Integrated Population Pharmacokinetic Analysis of Voriconazole in Children, Adolescents, and Adults

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bTo assess the pharmacokinetics (PK) of voriconazole and anidulafungin in patients with invasive aspergillosis (IA) in comparison with other populations, sparse PK data were obtained for 305 adults from a prospective phase 3 study comparing voriconazole and anidulafungin in combination versus voriconazole monotherapy (voriconazole, 6 mg/kg intravenously [IV] every 12 h [q12h] for 24 h followed by 4 mg/kg IV q12h, switched to 300 mg orally q12h as appropriate; with placebo or anidulafungin IV, a 200-mg loading dose followed by 100 mg q24h). Voriconazole PK was described by a two-compartment model with first-order absorption and mixed linear and time-dependent nonlinear (Michaelis-Menten) elimination; anidulafungin PK was described by a two-compartment model with first-order elimination. For voriconazole, the normal inverse Wishart prior approach was implemented to stabilize the model. Compared to previous models, no new covariates were identified for voriconazole or anidulafungin. PK parameter estimates of voriconazole and anidulafungin are in agreement with those reported previously except for voriconazole clearance (the nonlinear clearance component became minimal). At a 4-mg/kg IV dose, voriconazole exposure tended to increase slightly as age, weight, or body mass index increased, but the difference was not considered clinically relevant. Estimated voriconazole exposures in IA patients at 4 mg/kg IV were higher than those reported for healthy adults (e.g., the average area under the curve over a 12-hour dosing interval [AUC 0 -12 ] at steady state was 46% higher); while it is not definitive, age and concomitant medications may impact this difference. Estimated anidulafungin exposures in IA patients were comparable to those reported for the general patient population. This study was approved by the appropriate institutional review boards or ethics committees and registered on ClinicalTrials.gov (NCT00531479). Invasive aspergillosis (IA) is an important cause of morbidity and mortality in patients with hematological malignancies, as well as those who have undergone allogeneic hematopoietic stem cell transplantation (HSCT) or solid organ transplantation. Antifungal combination therapy with voriconazole (an azole; both intravenous [IV] and oral formulations are available) and anidulafungin (an echinocandin; IV only) is an intriguing possibility for the treatment of IA, due to their different mechanisms of action and lack of pharmacokinetic (PK) drug-drug interaction (1-3). Voriconazole inhibits fungal cytochrome P450 (CYP)-dependent 14-␣-sterol demethylase, an essential enzyme in the synthesis of ergosterol (a component of the fungal cell membrane). Anidulafungin is a 1,3-␤-D-glucan synthase inhibitor which interferes with fungal cell wall synthesis. A number of in vitro studies and animal models have demonstrated additive or synergistic activities of voriconazole and echinocandins against Aspergillus species (4-7), indicating that two mechanisms of action may provide an additional benefit over one mechanism alon...

Section: Methodsmentioning

confidence: 99%

“…The graphic processing of the NONMEM output was performed with R (version 2.12.2). The previously developed population PK models for anidulafungin and voriconazole were adapted to fit the current data separately (13,14).…”

Section: Methodsmentioning

confidence: 99%

Population Pharmacokinetic Analysis of Voriconazole and Anidulafungin in Adult Patients with Invasive Aspergillosis

Liu

Mould

2014

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“…Voriconazole (Pfizer, Inc.) was administered according to dosing regimens derived from the recent population pharmacokinetic modeling (17), as shown in Table 1. The intravenous formulation was prepared at a final concentration of 0.5 to 5 mg/ml and infused at rate of 3 mg/kg/h (i.e., the doses of 9, 8, 6, and 4 mg/kg were administered over 180, 160, 120, and 80 min, respectively).…”

Section: Methodsmentioning

confidence: 99%

“…NCT01383993) aimed to evaluate the pharmacokinetics, safety, and tolerability of voriconazole in Japanese pediatric patients following these recommended intravenous-to-oral switch regimens (17). This study aimed to confirm whether the proposed doses based on population pharmacokinetic modeling were appropriate for pediatric patients.…”

mentioning

confidence: 99%

Pharmacokinetics and Safety of Voriconazole Intravenous-to-Oral Switch Regimens in Immunocompromised Japanese Pediatric Patients

Mori

Kobayashi

Kato³

et al. 2015

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The aim of this study was to investigate the pharmacokinetics, safety, and tolerability of voriconazole following intravenous-tooral switch regimens used with immunocompromised Japanese pediatric subjects (age 2 to <15 years) at high risk for systemic fungal infection. Twenty-one patients received intravenous-to-oral switch regimens based on a recent population pharmacokinetic modeling; they were given 9 mg/kg of body weight followed by 8 mg/kg of intravenous (i.v.) voriconazole every 12 h (q12h), and 9 mg/kg (maximum, 350 mg) of oral voriconazole q12h (for patients age 2 to <12 or 12 to <15 years and <50 kg) or 6 mg/kg followed by 4 mg/kg of i.v. voriconazole q12h and 200 mg of oral voriconazole q12h (for patients age 12 to <15 years and >50 kg). The steady-state area under the curve over the 12-h dosing interval (AUC 0 -12,ss ) was calculated using the noncompartmental method and compared with the predicted exposures in Western pediatric subjects based on the abovementioned modeling. The geometric mean (coefficient of variation) AUC 0 -12,ss values for the intravenous and oral regimens were 51.1 g · h/ml (68%) and 45.8 g · h/ml (90%), respectively; there was a high correlation between AUC 0 -12,ss and trough concentration. Although the average exposures were higher in the Japanese patients than those in the Western pediatric subjects, the overall voriconazole exposures were comparable between these two groups due to large interindividual variability. The exposures in the 2 cytochrome P450 2C19 poor metabolizers were among the highest. Voriconazole was well tolerated. The most common treatment-related adverse events were photophobia and abnormal hepatic function. These recommended doses derived from the modeling appear to be appropriate for Japanese pediatric patients, showing no additional safety risks compared to those with adult patients. (This study has been registered at ClinicalTrials.gov under registration no. NCT01383993.) V oriconazole is a triazole antifungal drug that has been recommended in guidelines for the treatment of invasive fungal infections in adults in Japan (1) and the rest of the world (2-5). A 2009 nationwide survey regarding treatment for pediatric patients with invasive fungal infections in Japan found that antifungal agents not approved for pediatric use, including voriconazole, were frequently being used in clinical practice at a wide range of doses (6).Voriconazole is metabolized by the human hepatic cytochrome P450 enzymes, primarily CYP2C19 but also CYP3A4 and, to a lesser extent, CYP2C9, to its main circulating N-oxide metabolite (UK-121,265) (7, 8), with a significantly faster clearance of voriconazole in children than that in adults (9, 10). The CYP2C19 enzyme exhibits genetic polymorphisms, and the CYP2C19 genotype can be a key factor in the pharmacokinetics of voriconazole in individual patients. A marked interethnic difference in the frequency of CYP2C19 poor metabolizers (PM) has been noted (11). The frequencies of CYP2C19 PM have been estimated at 2.2% of Caucasian compare...

“…Subtherapeutic concentrations have been linked to higher failure rates in patients with life-threatening invasive fungal infections, and supratherapeutic concentrations are associated with neurological and hepatic toxicity (9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19). Voriconazole is primarily metabolized by CYP2C19, which commonly exhibits genetic polymorphism, leading to variable PK and leaving certain populations susceptible to decreased metabolism and increased plasma concentrations of voriconazole (20)(21)(22)(23). Patients of Asian descent with polymorphisms in CYP2C19 have up to a 20% incidence of being poor metabolizers while this value is up to 5% for Caucasian and African American individuals (24).…”

mentioning

confidence: 99%

Comparative Evaluation of the Predictive Performances of Three Different Structural Population Pharmacokinetic Models To Predict Future Voriconazole Concentrations

Farkas

Daróczi²,

Villasurda

et al. 2016

i Bayesian methods for voriconazole therapeutic drug monitoring (TDM) have been reported previously, but there are only sparse reports comparing the accuracy and precision of predictions of published models. Furthermore, the comparative accuracy of linear, mixed linear and nonlinear, or entirely nonlinear models may be of high clinical relevance. In this study, models were coded into individually designed optimum dosing strategies (ID-ODS) with voriconazole concentration data analyzed using inverse Bayesian modeling. The data used were from two independent data sets, patients with proven or suspected invasive fungal infections (n ‫؍‬ 57) and hematopoietic stem cell transplant recipients (n ‫؍‬ 10). Observed voriconazole concentrations were predicted whereby for each concentration value, the data available to that point were used to predict that value. The mean prediction error (ME) and mean squared prediction error (MSE) and their 95% confidence intervals (95% CI) were calculated to measure absolute bias and precision, while ⌬ME and ⌬MSE and their 95% CI were used to measure relative bias and precision, respectively. A total of 519 voriconazole concentrations were analyzed using three models. Voriconazole is a triazole antifungal that exhibits broad-spectrum activity and is a first-line agent for the treatment of Candida sp. infections (1), invasive aspergillosis (2), and other serious fungal infections. With increasing numbers of at-risk immunocompromised populations, such as those undergoing solid-organ transplantation or those with HIV infections, the incidence of invasive mycoses is on the rise (3, 4). Despite the advent of newer antifungals, Aspergillus sp. and Candida sp. infections have exhibited high mortality rates of 60% and 30%, respectively (5, 6).Recent published studies of voriconazole have shed light on the clinical relevance of therapeutic drug monitoring (TDM) for optimization of dosing based on voriconazole's highly variable pharmacokinetics (PK) and the resultant poor predictability of plasma concentrations (7,8). Subtherapeutic concentrations have been linked to higher failure rates in patients with life-threatening invasive fungal infections, and supratherapeutic concentrations are associated with neurological and hepatic toxicity (9-19). Voriconazole is primarily metabolized by CYP2C19, which commonly exhibits genetic polymorphism, leading to variable PK and leaving certain populations susceptible to decreased metabolism and increased plasma concentrations of voriconazole (20-23). Patients of Asian descent with polymorphisms in CYP2C19 have up to a 20% incidence of being poor metabolizers while this value is up to 5% for Caucasian and African American individuals (24). Poor metabolizers can have a PK exposure up to four times higher than that of homozygous comparators.Nonlinearity in voriconazole PK relating to saturable clearance mechanisms has been reported (8), which together with its extensive variability makes dosing profoundly challenging, especially when higher doses are used. Conve...