RESUMO
BACKGROUND: Cognitive impairment associated with schizophrenia predicts poor functional outcomes, but currently no efficacious pharmacotherapies are available. AIMS: Four phase I trials examined the safety, tolerability and pharmacokinetics of the phosphodiesterase 2 inhibitor BI 474121, along with potential drug-drug interactions. METHODS: Trial 1 evaluated single rising doses (SRDs) of BI 474121 versus placebo in healthy males. The influence of drug formulation and food on drug bioavailability was also examined. Trial 2 evaluated SRD of BI 474121 versus placebo in healthy Japanese males. Trial 3 evaluated multiple rising doses of BI 474121 in healthy young (with/without midazolam) and elderly (without midazolam) participants versus placebo. Trial 4 investigated interactions between itraconazole and single-dose BI 474121 in healthy males. RESULTS/OUTCOMES: No deaths, serious adverse events (AEs), severe AEs or protocol-specified AEs of special interest were observed. BI 474121 absorbed rapidly during fasting, achieved maximum concentration of analyte in plasma and dose proportionality via tablet formulation, and decreased in a multiphasic manner. BI 474121 steady state occurred within 11 days of multiple oral administration. Multiple doses increased BI 474121 plasma concentrations, but did not alter the time course of plasma concentrations. Urinary excretion of unchanged BI 474121 was negligible. No clinically relevant inhibition or induction of CYP3A4 by BI 474121 was observed. Itraconazole co-administration produced higher exposures of BI 474121 versus BI 474121 alone. CONCLUSIONS/INTERPRETATION: BI 474121 demonstrated favourable safety and pharmacokinetic profiles in healthy Caucasian and Japanese individuals, supporting further clinical development.
Assuntos
Interações Medicamentosas , Voluntários Saudáveis , Itraconazol , Humanos , Masculino , Adulto , Pessoa de Meia-Idade , Itraconazol/efeitos adversos , Itraconazol/administração & dosagem , Itraconazol/farmacocinética , Itraconazol/farmacologia , Adulto Jovem , Idoso , Disponibilidade Biológica , Interações Alimento-Droga , Relação Dose-Resposta a Droga , Midazolam/farmacocinética , Midazolam/administração & dosagem , Midazolam/efeitos adversos , Inibidores de Fosfodiesterase/farmacocinética , Inibidores de Fosfodiesterase/efeitos adversos , Inibidores de Fosfodiesterase/administração & dosagem , Método Duplo-Cego , FemininoRESUMO
Olverembatinib (HQP1351) is a BCR-ABL1 tyrosine kinase inhibitor with promising clinical activity. It is approved in China for the treatment of patients with chronic myeloid leukemia harboring drug-resistant mutations, such as T315I. In vitro studies suggested that metabolism of olverembatinib is primarily mediated by cytochrome P450 (CYP3A4). The effects of CYP3A4 inhibition and induction on the pharmacokinetics of olverembatinib were evaluated in an open-label, 2-part, fixed-sequence study in healthy volunteers. In Part 1 of this study, 16 participants received a single oral dose of olverembatinib (20 mg) and the oral CYP3A4 inhibitor itraconazole (200 mg). In Part 2, 16 participants received a single oral dose of olverembatinib (40 mg) and the oral CYP3A4 inducer rifampin (600 mg). To measure pharmacokinetic parameters, serial blood samples were collected after administration of olverembatinib alone and combined with itraconazole or rifampin. Coadministration of olverembatinib with itraconazole increased the peak plasma concentration of olverembatinib, its area under the time-concentration curve (AUC)0-last, and AUC0-inf by 75.63%, 147.06%, and 158.66%, respectively. Coadministration with rifampin decreased these same variables by 61.27%, 74.21%, and 75.19%, respectively. These results confirm that olverembatinib is primarily metabolized by CYP3A4 in humans, suggesting that caution should be exercised with concurrent use of olverembatinib and strong CYP3A4 inhibitors or inducers.
Assuntos
Indutores do Citocromo P-450 CYP3A , Inibidores do Citocromo P-450 CYP3A , Citocromo P-450 CYP3A , Interações Medicamentosas , Voluntários Saudáveis , Itraconazol , Rifampina , Humanos , Masculino , Itraconazol/farmacocinética , Itraconazol/administração & dosagem , Itraconazol/farmacologia , Inibidores do Citocromo P-450 CYP3A/farmacocinética , Inibidores do Citocromo P-450 CYP3A/administração & dosagem , Inibidores do Citocromo P-450 CYP3A/farmacologia , Adulto , Rifampina/administração & dosagem , Rifampina/farmacocinética , Rifampina/farmacologia , Indutores do Citocromo P-450 CYP3A/administração & dosagem , Indutores do Citocromo P-450 CYP3A/farmacocinética , Indutores do Citocromo P-450 CYP3A/farmacologia , Feminino , Adulto Jovem , Citocromo P-450 CYP3A/metabolismo , Pessoa de Meia-Idade , Administração Oral , Área Sob a Curva , Inibidores de Proteínas Quinases/farmacocinética , Inibidores de Proteínas Quinases/administração & dosagemRESUMO
Active pharmaceutical ingredient (API) embedded dry powder for inhalation (AeDPI) shows higher drug loading and delivery dose for directly treating various lung infections. Inspired by the dandelion, we propose a novel kind of AeDPI microparticle structure fabricated by spray freeze drying technology, which would potentially enhance the alveoli deposition efficiency. When inhaling, such microparticles are expected to be easily broken-up into fragments containing API that acts as 'seed' and could be delivered to alveoli aided by the low density 'pappus' composed of excipient. Herein, itraconazole (ITZ), a first-line drug for treating pulmonary aspergillosis, was selected as model API. TPGS, an amphiphilic surfactant, was used to achieve stable primary ITZ nanocrystal (INc) suspensions for spray freeze drying. A series of microparticles were prepared, and the dandelion-like structure was successfully achieved. The effects of feed liquid compositions and freezing parameters on the microparticle size, morphology, surface energy, crystal properties and in vitro aerosol performance were systematically investigated. The optimal sample (SF(-50)D-INc7Leu3-2) in one-way experiment showed the highest fine particle fraction of â¼ 68.96â¯% and extra fine particle fraction of â¼ 36.87â¯%, equivalently â¼ 4.60â¯mg and â¼ 2.46â¯mg could reach the lung and alveoli, respectively, when inhaling 10â¯mg dry powders. The response surface methodology (RSM) analysis provided the optimized design space for fabricating microparticles with higher deep lung deposition performance. This study demonstrates the advantages of AeDPI microparticle with dandelion-like structure on promoting the delivery efficiency of high-dose drug to the deep lung.
Assuntos
Sistemas de Liberação de Medicamentos , Itraconazol , Pulmão , Tamanho da Partícula , Itraconazol/química , Itraconazol/administração & dosagem , Itraconazol/farmacocinética , Pulmão/metabolismo , Administração por Inalação , Taraxacum/química , Pós/química , Liofilização , Aerossóis/química , Nanopartículas/química , Propriedades de Superfície , Antifúngicos/química , Antifúngicos/administração & dosagem , Vitamina ERESUMO
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]).
Assuntos
Bronquiectasia , Catepsina C , Voluntários Saudáveis , Humanos , Bronquiectasia/tratamento farmacológico , Masculino , Adulto , Feminino , Catepsina C/antagonistas & inibidores , Catepsina C/metabolismo , Pessoa de Meia-Idade , Adulto Jovem , Relação Dose-Resposta a Droga , Itraconazol/administração & dosagem , Itraconazol/farmacocinética , Itraconazol/efeitos adversos , Itraconazol/farmacologia , Interações Alimento-Droga , Método Duplo-Cego , Adolescente , Interações MedicamentosasRESUMO
Conventional itraconazole (c-ITZ) can be used for a variety of fungal infections although variable absorption has been a significant limitation. Super-bioavailable itraconazole (SUBA-ITZ) is a novel formulation that overcomes absorption concerns by utilizing a polymer-matrix to disperse active drug and facilitate dissolution. The pH-driven matrix allows concurrent proton pump inhibitor administration without significant effects on drug concentrations. The enhanced bioavailability of SUBA-ITZ allows for lower dosing, while achieving similar serum concentrations as c-ITZ and SUBA-ITZ is now US FDA approved in the treatment of blastomycosis, histoplasmosis and aspergillosis. Common side effects of SUBA-ITZ include gastrointestinal disorders, peripheral edema and drug-induced hypertension. Given the significant differences in pharmacokinetics between the formulations, c-ITZ and SUBA-ITZ capsules are not considered interchangeable. It is important to note that drug errors may occur when transitioning a patient from one formulation to another.
Itraconazole is an antifungal agent used in the treatment of a number of mycoses. Prior formulations (versions) of itraconazole required strict dietary requirements and often had poor absorption. A new itraconazole formulation has since been developed super bioavailable itraconazole (SUBA-itraconazole). This has no food requirements, has superior absorption and maintains effectiveness against a number of fungal infections.
Assuntos
Antifúngicos , Itraconazol , Humanos , Itraconazol/uso terapêutico , Itraconazol/farmacocinética , Itraconazol/administração & dosagem , Antifúngicos/uso terapêutico , Antifúngicos/farmacocinética , Antifúngicos/efeitos adversos , Antifúngicos/administração & dosagem , Micoses/tratamento farmacológico , Micoses/microbiologia , Histoplasmose/tratamento farmacológico , Aspergilose/tratamento farmacológico , Aspergilose/microbiologia , Blastomicose/tratamento farmacológico , Infecções Fúngicas Invasivas/tratamento farmacológico , Infecções Fúngicas Invasivas/microbiologia , Disponibilidade BiológicaRESUMO
Itraconazole (ITZ) is the most used drug to treat feline sporotrichosis; however, little is known about its pharmacokinetics in cats with this mycosis. The aim of this study was to determine plasma ITZ concentrations in cats with sporotrichosis treated with ITZ as monotherapy or in combination with potassium iodide (KI). Cats diagnosed with sporotrichosis received orally ITZ (100 mg/cat/day) or combination therapy with ITZ (100 mg/cat/day) and KI (2.5-5 mg/kg/day) in the case of worsening or stagnation of the clinical condition. At each monthly visit, blood samples were collected at an interval of 4 h for analysis of trough and peak plasma ITZ concentrations by HPLC. Clinical features and laboratory parameters were evaluated during follow-up. Sixteen cats were included in the study. The median plasma ITZ concentration of all cats was 0.75 µg/mL. The median plasma ITZ concentration was 0.5 µg/mL in cats that received ITZ monotherapy (n = 12) and 1.0 µg/mL in those treated with ITZ + KI (n = 4). The clinical cure rate was 56.3% (n = 9) and the median treatment duration was 8 weeks. Nine cats (56.3%) developed adverse clinical reactions, and hyporexia was the most frequent (n = 8; 88.9%). Serum alanine aminotransferase was elevated in four cats (25%). The median plasma ITZ concentration detected in cats was considered to be therapeutic (>0.5 µg/mL) and was reached after 4 weeks of treatment. Plasma ITZ concentrations were higher in cats that received ITZ + KI compared to those treated only with ITZ, suggesting pharmacokinetic synergism between these drugs.
Itraconazole is the most common therapy for feline sporotrichosis, and combination therapy with potassium iodide is used in nonresponsive cases. Our study showed that all cats achieved a therapeutic plasma concentration of itraconazole, with higher levels in cats treated with the combination therapy.
Assuntos
Antifúngicos , Doenças do Gato , Itraconazol , Iodeto de Potássio , Esporotricose , Animais , Gatos , Esporotricose/tratamento farmacológico , Esporotricose/veterinária , Esporotricose/sangue , Itraconazol/sangue , Itraconazol/farmacocinética , Itraconazol/administração & dosagem , Itraconazol/uso terapêutico , Doenças do Gato/tratamento farmacológico , Doenças do Gato/sangue , Doenças do Gato/microbiologia , Antifúngicos/farmacocinética , Antifúngicos/sangue , Antifúngicos/uso terapêutico , Antifúngicos/administração & dosagem , Masculino , Iodeto de Potássio/uso terapêutico , Iodeto de Potássio/administração & dosagem , Iodeto de Potássio/farmacocinética , Feminino , Resultado do Tratamento , Quimioterapia Combinada , Administração Oral , Plasma/químicaRESUMO
Cytochrome P450 (CYP) 3A4 is an enzyme involved in the metabolism of many drugs that are currently on the market and is therefore a key player in drug-drug interactions (DDIs). ACT-1004-1239 is a potent and selective, first-in-class ACKR3/CXRC7 antagonist being developed as a treatment for demyelinating diseases including multiple sclerosis. Based on the human absorption, distribution, metabolism, and excretion (ADME) study results, ACT-1004-1239 is predominantly metabolized by CYP3A4. This study investigated the effect of the strong CYP3A4 inhibitor, itraconazole, on the pharmacokinetics of single-dose ACT-1004-1239 in healthy male subjects. In the open-label, fixed-sequence DDI study, a total of 16 subjects were treated. Each subject received a single dose of 10 mg ACT-1004-1239 (Treatment A) in the first period followed by concomitant administration of multiple doses of 200 mg itraconazole and a single dose of 10 mg ACT-1004-1239 in the second period. We report a median of difference in tmax (90% confidence interval, CI) of 0.5 h (0.0, 1.0) comparing both treatments. The geometric mean ratio (GMR) (90% CI) of Cmax and AUC0-∞ was 2.16 (1.89, 2.47) and 2.77 (2.55, 3.00), respectively. The GMR (90% CI) of t1/2 was 1.46 (1.26, 1.70). Both treatments were well-tolerated with an identical incidence in subjects reporting treatment-emergent adverse events (TEAE). The most frequently reported TEAEs were headache and nausea. In conclusion, ACT-1004-1239 is classified as a moderately sensitive CYP3A4 substrate (i.e., increase of AUC ≥2- to <5-fold), and this should be considered in further clinical studies if CYP3A4 inhibitors are concomitantly administered.
Assuntos
Inibidores do Citocromo P-450 CYP3A , Citocromo P-450 CYP3A , Interações Medicamentosas , Itraconazol , Humanos , Masculino , Itraconazol/farmacocinética , Itraconazol/administração & dosagem , Itraconazol/farmacologia , Adulto , Inibidores do Citocromo P-450 CYP3A/farmacocinética , Inibidores do Citocromo P-450 CYP3A/administração & dosagem , Inibidores do Citocromo P-450 CYP3A/farmacologia , Adulto Jovem , Citocromo P-450 CYP3A/metabolismo , Pessoa de Meia-Idade , Voluntários Saudáveis , Área Sob a CurvaRESUMO
OBJECTIVES: 1) Identify processes limiting the arrival of itraconazole at the intestinal epithelium when Sporanox® amorphous solid dispersion (ASD) pellets are transferred from the stomach through the upper small intestine, after a high-calorie, high-fat meal. 2) Evaluate whether itraconazole concentrations in the colloidal phase of aqueous contents of the upper small intestine are useful for the assessment of dose effects in the fed state and food effects on plasma levels. METHODS: Itraconazole concentrations, apparent viscosity, and solubilization capacity were measured in aspirates from the upper gastrointestinal lumen collected during a recently performed clinical study in healthy adults. Published itraconazole concentrations in plasma, after a high-calorie high-fat meal and Sporanox® ASD pellets, and in contents of the upper small intestine of healthy adults, after administration of Sporanox® ASD pellets in the fasted state, were used to achieve the second objective. RESULTS: When Sporanox® ASD pellets (up to 200 mg) are transferred from the stomach through the upper small intestine, after a high-calorie, high-fat meal, itraconazole concentrations in the colloidal phase or the micellar phase of aqueous contents of the upper small intestine are unsaturated, in most cases. During the first 3 h post-dosing after a high-calorie, high-fat meal, the impact of dose (200 mg vs. 100 mg) on itraconazole concentrations in the colloidal phase of aqueous contents of the upper small intestine seems to underestimate the impact of dose on plasma levels. When Sporanox® ASD pellets are administered after a high-calorie, high-fat meal at the 200 mg dose level, itraconazole concentrations in the colloidal phase of aqueous contents of the upper small intestine are, on average, lower than those achieved in fasted state. CONCLUSIONS: When Sporanox® ASD pellets are transferred from the stomach to the upper small intestine after a high-calorie, high-fat meal, itraconazole's arrival at the intestinal epithelium seems to be limited by its arrival at the colloidal phase of aqueous contents of the upper small intestine. The impact of dose (100 mg vs. 200 mg) on plasma levels after a high-calorie, high-fat meal and during the gastrointestinal transfer of Sporanox® pellets requires consideration of pre-systemic itraconazole metabolism. At the 200 mg dose level, after taking into consideration differences in the volume of the contents of the upper small intestine between the fasted and the fed state during the gastrointestinal transfer of Sporanox® ASD pellets, itraconazole concentrations in the colloidal phase of aqueous contents of the upper small intestine suggest a mild negative food effect on average plasma levels; published clinical data are inconclusive.
Assuntos
Itraconazol , Itraconazol/farmacocinética , Itraconazol/administração & dosagem , Itraconazol/sangue , Itraconazol/química , Administração Oral , Humanos , Adulto , Antifúngicos/farmacocinética , Antifúngicos/administração & dosagem , Antifúngicos/sangue , Masculino , Absorção Intestinal , Solubilidade , Interações Alimento-Droga , Dieta Hiperlipídica , Intestino Delgado/metabolismo , Viscosidade , Feminino , Adulto JovemRESUMO
BACKGROUND: Invasive fungal infections (IFIs) are severe and difficult-to-treat infections affecting immunocompromised patients. Antifungal drug penetration at the site of infection is critical for outcome and may be difficult to achieve. Data about antifungal drug distribution in infected human tissues under real circumstances of IFI are scarce. METHODS: Multiple samples were obtained from soft tissue abscesses of a lung transplant patient with Candida albicans invasive candidiasis who underwent recurrent procedures of drainage, while receiving different consecutive courses of antifungal therapy [itraconazole (ITC), fluconazole, caspofungin]. Antifungal drug concentrations were measured simultaneously at the site of infection (surrounding inflammatory tissue and fluid content of the abscess) and in plasma for calculation of the tissue/plasma ratio (R). The concentration within the infected tissue was interpreted as appropriate if it was equal or superior to the MIC of the causal pathogen. RESULTS: A total of 30 tissue samples were collected for measurements of ITC (nâ=â12), fluconazole (nâ=â17) and caspofungin (nâ=â1). Variable concentrations were observed in the surrounding tissue of the lesions with median R of 2.79 (range 0.51-15.9) for ITC and 0.94 (0.21-1.37) for fluconazole. Concentrations ranges within the fluid content of the abscesses were 0.39-1.83 for ITC, 0.66-1.02 for fluconazole and 0.23 (single value) for caspofungin. The pharmacodynamic target (tissue concentrationâ≥âMIC) was achieved in all samples for all three antifungal drugs. CONCLUSIONS: This unique dataset of antifungal drug penetration in infected human soft tissue abscesses suggests that ITC, fluconazole and caspofungin could achieve appropriate concentrations in soft tissue abscesses.
Assuntos
Abscesso , Antifúngicos , Caspofungina , Infecções dos Tecidos Moles , Humanos , Antifúngicos/farmacocinética , Antifúngicos/uso terapêutico , Antifúngicos/administração & dosagem , Abscesso/tratamento farmacológico , Abscesso/microbiologia , Caspofungina/farmacocinética , Caspofungina/uso terapêutico , Infecções dos Tecidos Moles/tratamento farmacológico , Infecções dos Tecidos Moles/microbiologia , Fluconazol/farmacocinética , Fluconazol/uso terapêutico , Fluconazol/administração & dosagem , Candida albicans/efeitos dos fármacos , Candidíase Invasiva/tratamento farmacológico , Candidíase Invasiva/microbiologia , Testes de Sensibilidade Microbiana , Masculino , Itraconazol/farmacocinética , Itraconazol/uso terapêutico , Itraconazol/administração & dosagem , Pessoa de Meia-Idade , Feminino , AdultoRESUMO
The aim of this study was to develop cholic-acid-stabilized itraconazole nanosuspensions (ITZ-Nanos) with the objective of enhancing drug dissolution and oral absorption. A laboratory-scale microprecipitation-high-pressure homogenization method was employed for the preparation of the ITZ-Nanos, while dynamic light scattering, transmission electron microscope analysis, X-ray diffraction, differential scanning calorimetry, and high-performance liquid chromatography analysis were utilized to evaluate their physicochemical properties. The absorption and bioavailability of the ITZ-Nanos were assessed using Caco-2 cells and rats, with Sporanox® pellets as a comparison. Prior to lyophilization, the particle size of the ITZ-Nanos measured approximately 225.7 nm. Both X-ray diffraction and differential scanning calorimetry confirmed that the ITZ remained crystalline within the nanocrystals. Compared to the pellets, the ITZ-Nanos exhibited significantly higher levels of supersaturation dissolution and demonstrated enhanced drug uptake by the Caco-2 cells. The AUC(0-t) value for the ITZ-Nanos in rats was 1.33-fold higher than that observed for the pellets. These findings suggest that cholic acid holds promise as a stabilizer for ITZ nanocrystals, as well as potentially other nanocrystals.
Assuntos
Itraconazol , Nanopartículas , Solubilidade , Tensoativos , Itraconazol/química , Itraconazol/farmacocinética , Itraconazol/administração & dosagem , Nanopartículas/química , Humanos , Células CACO-2 , Animais , Ratos , Administração Oral , Tensoativos/química , Masculino , Disponibilidade Biológica , Tamanho da Partícula , Difração de Raios X , Varredura Diferencial de Calorimetria , Ácido Cólico/químicaRESUMO
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.
Assuntos
Carbolinas , Inibidores do Citocromo P-450 CYP3A , Interações Medicamentosas , Compostos Heterocíclicos de 4 ou mais Anéis , Itraconazol , Neoplasias , Humanos , Itraconazol/farmacocinética , Itraconazol/administração & dosagem , Itraconazol/efeitos adversos , Masculino , Pessoa de Meia-Idade , Feminino , Idoso , Neoplasias/tratamento farmacológico , Compostos Heterocíclicos de 4 ou mais Anéis/farmacocinética , Compostos Heterocíclicos de 4 ou mais Anéis/administração & dosagem , Compostos Heterocíclicos de 4 ou mais Anéis/efeitos adversos , Inibidores do Citocromo P-450 CYP3A/administração & dosagem , Inibidores do Citocromo P-450 CYP3A/farmacocinética , Inibidores do Citocromo P-450 CYP3A/farmacologia , Carbolinas/farmacocinética , Carbolinas/administração & dosagem , Carbolinas/efeitos adversos , Adulto , Compostos Heterocíclicos com 3 Anéis/farmacocinética , Compostos Heterocíclicos com 3 Anéis/administração & dosagem , Compostos Heterocíclicos com 3 Anéis/efeitos adversos , Área Sob a Curva , Antineoplásicos/farmacocinética , Antineoplásicos/efeitos adversos , Antineoplásicos/administração & dosagemRESUMO
Avacopan, a complement 5a receptor (C5aR) antagonist approved for treating severe active antineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis, was evaluated in 2 clinical drug-drug interaction studies. The studies assessed the impact of avacopan on the pharmacokinetics (PK) of CYP3A4 substrates midazolam and simvastatin and CYP2C9 substrate celecoxib, and the influence of CYP3A4 inhibitor itraconazole and inducer rifampin on the PKs of avacopan. The results indicated that twice-daily oral administration of 30 mg of avacopan increased the area under the curve (AUC) of midazolam by 1.81-fold and celecoxib by 1.15-fold when administered without food, and twice-daily oral administration of 30 or 60 mg of avacopan increased the AUC of simvastatin by approximately 2.6-3.5-fold and the AUC of the active metabolite ß-hydroxy-simvastatin acid by approximately 1.4-1.7-fold when co-administered with food. Furthermore, the AUC of avacopan increased by approximately 2.19-fold when co-administered with itraconazole and decreased by approximately 13.5-fold when co-administered with rifampin. These findings provide critical insights into the potential drug-drug interactions involving avacopan, which could have significant implications for patient care and treatment planning. (NCT06207682).
Assuntos
Citocromo P-450 CYP2C9 , Inibidores do Citocromo P-450 CYP3A , Citocromo P-450 CYP3A , Interações Medicamentosas , Voluntários Saudáveis , Itraconazol , Midazolam , Rifampina , Sinvastatina , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem , Administração Oral , Área Sob a Curva , Citocromo P-450 CYP2C9/metabolismo , Citocromo P-450 CYP3A/metabolismo , Inibidores do Citocromo P-450 CYP3A/farmacologia , Inibidores do Citocromo P-450 CYP3A/administração & dosagem , Inibidores do Citocromo P-450 CYP3A/farmacocinética , Interações Alimento-Droga , Itraconazol/farmacologia , Itraconazol/administração & dosagem , Itraconazol/farmacocinética , Midazolam/farmacocinética , Midazolam/administração & dosagem , Rifampina/farmacologia , Rifampina/administração & dosagem , Rifampina/farmacocinética , Sinvastatina/farmacocinética , Sinvastatina/administração & dosagem , Sinvastatina/efeitos adversosRESUMO
Sotorasib is a small molecule that irreversibly inhibits the Kirsten rat sarcoma viral oncogene homolog (KRAS) protein with a G12C amino acid substitution mutant protein. The impact of cytochrome P450 (CYP) 3A4 inhibition and induction on sotorasib pharmacokinetics (PKs) was evaluated in 2 separate studies in healthy volunteers (N = 14/study). The impact of CYP3A4 inhibition was interrogated utilizing repeat doses of 200 mg of itraconazole, a strong CYP3A4 inhibitor, on 360 mg of sotorasib PKs. The impact of CYP3A4 induction was interrogated utilizing multiple doses of 600 mg of rifampin, a strong CYP3A4 inducer. Additionally, the impact of organic anion transporting polypeptide (OATP) 1B1/3 inhibition on 960 mg of sotorasib PKs was interrogated after a single dose of 600 mg of rifampin. CYP3A4 inhibition did not significantly impact sotorasib Cmax but did lead to a 26% increase in sotorasib AUCinf. CYP3A4 induction decreased sotorasib Cmax by 35% and AUCinf by 51%. OATP1B1/3 inhibition decreased sotorasib Cmax and AUCinf by 16% and 23%, respectively. These results support that sotorasib can be given together with strong CYP3A4 and OATP1B1/3 inhibitors but the co-administration of sotorasib and strong CYP3A4 inducers should be avoided.
Assuntos
Indutores do Citocromo P-450 CYP3A , Inibidores do Citocromo P-450 CYP3A , Citocromo P-450 CYP3A , Interações Medicamentosas , Transportador 1 de Ânion Orgânico Específico do Fígado , Rifampina , Membro 1B3 da Família de Transportadores de Ânion Orgânico Carreador de Soluto , Humanos , Transportador 1 de Ânion Orgânico Específico do Fígado/antagonistas & inibidores , Transportador 1 de Ânion Orgânico Específico do Fígado/metabolismo , Masculino , Membro 1B3 da Família de Transportadores de Ânion Orgânico Carreador de Soluto/antagonistas & inibidores , Membro 1B3 da Família de Transportadores de Ânion Orgânico Carreador de Soluto/metabolismo , Adulto , Inibidores do Citocromo P-450 CYP3A/farmacologia , Inibidores do Citocromo P-450 CYP3A/administração & dosagem , Citocromo P-450 CYP3A/metabolismo , Rifampina/farmacologia , Rifampina/administração & dosagem , Indutores do Citocromo P-450 CYP3A/farmacologia , Feminino , Adulto Jovem , Administração Oral , Pessoa de Meia-Idade , Voluntários Saudáveis , Área Sob a Curva , Itraconazol/farmacologia , Itraconazol/administração & dosagem , Itraconazol/farmacocinética , Compostos de Espiro/farmacocinética , Compostos de Espiro/administração & dosagem , Compostos de Espiro/farmacologiaRESUMO
BACKGROUND: Tirabrutinib is an orally effective, approved, and highly selective second-generation Bruton's tyrosine kinase (BTK) inhibitor for the treatment of recurrent or refractory primary central nervous system lymphoma (PCNSL). OBJECTIVE: This study aimed to develop an ultra-high performance liquid chromatography- tandem mass spectrometry (UPLC-MS/MS) method for the determination of tirabrutinib concentration in rat plasma, where zanubrutinib was used as an internal standard (IS). This method was also applied to study whether tirabrutinib would interact with voriconazole, itraconazole, and fluconazole in rats, providing a reference value for clinical medication guidance. METHODS: In the current study, the organic solvent protein precipitation method was used to treat plasma samples, which is simple and reproducible. Tirabrutinib (m/z 455.32 â 320.21) and zanubrutinib (m/z 472.13 â 455.04) were separated on a Waters Acquity BEH C18 column (2.1 × 50 mm, 1.7 µm) and detected by multiple reaction monitoring (MRM) in positive ionization mode. RESULTS: The method showed good linearity in the range of 5-3000 ng/mL for tirabrutinib with the lower limit of quantification (LLOQ) of 5 ng/mL. The recovery and matrix effects were 85.7-91.0% and 102.0-113.3%, respectively. The accuracy, precision, stability, and carry-over effect were also acceptable. The method could also be used for determining the pharmacokinetic interaction of tirabrutinib in rats. The results showed AUC0â∞ of tirabrutinib to be increased by 139.3% and 83.9% in the presence of voriconazole and fluconazole, respectively, while itraconazole had little effect. CONCLUSION: It is necessary to monitor the concentration of tirabrutinib in patients when it is combined with voriconazole and fluconazole to achieve a better therapeutic effect and reduce the risk of adverse reaction. Further research should be conducted in the future.
Assuntos
Fluconazol , Itraconazol , Pirimidinas , Ratos Sprague-Dawley , Espectrometria de Massas em Tandem , Voriconazol , Animais , Espectrometria de Massas em Tandem/métodos , Voriconazol/farmacocinética , Fluconazol/farmacocinética , Cromatografia Líquida de Alta Pressão/métodos , Pirimidinas/farmacocinética , Pirimidinas/química , Pirimidinas/sangue , Ratos , Itraconazol/farmacocinética , Itraconazol/química , Masculino , Interações Medicamentosas , Imidazóis/farmacocinética , Imidazóis/química , Imidazóis/sangue , Espectrometria de Massa com Cromatografia LíquidaRESUMO
Lumacaftor/ivacaftor (Orkambi®, LUM/IVA) is indicated for the treatment of cystic fibrosis (CF) patients aged ≥ 2 years with homozygous F580del mutation in the CFTR gene. Triazole fungal agents are used to treat fungal disease in CF. The use of triazoles is limited by pharmacokinetic challenges, such as drug-drug interactions. The most notable drug-drug interaction between triazoles and LUM/IVA is due to strong induction of CYP3A4 and UGT by LUM. In this real-world retrospective observational study, we described the effect of LUM/IVA on the trough concentration of triazoles. Concomitant use of LUM/IVA with itraconazole, posaconazole or voriconazole resulted in subtherapeutic triazole levels in 76% of the plasma samples. In comparison, in patients with triazole agents without LUM/IVA only 30.6% of the plasma samples resulted in subtherapeutic concentrations. Subtherapeutic plasma concentrations of triazoles should be considered in CF patients on LUM/IVA and further research is warranted for other dosing strategies and alternative antifungal therapy.
Assuntos
Aminofenóis , Aminopiridinas , Antifúngicos , Benzodioxóis , Fibrose Cística , Combinação de Medicamentos , Interações Medicamentosas , Quinolonas , Triazóis , Humanos , Fibrose Cística/tratamento farmacológico , Fibrose Cística/microbiologia , Quinolonas/farmacocinética , Triazóis/farmacocinética , Triazóis/administração & dosagem , Estudos Retrospectivos , Benzodioxóis/farmacocinética , Masculino , Aminofenóis/farmacocinética , Feminino , Aminopiridinas/farmacocinética , Antifúngicos/farmacocinética , Antifúngicos/administração & dosagem , Criança , Adolescente , Adulto , Agonistas dos Canais de Cloreto/farmacocinética , Voriconazol/farmacocinética , Itraconazol/farmacocinética , Itraconazol/administração & dosagemRESUMO
PURPOSE: Entrectinib (ENT) is a potent c-ros oncogene 1(ROS1) and neurotrophic tyrosine receptor kinase (NTRKA/B/C) inhibitor. To determine the optimum dosage of ENT using ROS1 and NTRKA/B/C occupancy in plasma and cerebrospinal fluid (CSF) in drug-drug interactions (DDIs), physiologically-based pharmacokinetic (PBPK) models for healthy subjects and cancer population were developed for ENT and M5 (active metabolite). METHODS: The PBPK models were built using the modeling parameters of ENT and M5 that were mainly derived from the published paper on the ENT PBPK model, and then validated by the observed pharmacokinetics (PK) in plasma and CSF from healthy subjects and patients. RESULTS: The PBPK model showed that AUC, Cmax, and Ctrough ratios between predictions and observations are within the range of 0.5-2.0, except that the M5 AUC ratio is slightly above 2.0 (2.34). Based on the efficacy (> 75% occupancy for ROS1 and NTRKA/B/C) and safety (AUC < 160 µM·h and Cmax < 8.9 µM), the appropriate dosing regimens were identified. The appropriate dosage is 600 mg once daily (OD) when administered alone, reduced to 200 mg and 400 mg OD with itraconazole and fluconazole, respectively. ENT is not recommended for co-administration with rifampicin or efavirenz, but is permitted with fluvoxamine or dexamethasone. CONCLUSION: The PBPK models can serve as a powerful approach to predict ENT concentration as well as ROS1 and NTRKA/B/C occupancy in plasma and CSF.
Assuntos
Benzamidas , Indazóis , Proteínas Tirosina Quinases , Proteínas Proto-Oncogênicas , Humanos , Interações Medicamentosas , Itraconazol/farmacocinética , Modelos BiológicosRESUMO
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, 54 years). The 8-day study had 3 stages: Participants received a single dose of capivasertib 80 mg in Stage 1, 4 doses of itraconazole 200 mg over 3 days in Stage 2, and a final dose of capivasertib 80 mg coadministered with itraconazole 200 mg 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.
Assuntos
Inibidores do Citocromo P-450 CYP3A , Itraconazol , Humanos , Pessoa de Meia-Idade , Citocromo P-450 CYP3A/metabolismo , Inibidores do Citocromo P-450 CYP3A/farmacologia , Interações Medicamentosas , Voluntários Saudáveis , Itraconazol/farmacocinética , Inibidores de Proteínas Quinases/farmacocinética , Proteínas Proto-Oncogênicas c-akt , Serina , TreoninaRESUMO
Along with the increasing demand for complex formulations comes the need for appropriate in vitro methodologies capable of predicting their corresponding in vivo performance and the mechanisms controlling the drug release which can impact on in vivo drug absorption. In vitro dissolution-permeation (D/P) methodologies that can account for the effects of enabling formulations on the permeability of drugs are increasingly being used in performance ranking during early development stages. This work comprised the application of two different cell-free in vitro D/P setups: BioFLUX™ and PermeaLoop™ to evaluate the dissolution-permeation interplay upon drug release from itraconazole (ITZ)- HPMCAS amorphous solid dispersions (ASDs) of different drug loads. A solvent-shift approach was employed, from a simulated gastric environment to a simulated intestinal environment in the donor compartment. PermeaLoop™ was then combined with microdialysis sampling to separate the dissolved (free) drug from other species present in solution, like micelle-bound drug and drug-rich colloids, in real time. This setup was applied to clarify the mechanisms for drug release and permeation from these ASDs. In parallel, a pharmacokinetic study (dog model) was conducted to assess the drug absorption from these ASDs and to compare the in vivo results with the data obtained from each in vitro D/P setup, allowing to infer which would be the most adequate setup for ASD ranking. Even though both D/P systems resulted in the same qualitative ranking, BioFLUX™ overpredicted the difference between the in vivo AUC of two ASDs, whereas PermeaLoop™ permeation flux resulted in a good correlation with the AUC observed in pharmacokinetic studies (dog model) (R2 ≈ 0.98). Also, PermeaLoop™ combined with a microdialysis sampling probe clarified the mechanisms for drug release and permeation from these ASDs. It demonstrated that the free drug was the only driving force for permeation, while the drug-rich colloids kept permeation active for longer periods by acting as drug reservoirs and maintaining constant high levels of free drug in solution, which are then immediately able to permeate. Hence, the data obtained points BioFLUX™ and PermeaLoop™ applications to different momentums in the drug product development pipeline: while BioFLUX™, an automated standardized method, poses as a valuable tool for initial ASD ranking during the early development stages, PermeaLoop™ combined with microdialysis sampling allows to gain mechanistic understanding of the dissolution-permeation interplay, being crucial to fine tune and identify leading ASD candidates prior to in vivo testing.
Assuntos
Coloides , Itraconazol , Animais , Cães , Solubilidade , Disponibilidade Biológica , Liberação Controlada de Fármacos , Itraconazol/farmacocinéticaRESUMO
Itraconazole is a potent inhibitor of cytochrome P450 3A4 (CYP3A4), associated with numerous drug-drug interactions (DDI). PUR1900, a dry powder formulation of itraconazole for oral inhalation, results in high lung and low systemic exposure. This project used physiologically based pharmacokinetic (PBPK) modeling to assess the DDI potential of inhaled PUR1900, using midazolam as a "victim drug." The basic and mechanistic static models evaluated the DDI potential of PUR1900, assuming 5 mg of midazolam coadministration at steady-state itraconazole exposure. Subsequently, Simcyp® PBPK simulation software and pharmacokinetic data from a Phase 1 clinical trial with PUR1900 (NCT03479411) were used to optimize an existing itraconazole PBPK model. The model was applied to investigate the potential for CYP3A4 DDI when 5 mg of midazolam is co-administered with inhaled PUR1900 at a steady state in a virtual healthy population at PUR1900 doses up to 40 mg per day. The basic static and mechanistic static models suggested a strong likelihood for DDI with inhaled PUR1900. The PBPK model was consistent with PUR1900 Phase 1 trial data. The geometric mean Cmax and AUC ratios of midazolam at a maximum dose of 40 mg PUR1900 were 1.14 and 1.26, respectively, indicating a minimal likelihood of DDI with inhaled PUR1900. The low systemic exposure of itraconazole when administered as PUR1900 results in minimal to no CYP3A4 inhibition, reducing the concern of drug-drug interactions. As the risk of CYP3A4 DDI is predicted to be significantly lower when itraconazole is administered via oral inhalation as PUR1900, it is likely that PUR1900 can be safely used for the treatment of pulmonary fungal infections in patients taking pharmaceuticals currently contraindicated with oral itraconazole.
Assuntos
Itraconazol , Midazolam , Humanos , Itraconazol/farmacocinética , Midazolam/farmacocinética , Modelos Biológicos , Inibidores do Citocromo P-450 CYP3A/farmacocinética , Citocromo P-450 CYP3A , Interações MedicamentosasRESUMO
Abnormal gastric acidity, including achlorhydria, can act as a significant source of variability in orally administered drugs especially with pH-sensitive solubility profiles, such as weak bases, potentially resulting in an undesirable therapeutic response. This study aimed to evaluate the utility of physiologically-based pharmacokinetic (PBPK) modeling in the prediction of gastric pH-mediated drug exposure by using itraconazole, a weak base, as a case. An itraconazole PBPK model was developed on the mechanistic basis of its absorption kinetics in a middle-out manner from a stepwise in vitro-in vivo extrapolation to in vivo refinement. Afterward, an independent prospective clinical study evaluating gastric pH and itraconazole pharmacokinetics (PKs) under normal gastric acidity and esomeprazole-induced gastric hypoacidity was conducted for model validation. Validation was performed by comparing the predicted data with the clinical observations, and the valid model was subsequently applied to predict PK changes under achlorhydria. The developed itraconazole PBPK model showed reasonable reproducibility for gastric pH-mediated exposure observed in the clinical investigation. Based on the model-based simulations, itraconazole exposure was expected to be decreased up to 65% under achlorhydria, and furthermore, gastric pH-mediated exposure could be mechanistically interpreted according to sequential variation in total solubility, dissolution, and absorption. This study suggested the utility of PBPK modeling in the prediction of gastric pH-mediated exposure, especially for drugs whose absorption is susceptible to gastric pH. Our findings will serve as a leading model for further mechanistic assessment of exposure depending on gastric pH for various drugs, ultimately contributing to personalized pharmacotherapy.