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1.
Mol Pharm ; 20(12): 6213-6225, 2023 Dec 04.
Artigo em Inglês | MEDLINE | ID: mdl-37917742

RESUMO

Lenacapavir (LEN) is a picomolar first-in-class capsid inhibitor of human immunodeficiency virus type 1 (HIV-1) with a multistage mechanism of action and no known cross resistance to other existing antiretroviral (ARV) drug classes. LEN exhibits a low aqueous solubility and exceptionally low systemic clearance following intravenous (IV) administration in nonclinical species and humans. LEN formulated in an aqueous suspension or a PEG/water solution formulation showed sustained plasma exposure levels with no unintended rapid drug release following subcutaneous (SC) administration to rats and dogs. A high total fraction dose release was observed with both formulations. The long-acting pharmacokinetics (PK) were recapitulated in humans following SC administration of both formulations. The SC PK profiles displayed two-phase absorption kinetics in both animals and humans with an initial fast-release absorption phase, followed by a slow-release absorption phase. Noncompartmental and compartmental analyses informed the LEN systemic input rate from the SC depot and exit rate from the body. Modeling-enabled deconvolution of the input rates from two processes: absorption of the soluble fraction (minor) from a direct fast-release process leading to the early PK phase and absorption of the precipitated fraction (major) from an indirect slow-release process leading to the later PK phase. LEN SC PK showed flip-flop kinetics due to the input rate being substantially slower than the systemic exit rate. LEN input rates via the slow-release process in humans were slower than those in both rats and dogs. Overall, the combination of high potency, exceptional stability, and optimal release rate from the injection depot make LEN well suited for a parenteral long-acting formulation that can be administered once up to every 6 months in humans for the prevention and treatment of HIV-1.


Assuntos
Fármacos Anti-HIV , HIV-1 , Humanos , Ratos , Animais , Cães , Antirretrovirais , Capsídeo , Fármacos Anti-HIV/farmacologia , Proteínas do Capsídeo
2.
Pharm Res ; 40(7): 1601-1631, 2023 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-36811809

RESUMO

Long-acting injectable (LAI) formulations can provide several advantages over the more traditional oral formulation as drug product opportunities. LAI formulations can achieve sustained drug release for extended periods of time, which results in less frequent dosing requirements leading to higher patient adherence and more optimal therapeutic outcomes. This review article will provide an industry perspective on the development and associated challenges of long-acting injectable formulations. The LAIs described herein include polymer-based formulations, oil-based formulations, and crystalline drug suspensions. The review discusses manufacturing processes, including quality controls, considerations of the Active Pharmaceutical Ingredient (API), biopharmaceutical properties and clinical requirements pertaining to LAI technology selection, and characterization of LAIs through in vitro, in vivo and in silico approaches. Lastly, the article includes a discussion around the current lack of suitable compendial and biorelevant in vitro models for the evaluation of LAIs and its subsequent impact on LAI product development and approval.


Assuntos
Antipsicóticos , Esquizofrenia , Humanos , Antipsicóticos/uso terapêutico , Esquizofrenia/tratamento farmacológico , Preparações de Ação Retardada , Injeções , Liberação Controlada de Fármacos
3.
Future Oncol ; 15(31): 3531-3545, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31516032

RESUMO

Glasdegib, an oral Hedgehog pathway inhibitor, has been associated with significantly improved survival when combined with low-dose cytarabine in patients with untreated acute myeloid leukemia (AML) who were unsuitable for intensive chemotherapy, when compared with low-dose cytarabine alone. BRIGHT AML 1019 (NCT03416179) comprises two independently powered Phase III, randomized (1:1), double-blind global trials evaluating oral glasdegib 100 mg once daily or placebo plus one of two standard chemotherapy regimens in adults with untreated AML. The intensive trial combines glasdegib/placebo with cytarabine and daunorubicin (7 + 3), while the nonintensive trial combines glasdegib/placebo with azacitidine. The primary end point of both studies is overall survival. Secondary end points include response, time to and duration of response, event-free survival, safety, patient-reported outcomes and pharmacokinetics. Trial registration number: ClinicalTrials.gov identifier: NCT03416179.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos Clínicos , Leucemia Mieloide Aguda/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Benzimidazóis/administração & dosagem , Feminino , Humanos , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/etiologia , Masculino , Compostos de Fenilureia/administração & dosagem , Projetos de Pesquisa
4.
Blood ; 119(20): 4597-607, 2012 May 17.
Artigo em Inglês | MEDLINE | ID: mdl-22383795

RESUMO

Mantle cell lymphoma (MCL) carries an unfavorable prognosis and requires new treatment strategies. The associated t(11:14) translocation results in enhanced cyclin D1 expression and cyclin D1-dependent kinase activity to promote cell-cycle progression. A pharmacodynamic study of the selective CDK4/6 inhibitor PD0332991 was conducted in 17 patients with relapsed disease, using 2-deoxy-2-[(18)F]fluoro-D-glucose (FDG) and 3-deoxy-3[(18)F]fluorothymidine (FLT) positron emission tomography (PET) to study tumor metabolism and proliferation, respectively, in concert with pre- and on-treatment lymph node biopsies to assess retinoblastoma protein (Rb) phosphorylation and markers of proliferation and apoptosis. Substantial reductions in the summed FLT-PET maximal standard uptake value (SUV(max)), as well as in Rb phosphorylation and Ki-67 expression, occurred after 3 weeks in most patients, with significant correlations among these end points. Five patients achieved progression-free survival time of > 1 year (range, 14.9-30.1+ months), with 1 complete and 2 partial responses (18% objective response rate; 90% confidence interval, 5%-40%). These patients demonstrated > 70%, > 90%, and ≥ 87.5% reductions in summed FLT SUV(max) and expression of phospho-Rb and Ki67, respectively, parameters necessary but not sufficient for long-term disease control. The results of the present study confirm CDK4/6 inhibition by PD0332991 at a well-tolerated dose and schedule and suggest clinical benefit in a subset of MCL patients. This study is registered at www.clinicaltrials.gov under identifier NCT00420056.


Assuntos
Linfoma de Célula do Manto/tratamento farmacológico , Piperazinas/uso terapêutico , Piridinas/uso terapêutico , Adulto , Idoso , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Feminino , Humanos , Linfoma de Célula do Manto/sangue , Linfoma de Célula do Manto/diagnóstico , Linfoma de Célula do Manto/metabolismo , Masculino , Pessoa de Meia-Idade , Piperazinas/administração & dosagem , Piperazinas/efeitos adversos , Piperazinas/farmacocinética , Prognóstico , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/farmacocinética , Inibidores de Proteínas Quinases/uso terapêutico , Piridinas/administração & dosagem , Piridinas/efeitos adversos , Piridinas/farmacocinética , Especificidade por Substrato , Resultado do Tratamento
5.
J Clin Pharmacol ; 64(1): 80-93, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-37731282

RESUMO

Glasdegib (DAURISMO) is a hedgehog pathway inhibitor approved for the treatment of acute myeloid leukemia (AML). Cytochrome P450 3A4 (CYP3A4) has been identified as a major metabolism and clearance pathway for glasdegib. The role of CYP3A4 in the clearance of glasdegib has been confirmed with clinical drug-drug interaction (DDI) studies following the coadministration of glasdegib with the strong CYP3A4 inhibitor ketoconazole and the strong inducer rifampin. To evaluate potential drug interactions with CYP3A4 modulators, the coadministration of glasdegib with a moderate CYP3A4 inducer, efavirenz, was evaluated using physiologically based pharmacokinetic (PBPK) modeling using the Simcyp simulator. The glasdegib compound file was developed using measured physicochemical properties, data from human intravenous and oral pharmacokinetics, absorption, distribution, metabolism, and excretion studies, and in vitro reaction phenotyping results. The modeling assumptions, model parameters, and assignments of fractional CYP3A4 metabolism were verified using results from clinical pharmacokinetics (PK) and DDI studies with ketoconazole and rifampin. The verified glasdegib and efavirenz compound files, the latter of which was available in the Simcyp simulator, were used to estimate the potential impact of efavirenz on the PK of glasdegib. PBPK modeling predicted a glasdegib area under the concentration-time curve ratio of 0.45 and maximum plasma concentration ratio of 0.75 following coadministration with efavirenz. The PBPK results, in lieu of a formal clinical study, informed the drug label, with the recommendation to double the clinical dose of glasdegib when administered in conjunction with a moderate CYP3A4 inducer, followed by a resumption of the original dose 7 days post-discontinuation.


Assuntos
Indutores do Citocromo P-450 CYP3A , Rifampina , Humanos , Cetoconazol/farmacologia , Citocromo P-450 CYP3A/metabolismo , Proteínas Hedgehog , Inibidores do Citocromo P-450 CYP3A , Interações Medicamentosas , Modelos Biológicos
6.
Clin Pharmacol Ther ; 2024 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-38940465

RESUMO

There is an unmet need for safe and efficacious oral therapies for COVID-19 with low potential for drug-drug interactions. Obeldesivir is an orally administered nucleoside prodrug that has shown antiviral potency in nonclinical studies against SARS-CoV-2 and its circulating variants. Obeldesivir is metabolized to the active nucleoside triphosphate (GS-443902), which acts as an inhibitor of the SARS-CoV-2 RNA-dependent RNA polymerase, thereby inhibiting viral RNA synthesis. Here, we report the safety, tolerability, and pharmacokinetics from a first-in-human, randomized, placebo-controlled, phase I study following oral administration of obeldesivir and a phase I, open-label absorption, distribution, metabolism, and excretion study following oral administration of [14C]-obeldesivir. Overall, obeldesivir was safe and well tolerated at single and multiple doses between 100 and 1,600 mg, with low potential for QT prolongation as assessed by QT-concentration analysis. The exposures to GS-441524 increased dose proportionally in the 100-900-mg dose range. GS-441524 accumulated by 35% after twice-daily and 12% after once-daily dosing for 5 days. Dose-proportional increases in the intracellular concentration of GS-443902 were also observed in peripheral blood mononuclar cells. Plasma exposure of GS-441524 was not significantly altered by food intake. Following oral administration of [14C]-obeldesivir (500 mg; 100 µCi), the mean cumulative [14C]-dose recovery was 90.7% with 58.5% in urine and 32.2% in feces. GS-441524 was the predominant plasma component (90% of 14C-area under the concentration-time curve) and was primarily eliminated via renal excretion. Collectively, data from these studies support selection of the obeldesivir 350 mg twice-daily dosing regimen for further evaluation in phase III studies for COVID-19.

7.
CPT Pharmacometrics Syst Pharmacol ; 12(11): 1619-1625, 2023 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36394153

RESUMO

The optimal dose for targeted oncology therapeutics is often not the maximum tolerated dose. Pharmacokinetic/pharmacodynamic (PK/PD) modeling can be an effective tool to integrate clinical data to help identify the optimal dose. This case study shows the utility of population PK/PD modeling in selecting the recommended dose for expansion (RDE) for the first-in-patient (FIP) study of PF-06939999, a small-molecule inhibitor of protein arginine methyltransferase 5. In the dose escalation part of the FIP trial (NCT03854227), 28 patients with solid tumors were administered PF-06939999 at 0.5 mg, 4 mg, 6 mg, or 8 mg once daily (q.d.) or 0.5 mg, 1 mg, 2 mg, 4 mg, or 6 mg twice daily (b.i.d.). Tolerability, safety, PK, PD biomarkers (plasma symmetrical dimethyl-arginine [SDMA]), and antitumor response were assessed. Semimechanistic population PK/PD modeling analyses were performed to characterize the time-courses of plasma PF-06939999 concentrations, plasma SDMA, and platelet counts collected from 28 patients. Platelet counts were evaluated because thrombocytopenia was the treatment-related adverse event with clinical safety concern. The models adequately described the PK, SDMA, and platelet count profiles both at individual and population levels. Simulations suggested that among a range of dose levels, 6 mg q.d. would yield the optimal balance between achieving the PD target (i.e., 78% reduction in plasma SDMA) and staying below an acceptable probability of developing grade ≥3 thrombocytopenia. As a result, 6 mg q.d. was selected as the RDE. The model-informed drug development approach informed the rational dose selection for the early clinical development of PF-06939999.


Assuntos
Neoplasias , Trombocitopenia , Humanos , Biomarcadores , Inibidores Enzimáticos , Neoplasias/tratamento farmacológico , Contagem de Plaquetas , Proteína-Arginina N-Metiltransferases , Trombocitopenia/induzido quimicamente
8.
Leukemia ; 37(10): 2017-2026, 2023 10.
Artigo em Inglês | MEDLINE | ID: mdl-37604981

RESUMO

This is the primary report of the randomized, placebo-controlled phase 3 BRIGHT AML 1019 clinical trial of glasdegib in combination with intensive chemotherapy (cytarabine and daunorubicin) or non-intensive chemotherapy (azacitidine) in patients with untreated acute myeloid leukemia. Overall survival (primary endpoint) was similar between the glasdegib and placebo arms in the intensive (n = 404; hazard ratio [HR] 1.05; 95% confidence interval [CI]: 0.782-1.408; two-sided p = 0.749) and non-intensive (n = 325; HR 0.99; 95% CI: 0.768-1.289; two-sided p = 0.969) studies. The proportion of patients who experienced treatment-emergent adverse events was similar for glasdegib versus placebo (intensive: 99.0% vs. 98.5%; non-intensive: 99.4% vs. 98.8%). The most common treatment-emergent adverse events were nausea, febrile neutropenia, and anemia in the intensive study and anemia, constipation, and nausea in the non-intensive study. The addition of glasdegib to either cytarabine and daunorubicin or azacitidine did not significantly improve overall survival and the primary efficacy endpoint for the BRIGHT AML 1019 phase 3 trial was not met. Clinical trial registration: ClinicalTrials.gov: NCT03416179.


Assuntos
Anemia , Leucemia Mieloide Aguda , Humanos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Daunorrubicina , Citarabina , Azacitidina/uso terapêutico , Anemia/tratamento farmacológico , Náusea/tratamento farmacológico
9.
Curr Opin HIV AIDS ; 17(1): 15-21, 2022 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-34871187

RESUMO

PURPOSE OF REVIEW: This review summarizes available data for lenacapavir, an investigational first-in-class agent that disrupts functioning of HIV capsid protein across multiple steps in the viral life cycle. RECENT FINDINGS: Lenacapavir demonstrated picomolar potency in vitro with no cross resistance to existing antiretroviral classes and potent antiviral activity in persons with HIV-1. In persons with HIV-1, there was no preexisting resistance to lenacapavir regardless of treatment history. Lenacapavir can be administered orally either daily or weekly and subcutaneously up to every 6 months. In heavily treatment-experienced persons with multidrug-resistant HIV-1 and in treatment-naive persons with HIV-1, lenacapavir in combination with other antiretroviral agents led to high rates of virologic suppression and was well tolerated. SUMMARY: Ongoing studies are evaluating long-acting dosing of lenacapavir for treating HIV-1 in combination with other antiretrovirals and preventing HIV-1 as a single agent.


Assuntos
Fármacos Anti-HIV , Infecções por HIV , HIV-1 , Fármacos Anti-HIV/farmacologia , Fármacos Anti-HIV/uso terapêutico , Capsídeo , Proteínas do Capsídeo , Farmacorresistência Viral , Infecções por HIV/tratamento farmacológico , Humanos
10.
Cancer Chemother Pharmacol ; 87(2): 241-250, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33388951

RESUMO

PURPOSE: Glasdegib is being developed for indications in myeloid malignancies. The effect of renal impairment on the pharmacokinetics (PK) of a single, oral, 100-mg glasdegib dose under fasted conditions was assessed. METHODS: Open-label, parallel-group study (NCT03596567). Participants of good general health were selected and categorized, based on their estimated glomerular filtration rate, into normal (≥ 90 mL/min), moderate (≥ 30 to < 60 mL/min), or severe (< 30 mL/min) renal impairment groups. Blood samples were collected up to 120 h post-dose. PK exposure parameters were calculated using non-compartmental analysis. RESULTS: All 18 participants completed the study. Respectively, ratios of adjusted geometric means (90% confidence interval) for glasdegib area under the curve from time 0 to infinity and peak plasma concentration versus normal participants were 205% (142-295%) and 137% (97-193%) in the moderate group, and 202% (146-281%) and 120% (77-188%) in the severe group. Glasdegib median time to peak plasma concentration was 2.0 h in both impairment groups and 1.5 h in the normal group. Mean oral clearance was decreased by approximately 50% in both renal impairment groups compared with the normal group. The plasma-free fraction of glasdegib was not altered by renal impairment. Five all-causality adverse events were reported in three participants; two were considered treatment-related. CONCLUSION: The similar changes in exposure observed for participants with renal impairment, coupled with the known safety data from clinical experience, suggest that a lower starting dose of glasdegib may not be required for moderate or severe renal impairment. TRIAL REGISTRATION: ClinicalTrials.gov: NCT03596567 (started May 17, 2018).


Assuntos
Antineoplásicos/farmacocinética , Benzimidazóis/farmacocinética , Compostos de Fenilureia/farmacocinética , Insuficiência Renal/fisiopatologia , Administração Oral , Idoso , Antineoplásicos/efeitos adversos , Área Sob a Curva , Benzimidazóis/efeitos adversos , Feminino , Taxa de Filtração Glomerular , Humanos , Masculino , Pessoa de Meia-Idade , Compostos de Fenilureia/efeitos adversos , Índice de Gravidade de Doença
11.
Clin Pharmacol Drug Dev ; 10(7): 707-717, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33356019

RESUMO

This phase I open-label trial (NCT03627754) assessed glasdegib pharmacokinetics and safety in otherwise healthy participants with moderate (Child-Pugh B) or severe (Child-Pugh C) hepatic impairment. Participants with hepatic impairment and age/weight-matched controls with normal hepatic function received a single oral 100-mg glasdegib dose under fasted conditions. The primary end points were area under the plasma concentration-time curve from time zero to infinity (AUCinf ) and maximum plasma concentration (Cmax ). Twenty-four participants (8/cohort) were enrolled. Glasdegib plasma exposures in moderate hepatic impairment were similar to controls, with adjusted geometric mean ratios (GMRs) of 110.8% (90% confidence interval [CI], 78.0-157.3) for AUCinf and 94.8% (69.9-128.4) for Cmax versus controls. In severe hepatic impairment, glasdegib plasma exposures were lower than controls (AUCinf GMR, 75.7%; 90%CI, 51.5-111.0; Cmax GMR, 58.0%; 90%CI, 37.8-89.0). Unbound glasdegib exposures were similar to controls for moderate (AUCinf,u GMR, 118.1%; 90%CI, 88.7-157.2; Cmax,u GMR, 101.1%; 90%CI, 78.4-130.3) and severe hepatic impairment (AUCinf,u GMR, 116.3%; 90%CI 81.8-165.5; Cmax,u GMR, 89.2%, 90%CI, 60.2-132.3). No treatment-related adverse events or clinically significant changes in laboratory values, vital signs, or electrocardiograms were observed. Together with previous findings, this suggests glasdegib dose modifications are not required based on hepatic impairment.


Assuntos
Antineoplásicos/farmacocinética , Benzimidazóis/farmacocinética , Hepatopatias/fisiopatologia , Compostos de Fenilureia/farmacocinética , Idoso , Antineoplásicos/efeitos adversos , Área Sob a Curva , Benzimidazóis/efeitos adversos , Estudos de Casos e Controles , Jejum , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Compostos de Fenilureia/efeitos adversos , Índice de Gravidade de Doença
12.
Expert Rev Clin Pharmacol ; 14(7): 927-935, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33993815

RESUMO

PURPOSE: To characterize the effect of glasdegib on cardiac repolarization (QTc) in patients with advanced cancer. METHODS: A concentration-QTc model was developed using data from two glasdegib single-agent, dose-escalation trials. Triplicate electrocardiogram was performed at pre-specified timepoints paired with pharmacokinetic blood collections after a single dose and at steady-state. Changes in QTc from baseline were predicted by model-based simulations at the clinical dose (100 mg QD) and in a supratherapeutic setting. RESULTS: Glasdegib did not affect the heart rate, but had a positive effect on the corrected QT interval, described by a linear mixed-effects model with ΔQTcF (QTc using Fridericia's formula) as the dependent variable with glasdegib plasma concentrations from doses of 5-640 mg QD. The predicted mean QTcF change (upper bound of the 95% CI) was 5.30 (6.24) msec for the therapeutic 100-mg QD dose; at supratherapeutic concentrations (40% and 100% increase over the therapeutic Cmax), it was 7.42 (8.74) and 12.09 (14.25) msec, respectively. CONCLUSIONS: The relationship of glasdegib exposure and QTc was well characterized by the model. The effect of glasdegib on the QTc interval did not cross the threshold of clinical concern for an oncology drug. TRIAL REGISTRATION: ClinicalTrials.gov ID: NCT01286467 and NCT00953758.


Assuntos
Antineoplásicos/administração & dosagem , Benzimidazóis/administração & dosagem , Eletrocardiografia , Neoplasias/tratamento farmacológico , Compostos de Fenilureia/administração & dosagem , Antineoplásicos/efeitos adversos , Benzimidazóis/efeitos adversos , Ensaios Clínicos Fase I como Assunto , Simulação por Computador , Relação Dose-Resposta a Droga , Frequência Cardíaca/efeitos dos fármacos , Humanos , Compostos de Fenilureia/efeitos adversos
13.
J Clin Pharmacol ; 61(3): 349-359, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-32974950

RESUMO

Glasdegib is approved for treating acute myeloid leukemia in elderly patients at 100 mg once daily in combination with low-dose cytarabine. Exposure-efficacy analysis showed that the survival benefit of glasdegib was not glasdegib exposure-dependent. The relationship between glasdegib exposure and adverse event (AE) cluster terms of clinical concern was explored in this analysis. The incidence and severity of dysgeusia, muscle spasms, renal toxicity, and QT interval prolonged was modeled using ordinal logistic regression. AEs were graded using the National Cancer Institute Common Terminology Criteria for Adverse Events (version 4.03). Estimated pharmacokinetic parameters were used to derive glasdegib exposure metrics. Demographic characteristics, disease factors, and other variables of interest as potential moderators of safety signals were evaluated. Clinical trial data from patients who received single-agent glasdegib (N = 70; 5-640 mg once daily); or glasdegib (N = 202, 100-200 mg once daily) with low-dose cytarabine, decitabine, or daunorubicin and cytarabine were analyzed. Glasdegib exposure was statistically significantly associated with the cluster term safety end points dysgeusia, muscle spasms, renal toxicity, and QT interval prolonged. The impact of age on muscle spasms and baseline body weight and creatinine clearance on renal toxicity helped explain the AE grade distribution. At the 100 mg once daily clinical dose, the predicted probabilities of the highest AE grade were 11.3%, 6.7%, 7.7%, and 2.5% for dysgeusia, muscle spasms, renal toxicity, and QT interval prolonged, respectively. Overall, the predicted probability of developing an AE of any severity for these safety end points was low. Therefore, no starting dose adjustments are recommended for glasdegib based on the observed safety profile.


Assuntos
Antineoplásicos/administração & dosagem , Benzimidazóis/administração & dosagem , Modelos Biológicos , Neoplasias/tratamento farmacológico , Compostos de Fenilureia/administração & dosagem , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Benzimidazóis/efeitos adversos , Benzimidazóis/farmacocinética , Relação Dose-Resposta a Droga , Feminino , Neoplasias Hematológicas/tratamento farmacológico , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Compostos de Fenilureia/efeitos adversos , Compostos de Fenilureia/farmacocinética , Ensaios Clínicos Controlados Aleatórios como Assunto , Índice de Gravidade de Doença , Taxa de Sobrevida
14.
Clin Pharmacol Drug Dev ; 10(3): 272-282, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-32790066

RESUMO

Glasdegib is a potent, selective oral inhibitor of the Hedgehog signaling pathway. This phase 1 double-blind thorough QT study (NCT03162900) evaluated the effects of glasdegib on QTc interval. The study enrolled 36 healthy volunteers to receive a single dose of 150 mg glasdegib (representing a therapeutic dose), 300 mg glasdegib (representing a supratherapeutic dose), 400 mg moxifloxacin (positive control), or placebo under fasted conditions. The study demonstrated that therapeutic and supratherapeutic doses of glasdegib had no significant effect on QTc interval; the upper bound of the 2-sided 90% confidence intervals (CIs) for all time-matched least-squares mean differences in QT interval corrected using Fridericia's formula (QTcF) between glasdegib and placebo was below the prespecified criterion of 20 milliseconds (Food and Drug Administration correspondence reviewed and accepted). Based on an exposure-response analysis, glasdegib was determined not to have a meaningful effect on heart rate (change in RR interval). The mean (90%CI) model-derived baseline and placebo-adjusted QTcF at the average maximum observed concentration values corresponding to therapeutic and supratherapeutic glasdegib doses was 7.3 milliseconds (6.5-8.2 milliseconds) and 13.7 milliseconds (12.0-15.5 milliseconds), respectively. Together these results demonstrated that following therapeutic and supratherapeutic glasdegib dosing, the change in QTc from baseline was well below the 20-millisecond threshold of clinical concern in oncology.


Assuntos
Benzimidazóis/farmacocinética , Coração/efeitos dos fármacos , Proteínas Hedgehog/antagonistas & inibidores , Compostos de Fenilureia/farmacocinética , Receptor Smoothened/antagonistas & inibidores , Adulto , Benzimidazóis/farmacologia , Estudos de Casos e Controles , Estudos Cross-Over , Relação Dose-Resposta a Droga , Método Duplo-Cego , Eletrocardiografia/efeitos dos fármacos , Eletrocardiografia/métodos , Jejum , Voluntários Saudáveis/estatística & dados numéricos , Coração/fisiologia , Humanos , Masculino , Pessoa de Meia-Idade , Moxifloxacina/administração & dosagem , Compostos de Fenilureia/farmacologia , Placebos/administração & dosagem , Inibidores da Topoisomerase II/administração & dosagem
15.
Cancer Chemother Pharmacol ; 86(4): 451-459, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32885274

RESUMO

PURPOSE: Glasdegib, an oral inhibitor of the Hedgehog signaling pathway, is approved in the United States in combination with low-dose cytarabine (LDAC) to treat patients with newly diagnosed acute myeloid leukemia (AML) ineligible to receive intensive chemotherapy. This population pharmacokinetic/pharmacodynamic analysis characterized the time course of survival with glasdegib + LDAC relative to LDAC alone, and explored whether the differences in glasdegib exposure at the clinical dose of 100 mg once daily (QD) significantly affected overall survival (OS). METHODS: Data from the BRIGHT AML 1003 trial in patients with AML were included in treatment-response (glasdegib + LDAC, n = 78; LDAC alone, n = 38) and exposure-response (glasdegib + LDAC, n = 75) analyses. RESULTS: The analyses demonstrate that patients treated with glasdegib + LDAC (vs LDAC alone) at any time point during the study period were 58% less likely to die, translating to prolonging of median OS by ~ 5 months (hazard ratio 0.42 [95% confidence interval 0.28-0.66]). Variability in glasdegib exposures did not impact the risk of death. Additionally, potential covariates such as patient demographics, prior treatment with a hypomethylating agent, baseline safety laboratory values, and disease characteristics, did not impact the probability of OS. CONCLUSION: Together these results confirm that glasdegib + LDAC treatment (vs. LDAC alone) is associated with a significant survival benefit in patients with newly diagnosed AML, and that variability in glasdegib doses (e.g., for dose reductions) and exposures do not compromise the survival benefit of glasdegib 100 mg QD. CLINICAL TRIAL NUMBER: NCT01546038.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Benzimidazóis/administração & dosagem , Citarabina/administração & dosagem , Leucemia Mieloide Aguda/tratamento farmacológico , Compostos de Fenilureia/administração & dosagem , Administração Oral , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Área Sob a Curva , Benzimidazóis/farmacocinética , Citarabina/farmacocinética , Relação Dose-Resposta a Droga , Esquema de Medicação , Proteínas Hedgehog/antagonistas & inibidores , Proteínas Hedgehog/metabolismo , Humanos , Estimativa de Kaplan-Meier , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/mortalidade , Masculino , Pessoa de Meia-Idade , Compostos de Fenilureia/farmacocinética , Fatores de Tempo , Resultado do Tratamento , Estados Unidos
16.
J Clin Pharmacol ; 60(5): 605-616, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-31769065

RESUMO

Glasdegib is an inhibitor of the Hedgehog pathway recently approved in the United States for the treatment of acute myeloid leukemia. A population pharmacokinetic analysis was conducted to characterize the kinetic behavior of glasdegib and its sources of variability (covariates) by utilizing data from 269 patients with cancer treated with oral glasdegib doses ranging from 5 to 640 mg/d. Nonlinear mixed-effects modeling was conducted using NONMEM (v.7.3) and Perl-speaks NONMEM (v.4.2.0). The estimated apparent total clearance, apparent central volume of distribution, and apparent peripheral volume of distribution were 6.27 L/h, 3.32 L, and 279.2 L, respectively. Age, sex, race, and hepatic function were not significant covariates on glasdegib pharmacokinetic parameters. Baseline body weight, percentage bone marrow blasts, creatinine clearance, and use of moderate or strong cytochrome P450 3A inhibitors were statistically significant covariates on apparent total clearance; however, the magnitude of the effects was not considered clinically meaningful.

17.
J Pharmacol Exp Ther ; 330(3): 956-63, 2009 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-19491323

RESUMO

The novel tyrosine kinase inhibitor dasatinib (Sprycel; BMS-354825) is approved for use in imatinib (Gleevec; STI 571)-resistant or -intolerant chronic myelogenous leukemia and may be useful for other tumors in the central nervous system (CNS). The objective of this study was to investigate the role of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) in modulating the CNS penetration of dasatinib. Results from the in vitro studies indicate that cellular delivery of dasatinib is significantly limited by active efflux due to both P-gp and BCRP. Permeability studies indicated greater permeability in the basolateral-to-apical direction than in the apical-to-basolateral direction due to active efflux by P-gp or BCRP. Selective inhibitors of P-gp and BCRP, such as (R)-4-((1aR,6R,10bS)-1,2-difluoro-1,1a,6,10b-tetrahydrodibenzo-(a,e)cyclopropa(c) cycloheptan-6-yl)-alpha-((5-quinoloyloxy)methyl)-1-piperazineethanol, trihydrochloride (zosuquidar; LY335979) and 3-(6-isobutyl-9-methoxy-1,4-dioxo-1,2,3,4,6,7,12,12alpha-octahydropyrazino1',2': 1,6pryrido3,4-bindol-3-yl)-propionic acid tert-butyl ester (Ko143), were able to restore the intracellular accumulation and abolish the directionality in net flux of dasatinib. In vivo brain distribution studies showed that the CNS distribution of dasatinib is limited, with the brain-to-plasma concentration ratios less than 0.12 in wild-type mice, which increased approximately 8-fold in Mdr1a/b(-/-) Bcrp1(-/-) mice. Dasatinib brain distribution was significantly increased in Mdr1a/b(-/-) mice and when wild-type mice were pretreated with LY335979. Simultaneous inhibition of P-gp and BCRP by elacridar [N-(4-[2-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-isoquinolinyl)ethyl]-phenyl)-9,10-dihydro-5-methoxy-9-oxo-4-acridine carboxamide] (GF120918) resulted in a 5-fold increase in brain concentration. These in vitro and in vivo studies demonstrate that dasatinib is a substrate for the important efflux transporters p-glycoprotein and BCRP. These transport systems play a significant role in limiting the CNS delivery of dasatinib and may have direct implications in the treatment of primary and metastatic brain tumors.


Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Transportadores de Cassetes de Ligação de ATP/metabolismo , Encéfalo/metabolismo , Inibidores de Proteínas Quinases/farmacocinética , Pirimidinas/farmacocinética , Tiazóis/farmacocinética , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/antagonistas & inibidores , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP , Transportadores de Cassetes de Ligação de ATP/genética , Acridinas/farmacocinética , Animais , Antineoplásicos Fitogênicos/farmacocinética , Barreira Hematoencefálica , Linhagem Celular , Permeabilidade da Membrana Celular , Dasatinibe , Dibenzocicloeptenos/farmacologia , Cães , Resistencia a Medicamentos Antineoplásicos , Indicadores e Reagentes , Espectrometria de Massas , Camundongos , Camundongos Knockout , Neurônios/metabolismo , Quinolinas/farmacologia , Tetra-Hidroisoquinolinas/farmacocinética , Vimblastina/farmacocinética
18.
Drug Metab Dispos ; 37(3): 560-70, 2009 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-19056916

RESUMO

In vitro assays are frequently used for the screening of substrates and inhibitors of transporter-mediated efflux. Examining directional flux across Madin-Darby canine kidney (MDCK) II cell monolayers that overexpress a transporter protein is particularly useful in identifying whether or not a candidate compound is an inhibitor or substrate for that transport system. Studies that use a single substrate or inhibitor in competition assays can be challenging to interpret because of the possible multiple mechanisms involved in substrate/inhibitor-protein interactions. During our previous studies of substrate-inhibitor-transporter interactions, we observed differences in breast cancer resistance protein (BCRP) inhibition, depending on the substrate and the inhibitor. Therefore, we investigated BCRP-mediated interactions with a 4 x 4 matrix of substrates and inhibitors using monolayers formed from MDCKII cells transfected with murine BCRP (Bcrp1/Abcg2). The selective BCRP inhibitor 3-(6-isobutyl-9-methoxy-1,4-dioxo-1,2,3,4,6,7,12,12a-octahydropyrazino [1',2':1,6] pyrido [3,4-b]indol-3-yl)-propionic acid tert-butyl ester (Ko143) effectively inhibited the Bcrp1-mediated transport of all substrates examined. However, N-(4-[2-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-isoquinolinyl)ethyl]-phenyl)-9,10-dihydro-5-methoxy-9-oxo-4-acridine carboxamide (GF120918), nelfinavir, and Pluronic P85 exhibited differences in inhibition depending on the substrate examined. Our findings support recent reports suggesting that the interactions of substrate molecules with BCRP involve multiple binding regions in the protein. The nucleoside substrates zidovudine and abacavir seem to bind to a region on BCRP that may have little or no overlap with the binding regions of either prazosin or imatinib. In conclusion, the choice of substrate or inhibitor molecules for an in vitro assay system can be crucial for the optimal design of experiments to evaluate transporter-mediated drug-drug interactions.


Assuntos
Adenosina/análogos & derivados , Proteínas de Neoplasias/metabolismo , Acridinas/farmacologia , Adenosina/farmacologia , Animais , Sítios de Ligação , Linhagem Celular , Dicetopiperazinas , Cães , Compostos Heterocíclicos de 4 ou mais Anéis , Nelfinavir/farmacologia , Proteínas de Neoplasias/antagonistas & inibidores , Poloxâmero/farmacologia , Ligação Proteica , Tetra-Hidroisoquinolinas/farmacologia
19.
Clin Pharmacol Drug Dev ; 8(7): 895-902, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-30977980

RESUMO

Glasdegib (PF-04449913) is an oral small-molecule inhibitor of the Hedgehog signaling pathway under development for treating myeloid malignancies. This was an open-label phase 1, randomized, 2-sequence, 2-treatment, 2-period, crossover study evaluating the absolute bioavailability of glasdegib in healthy volunteers under fasting condition (NCT03270878). In period 1, 12 eligible subjects received either a single oral dose of glasdegib 100 mg (tablet) or a single intravenous (IV) dose of glasdegib 50 mg. Following ≥6-day washout, subjects received the treatment that they did not receive in the first period. Blood samples were collected for up to 96 hours after dosing. Drug plasma concentrations were determined by high-performance liquid chromatography-tandem mass spectrometry. Glasdegib pharmacokinetic parameters were calculated using noncompartmental analysis. The mean terminal half-life was 14.3 hours for oral tablet treatment vs 13.8 hours for glasdegib IV treatment. The absolute oral bioavailability measured as the ratios (oral/IV) of adjusted geometric mean (90% confidence interval) of dose normalized area under the plasma concentration-time curve was 77.12% (71.83%-82.81%). Two adverse events (1 mild and 1 moderate in severity) were reported by 2 subjects following oral tablet administration; these were fully resolved by the end of the study.


Assuntos
Benzimidazóis/farmacocinética , Jejum/sangue , Compostos de Fenilureia/farmacocinética , Receptor Smoothened/antagonistas & inibidores , Administração Intravenosa , Administração Oral , Adulto , Benzimidazóis/administração & dosagem , Benzimidazóis/efeitos adversos , Disponibilidade Biológica , Estudos Cross-Over , Feminino , Meia-Vida , Voluntários Saudáveis , Humanos , Masculino , Pessoa de Meia-Idade , Compostos de Fenilureia/administração & dosagem , Compostos de Fenilureia/efeitos adversos , Comprimidos/farmacocinética
20.
Cancer Chemother Pharmacol ; 83(3): 463-472, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30536154

RESUMO

PURPOSE: To demonstrate the bioequivalence of the planned maleate salt-based commercial glasdegib tablet formulation [International Council for Harmonization (ICH) glasdegib] to the clinical di-hydrochloride (di-HCl) salt-based glasdegib formulation (di-HCl glasdegib). Additionally, to estimate the effects of a high-fat, high-calorie meal and proton-pump inhibitor (PPI) on the pharmacokinetics of ICH glasdegib. METHODS: This Phase I open-label study (ClinicalTrials.gov: NCT03130556) enrolled 24 healthy subjects to receive two different tablet formulations of single-dose 100-mg glasdegib under fasted conditions. A subset of healthy volunteers (n = 12) received single-dose 100-mg ICH glasdegib following a high-fat, high-calorie meal or concurrently with a PPI (rabeprazole). RESULTS: The adjusted geometric mean ratio (ICH glasdegib:di-HCl glasdegib) and 90% confidence intervals (CI) of area under the plasma concentration-time curve from time zero to infinity (AUCinf) and maximum plasma concentration (Cmax) were 104.0% (99.7‒108.5%) and 101.6% (96.1‒107.4%), respectively, within the acceptance range for bioequivalence (80‒125%). The adjusted geometric mean ratio (90% CIs) for AUCinf and Cmax under fed conditions were 84.3% (78.6‒90.6%) and 69.0% (61.8‒77.0%), respectively, relative to fasted conditions. When ICH glasdegib was administered concurrently with the PPI, the adjusted geometric mean ratio (90% CI) of AUCinf and Cmax were 100.6% (93.2‒108.6%) and 80.5% (70.7‒91.6%), respectively, relative to fasted conditions. Glasdegib was generally well tolerated under all conditions studied. CONCLUSIONS: The ICH glasdegib tablet formulation was bioequivalent to the clinical di-HCl formulation under fasted conditions. A high-fat, high-calorie meal or concurrent PPI treatment had a minimal effect on glasdegib exposure, and was not considered clinically meaningful.


Assuntos
Benzimidazóis/farmacocinética , Dieta Hiperlipídica , Interações Alimento-Droga , Compostos de Fenilureia/farmacocinética , Inibidores da Bomba de Prótons/farmacocinética , Administração Oral , Adolescente , Adulto , Área Sob a Curva , Benzimidazóis/administração & dosagem , Interações Medicamentosas , Jejum , Feminino , Voluntários Saudáveis , Humanos , Masculino , Pessoa de Meia-Idade , Compostos de Fenilureia/administração & dosagem , Inibidores da Bomba de Prótons/administração & dosagem , Comprimidos , Equivalência Terapêutica , Adulto Jovem
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