Breakthrough Invasive Fungal Infections in Patients With High-Risk Hematological Disorders Receiving Voriconazole and Posaconazole Prophylaxis: A Systematic Review.

BACKGROUND: Primary antifungal prophylaxis with mold-active azoles is used to prevent invasive fungal infections in patients with high-risk hematological disorders; however, breakthrough infections occur, and the reasons for treatment failure are still not fully understood. To help inform clinical decisions, we sought to define microbiological, clinical, and pharmacological characteristics of proven and probable breakthrough invasive fungal infections (bIFIs) in patients with high-risk hematological disorders receiving voriconazole or posaconazole prophylaxis. METHODS: We performed a systematic review of the literature following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The search strategy was last conducted on 19 April 2023. RESULTS: We assessed 5293 studies for eligibility, and 300 were selected for data extraction. These studies described 1076 cases of bIFIs occurring under voriconazole (42.5%) or posaconazole (57.5%). The most commonly found pathogens were Aspergillus (40%), Mucorales (20%), Candida (18%), and Fusarium (9%) species. Mucorales were more frequent among voriconazole-emerging cases, whereas Aspergillus and Fusarium were more prevalent among posaconazole-emerging cases. Definitive, putative, or probable antifungal resistance was found in 31% of cases. Therapeutic drug monitoring showed subtherapeutic azole concentration in 32 of 90 (36%) cases. Infection-related mortality was reported in 117 cases and reached 35%. CONCLUSIONS: In our systemic review, the most common bIFIs were aspergillosis, mucormycosis, candidiasis, and fusariosis. Antifungal resistance explains only a minority of cases. Subtherapeutic prophylaxis was frequent but rarely reported. Prospective studies are needed to better understand these infections and to establish optimal management.

Ivosidenib significantly reduces triazole levels in patients with acute myeloid leukemia and myelodysplastic syndrome.

BACKGROUND: Ivosidenib is primarily metabolized by CYP3A4; however, it induces CYP450 isozymes, including CYP3A4 and CYP2C9, whereas it inhibits drug transporters, including P-glycoprotein. Patients with acute myeloid leukemia are at risk of invasive fungal infections, and therefore posaconazole and voriconazole are commonly used in this population. Voriconazole is a substrate of CYP2C9, CYP2C19, and CYP3A4; therefore, concomitant ivosidenib may result in decreased serum concentrations. Although posaconazole is a substrate of P-glycoprotein, it is metabolized primarily via UDP glucuronidation; thus, the impact of ivosidenib on posaconazole exposure is unknown. METHODS: Patients treated with ivosidenib and concomitant triazole with at least one serum trough level were included. Subtherapeutic levels were defined as posaconazole <700 ng/mL and voriconazole <1.0 µg/mL. The incidences of breakthrough invasive fungal infections and QTc prolongation were identified at least 5 days after initiation of ivosidenib with concomitant triazole. RESULTS: Seventy-eight serum triazole levels from 31 patients receiving ivosidenib-containing therapy and concomitant triazole were evaluated. Of the 78 concomitant levels, 47 (60%) were subtherapeutic (posaconazole: n = 20 of 43 [47%]; voriconazole: n = 27 of 35 [77%]). Compared to levels drawn while patients were off ivosidenib, median triazole serum levels during concomitant ivosidenib were significantly reduced. There was no apparent increase in incidence of grade 3 QTc prolongation with concomitant azole antifungal and ivosidenib 500 mg daily. CONCLUSIONS: This study demonstrated that concomitant ivosidenib significantly reduced posaconazole and voriconazole levels. Voriconazole should be avoided, empiric high-dose posaconazole (>300 mg/day) may be considered, and therapeutic drug monitoring is recommended in all patients receiving concomitant ivosidenib.

Repurposing a human acetyl-CoA carboxylase inhibitor firsocostat to treat fungal candidiasis alone and in combination.

Opportunistic fungal infections, particularly caused by Candida albicans, remain a common cause of high morbidity and mortality in immunocompromised patients. The escalating prevalence of antifungal drug resistance necessitates the immediate exploration of alternative treatment strategies to combat these life-threatening fungal diseases. In this study, we investigated the antifungal efficacy of firsocostat, a human acetyl-CoA carboxylase (ACC) inhibitor, against C. albicans. Firsocostat alone displayed moderate antifungal activity, while combining it with voriconazole, itraconazole, or amphotericin B exhibited synergistic effects across almost all drug-sensitive and drug-resistant C. albicans strains tested. These observed synergies were further validated in two mouse models of oropharyngeal and systemic candidiasis, where the combination therapies demonstrated superior fungicidal effects compared to monotherapy. Moreover, firsocostat was shown to directly bind to C. albicans ACC and inhibit its enzymatic activity. Sequencing spontaneous firsocostat-resistant mutants revealed mutations mapping to C. albicans ACC, confirming that firsocostat has retained its target in C. albicans. Overall, our findings suggest that repurposing firsocostat, either alone or in combination with other antifungal agents, holds promising potential in the development of antifungal drugs and the treatment of candidiasis.

Therapeutic drug monitoring and safety of voriconazole in patients with liver dysfunction.

This study aims to describe the distribution characteristics of voriconazole (VRC) plasma trough concentrations (Ctrough) in patients with liver dysfunction, identify factors influencing VRC Ctrough, and provide recommendations for the use of VRC in this population. We retrospectively collected medical records of hospitalized patients with liver dysfunction who used VRC and underwent therapeutic drug monitoring (TDM) at the First Hospital of Changsha. The severity of liver dysfunction was assessed by the Child-Pugh (CP) score. Multiple linear regression was employed to explore factors affecting VRC Ctrough in these patients. A total of 147 Ctrough from 102 patients with liver dysfunction were analyzed. Patients were categorized into a control group (n = 40), CP-A (n = 39), CP-B (n = 11), and CP-C group (n = 12). The initial probability of target attainment of Ctrough was 70.6%, with 6.9% of patients obtaining subtherapeutic Ctrough and 22.5% obtaining supertherapeutic Ctrough. The initial Ctrough in CP-A and B were 5.05 (0.64-9.57) mg/L and 5.37 (0.26-10.01) mg/L, respectively, significantly higher than the control group (P = 0.021 and P = 0.010). The proportion of VRC Ctrough of >5.5 mg/L in CP-A and B was 33.3% and 45.5%, respectively. Multiple linear regression analysis revealed that factors such as age ≥70 years, CP class, C-reactive protein (CRP), and direct bilirubin were significantly related to the initial VRC Ctrough. Among all measurements, patients with severe inflammation (CRP >100 mg/L), aged ≥70 years, and albumin levels of <30 or <25 g/L had significantly higher VRC Ctrough. The treatment success rate of VRC was 69.6% (71 of 102), and the rate of VRC-related adverse drug reactions was 29.4% (30 of 102). The recommended half-maintenance dose may lead to elevated VRC Ctrough in patients with CP-A and CP-B. TDM is essential for patients with advanced age, severe infections, or hypoalbuminemia to prevent excessive VRC trough levels.

Development of a therapeutic drug-monitoring algorithm for outpatients receiving voriconazole: A multicentre retrospective study.

AIMS: Although therapeutic drug monitoring (TDM) of voriconazole is performed in outpatients to prevent treatment failure and toxicity, whether TDM should be performed in all or only selected patients remains controversial. This study evaluated the association between voriconazole trough concentrations and clinical events. METHODS: We investigated the aggravation of clinical symptoms, incidence of hepatotoxicity and visual disturbances, change in co-medications and interaction between voriconazole and co-medications in outpatients receiving voriconazole between 2017 and 2021 in three facilities. Abnormal trough concentrations were defined as <1.0 mg/L (low group) and >4.0 mg/L (high group). RESULTS: A total of 141 outpatients (578 concentration measurements) met the inclusion criteria (treatment, 37 patients, 131 values; prophylaxis, 104 patients, 447 values). The percentages of patients with abnormal concentrations were 29.0% and 31.5% in the treatment and prophylaxis groups, respectively. Abnormal concentrations showed 50% of the concentrations at the first measurement in both therapies. Aggravation of clinical symptoms was most frequently observed in the low treatment group (18.2%). Adverse events were most common in the high group for both therapies (treatment, hepatotoxicity 6.3%, visual disturbance 18.8%; prophylaxis, hepatotoxicity 27.9%). No differences were found in changes to co-medications and drug interactions. In the prophylaxis group, prescription duration in the presence of clinical events tended to be longer than in their absence (47.4 ± 23.4 days vs 39.7 ± 21.9 days, P = .1132). CONCLUSIONS: We developed an algorithm based on clinical events for appropriate implementation of TDM in outpatients. However, future interventions based on this algorithm should be validated.

Individualized treatment with voriconazole in the Chinese population: Inflammation level as a novel marker for dose optimization.

AIMS: The aim of this study was to explore the influence and possible mechanisms of pharmacokinetics-related gene polymorphisms, especially CYP2C19 polymorphisms, and non-genetic factors combined with the inflammatory status on the voriconazole (VRC) metabolism of the Chinese population. METHODS: Clinical studies were performed by collecting more than one VRC trough concentration and C-reactive protein (CRP) level. A total of 265 blood samples were collected from 120 patients. RESULTS: Results of multiple regression analyses demonstrated that CYP2C19 genotypes and albumin (Alb) level remained predictors of Cmin ss/D in patients with no to mild inflammation (R2 = 0.12, P < .001). In addition, in patients with moderate to severe inflammation, it resulted in a significant model containing factors of CRP and total bilirubin (T-Bil) levels (R2 = 0.19, P < .001). In non-clinical studies, 32 rats were divided into control and inflammatory groups, and it was found that the mean residence time (MRT(0-t) ) of VRC in the inflammatory group was significantly longer than that in the control group (P < .001), which may be due to down-regulation of mRNA and protein expression of CYP2C19 (CYP2C6 in rats) through interleukin (IL)-6/signal transducer and activator of transcription (STAT) 3 pathway. CONCLUSIONS: Therefore, the effect of CYP2C19 polymorphisms on VRC metabolism may be masked by inflammatory status, which should be of more concern than CYP2C19 polymorphisms in patients with moderate to severe inflammation. Additionally, the impact of Alb and T-Bil on VRC metabolism should not be disregarded.

Immune outcomes of lung transplant recipients with different cytochrome P450 3A5 phenotypes after discontinuation of voriconazole antifungal prophylaxis.

INTRODUCTION: Tacrolimus forms the backbone of immunosuppression regimens in lung transplant recipients (LTRs). It is extensively metabolized by cytochrome P450 (CYP) 3A5 enzymes, of which polymorphisms can significantly affect tacrolimus dose requirements. It is unknown how coadministration of tacrolimus with voriconazole, a potent CYP3A5 inhibitor, affects rejection rates or empiric dose adjustments needed after voriconazole discontinuation. METHODS: This retrospective cohort study compares LTRs with poor (PR) versus intermediate/extensive (IE) CYP3A5 metabolizer phenotypes. The primary endpoint is cumulative immune outcomes within three months of voriconazole discontinuation; secondary endpoints include change in tacrolimus dose-to-concentration ratios after voriconazole discontinuation. RESULTS: Thirty-four patients underwent full analysis: 13 IE and 21 PR metabolizers. A higher proportion of IE metabolizers were African American (46.2% vs. 9.5%, p = .03). There was no significant difference in composite immune outcomes, though there was a proportionally higher frequency of new donor-specific antibody development in PR metabolizers (14.3% vs 7.7%, p = .56). Both groups required approximately 2.5 to 3-fold tacrolimus dose increases post-voriconazole discontinuation to re-attain therapeutic levels. CONCLUSION: This novel investigation sheds light on how CYP3A5 phenotype could be used to guide tacrolimus dosing, with the goal of preventing both toxicity and organ rejection.

Multi-organ involvement caused by Scedosporium apiospermum infection after near drowning: a case report and literature review.

BACKGROUND: Scedosporium apiospermum (S. apiospermum) is a rare fungal pathogen that causes disseminated infections. It rarely affects immunocompetent individuals and has a poor prognosis. CASE PRESENTATION: A 37-year-old woman presented with multiple lesions in the lungs, brain, and eyes, shortly after near drowning in a car accident. The primary symptoms were chest tightness, limb weakness, headache, and poor vision in the left eye. S. apiospermum infection was confirmed by metagenomic next-generation sequencing (mNGS) of intracranial abscess drainage fluid, although intracranial metastases were initially considered. After systemic treatment with voriconazole, her symptoms improved significantly; however, she lost vision in her left eye due to delayed diagnosis. CONCLUSION: While S. apiospermum infection is rare, it should be considered even in immunocompetent patients. Prompt diagnosis and treatment are essential. Voriconazole may be an effective treatment option.

Association of procalcitonin with voriconazole concentrations: a retrospective cohort study.

Inflammation is a potential risk factor of voriconazole (VCZ) overdose, procalcitonin (PCT) is reported to act as a diagnostic marker for bacterial infections. However, the association of PCT with VCZ trough serum concentrations (VCZ-Cmin) is not fully clear. Our study aims to investigate the associations between PCT and VCZ-Cmin. In this retrospective cohort study, we collected the clinical data of 147 patients who received VCZ and monitored the VCZ concentration of them in our hospital from August 2017 to August 2021. All patients underwent routine clinical examinations on the day or the day before VCZ administration. General information and clinical symptoms of these patients were recorded. Multivariate liner analysis showed that PCT was significantly associated with VCZ-Cmin (p < 0.001). Overall, it was shown that VCZ-Cmin was significantly increased by 0.32 µg/mL for each fold increment in PCT in crude model. In the minor adjusted model (Model 1, adjustment for sex, age, albumin, direct bi1irubin, WBC) and fully adjusted model (Model 2, adjustment for sex, age, albumin, direct bilirubin, WBC, AST and ALT), VCZ-Cmin was significantly increased by 0.23 µg/mL and 0.21 µg/mL, respectively, for each fold increment in PCT. In conclusion, this research reveals the correlation between PCT and VCZ-Cmin, indicating that PCT has the potential to serve as a valuable biomarker for drug monitoring in the treatment of VCZ.

Pulmonary cryptococcosis complicated with pulmonary aspergillosis: a series of studies and a literature review.

BACKGROUND/OBJECTIVE: With the development of society, pulmonary fungal diseases, represented by pulmonary aspergillosis and pulmonary cryptococcosis, have become increasingly common. However, there is a lack of clear understanding regarding coinfection by these two types of fungi in immunocompetent individuals. METHODS: A retrospective study from 2014 to 2022 and a systematic literature review of original articles published in English were performed. Patients with pulmonary cryptococcosis complicated with pulmonary aspergillosis including 5 in the retrospective study and 6 in the systematic literature review. RESULT: The diagnosis of concurrent pulmonary cryptococcosis and pulmonary aspergillosis in patients was confirmed through repeated biopsies or surgical resection. Pulmonary cryptococcosis is often diagnosed initially (6/11, 55%), while the diagnosis of pulmonary aspergillosis is established when the lesions become fixed or enlarged during treatment. Transbronchial lung biopsy (3/11, 27%), thoracoscopic lung biopsy (2/11, 18%), and percutaneous aspiration biopsy of the lung (1/11, 9%) were the main methods to confirm concurrent infection. Most patients were treated with voriconazole, resulting in a cure for the coinfection (6/11, 55%). CONCLUSION: Pulmonary cryptococcosis complicated with pulmonary Aspergillus is an easily neglected mixed fungal infection. During the treatment of lesion enlargement in clinical cryptococcus, we need to watch out for Aspergillus infection.

Clinico-mycological and therapeutic updates on cutaneous dermatophytic infections in the era of Trichophyton indotineae.

Trichophyton indotineae has emerged as a novel dermatophyte species resulting in treatment recalcitrant skin infections. While the earliest reports came from India, T. indotineae has now spread to many parts of the world and is rapidly becoming a global health concern. Accurate identification of T. indotineae requires elaborate mycological investigations which is beyond the domain of routine microbiology testing. Extensive, non-inflammatory and atypical presentations are commonly seen with this novel species. T. indotineae shows an alarmingly high rate of mutations in the squalene epoxidase gene leading to lowered in vitro susceptibility to terbinafine. This has also translated into a lowered clinical response and requirement of a higher dose and much longer durations of treatment with the drug. Although the species remains largely susceptible to itraconazole, prolonged treatment durations are required to achieve cure with itraconazole. Fluconazole and griseofulvin do not have satisfactory in vitro or clinical activity. Apart from requirement of prolonged treatment durations, relapse postsuccessful treatment is a distressing and yet unexplained consequence of this "species-shift." Use of third generation azoles and combinations of systemic antifungals is unwarranted as both have not demonstrated clear superiority over itraconazole given alone, and the former is an important class of drugs for invasive mycoses.

A novel approach to reducing hepatotoxicity related to fungal prophylaxis in pediatric lung transplant recipients.

BACKGROUND: Pediatric lung transplant patients are at risk for developing invasive fungal infections post-transplant. No consensus exists on optimal antifungal regimens and voriconazole, a common first-line agent, has been shown to cause hepatotoxicity. We describe a single-center experience utilizing a novel antifungal regimen of intravenous micafungin and nebulized amphotericin B immediately post-transplant with conversion to an azole at the time of hospital discharge and compare it to a historical cohort of patients who received voriconazole monotherapy throughout their immediate post-operative course. METHODS: This is a retrospective review of patients in the age 0-18 who received a lung transplant from June 2016-May 2021. Data points collected included: demographic data, transplant date and discharge date, Aspergillus colonization, type of lung transplant, hospitalization and level of care information, induction and antifungal medication regimen; AST, ALT, GGT, bilirubin, and direct bilirubin at various timepoints; and respiratory and blood culture results. The two patient groups were compared by assessment of changes in LFTs and culture results. RESULTS: Forty-two patients were included in the analysis, with 24 patients receiving micafungin and nebulized amphotericin and 18 patients receiving voriconazole. All patients in both groups experienced a post-operative elevation in at least one transaminase or bilirubin. More patients in the micafungin/amphotericin group had resolution of all abnormal LFTs by 1 month post-transplant (p = .036). Additionally, patients in the micafungin/amphotericin group experienced faster normalization of their LFTs compared with the voriconazole group (p < .001). Ten patients in the micafungin/amphotericin group and five patients in the voriconazole group were found to have fungal growth on culture post-transplant, but this difference was not found to be statistically significant (p = .507). CONCLUSIONS: An antifungal regimen of micafungin and nebulized amphotericin B liposomal may be useful at decreasing the duration of elevated liver enzymes in pediatric patients in the immediate post-lung transplant period when compared with voriconazole monotherapy. Larger prospective studies looking at antifungal regimens in pediatric patients post-lung transplant are warranted.

Evaluation of the predictive performance of an online voriconazole dose calculator in children.

BACKGROUND: The dosing of voriconazole is challenging in pediatrics. One approach to improve the dosing is through the use of Bayesian concentration-guided dosing software. Our study assessed the predictive performance of a freely available online voriconazole dose calculator in pediatric patients "NextDose" ( https://www.nextdose.org/ ). METHODS: Per each dose calculator, we predicted voriconazole concentrations. We did both a priori and a posteriori Bayesian predictions. RESULTS: A total of 51 patients were included in this study. For a priori predictions, bias was + 26% while imprecision was 70%. For a posteriori predictions, bias and imprecision were 0.01% and 46%. DISCUSSION: In conclusion, the available online dose calculator was overpredicting the concentrations before voriconazole observations were available. However, with just one measured concentration, the predictions improved with minimal bias and an acceptable level of imprecision. There is a need for more prospective studies evaluating the use of voriconazole dosing calculators in the pediatric population to assess if they can improve the achievement of therapeutic target concentrations compared to standard of care.

Voriconazole therapeutic drug monitoring including analysis of CYP2C19 phenotype in immunocompromised pediatric patients with invasive fungal infections.

PURPOSE: Therapeutic drug monitoring (TDM) of voriconazole (VCZ) should be mandatory for all pediatric patients with invasive fungal infections (IFIs). The narrow therapeutic index, inter-individual variability in VCZ pharmacokinetics, and genetic polymorphisms cause achieving therapeutic concentration during therapy to be challenging in this population. METHODS: The study included 44 children suffering from IFIs treated with VCZ. Trough concentrations (Ctrough) of VCZ ware determined by the HPLC-FLD method. Identification of the CYP2C19*2 and CYP2C19*17 genetic polymorphisms was performed by PCR-RFLP. The correlation between polymorphisms and VCZ Ctrough was analyzed. Moreover, the effect of factors such as dose, age, sex, route of administration, and drug interactions was investigated. RESULTS: VCZ was administered orally and intravenously at a median maintenance dosage of 14.7 mg/kg/day for a median of 10 days. The VCZ Ctrough was highly variable and ranged from 0.1 to 6.8 mg/L. Only 45% of children reached the therapeutic range. There was no significant association between Ctrough and dosage, age, sex, route of administration, and concomitant medications. The frequencies of variant phenotype normal (NM), intermediate (IM), rapid (RM) and ultrarapid metabolizers (UM) were 41%, 18%, 28%, and 13%, respectively. Ctrough of VCZ were significantly higher in NM and IM groups compared with RM, and UM groups. CONCLUSION: The Ctrough of VCZ is characterized by inter-individual variability and a low rate of patients reaching the therapeutic range. The significant association exists in children between VCZ Ctrough and CYPC19 phenotype. The combination of repeated TDM and genotyping is necessary to ensure effective treatment.

Disseminated protothecosis: Case report and review of the literature.

BACKGROUND: Human protothecosis is an uncommon infection caused by Prototheca spp that rarely infects humans. AIM: Description of a rare disease and a review of its articles. MATERIALS AND METHODS: We reported a 24-year-old man who presented with red-brown papules and plaques on the trunk's lateral side. We reviewed the literature about disseminated protothecosis and reported our experience with a patient with protothecosis between 2021 and 2023. RESULTS: Overall, 54 cases of disseminated protothecosis were evaluated, 39 were due to P. wickerhamii, 12 were due to P. zopfii (22.2%), and three were due to Prototheca spp. We found that males were more affected (37 cases, 68.5%) than females (16 cases, 29.6%). The mean age of patients was 39.53 ± 22.48 years. However, disseminated protothecosis can affect people of any age (1-80 years). In contrast to P. wickerhamii, which causes blood, skin, brain, and gastrointestinal tract infections, P. zopfii was mainly found in the blood (7/22) and did not have a significant difference in the mortality rate (P = 0.11). DISCUSSION: Disseminated protothecosis is a rare disease in immunocompromised patients but is generally rarer in immunocompetent hosts. Several underlying disorders include immunocompromised patients, prolonged application of steroids, diabetes mellitus, malignancies, organ transplantation, AIDS, and surgeries. Amphotericin B has been the most effective agent for protothecosis and is reserved for visceral and disseminated infections. Regarding localized cutaneous types, excision or surgical debridement is used. CONCLUSION: Mulberry's appearance and appropriate cultural environments are helpful in diagnosing it.

Clinical features and antifungal treatment of invasive Scedosporium boydii infection: report of a case and literature overview.

OBJECTIVE: This study aims to present a case of persistent mycetoma caused by Scedosporium boydii and undertake a systematic literature overview to elucidate the clinical characteristics and antifungal treatment exhibited by such patients. METHODS: We report the case of a 24-year-old female who sustained a Scedosporium boydii infection in her right foot over a decade ago following a nail puncture. Concurrently, a comprehensive literature overview was conducted on PubMed, focusing on documented cases of Scedosporium boydii infections with the intent of extracting relevant clinical data. RESULTS: Our analysis revealed that post-transplantation, trauma, near drowning, corticosteroid administration, and prior surgical history were the main risk factors for Scedosporium boydii infection. Prevalent infection sites included skin/bone tissues, the central nervous system, and ocular regions. Among the 49 patients identified, 24 received itraconazole therapy and 25 received voriconazole, with no significant difference in patient outcomes (P = 0.158). Of these, 12 patients experienced treatment failure. Notably, prolonged antifungal treatment duration was identified as a protective factor against mortality in Scedosporium boydii infections [P = 0.022, OR(95%CI): 0.972(0.949-0.996)]. Conversely, a history of post-transplantation emerged as a potential risk factor for mortality[P = 0.046, OR(95%CI): 7.017(1.034-47.636)]. CONCLUSION: While uncommon, Scedosporium boydii infections carry a significant burden of morbidity and adverse outcomes. Heightened clinical vigilance is warranted in individuals presenting with risk factors for this pathogen. Timely and effective antifungal intervention is crucial, with both voriconazole and itraconazole demonstrating positive treatment outcomes for Scedosporium boydii infection. Therefore, prioritizing these antifungal agents should be considered a key therapeutic strategy in the management of this patient population.

Continuous chiral separation process for high-speed countercurrent chromatography established and scaled up: A case of Voriconazole enantioseparation.

An efficient method for the continuous separation of Voriconazole enantiomers was developed using sulfobutyl ether-ß-cyclodextrin (SBE-ß-CD) as a chiral selector in high-speed countercurrent chromatography (HSCCC) with different types. The separation was performed using a two-phase solvent system consisting of n-hexane/ethyl acetate/100 mmol/L phosphate buffer solution (pH = 3.0, containing 50 mmol/L SBE-ß-CD) (1.5:0.5:2, v/v/v). A fast and predictable scale-up process was achieved using an analytical DE HSCCC instrument. The optimized parameters were subsequently applied to a preparative Tauto HSCCC instrument, resulting in consistent separation time and enantiomeric purity, with throughput boosted by a remarkable 11-fold. Preparative HSCCC successfully separated 506 mg of the racemate, delivering enantiomers exceeding 99% purity as confirmed by high-performance liquid chromatography analysis. This investigation presents an effective methodology for forecasting the HSCCC scale-up process and attaining continuous separation of chiral drugs.

Notable drug-drug interaction between omeprazole and voriconazole in CYP2C19 *1 and *2 (rs4244285, 681G>A) alleles in vitro.

The drug-drug interaction (DDI) and CYP2C19 genetic variation can lead to a high blood concentration of voriconazole. CYP2C19 is a highly genetically polymorphic enzyme, and CYP2C19*2 is more frequent among Asians associated with reduced metabolism of drugs. Clinical study found that co-administration with omeprazole significantly increased voriconazole concentrations and there was an additive effect in CYP2C19*2 allele.CYP2C19 rs4244285 (681G>A) is the key polymorphism of CYP2C19*2 allele. This study aims to describe the in vitro effects of omeprazole on CYP2C19*1 and *2 (681G>A), and determine how CYP2C19 polymorphisms influence the DDI between omeprazole and voriconazole.Using the lentiviral expression system, we successfully generated HepG2-derived cell lines stably expressing CYP2C19*1 and *2 (681G>A). The results showed that the CYP2C19 mRNA level, protein level, and enzymatic activity were lower in HepG2-CYP2C19*2 (681G>A) than HepG2-CYP2C19*1 cells. Our study also showed that the inhibition rates of omeprazole on voriconazole had no significantly differences between CYP2C19*1 and *2 (681G>A). But the IC50 of omeprazole on CYP2C19*1 slightly lower than CYP2C19*2 (681G>A).Moreover, omeprazole inhibited CYP2C19 protein level in cells carrying CYP2C19*1 and CYP2C19*2 (681G>A). Our study demonstrated that omeprazole could inhibit voriconazole metabolism in both CYP2C19*1 and CYP2C19*2 (681G>A).

Pharmacogenetic implementation for CYP2C19 and pharmacokinetics of voriconazole in children with malignancy or inborn errors of immunity.

BACKGROUND: Voriconazole pharmacokinetics (PK) are known to be affected by genetic polymorphisms of drug-metabolizing enzymes such as CYP2C19; however, such information is limited for the pediatric population. The primary aim of this study is to establish a voriconazole PK model incorporating CYP2C19 phenotypes in Japanese children with malignancy or inborn errors of immunity. METHODS: CYP2C19 genotypes were assessed by whole-genome genotyping and defined as follows: *17/*17: ultrarapid metabolizer (URM), *1/*17: rapid metabolizer (RM), *1/*1:normal metabolizer (NM), *1/*2, *1/*3, *2/*17:intermediate metabolizer (IM), and *2/*2, *2/*3, *3/*3: poor metabolizer (PM). Population PK analysis was performed. The voriconazole serum concentration profile was described by a two-compartment model with first-order absorption, mixed linear and nonlinear (Michaelis-Menten) elimination. RESULTS: Voriconazole concentration data were available from 60 patients with a median age of 5.3 years. The phenotypes predicted from CYP2C19 genotypes were RM in 1 (2 %), NM in 21 (35 %) patients, IM in 27 (45 %) patients, and PM in 11 (18 %) patients. Underlying diseases included 38 (63%) patients with hematological malignancy and 18 (30 %) patients with inborn errors of immunity. Among the CYP2C19 phenotypes, PM was predicted to show complete inhibition (the degree of Vmax inhibition [Vmax, inh] = 100 %; Vmax = 0). The estimated parameters of Vmax,inh were +0.8 higher in patients with gamma-glutamyl transpeptidase (γ-GTP) Grade 2 or higher and +2.7 higher when C-reactive protein (CRP) levels were 2.0 mg/dL or higher. CONCLUSION: CYP2C19 genetic polymorphisms, γ-GTP, and CRP affect Vmax,inh of voriconazole in children with malignancy or inborn errors of immunity.

Effectiveness and safety of the simulation-based first-dose design of voriconazole.

BACKGROUND: We investigated whether the initial voriconazole (VRCZ) dosing design, as determined using simulation software with a population pharmacokinetic model of Japanese patients, impacts the effectiveness and safety when compared with VRCZ initiation according to the package insert. METHODS: In this single-center retrospective observational study, we employed records from Tosei General Hospital (a 633-bed hospital), dated April 2017 to September 2023. Eligible patients were divided into the software-based simulation group, comprising patients administered initial VRCZ dosage adjustment by pharmacists using software-based simulation, and the standard therapy group, whose dosage was administered by a physician following the package insert recommendations without simulation. The primary objective of this study was to determine the efficacy of VRCZ first-dose design in reducing the incidence of hepatotoxicity and visual symptoms. RESULTS: The median ages of enrolled participants (n = 93) were 75 (68-79) and 72 (65-78) years in the software-based simulation and standard therapy groups, respectively. Regardless of formulation, initial trough concentrations were lower in the VRCZ software-based first dosage adjustment group and higher rate within the appropriate range (1-4 µg/mL). The incidence of all-grade hepatotoxicity or visual symptoms was significantly lower in the software-based simulation group. The log-rank test revealed a significant impact on the occurrence of ≥grade 2 hepatotoxicity in the software-based first dosage adjustment group compared to that in the standard therapy group. CONCLUSIONS: The initial VRCZ dosing design using simulation software improved the achievement of appropriate initial trough concentrations and resulted in fewer occurrences of hepatotoxicity (≥grade 2) when compared with the standard therapy.