on day 3 of treatment. An area under the concentration-time curve over 24 hours (AUC0-24h) of 98 mg*h/L was considered adequate exposure. In case of low exposure (i.e. <79 mg*h/L; ≥20% lower AUC0-24h), the caspofungin dose was increased and the exposure re-evaluated. Twenty patients were included in the study, of which 5 had a positive blood culture. The median caspofungin AUC0-24h at day 3 was 78 mg*h/L (interquartile range (IQR), 69 - 97 mg*h/L). A low AUC0-24h (<79 mg*h/L) was seen in 10 patients. The AUC0-24h was significantly and positively correlated with the caspofungin dose in mg/kg/day (P = 0.011). The median AUC0-24h with a caspofungin dose of 1 mg/kg was estimated using a pharmacokinetic model and was 114.9 mg*h/L (IQR, 103.2 - 143.5 mg*h/L). In conclusion, the caspofungin exposure in ICU patients in this study was low compared with healthy volunteers and other (non-)critically ill patients, most likely due to a larger volume of distribution. A weight-based dose regimen is probably more suitable for patients with substantially altered drug distribution