Dose Of Itraconazole Research Articles

Evaluation of drug-drug interactions of a novel potent FLT3 inhibitor SKLB1028 in healthy subjects.

SKLB1028 is a novel multi-target protein kinase inhibitor under investigation for the treatment of FLT3-ITD mutated acute myeloid leukemia. Based on the preclinical characterization of SKLB1028 metabolism, three drug-drug interaction clinical studies were performed to investigate the effects of itraconazole, rifampin (CYP3A4 inhibitor and inducer, respectively), and gemfibrozil (CYP2C8 inhibitor) on the metabolism of SKLB1028. Fourteen healthy Chinese male subjects were enrolled in each study. In Study 1, subjects were administered a single dose of SKLB1028 (100 mg on days 1 and 11) and multiple doses of itraconazole (200 mg twice daily on day 8 and 200 mg once daily from days 9 to 18). Itraconazole was given with a loading dose on Day 8 and the total administration of itraconazole was 11 days. In Study 2, subjects were administered a single dose of SKLB1028 (100 mg on days 1 and 12) and multiple doses of gemfibrozil (600 mg twice daily from days 8 to 19). In Study 3, subjects were administered a single dose of SKLB1028 (150 mg on days 1 and 15) and multiple doses of rifampin (600 mg once daily from day 8 to 22). Itraconazole increased the AUC and Cmax of SKLB1028 by approximately 28% and 41%, respectively. Compared to the single drug, co-administration with gemfibrozil increased the AUC of SKLB1028 by ~26% and the Cmax by ~21%. Co-administration with rifampin reduced the AUC of SKLB1028 by ~30%, while the Cmax did not change significantly. All treatments were well tolerated in all three studies.

Novel cathepsin C inhibitor, BI 1291583, intended for treatment of bronchiectasis: Phase I characterization in healthy volunteers.

Novel treatments are needed to reduce inflammation, improve symptoms, address exacerbations, and slow disease progression in bronchiectasis. Cathepsin C (CatC) inhibition promises to achieve this through reduction of neutrophil-derived serine protease (including neutrophil elastase [NE] and proteinase 3 [PR3]) activation. Here, we present the phase I characterization of the novel CatC inhibitor, BI 1291583. Five phase I trials of BI 1291583 in healthy subjects are presented: a single-rising-dose study (NCT03414008) and two multiple-rising-dose studies (NCT03868540 and NCT04866160) assessing the safety, tolerability, pharmacodynamics, and pharmacokinetics of BI 1291583; a food effect study (NCT03837964); and a drug-drug interaction study (NCT03890887) of BI 1291583 and itraconazole. BI 1291583 was safe and well tolerated across the doses tested in these trials. Most adverse events (AEs) were mild or moderate in intensity, with no serious AEs, AEs of special interest or deaths reported in any trial. Drug-related skin exfoliation was not reported more frequently in subjects treated with BI 1291583 compared with placebo. BI 1291583 was readily absorbed, and pharmacokinetics were supra-proportional over the dose ranges assessed. Additionally, BI 1291583 inhibited CatC in a dose-dependent manner, inhibited downstream NE activity, and decreased PR3 levels. No food effect was observed. Co-administration of multiple doses of itraconazole increased BI 1291583 exposure approximately twofold. Due to these promising phase I results, a multinational phase II program of BI 1291583 in adults with bronchiectasis is ongoing (Airleaf™ [NCT05238675], Clairafly™ [NCT05865886], and Clairleaf™ [NCT05846230]).

Comparison of Efficacy of Single Oral Dose Fluconazole Versus Single Oral Dose Itraconazole in Patients with Pityriasis Versicolor

Objective: To compare the efficacy of single oral dose Fluconazole and Itraconazole in patients with Pityriasis Versicolor. Methodology: This Randomized control trial study was conducted at the Department of Dermatology, Combined Military Hospital, Abbottabad, Pakistan from March 2022 to August 2022. A total of 60 patients coming to OPD of derma department and diagnosed with Tinea Versicolor were randomized in 2 equal groups of 30 patients each. Patients diagnosed on odd serial number were allocated to group A and were prescribed oral Fluconazole (400 mg stat) while patients diagnosed on even serial number were allocated to group B and were prescribed oral Itraconazole (1000 mg stat). Diagnosis was made clinically and then by using mycological tests. Follow up visits were made at completion of 2nd and 4th weeks of start of treatment. Primary outcome was set as efficacy of the treatments at completion of 4 weeks that was assessed using mycological tests. Results: In this study, age ranged was from 19 to 40 years with mean age of 30.066±7.74 years. Mean duration of disease was 4.216±1.29 months. At completion of study (4 weeks), treatment was effective in 25 patients (83.33%) in group A while in 17 patients (56.6%) in group B with a significant difference in efficacy between two groups (p=0.024). There was a good tolerability in both groups without any serious adverse reactions reported. Conclusion: Single oral dose of Fluconazole is more effective compared to single oral dose of Itraconazole in the treatment of Pityriasis Versicolor.

Pharmacokinetics of the Akt Serine/Threonine Protein Kinase Inhibitor, Capivasertib, Administered to Healthy Volunteers in the Presence and Absence of the CYP3A4 Inhibitor Itraconazole.

Capivasertib is a potent, selective inhibitor of all 3 Akt isoforms (Akt1/2/3), and it is currently being tested in Phase III trials for the treatment of prostate and breast cancer. To investigate the effect of a cytochrome P450 3A4 (CYP3A4) inhibitor on the pharmacokinetics of capivasertib, a Phase I drug-drug interaction study of capivasertib and itraconazole was conducted in 11 healthy volunteers (median age, 54years). The 8-day study had 3 stages: Participants received a single dose of capivasertib 80mg in Stage 1, 4 doses of itraconazole 200mg over 3days in Stage 2, and a final dose of capivasertib 80mg coadministered with itraconazole 200mg in Stage 3. Capivasertib pharmacokinetics were examined in Stages 1 and 3. Itraconazole coadministration increased the maximum plasma concentration of capivasertib and total capivasertib exposure (area under the concentration-time curve from time of administration to infinity) by 1.70-fold (90% confidence interval, 1.56-1.86) and 1.95-fold (90% confidence interval, 1.82-2.10), respectively.

Itraconazole interferes in the pharmacokinetics of fuzuloparib in healthy volunteers.

Fuzuloparib is an orally administered poly [ADP-ribose] polymerase 1 (PARP1) inhibitor and has potential anti-tumor effect on ovarian cancer (such as fallopian tube cancer and primary peritoneal cancer) in China. As fuzuloparib is metabolized mainly by CYP3A4, we explored the effect of itraconazole, a strong CYP3A4 inhibitor, on a single oral dose of fuzuloparib in healthy male subjects. An open-label, single-arm, fixed sequence study was conducted. Twenty healthy adult males received one single dose of fuzuloparib (20mg) with one dose administered alone and the other dose coadministered with itraconazole. Subjects received 200mg QD itraconazole for 6days during the study. Serials of blood samples were collected pre-dose of each fuzuloparib capsule administration and 48h post-dose, and were used to analyze the PK parameters of fuzuloparib. Coadministration of repeated 200mg QD oral doses of itraconazole for 6days increased fuzuloparib exposure by 1.51-fold and 4.81-fold for peak plasma concentration and area under the plasma concentration-time curve (AUC), respectively. Oral administration of 20mg fuzuloparib alone or together with itraconazole was safe and tolerable in healthy male subjects. The CYP3A4 inhibitor itraconazole has a significant influence on the PK behavior of fuzuloparib, suggesting to avoid using strong CYP3A4 inhibitors simultaneously with fuzuloparib. If it is necessary to use a strong CYP3A4 inhibitor, fuzuloparib would be discontinued and be restored to the original dose and frequency of administration after 5-7 half lives of CYP3A4 inhibitor stopped. http://www.chinadrugtrials.org.cn/index.html , CTR20191271.

Randomized control trial of itraconazole in the treatment of dermatophytosis: comparison of three different dose regimens

Introduction: Dermatophytosis is a superficial fungal infection of keratinized tissue caused by dermatophytes. The use of itraconazole in the standard dose and duration is commonly resulting in treatment failure. Aims and Objectives: To compare the efficacy and safety of three different dosage regimens of itraconazole in the treatment of dermatophytosis. Materials and Methods: Patients were enrolled and randomly assigned to three different groups A, B, and C after obtaining the proper consent. For four weeks, patients in Groups A, B, and C received itraconazole 100 mg once daily, 200 mg once daily, and 5 mg/kg or 400 mg daily, whichever was lesser, in two divided doses, respectively. All patients were advised to use topical eberconazole cream twice daily and levocetirizine 5 mg daily. Potassium hydroxide (KOH), culture for fungus, complete blood count (CBC), and liver function test (LFT) were done at the baseline visit and repeated in 4 weeks. A clinical assessment was done at both visits. Result: KOH was negative for fungal elements in 21.4%, 19%, and 17% of patients in groups A, B, and C respectively, after the completion of therapy. The culture was negative for fungal elements in 19%, 17.5%, and 19.5% of patients in groups A, B, and C respectively, post-therapy. At the end of four weeks, there was a statistically significant decrease in lesion count, body surface area involvement, erythema, and itching within all three groups. However, after 4 weeks of therapy, there was no significant difference in clinical outcome or mycological status among the three groups. Conclusion: Our study concludes that the higher dose of itraconazole does not prove to be more efficacious and has no added advantage over the conventional dose in the treatment of dermatophytosis at the end of four weeks. Therefore, we suggest for long-term (more than 4 weeks) itraconazole therapy with the conventional dose to achieve an adequate cure.

Disseminated aspergillosis in a German shepherd mixed breed dog with unusual initial localization to the iliac wing.

A female, 1.5 years old, mixed‑breed dog, was presented for left hind limb lameness. Radiographs revealed an irregular periosteal proliferation on the left iliac wing. The clinical condition worsened with generalised enlargement of the lymph nodes, azotaemia, and pyelonephritis. The magnetic resonance imaging of the pelvis and a surgical biopsy diagnosed a mycotic myositis and osteomyelitis of the iliac wing and gluteal muscles. Aspergillus terreus was isolated from culture of urine and lymph nodes aspirates. The antifungal susceptibility test showed moderate sensitivity to Itraconazole. After one month of therapy with itraconazole, the dog presented discospondylitis of L1‑L2 and partial ureteral obstruction due to mycotic bezoar that was resolved with medical treatment and itraconazole dose elevation. After twelve months, itraconazole was suspended; a severe osteomyelitis of the left femur developed, and the dog was euthanised. The necropsy confirmed the presence of mycotic osteomyelitis of the iliac wing and femur, discospondylitis, lymphadenitis and severe granulomatous pyelonephritis. Systemic aspergillosis has rarely been reported in the literature, especially in Italy. The pelvic bone involvement is rare both in dogs and humans. Although itraconazole treatment allowed remission of the clinical signs for one year, it was not able to cure the dog.

613. Novel use of Ritonavir boosting to achieve therapeutic itraconazole levels in disseminated Histoplasmosis

Abstract Background Itraconazole is a poorly soluble antifungal drug with variable pharmacokinetics. Serum levels vary between patients and over time, due to absorption issues and drug-drug interactions. Itraconazole suspension has more predictable absorption than capsules, but is poorly tolerated. Newer formulations dispersing drug in polymer aim to improve bioavailability, but are costly and not widely available. Standard therapy for histoplasmosis is induction with liposomal amphotericin B (LAmB) followed by 12+ months of itraconazole therapy with target pre-dose levels of 1-4 mg/L. Methods A 33yo M presented with weight loss, fever and dyspnoea, having returned to the UK from Nicaragua. He had been taking adalimumab for Crohn’s disease, quiescent for years following a prior small bowel resection. Empiric antifungal therapy with LAmB was commmenced, prior to confirmation of disseminated histoplasmosis by urinary antigen and blood culture. His course was complicated by significant bowel inflammation, requiring subtotal colectomy and end-ileostomy. Since surgery, he has had a high output stoma, with rapid transit time and reduced absorption. Results Despite itraconazole dose titration to 300mg TDS, levels were generally < 0.5 mg/L and maximum serum itraconazole level achieved was 0.64 mg/L. The patient was trained with a view to self-OPAT LAmB. On day 117 of antifungal therapy, ritonavir 100mg once daily was added. Four days after this, itraconazole level was 1.39 mg/L (from 0.34 mg/L) and maintained target concentration even after a switch from itraconazole suspension to capsules (Fig.1) with significant fungal marker response (Fig. 2). Figure 1.Itraconazole dosing and levels pre- and post-ritonavir Total daily itraconazole dose (suspension followed by capsules) was mapped over time. There is a period where LAmB alone was used surrounding the colorectal surgery. Serum itraconazole levels dramatically increased 2 days after the introduction of ritonavir 100mg once daily and remained above target trough even after switching to itraconazole capsules. Figure 2.Fungal marker (B-D-glucan and Histoplasma urinary Ag) response to antifungal therapy The response of serum beta-D-glucan and quantitative urinary Histoplasma antigen EIA (Miravista Labs) is represented alongside concurrent antifungal therapy. Of note, the first four urinary Histoplasma Ag levels were reporte as above the limit of detection (> 20 ng/mL) and are represented here as an arbitrary value of 25 ng/mL. Conclusion Use of ritonavir alone to boost itraconazole has not previously been described. It avoids the longer-term complications of intravenous access and adverse renal and other effects of LAmB. Itraconazole is both a substrate and inhibitor of cytochrome P450 3A4 (CYP3A4) and inhibits P-glycoprotein, resulting in considerable drug:drug interactions. Ritonavir is a more potent inhibitor of CYP3A4. Use of ritonavir-boosted itraconazole amounted to a 99% reduction in cost vs LAmB over 6 months. It may offer a reliable and cost-effective method of boosting itraconazole where other drug:drug interactions do not preclude its use. Disclosures All Authors: No reported disclosures.

Repositioning itraconazole for amelioration of bleomycin-induced pulmonary fibrosis: Targeting HMGB1/TLR4 Axis, NLRP3 inflammasome/NF-κB signaling, and autophagy

Background and aimsBleomycin (BLM) is one of the antitumor medications that had proven efficacy in the treatment of a wide range of malignant conditions. Pulmonary fibrosis which is frequently encountered during the course of bleomycin therapy may significantly reduce the potential efficacy of bleomycin in cancer therapy. This study tested the hypothesis that itraconazole may have mitigating effects on BLM-induced pulmonary fibrosis and tried to delineate the potential mechanisms of these effects. Materials and methodsIn a rat model of pulmonary fibrosis elicited by BLM, the effect of different doses of itraconazole was explored at the biochemical, histopathological, and electron microscopic levels. Key findingsItraconazole, in a dose-dependent manner, exhibited significant effects on the pro-oxidant/antioxidant balance, the inflammatory consequences, high-mobility group box 1/toll-like receptor-4 Axis, autophagy and nuclear factor kappa B/Nod-like receptor protein 3 inflammasome signaling and alleviated the histopathological, immunohistochemical, and electron microscopic perturbations induced by BLM in the pulmonary tissues. SignificanceIn view of the afore-mentioned data, itraconazole may be a promising drug that efficiently mitigates the deleterious effects of BLM on the pulmonary tissues.

Effect of Different Itraconazole Dosing Regimens on Cure Rates, Treatment Duration, Safety, and Relapse Rates in Adult Patients With Tinea Corporis/Cruris

With worldwide emergence of recalcitrant and resistant dermatophytosis, itraconazole is increasingly being used as the first-line drug for treatment of tinea corporis/cruris (TCC). Apparent inadequacy with low doses has led to empirical use of higher doses and antifungal combinations. To compare cure rates, treatment durations, safety profiles, and relapse rates of itraconazole 100, 200, and 400 mg/d for the treatment of TCC. This double-blind randomized clinical trial included adult patients with treatment-naive TCC involving at least 5% body surface area. Patients were recruited from the dermatology outpatient department of a tertiary care hospital in New Delhi, India between March 1, 2020, and August 31, 2021. Patients were randomized to 1 of the 3 treatment groups. Biweekly blinded assessments were performed until cure or treatment failure. Posttreatment follow-up of at least 8 weeks was conducted to detect relapses. Cure rates, treatment durations, safety profiles, and relapse rates were assessed. Secondary outcomes included comparison of rapidity of clinical response and cost-effectiveness between groups. Of the 149 patients assessed, the mean (SD) age was 34.3 (12.2) years, 69 patients (46.4%) were women, and 80 patients (53.6%) were men. The difference in cure rate between the 100- and 200-mg groups was statistically nonsignificant (hazard ratio [HR], 1.44; 95% CI, 0.91-2.30; P = .12), while the difference between the 100- and 400-mg groups (HR, 2.87; 95% CI, 1.78-4.62; P < .001) and between the 200- and 400-mg groups (HR, 1.99; 95% CI, 1.28-3.09; P = .002) was statistically significant. Mean (SD) treatment durations were statistically significantly different between the 100- and 400-mg groups (7.7 [4.7] weeks vs 5.2 [2.6] weeks; P = .03) and between the 200- and 400-mg groups (7.2 [3.8] weeks vs 5.2 [2.6] weeks; P = .004), but the difference between the 100- and 200-mg groups was not statistically significant. A total of 55 patients (47.4%) relapsed after treatment. Relapse rates were comparable across groups. No patient discontinued treatment due to adverse effects. Treatment with the 200-mg dose incurred a 63% higher cost and 400 mg a 120% higher cost over 100 mg in achieving cure. In this randomized clinical trial, high overall efficacy was observed among the 3 itraconazole doses for treatment of TCC, but with prolonged treatment durations and considerable relapse rates. Treatment with the 200- and 100-mg doses did not differ significantly in efficacy or treatment durations, while 400 mg scored over the other 2 on these outcomes. Considerable additional cost is incurred in achieving cure with the 200- and 400-mg doses. Clinical Trials Registry of India Identifier: CTRI/2020/03/024326.

Effects of Itraconazole and Diltiazem on the Pharmacokinetics and Pharmacodynamics of Milvexian, A Factor XIa Inhibitor.

IntroductionModulation of Factor XIa (FXIa) may provide a novel mechanism for systemic anticoagulation with the potential to improve the risk-benefit profile observed with existing anticoagulants through greater efficacy or a safer bleeding profile. This study assessed the effects of co-administration with strong and moderate CYP3A inhibitors itraconazole and diltiazem, respectively, on the pharmacokinetic and pharmacodynamic properties of milvexian, a Factor XIa inhibitor.MethodsThis was an open-label, non-randomized, two-period crossover study in healthy participants. In period 1, participants received a single oral dose of milvexian (30 mg) on day 1, followed by a washout on days 2 and 3. In period 2, participants received multiple oral doses of itraconazole (200 mg) or diltiazem (240 mg) with a single dose of milvexian.ResultsA total of 28 participants entered the treatment period. Following itraconazole co-administration, milvexian exposure was increased; AUC(0–T), AUC(INF), and C24 were 2.5-, 2.5-, and 3.8-fold higher, while mean Cmax was 28% higher versus milvexian alone. Diltiazem co-administration also increased milvexian exposure; AUC(0–T), AUC(INF), and C24 were 38, 38, and 64% higher, and mean Cmax was 9.6% higher versus milvexian alone. Prolongation of activated partial thromboplastin time was observed with milvexian in a concentration-dependent fashion irrespective of co-administration with itraconazole or diltiazem. Administration of a single dose of milvexian, alone or in combination with itraconazole or diltiazem, was generally safe and well tolerated; there were no deaths or serious adverse events.ConclusionsA moderate increase in milvexian exposure was observed following co-administration of itraconazole while a minimal increase was seen with diltiazem, consistent with the involvement of CYP3A metabolism and P-glycoprotein in drug absorption/elimination. Milvexian was generally safe and well tolerated in healthy participants.Trial RegistrationThe study was registered with ClinicalTrials.gov (NCT02807909; submitted June 17, 2016).Supplementary InformationThe online version contains supplementary material available at 10.1007/s40119-022-00266-6.

Effects of itraconazole and rifampicin on the pharmacokinetics and safety of youkenafil, a novel phosphodiesterase type 5 inhibitor, in healthy Chinese subjects

Youkenafil is a novel selective phosphodiesterase type 5 inhibitor to treat erectile dysfunction. In order to study the drug-drug interactions of youkenafil, in vitro experiments were conducted with human liver microsomes and recombinant isoenzymes to identify the effect of cytochrome P450 (CYP) enzymes on the metabolism of youkenafil. Then two clinical studies were performed to investigate the effects of itraconazole and rifampicin (potent CYP3A4/5 inhibitor and inducer, respectively) on the pharmacokinetics of youkenafil and its main metabolite, N-desethyl youkenafil (M1). Each study enrolled thirty healthy male subjects. In study 1, subjects were given a single dose of youkenafil (50 mg on Days 1 and 13) and multiple doses of itraconazole (200 mg once daily from Days 6 to 14). In study 2, subjects were given a single dose of youkenafil (100 mg on Days 1 and 20) and multiple doses of rifampicin (600 mg once daily from Days 6 to 20). The results showed that youkenafil was mainly metabolized through CYP3A4/5 in vitro. Itraconazole increased youkenafil AUC and Cmax by about 12- and 6-fold, respectively, and increased M1 AUC and Cmax by 5- and 1.3-fold, respectively. Conversely, rifampicin reduced youkenafil AUC and Cmax both by about 98%. It did not change the AUC of M1 significantly, but increased the Cmax by 30%. All treatments were well tolerated by subjects in both studies. Therefore, co-administration of youkenafil with potent inhibitors or inducers of CYP3A4/5 should be avoided or carefully monitored.

Koncentracije itrakonazola i hidroksi-itrakonazola nakon oralne primene leka kod zdravih ljudi - uticaj pola

Introduction: Itraconazole is an antifungal drug belonging to the triazole group. After oral application, it is rapidly absorbed, but its bioavailability is reduced due to an intensive first-pass through the liver metabolism effect. A large number of metabolites (the most important of which is hydroxyitraconazole) are produced by isoform CYP3A4 of cytochrome P450. The variability of itraconazole pharmacokinetics is the result of numerous factors that have not yet been fully clarified. Our study aimed to investigate the influence of gender on itraconazole and hydroxyitraconazole plasma concentrations in healthy adults after an oral application of a single dose of itraconazole. Methods: Pharmacokinetic analysis was performed after oral administration of itraconazole in a single dose of 100 mg to 22 male and 16 female healthy volunteers. Blood samples were collected before taking the drug and at appropriate time intervals up to 72 hours later. Itraconazole and hydroxyitraconazole concentrations were determined using a validated liquid chromatography method with mass spectrometric detection (LC-MS/MS) and their pharmacokinetic parameters were calculated by using the Kinetica programme, version 5.0: Cmax, Tmax, PIK (0-72), PIK (0-∞), T1/2, and Ke. Results: The median values of both itraconazole and hydroxyitraconazole were lower in women in comparison to men during the whole period of observation. Moreover, median values of Cmax, PIK(0-72) and PIK(0-∞) parameters were also significantly lower in women, concerning both itraconazole (p=0.005, 0.036 and 0.036, respectively) and its metabolite (p=0.004, 0.010 and 0.044, respectively). Elimination parameters - T1/2 and Ke did not differ between genders. Conclusion: Women were less exposed to itraconazole and its active metabolite than men following an oral application of the drug, possibly as a result of lower bioavailability due to a more intense pre-systemic metabolism, as a result of a higher expression and/or activity of the isoform enzyme, which metabolises itraconazole, and which would need to be confirmed by pharmacogenomic analysis.

Single-Dose Pharmacokinetics of Ozanimod and its Major Active Metabolites Alone and in Combination with Gemfibrozil, Itraconazole, or Rifampin in Healthy Subjects: A Randomized, Parallel-Group, Open-Label Study.

The aims of this study were to characterize the single-dose pharmacokinetics (PK) of the major active metabolites of ozanimod, CC112273 and CC1084037, and to evaluate the effect of gemfibrozil (a strong inhibitor of cytochrome P450 [CYP] 2C8), itraconazole (a strong inhibitor of CYP3A and P-glycoprotein [P-gp]), and rifampin (a strong inducer of CYP3A/P-gp and moderate inducer of CYP2C8) on the single-dose PK of ozanimod and its major active metabolites in healthy subjects. This was a phase1, randomized, parallel-group, open-label study with two parts. In part1, 40 subjects were randomized to receive a single oral dose of ozanimod 0.46mg (groupA, n = 20) or oral doses of gemfibrozil 600mg twice daily for 17days with a single oral dose of ozanimod 0.46mg on day4 (groupB, n = 20). In part2, 60 subjects were randomized to receive a single oral dose of ozanimod 0.92mg (groupC, n = 20), oral doses of itraconazole 200mg once daily for 17days with a single oral dose of ozanimod 0.92mg on day4 (groupD, n = 20), or oral doses of rifampin 600mg once daily for 21days with a single oral dose of ozanimod 0.92mg on day8 (groupE, n = 20). Plasma PK parameters for ozanimod, CC112273, and CC1084037 were estimated using noncompartmental methods. Dose-proportional increases in maximum observed concentration (Cmax) and area under the concentration-time curve (AUC) were observed for ozanimod, CC112273, and CC1084037. The mean terminal elimination half-life (t1/2) for ozanimod was approximately 20-22h while the mean t1/2 for CC112273 and CC1084037 were approximately 10days. CC112273 and CC1084037 exposures were highly correlated with or without interacting drugs. Itraconazole increased ozanimod AUC by approximately 13% while rifampin reduced ozanimod AUC by approximately 24%, suggesting a minor role of CYP3A and P-gp in the overall disposition of ozanimod. Gemfibrozil increased the AUC for CC112273 and CC1084037 by approximately 47% and 69%, respectively. Rifampin reduced the AUC for CC112273 and CC1084037, primarily via CYP2C8 induction, by approximately 60% and 55%, respectively. Ozanimod's major active metabolites, CC112273 and CC1084037, exhibited similar single-dose PK properties and their exposures were highly correlated. CYP2C8 is one of the important enzymes in the overall disposition of CC112273 and subsequently its direct metabolite CC1084037. Clinical trial: NCT03624959.

The Many Faces of Itraconazole Cardiac Toxicity.

Itraconazole is well known for carrying a black-box warning for new or worsening congestive heart failure. Single cases of other cardiac- and fluid-related disturbances have been reported periodically since its issuance. We describe a large cohort of patients on itraconazole experiencing a breadth of cardiac- and fluid-related toxicities, ranging from new-onset hypertension to cardiac arrest. A retrospective, single-center, large case series at a large tertiary medical center was conducted. Patients with itraconazole and cardiac toxicity—including hypertension, cardiomyopathy, reduced ejection fraction, and edema—in medical record between January 1, 1999, and May 21, 2019, were identified and assigned a Naranjo score; 31 patients were included with a Naranjo score of 5 or higher. There were slightly more male subjects than female subjects, average age was 66, and all subjects were Caucasian. Median time until presentation of adverse effects was 4 weeks (range: 0.3 to 104 weeks). Most common symptom was edema (74% of patients), followed by heart failure without and with preserved ejection fraction (19.4% and 22.6% of patients, respectively). Worsening or new hypertension was also common (25.8% of patients). Rarer were pulmonary edema, pericardial effusion, and cardiac arrest that occurred in 1 patient. In most cases, clinicians stopped itraconazole (74%) or decreased itraconazole dose (19%), resulting in improvement or resolution of symptoms. In 4 cases, the adverse effect did not resolve. Itraconazole can cause a range of possible serious cardiac and fluid-associated adverse events. Dose decrease or cessation usually resulted in symptomatic improvement or reversal.

Pharmacokinetic Drug Interactions of an Orally Available TRH Analog (Rovatirelin) With a CYP3A4/5 and P-Glycoprotein Inhibitor (Itraconazole).

The effects of itraconazole on the pharmacokinetics of rovatirelin were investigated in an open-label, single-sequence drug-drug interaction study in 16 healthy subjects. Subjects were administered a single oral dose of rovatirelin (1.6 mg) on day 1 and day 15. From day 8 through 16, subjects received daily oral doses of itraconazole (200 mg/day). Concentrations of rovatirelin and (thiazolylalanyl)methylpyrrolidine (TAMP), the major metabolite of rovatirelin formed by cytochrome P450 (CYP) 3A4/5, were determined in plasma and urine. Pharmacokinetic parameters were used to evaluate the drug-drug interaction potential of rovatirelin as a victim. With coadministration, maximum concentration (Cmax ) and area under the concentration-time curve extrapolated to infinity (AUCinf ) of rovatirelin increased 3.05-fold and 2.82-fold, respectively, and the 90% confidence intervals of the ratios for Cmax (2.64-3.52) and AUCinf (2.47-3.23) did not fall within the 0.8-1.25 boundaries. Urinary excretion of rovatirelin increased at almost the same ratio as the AUCinf ratio with coadministration; however, renal clearance did not change. Cmax , AUCinf , and urinary excretion of TAMP were decreased by coadministration. Itraconazole has the potential to inhibit drug transport via intestinal P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP); therefore, substrate assessments of rovatirelin for the 2 transporters were evaluated using Caco-2 cell monolayers. In vitro studies showed that rovatirelin is a substrate for P-gp but not for BCRP. The current study shows that itraconazole's effect on rovatirelin pharmacokinetics is mediated through inhibition of CYP3A4/5 and intestinal P-gp.

Plasma concentrations of itraconazole following a single oral dose in juvenile California sea lions (Zalophus californianus).

The objective of this study was to establish a single-dose pharmacokinetic profile for orally administered itraconazole in California sea lions (Zalophus californianus). Twenty healthy rehabilitated juvenile California sea lions were included in this study. Itraconazole capsules were administered orally with food at a target dose of 5-10mg/kg. Blood samples were collected from each animal at 0hr and attwo of the following timepoints: 0.5, 1, 2, 4, 6, 8, 12, 24, 48, and 72hr. Quantitative analysis of itraconazole in plasma samples was performed by high-performance liquid chromatography. An average maximum concentration of 0.22µg/ml±0.11 was detected 4hr after administration. The average concentration fell to 0.12µg/ml±0.11 by 6hr and 0.02µg/ml±0.02 at 12hr. At no point did concentrations reach 0.5µg/ml, the concentration commonly accepted for therapeutic efficacy. While this formulation was well tolerated by the sea lions, oral absorption was poor and highly variable among individuals. These data indicate that a single oral dose of itraconazole given as a capsule at 5-10mg/kg, under the conditions used in this study, does not achieve therapeutic plasma concentrations in California sea lions.

Preliminary Pilot Study of Itraconazole After a Single Oral Dose of a Veterinary Formulation Solution in African Penguins (Spheniscus demersus).

Aspergillosis is a common cause of morbidity and mortality in captive penguins. Itraconazole, an antifungal drug, is commonly used to treat aspergillosis infections in avian species; however, commercially available human formulations are costly, and studies have shown the effectiveness of compounded formulations to be unreliable. The US Food and Drug Administration (FDA) recently approved a veterinary formulation of itraconazole, Itrafungol, for use in cats. This study provides preliminary results from limited sampling evaluating whether this veterinary formulation is suitable for future studies in the African penguin (Spheniscus demersus). A 20 mg/kg PO itraconazole dose was administered to 9 African penguins. Blood samples were taken over the course of 24 hours; each sample was collected from a different bird to minimize stress to the animals. Plasma was analyzed by high-performance liquid chromatography for concentrations of itraconazole. The drug was absorbed in all penguins, and plasma concentrations in 5 of 9 penguins (56%) were found to be greater than the established therapeutic dose of 1.0 µg/ mL. To our knowledge, this is the first study that has investigated a 20 mg/kg dose of itraconazole in a penguin species. The small sample size limits the conclusions that can be drawn from this preliminary study. Nonetheless, we demonstrate encouraging evidence that the FDA-approved formulation of oral itraconazole solution should be considered for future study as a cost-effective treatment for aspergillosis in African penguins and other avian species.

Evaluation of the effect of P-glycoprotein inhibition and induction on talazoparib disposition in patients with advanced solid tumours.

AimsIn vitro data show that talazoparib is a substrate for P‐glycoprotein (P‐gp) and breast cancer resistance protein transporters. This open‐label, 2‐arm, drug–drug interaction Phase 1 study in patients with advanced solid tumours assessed the effect of a P‐gp inhibitor (itraconazole) and a P‐gp inducer (rifampicin) on the pharmacokinetics of a single dose of talazoparib. The safety and tolerability of a single dose of talazoparib with and without itraconazole or rifampicin were also assessed.MethodsThirty‐six patients were enrolled (Arm A [itraconazole], n = 19; Arm B [rifampicin], n = 17). Patients in both arms received 2 single oral doses of talazoparib (0.5 mg, Arm A; 1 mg, Arm B) alone and with multiple daily oral doses of itraconazole (Arm A) or rifampicin (Arm B).ResultsCoadministration of itraconazole and talazoparib increased talazoparib area under the plasma concentration–time profile from time 0 extrapolated to infinity by ~56% and maximum observed plasma concentration by ~40% relative to talazoparib alone. Coadministration of rifampicin and talazoparib increased talazoparib maximum observed plasma concentration by approximately 37% (geometric mean ratio 136.6% [90% confidence interval 103.2–180.9]); area under the curve was not affected relative to talazoparib alone (geometric mean ratio 102.0% [90% confidence interval 94.0–110.7]). Talazoparib had an overall safety profile consistent with that observed in prior studies in which talazoparib was administered as a single dose.ConclusionCoadministration of itraconazole increased talazoparib plasma exposure compared to talazoparib alone. A reduced talazoparib dose is recommended if coadministration of potent P‐gp inhibitors cannot be avoided. Similar exposure was observed when talazoparib was administered alone and with rifampicin suggesting that the effect of rifampicin on talazoparib exposure is limited.

A Study to Investigate the Effect of Multiple Doses of Itraconazole on the Pharmacokinetics of PF-06700841 in Healthy Participants

A Study to Investigate the Effect of Multiple Doses of Itraconazole on the Pharmacokinetics of PF-06700841 in Healthy Participants