Pharmacokinetics and tolerability of voriconazole and a combination oral contraceptive co‐administered in healthy female subjects

Voriconazole (VCZ) is considered first-line therapy for invasive aspergillosis and is often empirically prescribed to prevent the emergence of invasive fungal infections in patients undergoing a peripheral stem cell transplant (PSCT) (1, 2). In volunteers and patients, VCZ displays highly variable nonlinear pharmacokinetics, which are due primarily to polymorphic cytochrome P450 2C19 (CYP2C19) metabolism (3-6). Overall, the mean pharmacokinetic data of hematological-oncological patients are similar to those of healthy volunteers (7,8). After oral and intravenous administration, VCZ is extensively metabolized to inactive metabolites, including N-oxide VCZ, 4-hydroxy-VCZ, and dihydroxy-VCZ (5, 9, 10). The primary VCZ metabolite, Noxide VCZ, results from the N-oxidation of the fluoropyrimidine ring and accounts for 21% of the VCZ recovered dose (9). The formation of this metabolite is catalyzed primarily by CYP2C19 and CYP3A4 (9-12). VCZ pharmacokinetics are further influenced by the genetic polymorphisms of CYP2C19, other drugmetabolizing enzymes, and age-based differences in drug metabolism (10-17). The pharmacokinetics of VCZ have been studied, but those of N-oxide VCZ remain poorly characterized in PSCT patients. Therefore, the primary objective of this study was to characterize oral VCZ and N-oxide VCZ pharmacokinetics preand post-adult autologous PSCT.This was an open-label, single-center pharmacokinetic study of adults undergoing an autologous PSCT and receiving oral VCZ. Patients were Ͼ17 years old, medically stable, and prescribed VCZ for prophylactic antifungal therapy by their primary physician. All subjects in the study were diagnosed with multiple myeloma, were undergoing a melphalan-based autologous PSCT, and provided informed consent. Patients with clinical and laboratory evidence of veno-occlusive disease, aplastic anemia, liver disease (ChildPugh classification B or C), a history of gastrointestinal illness, or surgery that may affect drug absorption or galactose intolerance were excluded from this study. Patients with a history of anaphylaxis to VCZ or other triazole antifungal agents or who received a systemic antifungal agent within 7 days of receiving VCZ as well as other drugs that are known to be substrates of CYP2C19, CYP3A4, or CYP2C9 were excluded. All subjects received 400 mg VCZ orally every 12 h on day 1, followed by 200 mg orally every 12 h on days 2 to 17. As part of their standard immunosuppression regimen, all subjects received high-dose dexamethasone. Repeated blood sampling occurred 2 days following the loading dose (study day 3) and 6 days post-PSCT (study day 12) at predose and 0.5, 1.0, 1.5, 2.0, 3.0, 4.0, 6.0, 8.0, and 12.0 h after the a.m. dose. All blood samples were analyzed in singlet by PPD/Pharmaco for analysis by high-performance liquid chromatography (HPLC) and mass spectrometry according to PPD method LCMS 244 V 2.00 (18). The accuracy of data for the N-oxide VCZ assay was within the acceptable range for assay validation, but due to slow subject accrual, our sample ag...

supporting

confidence: 77%

Steady-State Pharmacokinetics of Oral Voriconazole and Its Primary Metabolite, N -Oxide Voriconazole, Pre- and Post-Autologous Peripheral Stem Cell Transplantation

Amsden

Gubbins

McConnell

et al. 2013

“…The sampling dates and times could be changed to fit the study site feasibility. PPD Development (Richmond, VA) (following good laboratory practice [GLP] standards) analyzed all the plasma samples using previously validated liquid chromatography coupled with tandem-mass spectrometry (LC-MS/MS) methods (11,12). Any interaction between the two drugs in the sample analysis was ruled out.…”

Section: Methodsmentioning

confidence: 99%

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

Liu

Mould

2014

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...

“…Plasma voriconazole and the N-oxide metabolite concentrations were analyzed using a previously validated liquid chromatography coupled to tandem mass spectrometry (18) at Pharmaceutical Product Development (Richmond, VA, USA). The lower limits of quantification for voriconazole and the N-oxide metabolite were 10 and 20 ng/ml, respectively.…”

Section: Methodsmentioning

confidence: 99%

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

Mori

Kobayashi

Kato³

et al. 2015

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...