Population pharmacokinetics and covariate-based dosing individualization of voriconazole in lung transplant recipients.

This study aimed to explore pharmacokinetics of voriconazole and its covariates in lung transplant recipients using population approach in order to propose dosing individualization. Data from routine therapeutic drug monitoring in adult lung transplant recipients treated with oral voriconazole were analysed with a three-stage population pharmacokinetic model using nonlinear mixed-effects modelling. Monte Carlo simulations based on final voriconazole pharmacokinetic model were used to generate the theoretical distribution of pharmacokinetic profiles at various dosing regimens. A total of 78 voriconazole serum concentrations collected from 40 patients were included in pharmacokinetic analysis. The only significant covariate was age for voriconazole clearance. Population voriconazole apparent clearance started at 32.26 L/h and decreased by 0.021 L/h with each year of patient's age, while population apparent volume of distribution was 964.46 L. Based on this model, we have proposed an easy-to-use dosing regimen consisting of a loading dose of 400 mg every 12 h for the first 48 h of treatment followed by maintenance dose of 300 mg every 12 h in patients aged up to 59 years, or by maintenance dose of 200 mg every 12 h in patients aged above 59 years.

Potential interactions between triazole antifungal agents and lorlatinib based on ultra-performance liquid chromatography-tandem mass spectrometry in rat plasma.

AIM: Our study is to investigate the effects of triazole antifungal drugs on the pharmacokinetics of lorlatinib in rats. METHODS: The samples were precipitated with methanol. Chromatographic separation was performed on a ultra-performance liquid chromatography (UPLC) system using a BEH C18 column. The mobile phase consisted of 0.1% formic acid water and methanol. Lorlatinib and crizotinib (internal standard) were detected in multiple reaction monitoring mode. The fragment ions were 407.3-228.07 for lorlatinib and m/z 450.3-260.0 for crizotinib. Lorlatinib and different triazole antifungal drugs were given to Sprague Dawley rats by gavage, and blood was collected from the tail vein at a certain time point. The validated UPLC-MS/MS method was applied to a drug interaction study of ketoconazole, voriconazole, itraconazole, and posaconazole with lorlatinib in rats. RESULTS: Ketoconazole and voriconazole significantly inhibited lorlatinib metabolism. When administration with ketoconazole and voriconazole, the area under the curve from time zero to infinity of lorlatinib increased by 49.0% and 104.3%, respectively; the clearance decreased by 40.0% and 40.0%, respectively. While itraconazole and posaconazole did not affect lorlatinib pharmacokinetics. CONCLUSION: The UPLC-MS/MS-based assay is helpful to further understand the pharmacokinetics of lorlatinib in rats, and confirmed the findings that the combination of lorlatinib with CYP3A inhibitors should be avoided as predicted by our pre-clinical studies.

Can we predict the influence of inflammation on voriconazole exposure? An overview.

Voriconazole is a triazole antifungal indicated for invasive fungal infections that exhibits a high degree of inter-individual and intra-individual pharmacokinetic variability. Voriconazole pharmacokinetics is non-linear, making dosage adjustments more difficult. Therapeutic drug monitoring is recommended by measurement of minimum plasma concentrations. Several factors are responsible for the high pharmacokinetic variability of voriconazole: age, feeding (which decreases absorption), liver function, genetic polymorphism of the CYP2C19 gene, drug interactions and inflammation. Invasive fungal infections are indeed very frequently associated with inflammation, which engenders a risk of voriconazole overexposure. Many studies have reviewed this topic in both the adult and paediatric populations, but few studies have focused on the specific point of the prediction, to evaluate the influence of inflammation on voriconazole pharmacokinetics. Predicting the impact of inflammation on voriconazole pharmacokinetics could help optimize antifungal therapy and improve patient management. This review summarizes the existing data on the influence of inflammation on voriconazole pharmacokinetics in adult populations. We also evaluate the role of C-reactive protein, the impact of inflammation on patient metabolic phenotypes, and the tools that can be used to predict the effect of inflammation on voriconazole pharmacokinetics.

Population pharmacokinetics of voriconazole and the role of CYP2C19 genotype on treatment optimization in pediatric patients.

The aim of this study was to evaluate factors that impact on voriconazole (VRC) population pharmacokinetic (PPK) parameters and explore the optimal dosing regimen for different CYP2C19 genotypes in Chinese paediatric patients. PPK analysis was used to identify the factors contributing to the variability in VRC plasma trough concentrations. A total of 210 VRC trough concentrations from 91 paediatric patients were included in the study. The median VRC trough concentration was 1.23 mg/L (range, 0.02 to 8.58 mg/L). At the measurement of all the trough concentrations, the target range (1.0~5.5 mg/L) was achieved in 52.9% of the patients, while subtherapeutic and supratherapeutic concentrations were obtained in 40.9% and 6.2% of patients, respectively. VRC trough concentrations were adjusted for dose (Ctrough/D), with normal metabolizers (NMs) and intermediate metabolizers (IMs) having significantly lower levels than poor metabolizers (PMs) (PN-P < 0.001, PI-P = 0.039). A one-compartment model with first-order absorption and elimination was suitable to describe the VRC pharmacokinetic characteristics. The final model of VRC PPK analysis contained CYP2C19 phenotype as a significant covariate for clearance. Dose simulations suggested that a maintenance dose of 9 mg/kg orally or 8 mg/kg intravenously twice daily was appropriate for NMs to achieve the target concentration. A maintenance dose of 9 mg/kg orally or 5 mg/kg intravenously twice daily was appropriate for IMs. Meanwhile, PMs could use lower maintenance dose and an oral dose of 6 mg/kg twice daily or an intravenous dose of 5mg/kg twice daily was appropriate. To increase the probability of achieving the therapeutic range and improving efficacy, CYP2C19 phenotype can be used to predict VRC trough concentrations and guide dose adjustments in Chinese pediatric patients.

Towards Model-Informed Precision Dosing of Voriconazole: Challenging Published Voriconazole Nonlinear Mixed-Effects Models with Real-World Clinical Data.

BACKGROUND AND OBJECTIVES: Model-informed precision dosing (MIPD) frequently uses nonlinear mixed-effects (NLME) models to predict and optimize therapy outcomes based on patient characteristics and therapeutic drug monitoring data. MIPD is indicated for compounds with narrow therapeutic range and complex pharmacokinetics (PK), such as voriconazole, a broad-spectrum antifungal drug for prevention and treatment of invasive fungal infections. To provide guidance and recommendations for evidence-based application of MIPD for voriconazole, this work aimed to (i) externally evaluate and compare the predictive performance of a published so-called 'hybrid' model for MIPD (an aggregate model comprising features and prior information from six previously published NLME models) versus two 'standard' NLME models of voriconazole, and (ii) investigate strategies and illustrate the clinical impact of Bayesian forecasting for voriconazole. METHODS: A workflow for external evaluation and application of MIPD for voriconazole was implemented. Published voriconazole NLME models were externally evaluated using a comprehensive in-house clinical database comprising nine voriconazole studies and prediction-/simulation-based diagnostics. The NLME models were applied using different Bayesian forecasting strategies to assess the influence of prior observations on model predictivity. RESULTS: The overall best predictive performance was obtained using the aggregate model. However, all NLME models showed only modest predictive performance, suggesting that (i) important PK processes were not sufficiently implemented in the structural submodels, (ii) sources of interindividual variability were not entirely captured, and (iii) interoccasion variability was not adequately accounted for. Predictive performance substantially improved by including the most recent voriconazole observations in MIPD. CONCLUSION: Our results highlight the potential clinical impact of MIPD for voriconazole and indicate the need for a comprehensive (pre-)clinical database as basis for model development and careful external model evaluation for compounds with complex PK before their successful use in MIPD.

CYP3A and CYP2C19 Activity Determined by Microdosed Probe Drugs Accurately Predict Voriconazole Clearance in Healthy Adults.

BACKGROUND AND OBJECTIVE: Voriconazole is an important broad-spectrum anti-fungal drug with nonlinear pharmacokinetics. The aim of this single centre fixed-sequence open-label drug-drug interaction trial in healthy participants (N = 17) was to determine whether microdosed probe drugs for CYP3A and CYP2C19 reliably predict voriconazole clearance (CLVRZ). METHODS: At baseline, a single oral microdose of the paradigm substrates midazolam (CYP3A) and omeprazole (CYP2C19) were given to estimate their clearances (CL). Thereafter, a single oral dose of voriconazole was administered (50, 100, 200 or 400 mg), followed by the microdosed probe drugs. RESULTS: The clearances of midazolam (CLMDZ 790-2790 mL/min at baseline; 248-1316 mL/min during voriconazole) and omeprazole (CLOMZ 66.4-2710 mL/min at baseline; 30.1-1420 mL/min during voriconazole) were highly variable. CLMDZ [geometric mean ratio (GMR) 0.586 at 50 mg voriconazole decreasing to GMR 0.196 at 400 mg voriconazole] and CLOMZ (GMR 0.590 at 50 mg decreasing to GMR 0.166 at 400 mg) were reduced with higher voriconazole doses. CLMDZ was linearly correlated with CLVRZ (slope 1.458; adjusted R2 0.528) as was CLOMZ (slope 0.807; adjusted R2 0.898). Multiple linear regression resulted in an adjusted R2 of 0.997 for the relationship CLVRZ ~ log CLOMZ + log CLMDZ using data during voriconazole treatment and an adjusted R2 of 0.997 for the relationship CLVRZ ~ log CLOMZ + log CLMDZ + voriconazole dose, using baseline data for CLMDZ and CLOMZ. CONCLUSION: Microdosed midazolam and omeprazole accurately described and predicted total CLVRZ TRIAL REGISTRATION: EudraCT No: 2020-001017-20, registered on March 5th, 2020. DRKS: DRKS00022547, registered on August 6th, 2020.

Pharmacokinetics of Voriconazole in Peritoneal Fluid of Critically Ill Patients.

Data on the distribution of voriconazole (VRC) in the human peritoneal cavity are sparse. This prospective study aimed to describe the pharmacokinetics of intravenous VRC in the peritoneal fluid of critically ill patients. A total of 19 patients were included. Individual pharmacokinetic curves, drawn after single (first dose on day 1) and multiple (steady-state) doses, displayed a slower rise and lower fluctuation of VRC concentrations in peritoneal fluid than in plasma. Good but variable penetration of VRC into the peritoneal cavity was observed, and the median (range) peritoneal fluid/plasma ratios of the area under the concentration-time curve (AUC) were 0.54 (0.34 to 0.73) and 0.67 (0.63 to 0.94) for single and multiple doses, respectively. Approximately 81% (13/16) of the VRC steady-state trough concentrations (Cmin,ss) in plasma were within the therapeutic range (1 to 5.5 µg/mL), and the corresponding Cmin,ss (median [range]) in peritoneal fluid was 2.12 (1.39 to 3.72) µg/mL. Based on the recent 3-year (2019 to 2021) surveillance of the antifungal susceptibilities for Candida species isolated from peritoneal fluid in our center, the aforementioned 13 Cmin,ss in peritoneal fluid exceeded the MIC90 of C. albicans, C. glabrata, and C. parapsilosis (0.06, 1.00, and 0.25 µg/mL, respectively), which supported VRC as a reasonable choice for initial empirical therapies against intraabdominal candidiasis caused by these three Candida species, prior to the receipt of susceptibility testing results.

Clinically relevant bidirectional drug-drug interaction between midostaurin and voriconazole.

Midostaurin is often prescribed with azole antifungals in patients with leukaemia, either for aspergillosis prophylaxis or treatment. Midostaurin is extensively metabolized by cytochrome (CYP) 3A4. In addition, it inhibits and induces various CYPs at therapeutic concentrations. Thus, midostaurin is associated with a high potential for drug-drug interactions (DDIs), both as a substrate (victim) and as a perpetrator. However, data on midostaurin as a perpetrator of DDIs are scarce, as most pharmacokinetic studies have focused on midostaurin as a victim drug. We report a clinically relevant bidirectional DDI between midostaurin and voriconazole during induction treatment. A 49-year-old woman with acute myeloid leukaemia developed invasive pulmonary aspergillosis after induction chemotherapy. She was treated with voriconazole at standard dosage. Six days after starting midostaurin, she developed visual hallucinations with a concurrent sharp increase in voriconazole blood concentration (Ctrough 10.3 mg L-1 , target Ctrough 1-5 mg L-1 ). Neurotoxicity was considered to be related to voriconazole overexposure. The concentration of midostaurin was concomitantly six-fold above the average expected level, but without safety issues. Midostaurin was stopped and the dosage of voriconazole was adjusted with therapeutic drug monitoring. The evolution was favourable, with quick resolution and no recurrence of visual hallucinations. To our knowledge, this is the first case suggesting that midostaurin and voriconazole reciprocally inhibit each other's metabolism, leading to increased exposure of both. This case highlights the knowledge gap regarding drug-drug interactions between midostaurin and azole antifungals. Close clinical and therapeutic drug monitoring is advised in such cases.

Pharmacokinetics and safety of two Voriconazole formulations after intravenous infusion in two doses in healthy Chinese subjects.

BACKGROUND: Voriconazole is a second-generation triazole that is used to prevent and treat invasive fungal infections. The purpose of this study was to evaluate the pharmacokinetic equivalency of a test formulation and reference formulation (Vfend®) of Voriconazole. MATERIALS AND METHODS: This was a randomized, open-label, single-dose, two-treatment, two-sequence, two-cycle, crossover phase I trial. The 48 subjects were equally divided into 4 mg/kg and 6 mg/kg groups. Within each group, the subjects were randomized 1:1 to the test or reference formulation.. After a 7-day washout period, crossover formulations were administered. The blood samples were collected at 0.5, 1.0, 1.33,1.42,1.5, 1.75, 2.0, 2.5, 3.0, 4.0, 6.0, 8.0, 12.0, 24.0, 36.0, 48.0 h later in the 4 mg/kg group, while at 0.5, 1.0, 1.5, 1.75, 2.0, 2.08, 2.17, 2.33, 2.5, 3.0, 4.0, 6.0, 8.0, 12.0, 24.0, 36.0, 48.0 h later in the 6 mg/kg group. The plasma concentrations of Voriconazole were determined by Liquid chromatography-tandem mass spectrometry (LC-MS/MS). The safety of the drug was evaluated. RESULTS: The 90% confidence intervals (CIs) of the ratio of geometric means (GMRs) of Cmax, AUC0-t, and AUC0-∞ in both 4 mg/kg and 6 mg/kg groups were within the prespecified bioequivalence limits between 80 ~ 125%. In the 4 mg/kg groups, 24 subjects were enrolled and completed the study. The mean Cmax was (2.552 ± 0.448) µg/mL, AUC0-t was (11.875 ± 7.157) h*µg/mL and AUC0-∞ was (12.835 ± 9.813) h*µg/mL after a single dose of 4 mg/kg test formulation. The mean Cmax was (2.615 ± 0.464) µg/mL, AUC0-t was (12.500 ± 7.257) h*µg/mL and AUC0-∞ was (13.416 ± 9.485) h*µg/mL after a single dose of 4 mg/kg reference formulation. In the 6 mg/kg groups, 24 subjects were enrolled and completed the study. The mean Cmax was (3.538 ± 0.691) µg/mL, AUC0-t was (24.976 ± 12.364) h*µg/mL and AUC0-∞ was (26.212 ± 14.057) h*µg/mL after a single dose of 6 mg/kg test formulation. The mean Cmax was (3.504 ± 0.667) µg/mL AUC0-t was (24.990 ± 12.455) h*µg/mL and AUC0-∞ was (26.160 ± 13.996) h*µg/mL after a single dose of 6 mg/kg reference formulation. Serious adverse event (SAE) was not observed. CONCLUSION: In both 4 mg/kg group and 6 mg/kg group, equivalent pharmacokinetic characteristics that satisfied the criteria of bioequivalence for both test and reference formulations of Voriconazole. TRIAL REGISTRATION: NCT05330000 (15/04/2022).

Voriconazole exposure is influenced by inflammation: A population pharmacokinetic model.

BACKGROUND: Voriconazole is an antifungal drug used for the treatment of invasive fungal infections. Due to highly variable drug exposure, therapeutic drug monitoring (TDM) has been recommended. TDM may be helpful to predict exposure accurately, but covariates, such as severe inflammation, that influence the metabolism of voriconazole have not been included in the population pharmacokinetic (popPK) models suitable for routine TDM. OBJECTIVES: To investigate whether the effect of inflammation, reflected by C-reactive protein (CRP), could improve a popPK model that can be applied in clinical care. PATIENTS AND METHODS: Data from two previous studies were included in the popPK modelling. PopPK modelling was performed using Edsim++. Different popPK models were compared using Akaike Information Criterion and goodness-of-fit plots. RESULTS: In total, 1060 voriconazole serum concentrations from 54 patients were included in this study. The final model was a one-compartment model with non-linear elimination. Only CRP was a significant covariate, and was included in the final model and found to affect the maximum rate of enzyme activity (Vmax). For the final popPK model, the mean volume of distribution was 145 L [coefficient of variation percentage (CV%)=61%], mean Michaelis-Menten constant was 5.7 mg/L (CV%=119%), mean Vmax was 86.4 mg/h (CV%=99%) and mean bioavailability was 0.83 (CV%=143%). Internal validation using bootstrapping resulted in median values close to the population parameter estimates. CONCLUSIONS: This one-compartment model with non-linear elimination and CRP as a covariate described the pharmacokinetics of voriconazole adequately.

Evaluation of Pharmacokinetics and Safety With Bioequivalence of Voriconazole Injection of 2 Formulations in Chinese Healthy Volunteers: Bioequivalence Study.

Voriconazole is a first-line medicine for treating invasive aspergillosis. We aimed to evaluate the bioequivalence (BE) of voriconazole injection in Chinese healthy volunteers (HVs). In this single-center, randomized, single-dose, 2-cycle, fasting-dose BE study, HVs (n = 24) were 1:1 divided into 2 groups (test [T]-reference [R] and R-T) and received 6 mg/kg of voriconazole intravenously with a 7-day washout. The plasma was collected for up to 72 hours at the time point after dosing on day 1/day 8. The plasma concentration of voriconazole was measured by liquid chromatography-tandem mass spectrometry. Pharmacokinetic parameters were ascertained on the basis of a noncompartmental model. In the BE study, the geometric mean ratios of the maximum concentration, area under the concentration-time curve from time 0 to the last measurable plasma concentration, and area under the concentration-time curve from time 0 to infinity were 101.1%, 105.6%, and 105.5%, respectively, and the 90%CI fell within 80%-125%. Adverse events were observed in 26.1% of subjects in the T formulation stage and 17.4% in the R formulation stage. Under the BE study, voriconazole values from T and R formulations were bioequivalent.

Microdialysis of Voriconazole and its N-Oxide Metabolite: Amalgamating Knowledge of Distribution and Metabolism Processes in Humans.

PURPOSE: Voriconazole is an essential antifungal drug whose complex pharmacokinetics with high interindividual variability impedes effective and safe therapy. By application of the minimally-invasive sampling technique microdialysis, interstitial space fluid (ISF) concentrations of VRC and its potentially toxic N-oxide metabolite (NO) were assessed to evaluate target-site exposure for further elucidating VRC pharmacokinetics. METHODS: Plasma and ISF samples of a clinical trial with an approved VRC dosing regimen were analyzed for VRC and NO concentrations. Concentration-time profiles, exposure assessed as area-under-the-curve (AUC) and metabolic ratios of four healthy adults in plasma and ISF were evaluated regarding the impact of multiple dosing and CYP2C19 genotype. RESULTS: VRC and NO revealed distribution into ISF with AUC values being ≤2.82- and 17.7-fold lower compared to plasma, respectively. Intraindividual variability of metabolic ratios was largest after the first VRC dose administration while interindividual variability increased with multiple dosing. The CYP2C19 genotype influenced interindividual differences with a maximum 6- and 24-fold larger AUCNO/AUCVRC ratio between the intermediate and rapid metabolizer in plasma and ISF, respectively. VRC metabolism was saturated/auto-inhibited indicated by substantially decreasing metabolic concentration ratios with increasing VRC concentrations and after multiple dosing. CONCLUSION: The feasibility of the simultaneous microdialysis of VRC and NO in vivo was demonstrated and provided new quantitative insights by leveraging distribution and metabolism processes of VRC in humans. The exploratory analysis suggested substantial dissimilarities of VRC and NO pharmacokinetics in plasma and ISF. Ultimately, a thorough understanding of target-site pharmacokinetics might contribute to the optimization of personalized VRC dosing regimens.

Quantification of the Time Course of CYP3A Inhibition, Activation, and Induction Using a Population Pharmacokinetic Model of Microdosed Midazolam Continuous Infusion.

BACKGROUND: Cytochrome P450 (CYP) 3A contributes to the metabolism of many approved drugs. CYP3A perpetrator drugs can profoundly alter the exposure of CYP3A substrates. However, effects of such drug-drug interactions are usually reported as maximum effects rather than studied as time-dependent processes. Identification of the time course of CYP3A modulation can provide insight into when significant changes to CYP3A activity occurs, help better design drug-drug interaction studies, and manage drug-drug interactions in clinical practice. OBJECTIVE: We aimed to quantify the time course and extent of the in vivo modulation of different CYP3A perpetrator drugs on hepatic CYP3A activity and distinguish different modulatory mechanisms by their time of onset, using pharmacologically inactive intravenous microgram doses of the CYP3A-specific substrate midazolam, as a marker of CYP3A activity. METHODS: Twenty-four healthy individuals received an intravenous midazolam bolus followed by a continuous infusion for 10 or 36 h. Individuals were randomized into four arms: within each arm, two individuals served as a placebo control and, 2 h after start of the midazolam infusion, four individuals received the CYP3A perpetrator drug: voriconazole (inhibitor, orally or intravenously), rifampicin (inducer, orally), or efavirenz (activator, orally). After midazolam bolus administration, blood samples were taken every hour (rifampicin arm) or every 15 min (remaining study arms) until the end of midazolam infusion. A total of 1858 concentrations were equally divided between midazolam and its metabolite, 1'-hydroxymidazolam. A nonlinear mixed-effects population pharmacokinetic model of both compounds was developed using NONMEM®. CYP3A activity modulation was quantified over time, as the relative change of midazolam clearance encountered by the perpetrator drug, compared to the corresponding clearance value in the placebo arm. RESULTS: Time course of CYP3A modulation and magnitude of maximum effect were identified for each perpetrator drug. While efavirenz CYP3A activation was relatively fast and short, reaching a maximum after approximately 2-3 h, the induction effect of rifampicin could only be observed after 22 h, with a maximum after approximately 28-30 h followed by a steep drop to almost baseline within 1-2 h. In contrast, the inhibitory impact of both oral and intravenous voriconazole was prolonged with a steady inhibition of CYP3A activity followed by a gradual increase in the inhibitory effect until the end of sampling at 8 h. Relative maximum clearance changes were +59.1%, +46.7%, -70.6%, and -61.1% for efavirenz, rifampicin, oral voriconazole, and intravenous voriconazole, respectively. CONCLUSIONS: We could distinguish between different mechanisms of CYP3A modulation by the time of onset. Identification of the time at which clearance significantly changes, per perpetrator drug, can guide the design of an optimal sampling schedule for future drug-drug interaction studies. The impact of a short-term combination of different perpetrator drugs on the paradigm CYP3A substrate midazolam was characterized and can define combination intervals in which no relevant interaction is to be expected. CLINICAL TRIAL REGISTRATION: The trial was registered at the European Union Drug Regulating Authorities for Clinical Trials (EudraCT-No. 2013-004869-14).

Microdialysis of Drug and Drug Metabolite: a Comprehensive In Vitro Analysis for Voriconazole and Voriconazole N-oxide.

PURPOSE: Voriconazole is a therapeutically challenging antifungal drug associated with high interindividual pharmacokinetic variability. As a prerequisite to performing clinical trials using the minimally-invasive sampling technique microdialysis, a comprehensive in vitro microdialysis characterization of voriconazole (VRC) and its potentially toxic N-oxide metabolite (NO) was performed. METHODS: The feasibility of simultaneous microdialysis of VRC and NO was explored in vitro by investigating the relative recovery (RR) of both compounds in the absence and presence of the other. The dependency of RR on compound combination, concentration, microdialysis catheter and study day was evaluated and quantified by linear mixed-effects modeling. RESULTS: Median RR of VRC and NO during individual microdialysis were high (87.6% and 91.1%). During simultaneous microdialysis of VRC and NO, median RR did not change (87.9% and 91.1%). The linear mixed-effects model confirmed the absence of significant differences between RR of VRC and NO during individual and simultaneous microdialysis as well as between the two compounds (p > 0.05). No concentration dependency of RR was found (p = 0.284). The study day was the main source of variability (46.3%) while the microdialysis catheter only had a minor effect (4.33%). VRC retrodialysis proved feasible as catheter calibration for both compounds. CONCLUSION: These in vitro microdialysis results encourage the application of microdialysis in clinical trials to assess target-site concentrations of VRC and NO. This can support the generation of a coherent understanding of VRC pharmacokinetics and its sources of variability. Ultimately, a better understanding of human VRC pharmacokinetics might contribute to the development of personalized dosing strategies.

Effects of inflammation on voriconazole levels: A systematic review.

AIMS: This study aimed to review the studies evaluating the effect of the inflammatory state on voriconazole (VRZ) levels. METHODS: The study included randomized clinical trials, cohort studies, and case-control studies that focused on the influence of the inflammatory state on VRZ levels. Following the preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines, relevant articles published until 2021 were searched in several databases, including PubMed, Embase, Web of Science and the Cochrane Library. RESULTS: Twenty studies were included in this review, of which 15 described adult populations, three described paediatric populations, and two included both adult and paediatric populations. Seventeen studies used C-reactive protein (CRP) as an indicator of inflammation, six described a dose-response relationship for the effect of inflammation represented by CRP on VRZ concentrations, and four examined the effect of CRP on the metabolic rate of VRZ. CONCLUSIONS: Our findings showed that the level of inflammation can significantly affect VRZ levels. However, the effect of inflammation on VRZ concentrations in children is controversial and must be analysed along with age. Clinicians dosing VRZ should take into account the patient's inflammatory state. The impact of inflammation on genotype-based dosing decisions requires further study to explain the high pharmacokinetic variability of VRZ.

Impact of Inflammation on Intra-individual Variation in Trough Voriconazole Concentration in Patients with Hematological Malignancies.

The pharmacokinetics of voriconazole shows large intra-individual and inter-individual variability and is affected by various factors. Recently, inflammation has been focused as a significant factor affecting the variability. This study aimed to compare the influence of C-reactive protein (CRP) and other clinical laboratory parameters on intra-individual variability in trough voriconazole concentration and examine the impact of inflammation in patients with hematological malignancies. We conducted a retrospective, single-center, observational cohort study. Forty-two patients with hematological malignancy who received oral voriconazole for prophylaxis against deep mycosis and underwent multiple measurements of trough plasma voriconazole concentration were recruited. Quantitative changes in pharmacological and clinical laboratory parameters (Δ) were calculated as the difference between the current and preceding measurements. Voriconazole concentration/maintenance dose per weight (C/D) was found to correlate positively with CRP level (n = 202, rs = 0.314, p < 0.001). Furthermore, ΔC/D correlated positively with ΔCRP level (n = 160, rs = 0.442, p < 0.001), and ΔCRP showed the highest correlation coefficient among the laboratory parameters. Univariate and multivariate analyses identified ΔCRP (p < 0.001) and Δgamma-glutamyl transpeptidase (γGTP) (p = 0.019) as independent factors associated with ΔC/D. Partial R2 were 0.315 for ΔCRP and 0.024 for ΔγGTP, suggesting markedly greater contribution of ΔCRP to ΔC/D. In conclusion, since clinical laboratory parameters other than CRP had little influence on trough plasma voriconazole concentration, therapeutic drug monitoring and dose adjustment considering fluctuation in CRP level would be important for proper use of voriconazole in patients with hematological malignancies.

Development of Physiology Based Pharmacokinetic Model to Predict the Drug Interactions of Voriconazole and Venetoclax.

PURPOSE: Venetoclax (VEN), an anti-tumor drug that is a substrate of cytochrome P450 3A enzyme (CYP3A4), is used to treat leukemia. Voriconazole (VCZ) is an antifungal medication that inhibits CYP3A4. The goal of this study is to predict the effect of VCZ on VEN exposure. METHOD: Two physiological based pharmacokinetics (PBPK) models were developed for VCZ and VEN using the bottom-up and top-down method. VCZ model was also developed to describe the effect of CYP2C19 polymorphism on its pharmacokinetics (PK). The reversible inhibition constant (Ki) of VCZ for CYP3A4 was calibrated using drug-drug interaction (DDI) data of midazolam and VCZ. The clinical verified VCZ and VEN model were used to predict the DDI of VCZ and VEN at clinical dosing scenario. RESULT: VCZ model predicted VCZ exposure in the subjects of different CYP2C19 genotype and DDI related fold changes of sensitive CYP3A substrate with acceptable prediction error. VEN model can capture PK of VEN with acceptable prediction error. The DDI PBPK model predicted that VCZ increased the exposure of VEN by 4.5-9.6 fold. The increase in VEN exposure by VCZ was influenced by subject's CYP2C19 genotype. According to the therapeutic window, VEN dose should be reduced to 100 mg when co-administered with VCZ. CONCLUSION: The PBPK model developed here could support individual dose adjustment of VEN and DDI risk assessment. Predictions using the robust PBPK model confirmed that the 100 mg dose adjustment is still applicable in the presence of VCZ with high inter-individual viability.

Effects of CYP2C19, CYP2C9 and CYP3A4 gene polymorphisms on plasma voriconazole levels in Chinese pediatric patients.

OBJECTIVES: Voriconazole is the most commonly used antifungal agent in clinical application. Previous studies suggested that voriconazole was extensively metabolized by CYP450 enzyme system, including CYP2C19, CYP2C9 and CYP3A4, which contributed to the individual variability of the pharmacokinetic process of voriconazole. This study aimed to investigate the effects of CYP2C19, CYP2C9 and CYP3A4 gene polymorphisms on plasma voriconazole concentrations in Chinese pediatric patients. METHODS: This study prospectively evaluated pediatric patients administrating voriconazole for the treatment or prophylaxis of invasive fungal infections from October 2018 to July 2020. Seven single-nucleotide polymorphisms in CYP2C19 (CYP2C19*2, CYP2C19*3, and CYP2C19*17), CYP2C9 (CYP2C9*3, CYP2C9*13) and CYP3A4 (CYP3A4*22, rs4646437) were detected by real-time fluorescent PCR with TaqMan probes. The voriconazole trough plasma concentration was determined by UPLC-MS/MS. RESULTS: A total of 68 pediatric patients were enrolled in this study. Our results showed that voriconazole plasma concentrations of patients with CYP2C19*2 or CYP2C19*3 allele were significantly higher than that with wild-type carriers (P < 0.0001, P = 0.004, respectively). However, CYP2C9*3 and CYP3A4 rs4646437 were not significantly associated with voriconazole plasma levels. The CYP2C19*17, CYP2C9*13 and CYP3A4*22 alleles were not observed in our study. Additionally, multiple linear regression analysis indicated that CYP2C19*2 and CYP2C19*3 alleles remained predictors of voriconazole plasma concentration (r2 = 0.428; P < 0.0001). For CYP2C19 metabolizer phenotype, trough concentration of voriconazole was significantly lower in NM group compared with IM (P < 0.0001) and PM (P = 0.004) groups. CONCLUSION: Voriconazole plasma levels in pediatric patients are mainly affected by CYP2C19 gene polymorphisms.

Population pharmacokinetic model-guided optimization of intravenous voriconazole dosing regimens in critically ill patients with liver dysfunction.

STUDY OBJECTIVES: This study aimed to establish a population pharmacokinetic (PPK) model of intravenous voriconazole (VRC) in critically ill patients with liver dysfunction and to explore the optimal dosing strategies in specific clinical scenarios for invasive fungal infections (IFIs) caused by common Aspergillus and Candida species. DESIGN: Prospective pharmacokinetics study. SETTING: The intensive care unit in a tertiary-care medical center. PATIENTS: A total of 297 plasma VRC concentrations from 26 critically ill patients with liver dysfunction were included in the PPK analysis. METHODS: Model-based simulations with therapeutic range of 2-6 mg/L as the plasma trough concentration (Cmin ) target and the free area under the concentration-time curve from 0 to 24 h (ƒAUC24 ) divided by the minimum inhibitory concentration (MIC) (ie, ƒAUC24 /MIC) ≥25 as the effective target were performed to optimize VRC dosing regimens for Child-Pugh class A and B (CP-A/B) and Child-Pugh class C (CP-C) patients. RESULTS: A two-compartment model with first-order elimination adequately described the data. Significant covariates in the final model were body weight on both central and peripheral distribution volume and Child-Pugh class on clearance. Intravenous VRC loading dose of 5 mg/kg every 12 h (q12h) for the first day was adequate for CP-A/B and CP-C patients to attain the Cmin target at 24 h. The maintenance dose regimens of 100 mg q12h or 200 mg q24h for CP-A/B patients and 50 mg q12h or 100 mg q24h for CP-C patients could obtain the probability of effective target attainment of >90% at an MIC ≤0.5 mg/L and achieve the cumulative fraction of response of >90% against C. albicans, C. parapsilosis, C. glabrata, C. krusei, A. fumigatus, and A. flavus. Additionally, the daily VRC doses could be increased by 50 mg for CP-A/B and CP-C patients at an MIC of 1 mg/L, with plasma Cmin monitored closely to avoid serious adverse events. It is recommended that an appropriate alternative antifungal agent or a combination therapy could be adopted when an MIC ≥2 mg/L is reported, or when the infection is caused by C. tropicalis but the MIC value is not available. CONCLUSIONS: For critically ill patients with liver dysfunction, the loading dose of intravenous VRC should be reduced to 5 mg/kg q12h. Additionally, based on the types of fungal pathogens and their susceptibility to VRC, the adjusted maintenance dose regimens with lower doses or longer dosing intervals should be considered for CP-A/B and CP-C patients.

The Pharmacokinetic Effect of Itraconazole and Voriconazole on Ripretinib in Beagle Dogs by UPLC-MS/MS Technique.

BACKGROUND: A new UPLC-MS/MS technique for the determination of ripretinib in beagle dog plasma was developed, and the pharmacokinetic effects of voriconazole and itraconazole on ripretinib in beagle dogs were studied. METHODS: After extraction with ethyl acetate under alkaline conditions, ripretinib was detected using avapritinib as the internal standard (IS). The mobile phases were 0.1% formic acid-acetonitrile. The scanning method was multi-reaction monitoring using ESI+ source, and the ion pairs for ripretinib and IS were m/z 509.93→416.85 and 499.1→482.09, respectively. This animal experiment adopted a three period self-control experimental design. In the first period, ripretinib was orally administered to six beagle dogs at a dose of 5 mg/kg. In the second period, the same six beagle dogs were orally given itraconazole at a dose of 7 mg/kg, after 30 min, ripretinib was orally given. In the third period, voriconazole at a dose of 7 mg/kg was given orally, and then ripretinib was orally given. At different time points, the blood samples were collected. The concentration of ripretinib was detected, and the pharmacokinetic parameters of ripretinib were calculated. RESULTS: Ripretinib had a good linear relationship in the range of 1-1000 ng/mL. The precision, accuracy, recovery, matrix effect and stability met the requirements of the guiding principles. After erdafitinib combined with itraconazole, the Cmax and AUC0→t of ripretinib increased by 38.35% and 36.36%, respectively, and the t1/2 was prolonged to 7.53 h. After ripretinib combined with voriconazole, the Cmax and AUC0→t of ripretinib increased by 37.44% and 25.52%, respectively, and the t1/2 was prolonged to 7.33 h. CONCLUSION: A new and reliable UPLC-MS/MS technique was fully optimized and developed to detect the concentration of ripretinib in beagle dog plasma. Itraconazole and voriconazole could inhibit the metabolism of ripretinib in beagle dogs and increase the plasma exposure of ripretinib.