Effects of Strong Inhibition of Cytochrome P450 3A and UDP glucuronosyltransferase 1A9 and Strong Induction of Cytochrome P450 3A on the Pharmacokinetics, Safety, and Tolerability of Soticlestat: Two Drug-Drug Interaction Studies in Healthy Volunteers.

Two open-label, phase 1 studies (NCT05064449, NCT05098041) investigated the effects of cytochrome P450 (CYP) 3A inhibition (via itraconazole), UDP glucuronosyltransferase (UGT) 1A9 inhibition (via mefenamic acid), and CYP3A induction (via rifampin) on the pharmacokinetics of soticlestat and its metabolites M-I and M3. In period 1 of both studies, participants received a single dose of soticlestat 300 mg. In period 2, participants received itraconazole on days 1-11 and soticlestat 300 mg on day 5 (itraconazole/mefenamic acid study; part 1); mefenamic acid on days 1-7 and soticlestat 300 mg on day 2 (itraconazole/mefenamic acid study; part 2); or rifampin on days 1-13 and soticlestat 300 mg on day 11 (rifampin study). Twenty-eight healthy adults participated in the itraconazole/mefenamic acid study (14 per part) and 15 participated in the rifampin study (mean age, 38.1-40.7 years; male, 79-93%). For maximum observed concentration, the geometric mean ratios (GMRs) of soticlestat + itraconazole, mefenamic acid, or rifampin to soticlestat alone were 116.6%, 107.3%, and 13.2%, respectively, for soticlestat; 10.7%, 118.0%, and 266.1%, respectively, for M-I, and 104.6%, 88.2%, and 66.6%, respectively, for M3. For area under the curve from time 0 to infinity, the corresponding GMRs were 124.0%, 100.6%, and 16.4% for soticlestat; 13.3%, 117.0%, and 180.8% for M-I; and 120.3%, 92.6%, and 58.4% for M3. Soticlestat can be administered with strong CYP3A and UGT1A9 inhibitors, but not strong CYP3A inducers (except for antiseizure medications, which will be further evaluated in ongoing phase 3 studies). In both studies, all treatment-emergent adverse events were mild or moderate. SIGNIFICANCE STATEMENT: These drug-drug interaction studies improve our understanding of the potential changes that may arise in soticlestat exposure in patients being treated with CYP3A inhibitors, UGT1A9 inhibitors, or CYP3A inducers. The results build on findings from previously published soticlestat studies and provide important information to help guide clinical practice. Soticlestat has shown positive phase 2 results and is currently in phase 3 development for the treatment of seizures in patients with Dravet syndrome and Lennox-Gastaut syndrome.

Pharmacokinetics and Safety of Lurbinectedin Administrated with Itraconazole in Cancer Patients: A Drug-Drug Interaction Study.

This open-label, two-part, phase Ib drug-drug interaction study investigated whether the pharmacokinetic (PK) and safety profiles of lurbinectedin (LRB), a marine-derived drug, are affected by co-administration of itraconazole (ITZ), a strong CYP3A4 inhibitor, in adult patients with advanced solid tumors. In Part A, three patients were sequentially assigned to Sequence 1 (LRB 0.8 mg/m2, 1-h intravenous [IV] + ITZ 200 mg/day oral in Cycle 1 [C1] and LRB alone 3.2 mg/m2, 1 h, IV in Cycle 2 [C2]). In Part B, 11 patients were randomized (1:1) to receive either Sequence 1 (LRB at 0.9 mg/m2 + ITZ in C1 and LRB alone in C2) or Sequence 2 (LRB alone in C1 and LRB + ITZ in C2). Eleven patients were evaluable for PK analysis: three in Part A and eight in Part B (four per sequence). The systemic total exposure of LRB increased with ITZ co-administration: 15% for Cmax, area under the curve (AUC) 2.4-fold for AUC0-t and 2.7-fold for AUC0-∞. Co-administration with ITZ produced statistically significant modifications in the unbound plasma LRB PK parameters. The LRB safety profile was consistent with the toxicities described in previous studies. Co-administration with multiple doses of ITZ significantly altered LRB systemic exposure. Hence, to avoid LRB overexposure when co-administered with strong CYP3A4 inhibitors, an LRB dose reduction proportional to CL reduction should be applied.

FATAL ACUTE HEMOLYSIS FOLLOWING TRIAZOLE THERAPY IN AFRICAN PENGUINS (SPHENISCUS DEMERSUS).

Aspergillosis is a major cause of morbidity and mortality in penguins, with triazole antifungal drugs being commonly used for prophylaxis and treatment. This report describes 15 cases of fatal hemolysis associated with liquid itraconazole and voriconazole formulations administered to African penguins (Spheniscus demersus) from four institutions. All penguins underwent stressful events (e.g. relocation, induced molt) and were administered commercial liquid itraconazole formulations or compounded voriconazole liquid suspension. Observed clinical signs in affected penguins prior to death included hyporexia, weight loss, lethargy, dyspnea, red-tinged droppings, and obtunded mentation. Intra- and extravascular hemolysis and hemoglobinuric nephrosis were the primary pathologic manifestations on postmortem examination. The concentration-dependent hemolytic potentials of itraconazole, voriconazole, and commercial and compounded vehicle suspensions were evaluated in vitro by exposing chicken whole blood as a surrogate for penguin blood. Hemoglobin content in blood plasma was then measured by spectrophotometry. Neither itraconazole nor voriconazole alone induced hemolysis in vitro. The vehicle ingredients sorbitol and hydromellose induced hemolysis, but not at predicted plasma levels in chicken erythrocytes, suggesting neither the azole antifungals nor their major vehicles alone were likely to contribute to hemolysis in vivo in these penguins. Potential mechanisms of toxicosis include generation of an unmeasured reactive metabolite causing hemolysis, preexisting erythrocyte fragility, or species-specific differences in hemolytic thresholds that were not assessed in the chicken erythrocyte model. More research is needed on the potential for toxicosis of azole antifungal drugs and carrier molecules in this and other avian species.

Evaluation of the inhibitory effects of itraconazole on letermovir.

AIMS: Letermovir, a cytomegalovirus (CMV) DNA terminase complex inhibitor, is a substrate of ABCB1 (P-glycoprotein; P-gp), organic anion transporting polypeptide (OATP)1B1/3, UDP-glucuronosyltransferase (UGT)1A1, UGT1A3 and possibly ABCG2 (breast cancer resistance protein; BCRP). A study was conducted to evaluate the effects of itraconazole, a prototypic ABCB1/ABCG2 inhibitor, on letermovir pharmacokinetics (PK) and the effects of letermovir on itraconazole PK. METHODS: In an open-label, fixed-sequence study in 14 healthy participants, 200 mg oral itraconazole was administered once daily for 4 days. Following a 10-day washout, 480 mg oral letermovir was administered once daily for 14 days (Days 1-14) and then coadministered with 200 mg itraconazole once daily for 4 days (Days 15-18). Intensive PK sampling was performed for letermovir and itraconazole. PK and safety were evaluated. RESULTS: Letermovir geometric mean ratio (GMR; 90% confidence interval [CI]) for area under the concentration-time curve from time 0 to 24 h (AUC0-24 ) was 1.33 (1.17, 1.51) and for maximum concentration (Cmax ) was 1.21 (1.05, 1.39) following administration with/without itraconazole. Itraconazole GMR (90% CI) for AUC0-24 was 0.76 (0.71, 0.81) and for Cmax was 0.84 (0.76, 0.92) following administration with/without letermovir. Coadministration of letermovir with itraconazole was generally well tolerated. CONCLUSIONS: The increase in letermovir exposure with coadministration of itraconazole is likely predominantly due to inhibition of intestinal ABCB1 and potentially ABCG2 transport. The mechanism for the decrease in itraconazole exposure is unknown. The modest changes in letermovir and itraconazole PK are not considered clinically meaningful.

Effect of a strong CYP3A4 inhibitor and inducer on the pharmacokinetics of senaparib (IMP4297) in healthy volunteers: A drug-drug interaction study.

AIMS: A phase I open-label study assessed the effect of multiple oral doses of a potent CYP3A4 inhibitor (itraconazole) and inducer (rifampicin) on the pharmacokinetic profile of a single oral dose of senaparib, a novel, highly potent poly-(ADP-ribose) polymerase 1/2 inhibitor and CYP3A4 substrate, in Chinese healthy male volunteers (HMV). METHODS: Adult HMV were enrolled to the itraconazole or rifampicin group (n = 16 each). In Period 1, all participants received a single oral dose of senaparib 40 mg (itraconazole group) or 100 mg (rifampicin group). In Period 2, the same dose was coadministered with itraconazole (200 mg) and rifampicin (600 mg), respectively. The primary endpoints were senaparib exposure parameters. RESULTS: Coadministration with itraconazole significantly increased exposure of senaparib and decreased that of its major metabolites M9 and M14. Maximum plasma senaparib concentration (Cmax ) was increased by ~79% and area under the concentration-time curve (AUC) increased by ~2.8-fold. Coadministration with rifampicin significantly reduced the Cmax and AUC of senaparib by ~59 and 83%, respectively. The Cmax for both M9 and M14 was slightly increased, although AUC was decreased. All treatment-emergent adverse events were grade ≤2, regardless of the treatment administered. CONCLUSION: In Chinese HMV, the exposure of senaparib was significantly increased when coadministered with itraconazole and significantly decreased when coadministered with rifampicin. It is recommended to avoid concomitant use of senaparib and strong inhibitors or inducers of CYP3A4.

Effects of itraconazole and carbamazepine on the pharmacokinetics of nirmatrelvir/ritonavir in healthy adults.

AIMS: The objective of this study was to evaluate the effects of a strong cytochrome P450 family (CYP) 3A4 inhibitor (itraconazole) and inducer (carbamazepine) on the pharmacokinetics and safety of nirmatrelvir/ritonavir. METHODS: Pharmacokinetics were measured in two phase 1, open-label, fixed-sequence studies in healthy adults. During Period 1, oral nirmatrelvir/ritonavir 300 mg/100 mg twice daily was administered alone; during Period 2, it was administered with itraconazole or carbamazepine. Nirmatrelvir/ritonavir was administered as repeated doses or one dose in the itraconazole and carbamazepine studies, respectively. Nirmatrelvir and ritonavir plasma concentrations and adverse event (AE) rates in both periods were analysed. RESULTS: Each study included 12 participants. Following administration of nirmatrelvir/ritonavir with itraconazole (Test) or alone (Reference), test/reference ratios of the adjusted geometric means (90% CIs) for nirmatrelvir AUCtau and Cmax were 138.82% (129.25%, 149.11%) and 118.57% (112.50%, 124.97%), respectively. After administration of nirmatrelvir/ritonavir with carbamazepine (Test) or alone (Reference), test/reference ratios (90% CIs) of the adjusted geometric means for nirmatrelvir AUCinf and Cmax were 44.50% (33.77%, 58.65%) and 56.82% (47.04%, 68.62%), respectively. Nirmatrelvir/ritonavir was generally safe when administered with or without itraconazole or carbamazepine. No serious or severe AEs were reported. CONCLUSIONS: Coadministration of a strong CYP3A4 inhibitor with a strong CYP3A inhibitor used for pharmacokinetic enhancement (i.e., ritonavir) resulted in small increases in plasma nirmatrelvir exposure, whereas coadministration of a strong inducer substantially decreased systemic nirmatrelvir and ritonavir exposures suggesting a contraindication in the label with CYP3A4 strong inducers. Administration of nirmatrelvir/ritonavir alone or with itraconazole or carbamazepine was generally safe.

Real world co-prescribing contraindicated drugs with fluconazole and itraconazole.

PURPOSE: This study aimed to investigate co-prescribing of contraindicated drugs with fluconazole and itraconazole using real-world nationwide data. METHODS: This retrospective cross-sectional study was performed using claims data collected by the Health Insurance Review and Assessment Service (HIRA) of Korea during 2019-2020. To determine the drugs that should be avoided in patients taking fluconazole or itraconazole, Lexicomp® and Micromedex® were used. The co-prescribed medications, co-prescription rates, and potential clinical consequences of the contraindicated drug-drug interactions (DDIs) were investigated. RESULTS: Of the 197 118 prescriptions of fluconazole, 2847 co-prescriptions with drugs classified as contraindicated DDI by either Micromedex® or Lexicomp® were identified. Further, of the 74 618 prescriptions of itraconazole, 984 co-prescriptions with contraindicated DDI were identified. Solifenacin (34.9%), clarithromycin (18.1%), alfuzosin (15.1%), and donepezil (10.4%) were frequently found in the co-prescriptions of fluconazole, whereas tamsulosin (40.4%), solifenacin (21.3%), rupatadine (17.8%), and fluconazole (8.8%) were frequently found in the co-prescriptions of itraconazole. In 1105 and 95 co-prescriptions of fluconazole and itraconazole, accounting for 31.3% of all co-prescriptions, potential DDIs were associated with a risk of corrected QT interval (QTc) prolongation. Of the total 3831 co-prescriptions, 2959 (77.2%) and 785 (20.5%) were classified as contraindicated DDI by Micromedex® alone and by Lexicomp® alone, respectively, whereas 87 (2.3%) were classified as contraindicated DDI by both Micromedex® and Lexicomp®. CONCLUSIONS: Many co-prescriptions were associated with the risk of DDI-related QTc prolongation, warranting the attention of healthcare providers. Narrowing the discrepancy between databases that provide information on DDIs is required for optimized medicine usage and patient safety.

Characterization of endogenous markers of hepatic function in patients receiving itraconazole treatment for prophylaxis of deep mycosis.

BACKGROUND: Long-term use of itraconazole (ITZ) is associated with a risk of inducing hepatotoxicity. This study aimed to evaluate the associations of plasma concentrations of ITZ and its hydroxylated metabolite (OH-ITZ) with endogenous markers of hepatic function. METHODS: Thirty six patients treated with oral ITZ solution for prophylaxis of deep mycosis were enrolled. Plasma concentrations of ITZ and OH-ITZ were determined on the 14th day or later after administration of ITZ. Their associations with endogenous marker levels of hepatic function including plasma coproporphyrin (CP)-I and OATP1B1 genotypes were assessed. RESULTS: The serum level of total bilirubin (T-Bil) was moderately correlated with the plasma concentration of total ITZ (tITZ) and OH-ITZ (tOH-ITZ). T-Bil elevation above 0.3 mg/dL was observed in 19% of patients, although statistically significant difference was not identified. The plasma concentration of tITZ had no correlation with other endogenous markers levels including AST, ALT, albumin, and plasma CP-I. The serum AST and plasma CP-I levels were correlated with the plasma concentration of free OH-ITZ (fOH-ITZ). T-Bil and plasma CP-I, a marker of OATP1B1 activity, were not correlated with each other, and neither was associated with the OATP1B1 genotypes. CONCLUSIONS: Plasma ITZ and OH-ITZ had a positive association with T-Bil. The patients with a higher fOH-ITZ level had lower OATP1B1 activity on the basis of plasma CP-I level. ITZ and OH-ITZ have the potential to slightly increase endogenous marker levels of hepatic function, although most likely by different mechanisms.

Comparing the Efficacy for Pulse Versus Continuous Dose Terbinafine Therapy in Patients With Onychomycosis.

Recently, treatment outcomes in patients with toenail onychomycosis have improved considerably due to more effective oral antifungal medications such as terbinafine and itraconazole. These medications can either be used continuously for several weeks at a lower dose or intermittently (pulsed) at a higher dose. Previous literature comparing pulse and continuous therapy has generated mixed results.  Our study aims to compare the efficacy, in terms of clinical cure rate, of continuous vs pulse dose terbinafine regimens for toenail onychomycosis. Sixty patients with onychomycosis of Fitzpatrick skin types IV to VI, between 15 and 65 years of age, were divided into a continuous treatment group receiving 250 mg terbinafine once daily for 12 weeks and a pulse treatment group receiving 250 mg twice daily terbinafine for 1 week repeated every 4 weeks for 12 weeks. Each patient was followed up at weeks 4, 8, and 12.  Efficacy of the continuous treatment group was significantly greater at 76.67% compared with 26.67% in the pulse treatment group. Thus, we conclude that the clinical cure rate of a continuous dose regimen of terbinafine is a superior treatment option for toenail onychomycosis. However, we also suggest further studies including combinations of multiple agents and hybrid regimen models for the optimal onychomycosis treatment.   J Drugs Dermatol. 2023;22(10):     doi:10.36849/JDD.7323R1.

Antifungal Therapy with Azoles Induced the Syndrome of Acquired Apparent Mineralocorticoid Excess: a Literature and Database Analysis.

We aimed to estimate the risk of varied antifungal therapy with azoles causing the syndrome of acquired apparent mineralocorticoid excess (AME) in real-world practice. First, we conducted a disproportionality analysis based on data from the FDA Adverse Event Reporting System (FAERS) database to characterize the signal differences of triazoles-related AME. Second, a systematic review was conducted, and clinical features of AME cases reported in clinical practice were described. In the FAERS database, we identified 27 cases of triazoles-AME, posaconazole [ROR = 865.37; 95%CI (464.14; 1613.45)], and itraconazole [ROR = 556.21; 95% (303.05; 1020.85)] significantly increased the risk of AME events, while fluconazole, voriconazole, and isavuconazole did not affect any of the mineralocorticoid excess targets. Eighteen studies with 39 cases raised evidence of AME following posaconazole and itraconazole treatment, and another 27 cases were identified by analysis of the description of clinical features in the FAERS database. The average age of 66 patients was 55.5 years (6-87 years). AME mainly occurs in patients with posaconazole concentrations above 3 µg/mL (mean = 4.4 µg/mL, range 1.8∼9.5 µg/mL), and is less likely to occur when levels are below 2 µg/mL (6%). The median time to event onset was 11.5 weeks, and 50% of the adverse events occurred within 3 months for posaconazole. The presented study supports very recent findings that posaconazole and itraconazole, but not the other three azole antifungals investigated, are associated with AME and that the effects are dose-dependent, which allows for a dose de-escalation strategy and for substitution with fluconazole, isavuconazole, or voriconazole to resolve the adverse effects.

Clinical evaluation of the potential drug-drug interactions of savolitinib: Interaction with rifampicin, itraconazole, famotidine or midazolam.

AIMS: We investigated savolitinib pharmacokinetics (PK) when administered alone or in combination with rifampicin, itraconazole or famotidine, and investigated midazolam PK when administered with or without savolitinib in healthy males. METHODS: Savolitinib PK was evaluated before/after: rifampicin (600 mg once daily [QD] for 5 days); itraconazole (200 mg QD for 5 days); a single dose of famotidine (40 mg QD) 2 hours before savolitinib. Midazolam PK was evaluated before/after midazolam (1 mg QD) with or without savolitinib (600 mg QD). Each study enrolled 20, 16, 16 and 14 volunteers, respectively. Plasma samples were collected to determine the effect on PK. RESULTS: The geometric mean ratios (GMR, %) (90% confidence intervals [CIs]) for savolitinib alone and in combination for Cmax , AUC respectively, were 45.4 (41.4-49.9), 38.5 (34.2-43.3) in the rifampicin study (n = 18); 105.2 (87.7-126.3), 108.4 (96.3-122.1) in the itraconazole study (n = 16); and 78.8 (67.7-91.7), 87.4 (81.2-94.2) in the famotidine study (n = 16). The GMRs (90% CIs) for midazolam alone and in combination with savolitinib for Cmax , AUC respectively, were 84.1 (70.0-101.0), 96.7 (92.4-101.1) (n = 14). Savolitinib alone or in combination was well tolerated. CONCLUSIONS: Co-dosing of rifampicin significantly reduced exposure to savolitinib vs savolitinib alone; co-dosing of itraconazole or midazolam with savolitinib had no clinically significant effect on savolitinib or midazolam PK, respectively. Co-dosing of famotidine with savolitinib reduced exposure to savolitinib, although this was not considered clinically meaningful. No new savolitinib-related safety findings were observed.

Efficacy and safety of miconazole muco-adhesive tablet versus itraconazole in oropharyngeal candidiasis: A randomized, multi-centered, double-blind, phase 3 trial.

Oropharyngeal candidiasis (OPC) is an opportunistic infection treated with anti-fungal agents. Herein, we evaluate the efficacy and safety of miconazole buccal tablets (MBT) and itraconazole capsules in the localized treatment of patients with OPC. In this multi-centered, double-blinded, phase III trial (CTR20130414), both males and non-pregnant females (≥18 years) with OPC were randomized (1:1) to MBT plus placebo (experimental group) or itraconazole capsules plus placebo (control group). The primary endpoint was clinical cure at the end-of-treatment period [visit 4 (V4)] while secondary endpoints were clinical remission rates, partial remission rates, mycological cure, clinical relapse, and adverse events (AEs). All endpoints were statistically analyzed in both the full analysis set (FAS) and per-protocol (PP) set. A total of 431 (experimental: 216; control: 215) subjects were included. At V4, in the FAS set, the clinical cure was achieved in 68% and 59% patients in experimental and control groups, respectively with a treatment difference of 9% [95% confidence interval (CI): -1,19; P < .001] demonstrating non-inferiority of MBT over itraconazole. At V4, mycological cure rates were 68.2% and 42.0% in the experimental group and control groups (P < .001), respectively in FAS. The relapse rates were 5.4% and 6.6%, respectively, in the experimental and control groups. A total of 210 patients experienced AEs during treatment with 47.7% in the experimental group and 49.8% in the control group with no deaths. This study demonstrated that once-daily treatment with MBT was non-inferior to itraconazole with higher mycological cure rates and was tolerable with mild AE in patients with OPC.

Miconazole is an antifungal drug against certain types of fungus or yeast infections. In this study, we showed that treatment with once-daily miconazole buccal tablets was as effective as systemic itraconazole capsules in Chinese patients infected by oropharyngeal candidiasis with minimum side effects.

Risk factors of breakthrough aspergillosis in lung transplant recipients receiving itraconazole prophylaxis.

INTRODUCTION: Invasive Aspergillus infection (IA) in lung transplantation can result in poor outcomes. Itraconazole has been shown to be effective for fungal prophylaxis in lung transplant recipients. However, IA remains a major cause of death after lung transplantation. Therefore, we aimed to clarify the risk factors for IA on itraconazole prophylaxis. METHODS: We examined 120 recipients to uncover their IA epidemiology, clinical characteristics, and outcomes. In addition, a case-control study was performed to identify risk factors of IA. RESULTS: Of the 120 patients, 12 developed IA under itraconazole prophylaxis. The patient demographics and clinical characteristics were compared among the following two groups: IA group, 12 patients, and control group, 108 patients. Significant differences were observed in age (p = 0.004), history of interstitial pneumonia (p = 0.032), and CMV infection (p < 0.001) between the groups. Before the onset of IA, 92% (11/12) of the patients received itraconazole with trough concentrations above the therapeutic range. IA developed at 272.9 ± 114.1 days after lung transplantation. Of the 12 patients who developed IA, 66.7% (8/12) had early cessation of cytomegalovirus (CMV) prophylaxis due to toxicity of valganciclovir, as follows: leukocytopenia in 4 patients, and renal dysfunction in 4 patients. Of the 8 patients who stopped valganciclovir, 75% (6/8) developed CMV infection subsequently. CONCLUSION: This study suggests that older age, history of interstitial pneumonia, and CMV infection may be important risk factors for IA on itraconazole prophylaxis. These results may help clinicians optimize prophylactic strategies for IA.

Voriconazole is superior to combined itraconazole/isotretinoin therapy and itraconazole monotherapy in recalcitrant dermatophytosis.

BACKGROUND: There has been an emergence of recalcitrant, recurrent, and difficult-to-treat tinea. Monotherapy with oral antifungals leads to partial clearance or high recurrence of lesions. Isotretinoin is a good adjuvant to systemic antifungals in chronic dermatophytosis. Voriconazole could be a future alternative due to its efficacy against dermatophytes and little resistance. OBJECTIVE: To evaluate the efficacy and safety of oral itraconazole, combined itraconazole/isotretinoin therapy, and voriconazole for recalcitrant tinea. PATIENTS AND METHODS: This study included 90 patients with chronic, recurrent and/or recalcitrant tinea. They were equally divided into three groups: itraconazole monotherapy, combined itraconazole/isotretinoin therapy, and voriconazole monotherapy. All patients received treatments for 6 weeks. The clinical response was classified as either a complete or incomplete clinical cure. Potassium hydroxide microscopy and culture were performed to identify mycological cure. Patients with complete cure were followed up for another 6 months to detect any recurrence. RESULTS: Complete clinical cure was observed in 53.3% of the itraconazole group, 70% of the itraconazole/isotretinoin group, and 83.3% of the voriconazole group. Mycological cure was detected in 56.7% of the itraconazole group, 83.3% of the itraconazole/isotretinoin group, and 86.7% of the voriconazole group. There was a statistically significant difference between the three groups in favour of voriconazole, then the combined group. No significant adverse effects were observed. The recurrence rate was significantly lower in the voriconazole group compared with the other two groups. CONCLUSIONS: Voriconazole could be a future alternative for the treatment of recalcitrant dermatophytosis.

Voriconazole Versus Itraconazole for the Initial and Step-down Treatment of Histoplasmosis: A Retrospective Cohort.

BACKGROUND: Itraconazole is the preferred azole for histoplasmosis in the current Infectious Diseases Society of America guidelines. Voriconazole is increasingly used as treatment for histoplasmosis; it has in vitro activity against Histoplasma capsulatum and has shown success in case reports and small case series, but may have a lower barrier to resistance. No comparative studies have been published. METHODS: We constructed a single-center, retrospective cohort of adult patients diagnosed with histoplasmosis from 2002 to 2017. Individual charts were reviewed to gather clinical information, including demographics, clinical features, immune status, treatments, and mortality. Patients were categorized based on the choice of azole and use as an initial treatment or as a step-down therapy from amphotericin B. Initial therapies with other azoles were excluded. Mortality was compared using a multivariable Cox proportional hazards with Heaviside function at 42 days. RESULTS: We identified 261 cases of histoplasmosis from 2002 to 2017. After excluding patients not treated with itraconazole or voriconazole, 194 patients remained. Of these, 175 (90%) patients received itraconazole and 19 (10%) received voriconazole. There were no significant demographic differences between patient populations receiving either azole as their initial azole treatment. Death at 180 days occurred in 41 patients (23.4%) in the itraconazole group and 6 patients (31.6%) in the voriconazole group. Patients on voriconazole had a statistically significant increase in mortality during the first 42 days after initiation of treatment when compared to patients receiving itraconazole (hazard ratio, 4.30; 95% confidence interval, 1.3-13.9; P = .015), when controlled for other risk factors. CONCLUSIONS: Voriconazole in histoplasmosis was associated with increased mortality in the first 42 days when compared to itraconazole.

Terbinafine Hydrochloride Combined With Itraconazole for Fungal Skin Diseases: A Randomized Controlled Trial.

BACKGROUND: Terbinafine and itraconazole are the common antifungal drugs in clinic. In vitro experiments proved that terbinafine combined with itraconazole achieves better antifungal effects. However, clinical study addressing this issue was still scarce. STUDY QUESTION: Terbinafine combined with itraconazole achieves better therapeutic effects in fungal skin diseases. STUDY DESIGN: Approximately 178 patients with fungal skin diseases from Meizhou People's Hospital, China, between October 2016 and October 2017 were admitted to this study. Patients were randomly distributed to 3 groups by randomly selecting random numbers and were treated with terbinafine, itraconazole, monotherapy, or combined therapy. Both patients and study investigators were unaware of grouping situations during experiments. Fifteen patients were excluded due to poor compliance, and 11 patients were excluded due to incomplete data. Finally, 152 patients were analyzed for this study. MEASURES AND OUTCOMES: The therapeutic effects were evaluated by clinic symptom scores, mycology examination, the cure rate, and the cure time. Adverse events, relapse of disease, and patient's satisfaction level were recorded during follow-up. RESULTS: In the terbinafine + itraconazole group, at 14 days after treatment, the symptom scores were significantly decreased, compared with the terbinafine or itraconazole group (P1 < 0.05, P2 < 0.05). At 28 days after treatment, the fungal infection of 37 patients was eradicated, which were significantly more than 26 patients in the terbinafine group and 19 patients in the itraconazole group (P1 < 0.05, P2 < 0.05). The terbinafine + itraconazole group also exhibited 100% cure rate of patients with fungal skin diseases, shorter cure time, and increased number of cured patients during the same treatment period, which was better than terbinafine or itraconazole monotherapy (P1 < 0.05, P2 < 0.05). In addition, no adverse events and no relapse of fungal disease were reported in the terbinafine + itraconazole group during follow-up. Ninety-eight percent patients were satisfied with the therapeutic effects of combined treatment. CONCLUSIONS: Compared with terbinafine or itraconazole monotherapy, terbinafine + itraconazole combined treatment achieves better therapeutic effects in fungal skin diseases.

A Trial of Itraconazole or Amphotericin B for HIV-Associated Talaromycosis.

BACKGROUND: Talaromyces marneffei infection is a major cause of human immunodeficiency virus (HIV)-related death in South and Southeast Asia. Guidelines recommend initial treatment with amphotericin B deoxycholate, but this drug has substantial side effects, a high cost, and limited availability. Itraconazole is available in oral form, is associated with fewer unacceptable side effects than amphotericin, and is widely used in place of amphotericin; however, clinical trials comparing these two treatments are lacking. METHODS: In this open-label, noninferiority trial, we randomly assigned 440 HIV-infected adults who had talaromycosis, confirmed by either microscopy or culture, to receive either intravenous amphotericin B deoxycholate (amphotericin) (219 patients), at a dose of 0.7 to 1.0 mg per kilogram of body weight per day, or itraconazole capsules (221 patients), at a dose of 600 mg per day for 3 days, followed by 400 mg per day, for 11 days; thereafter, all the patients received maintenance therapy with itraconazole. The primary outcome was all-cause mortality at week 2. Secondary outcomes included all-cause mortality at week 24, the time to clinical resolution of talaromycosis, early fungicidal activity, relapse of talaromycosis, development of the immune reconstitution inflammatory syndrome (IRIS), and the side-effect profile. RESULTS: The risk of death at week 2 was 6.5% in the amphotericin group and 7.4% in the itraconazole group (absolute risk difference, 0.9 percentage points; 95% confidence interval [CI], -3.9 to 5.6; P<0.001 for noninferiority); however, the risk of death at week 24 was 11.3% in the amphotericin group and 21.0% in the itraconazole group (absolute risk difference, 9.7 percentage points; 95% CI, 2.8 to 16.6; P=0.006). Treatment with amphotericin was associated with significantly faster clinical resolution and fungal clearance and significantly lower rates of relapse and IRIS than itraconazole. The patients who received amphotericin had significantly higher rates of infusion-related reactions, renal failure, hypokalemia, hypomagnesemia, and anemia than patients in the itraconazole group. CONCLUSIONS: Amphotericin was superior to itraconazole as initial treatment for talaromycosis with respect to 6-month mortality, clinical response, and fungicidal activity. (Funded by the Medical Research Council and others; IVAP Current Controlled Trials number, ISRCTN59144167 .).

A phase 1/1b study of PUR1900, an inhaled formulation of itraconazole, in healthy volunteers and asthmatics to study safety, tolerability and pharmacokinetics.

AIMS: Oral itraconazole has variable pharmacokinetics and risks of adverse events associated with high plasma exposure. An inhalation formulation of itraconazole (PUR1900) is being developed to treat allergic bronchopulmonary aspergillosis, an allergic inflammatory disease occurring in asthmatics and patients with cystic fibrosis. METHODS: A 3-part, open-label Phase 1 study was conducted to evaluate safety, tolerability and pharmacokinetics of PUR1900. Healthy volunteers (n = 5-6/cohort) received either single (Part 1) or multiple (Part 2) ascending doses of PUR1900 for up to 14 days. In Part 3 stable, adult asthmatics received a single dose of 20 mg PUR1900 or 200 mg of oral Sporanox (itraconazole oral solution) in a 2-period randomized cross-over design. Itraconazole plasma and sputum concentrations were evaluated. RESULTS: None of the adverse events considered as at least possibly related to study treatment were moderate or severe, and none were classed as serious. The most common was the infrequent occurrence of mild cough. Itraconazole plasma exposure increased with increasing doses of PUR1900. After 14 days, PUR1900 resulted in plasma exposure (area under the concentration-time curve up to 24 h) 106- to 400-fold lower across doses tested (10-35 mg) than steady-state exposure reported for oral Sporanox 200 mg. In asthmatics, PUR1900 geometric mean maximum sputum concentrations were 70-fold higher and geometric mean plasma concentrations were 66-fold lower than with oral Sporanox. CONCLUSION: PUR1900 was safe and well-tolerated under the study conditions. Compared to oral dosing, PUR1900 achieved higher lung and lower plasma exposure. The pharmacokinetic profile of PUR1900 suggests the potential to improve upon the efficacy and safety profile observed with oral itraconazole.

Effects of itraconazole and rifampicin on the single-dose pharmacokinetics of the nonsteroidal mineralocorticoid receptor blocker esaxerenone in healthy Japanese subjects.

AIMS: To investigate the effects of the strong cytochrome P450 (CYP) 3A inhibitor itraconazole and the strong CYP3A inducer rifampicin on the pharmacokinetics of single-dose esaxerenone, a nonsteroidal mineralocorticoid receptor blocker, in healthy Japanese subjects. METHODS: Two open-label, single-sequence, crossover studies were conducted in healthy Japanese males aged 20-45 years. In Study 1 (n = 20), subjects received a single oral 2.5 mg dose of esaxerenone (Days 1, 13), with itraconazole 200 mg twice daily (Day 8) and once daily (Days 9-16). In Study 2 (n = 12), subjects received a single oral 5 mg dose of esaxerenone (Days 1, 13), with rifampicin 600 mg once daily (Days 8-16). The plasma concentration of esaxerenone and esaxerenone metabolites were measured using liquid chromatography-tandem mass spectrometry. Pharmacokinetic parameters were calculated using noncompartmental analysis, and safety was assessed. RESULTS: Esaxerenone exposure increased when coadministered with itraconazole. Geometric least-square mean ratios (90% confidence interval) of peak plasma esaxerenone concentration (Cmax ), area under the plasma concentration-time curve (AUC) from zero until the last measurable concentration (AUClast ) and AUC from zero until infinity (AUCinf ) were 1.13 (1.05, 1.20) ng mL-1 , 1.47 (1.40, 1.54) ng h mL-1 and 1.53 (1.45, 1.62) ng h mL-1 , respectively. Esaxerenone exposure decreased when coadministered with rifampicin. Geometric least-squares mean ratios (90% confidence interval) of esaxerenone Cmax , AUClast and AUCinf were 0.659 (0.599, 0.724), 0.315 (0.300, 0.332) and 0.312 (0.297, 0.328), respectively. CONCLUSION: Itraconazole increased esaxerenone AUCinf by 53.1%, and rifampicin decreased esaxerenone AUCinf by 68.8%. These results suggest that caution is recommended when coadministering esaxerenone with strong inhibitors and inducers of CYP3A.

Rising trends of symmetrical drug related intertriginous and flexural exanthem due to Itraconazole in patients with superficial dermatophytosis: A case series of 12 patients from eastern part of India.

SDRIFE (symmetrical drug related intertriginous and flexural exanthem) is a benign self-limiting adverse drug reaction (ADR) primarily affecting the intertriginous, gluteal and flexural regions symmetrically in the absence of systemic involvement. It is considered to be a variant of baboon syndrome. Pathogenesis is poorly understood but is thought to be result of a delayed hypersensitivity response after exposure to the drug. Commonly implicated drugs are beta-lactam antibiotics. With the rising incidence of dermatophytosis in the Indian subcontinent, the use of oral anti fungals has become rampant. SDRIFE due to itraconazole has been rarely reported in literature. We hereby present a series of 12 patients presenting with SDRIFE due to itraconazole, which is by far the largest reported in existing literature. This case series highlights the importance of identifying these cutaneous adverse drug reactions in a setting where itraconazole is commonly being used.