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1.
Br J Cancer ; 124(4): 728-735, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33230210

RESUMO

BACKGROUND: This open-label, phase 1 trial (NCT02316197) aimed to determine the maximum-tolerated dose (MTD) and/or recommended phase 2 dose (RP2D) of peposertib (formerly M3814), a DNA-dependent protein kinase (DNA-PK) inhibitor in patients with advanced solid tumours. Secondary/exploratory objectives included safety/tolerability, pharmacokinetic/pharmacodynamic profiles and clinical activity. METHODS: Adult patients with advanced solid tumours received peposertib 100-200 mg once daily or 150-400 mg twice daily (BID) in 21-day cycles. RESULTS: Thirty-one patients were included (median age 66 years, 61% male). One dose-limiting toxicity, consisting of mainly gastrointestinal, non-serious adverse events (AEs) and long recovery duration, was reported at 300 mg BID. The most common peposertib-related AEs were nausea, vomiting, fatigue and pyrexia. The most common peposertib-related Grade 3 AEs were maculopapular rash and nausea. Peposertib was quickly absorbed systemically (median Tmax 1.1-2.5 h). The p-DNA-PK/t-DNA-PK ratio decreased consistently in peripheral blood mononuclear cells 3-6 h after doses ≥100 mg. The best overall response was stable disease (12 patients), lasting for ≥12 weeks in seven patients. CONCLUSIONS: Peposertib was well-tolerated and demonstrated modest efficacy in unselected tumours. The MTD was not reached; the RP2D was declared as 400 mg BID. Further studies, mainly with peposertib/chemo-radiation, are ongoing. CLINICAL TRIAL REGISTRATION: NCT02316197.


Assuntos
Proteína Quinase Ativada por DNA/antagonistas & inibidores , Neoplasias/tratamento farmacológico , Piridazinas/administração & dosagem , Piridazinas/efeitos adversos , Quinazolinas/administração & dosagem , Quinazolinas/efeitos adversos , Adulto , Idoso , Proteína Quinase Ativada por DNA/metabolismo , Relação Dose-Resposta a Droga , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias/metabolismo , Neoplasias/patologia , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/farmacocinética , Piridazinas/farmacocinética , Quinazolinas/farmacocinética
2.
Int J Radiat Oncol Biol Phys ; 118(3): 743-756, 2024 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-37751793

RESUMO

PURPOSE: DNA-dependent protein kinase (DNA-PK) plays a key role in the repair of DNA double strand breaks via nonhomologous end joining. Inhibition of DNA-PK can enhance the effect of DNA double strand break inducing anticancer therapies. Peposertib (formerly "M3814") is an orally administered, potent, and selective small molecule DNA-PK inhibitor that has demonstrated radiosensitizing and antitumor activity in xenograft models and was well-tolerated in monotherapy. This phase 1 trial (National Clinical Trial 02516813) investigated the maximum tolerated dose, recommended phase 2 dose (RP2D), safety, and tolerability of peposertib in combination with palliative radiation therapy (RT) in patients with thoracic or head and neck tumors (arm A) and of peposertib in combination with cisplatin and curative-intent RT in patients with squamous cell carcinoma of the head and neck (arm B). METHODS AND MATERIALS: Patients received peposertib once daily in ascending dose cohorts as a tablet or capsule in combination with palliative RT (arm A) or in combination with intensity modulated curative-intent RT and cisplatin (arm B). RESULTS: The most frequently observed treatment-emergent adverse events were radiation skin injury, fatigue, and nausea in arm A (n = 34) and stomatitis, nausea, radiation skin injury, and dysgeusia in arm B (n = 11). Based on evaluations of dose-limiting toxicities, tolerability, and pharmacokinetic data, RP2D for arm A was declared as 200 mg peposertib tablet once daily in combination with RT. In arm B (n = 11), 50 mg peposertib was declared tolerable in combination with curative-intent RT and cisplatin. However, enrollment was discontinued because of insufficient exposure at that dose, and the RP2D was not formally declared. CONCLUSIONS: Peposertib in combination with palliative RT was well-tolerated up to doses of 200 mg once daily as tablet with each RT fraction. When combined with RT and cisplatin, a tolerable peposertib dose yielded insufficient exposure.


Assuntos
Cisplatino , Neoplasias de Cabeça e Pescoço , Piridazinas , Quinazolinas , Humanos , Cisplatino/efeitos adversos , Inibidores de Proteínas Quinases/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias de Cabeça e Pescoço/radioterapia , Náusea/etiologia , Comprimidos , DNA
3.
Clin Cancer Res ; 30(4): 695-702, 2024 02 16.
Artigo em Inglês | MEDLINE | ID: mdl-38051750

RESUMO

PURPOSE: Peposertib-an orally administered DNA-dependent protein kinase inhibitor-has shown potent radiosensitization in preclinical models. This dose-escalation study (NCT03770689) aimed to define the maximum tolerated dose (MTD) and recommended phase II dose (RP2D) of peposertib plus capecitabine-based chemoradiotherapy (CRT) and assessed its safety and efficacy in locally advanced rectal cancer. PATIENTS AND METHODS: Patients were treated for 5 to 5.5 weeks with 50- to 250-mg peposertib once daily, capecitabine 825 mg/m2 twice daily, and radiotherapy (RT), 5 days per week. Following clinical restaging (8 weeks after CRT completion), patients with clinical complete response (cCR) could opt for surveillance. Total mesorectal excision was recommended upon incomplete response (IR). RESULTS: Nineteen patients were treated with peposertib at doses of 50 mg (n = 1), 100 mg, 150 mg, and 250 mg (n = 6 each). Dose-limiting toxicities occurred in one out of five (100 mg), one out of six (150 mg), and three out of six (250 mg) evaluable patients. Peposertib ≤150 mg once daily was tolerable in combination with CRT. After 8 weeks of treatment with peposertib and CRT, the cCR was 15.8% (n = 3). Among the three patients with cCR, two underwent surgery and had residual tumors. Among the 16 patients with IR, seven underwent surgery and had residual tumors; five of the remaining nine patients opted for consolidative chemotherapy. The combined cCR/pathologic complete response (pCR) rate was 5.3% (n = 1, 100 mg cohort). CONCLUSIONS: Peposertib did not improve complete response rates at tolerable dose levels. The study was closed without declaring the MTD/RP2D.


Assuntos
Terapia Neoadjuvante , Piridazinas , Quinazolinas , Neoplasias Retais , Humanos , Capecitabina , Neoplasia Residual/patologia , Neoplasias Retais/tratamento farmacológico , Neoplasias Retais/patologia , Quimiorradioterapia , DNA , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Resultado do Tratamento , Fluoruracila , Estadiamento de Neoplasias
4.
Eur J Pharm Sci ; 27(2-3): 123-32, 2006 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-16219448

RESUMO

Suc-HSA is a potent HIV-inhibitor with possible application in man. To facilitate the assessment of dosing regimens for future phase I clinical studies, we predicted the pharmacokinetic properties of Suc-HSA in man. Slices prepared from rat, monkey and human liver were incubated with succinylated albumin, and the maximum uptake rate V(m) and Michaelis-Menten constant K(m) were calculated. The pharmacokinetics after multiple doses of Suc-HSA were studied in rats. The pharmacokinetic parameters of Suc-HSA in man were predicted from the results and data from literature, using pharmacokinetic modeling and interspecies scaling techniques, and potential intravenous dose regimens for HIV treatment in man were calculated. On the basis of in vitro uptake studies in rat, monkey and human liver slices and in vivo disposition data in monkey (data from earlier study) and rat, we predicted the following parameters for liver uptake in humans: V(m) 82.5 microg h(-1) kg(-1) and K(m) 0.228 microg ml(-1). The predicted steady-state concentration after daily intravenous bolus doses of 1 mg kg(-1) is between 4 and 30 microg ml(-1), i.e. well above the IC50 of about 0.4 microg ml(-1). Additional loading doses of 8 mg kg(-1) in total are needed to reach steady-state within a few days.


Assuntos
Fígado/metabolismo , Modelos Biológicos , Albumina Sérica/farmacocinética , Animais , Antivirais/administração & dosagem , Antivirais/farmacocinética , Humanos , Técnicas In Vitro , Injeções Intravenosas , Macaca fascicularis , Masculino , Ratos , Ratos Wistar , Reprodutibilidade dos Testes , Albumina Sérica/administração & dosagem
5.
Clin Ther ; 27(9): 1403-10, 2005 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-16291413

RESUMO

BACKGROUND: Solifenacin succinate (YM905; Vesicare, Astellas Pharma Inc., Tokyo, Japan) is a new once-daily, orally administered muscarinic receptor antagonist under investigation for the treatment of overactive bladder. OBJECTIVE: The aim of this study was to evaluate the effect of solifenacin on the pharmacokinetic (PK) parameters of an oral contraceptive (OC) containing ethinyl estradiol (EE) and levonorgestrel (LNG). METHODS: In a double-blind, placebo-controlled, 2-period, crossover study, 24 healthy, young, white women received a combined OC (EE 30 microg + LNG 150 microg) daily for two 21-day cycles, separated by a 7-day washout. On day 12 of each cycle, subjects began a 10-day regimen of solifenacin 10 mg QD, which is 2 times the suggested starting dose, or placebo. Subjects crossed over to the other treatment arm for the second cycle. Primary PK end points were C(max) and AUC from time 0 to 24 hours (AUC(0-24 h)) for EE and LNG. Women ranged in age from 20 to 37 years and had a mean body weight of 64 kg, mean height of 167.4 cm, and mean body mass index of 23 kg/m2. Seven women had never smoked, while 5 were former smokers and 12 were regular smokers. Safety assessments included the nature, frequency, and severity of spontaneously reported or observed adverse events, vital signs, electrocardiogram, laboratory values, and physical examination. RESULTS: Statistical analysis of AUC(0-24 h)/product of baseline concentration and total blood sampling time, and C(max)/baseline concentration ratios of solifenacin versus placebo for EE and LNG found the 90% CI to be within the predefined range of 0.8 to 1.25 (EE: 0.854-1.164 and 0.822-1.167; LNG: 0.920-1.125 and 0.910-1.139). The number of samples with non-quantifiable luteinizing hormone (LH) and folliclestimulating hormone (FSH) levels were comparable after administration of the OC with either solifenacin or placebo. The adverse event most frequently reported was dry mouth (solifenacin, n = 25 [9 mild, 13 moderate, and 3 severe] vs placebo, n = 1 [moderate]). There were no clinically relevant effects on vital signs, electrocardiogram, or laboratory parameters. CONCLUSIONS: A PK interaction between solifenacin and the OC containing EE and LNG was not found in this study. Solifenacin was not found to have altered suppression of LH or FSH. The drug was well tolerated in these healthy, young, white, adult female volunteers.


Assuntos
Anticoncepcionais Orais/farmacocinética , Etinilestradiol/farmacocinética , Levanogestrel/farmacocinética , Antagonistas Muscarínicos/administração & dosagem , Quinuclidinas/administração & dosagem , Tetra-Hidroisoquinolinas/administração & dosagem , Adulto , Área Sob a Curva , Anticoncepcionais Orais/administração & dosagem , Anticoncepcionais Orais/sangue , Estudos Cross-Over , Método Duplo-Cego , Etinilestradiol/administração & dosagem , Etinilestradiol/sangue , Feminino , Hormônio Foliculoestimulante/sangue , Humanos , Levanogestrel/administração & dosagem , Levanogestrel/sangue , Hormônio Luteinizante/sangue , Taxa de Depuração Metabólica , Pessoa de Meia-Idade , Quinuclidinas/sangue , Quinuclidinas/farmacocinética , Succinato de Solifenacina , Tetra-Hidroisoquinolinas/sangue , Tetra-Hidroisoquinolinas/farmacocinética , População Branca
6.
Drugs R D ; 5(2): 73-81, 2004.
Artigo em Inglês | MEDLINE | ID: mdl-15293866

RESUMO

OBJECTIVE: Solifenacin succinate (YM905; Vesicare) is a promising new bladder selective muscarinic receptor antagonist under investigation for the treatment of overactive bladder. This study was designed to assess the absolute bioavailability of a single oral dose of solifenacin 10 mg, which is twice the suggested starting dose. STUDY DESIGN: Single-centre, open-label, randomised, two-period, crossover, single-dose study. METHODS: Solifenacin was administered orally as a 10 mg dose and intravenously as a 5 mg dose. Oral and intravenous (IV) doses were divided by a washout period of > or =14 days. STUDY PARTICIPANTS: The study group consisted of 12 healthy young men, aged 20-45 years, nine of whom completed the study. RESULTS: The pharmacokinetic analysis comprised nine subjects. A single oral dose of solifenacin 10 mg had a high absolute bioavailability of 88.0% (95% confidence interval 75.8, 102.1), low clearance (9.39 L/h [SD 2.68]), and an extensive mean volume of distribution at steady state (599L [SD 86]). Only 7% of solifenacin was excreted intact in the urine. Single oral and IV administration of solifenacin was well tolerated in this study. The most common adverse events related to drug treatment were headache and somnolence. CONCLUSIONS: Pharmacokinetic analyses of single oral and IV doses of solifenacin demonstrated that the drug has a high absolute oral availability of 88%. This finding suggests that solifenacin may have a higher and less variable bioavailability than other antimuscarinic agents.


Assuntos
Antagonistas Muscarínicos/farmacocinética , Quinuclidinas/farmacocinética , Tetra-Hidroisoquinolinas/farmacocinética , Adulto , Disponibilidade Biológica , Estudos Cross-Over , Humanos , Masculino , Taxa de Depuração Metabólica , Pessoa de Meia-Idade , Succinato de Solifenacina
7.
Drug Deliv ; 9(1): 31-8, 2002.
Artigo em Inglês | MEDLINE | ID: mdl-11839206

RESUMO

Lactoferrin (Lf) is a potential drug candidate for the treatment of oropharyngeal Candida infections. However, for an effective therapeutic treatment an appropriate dosage form is required. Therefore a mucoadhesive tablet for buccal application was developed. Tablets of sufficient strength could be produced on high speed tabletting machines, but they could only be obtained when the protein contained at least 7% moisture. The tablet contained sodium alginate both for its release-controlling properties as well as for its mucoadhesive properties. Furthermore, phosphate buffer was added to keep the pH of the saliva in the mouth within the range of 6.5 to 7.5. In this pH range, Lf has shown to have its highest activity against Candida growth inhibition. The tablet formulation containing Lf had the same antifungal properties as compared with Lf alone, because in most cases identical inhibitory concentrations were observed against several clinical isolates of Candida albicans and Candida glabrata. In human volunteers the tablets, containing 250 mg Lf and placed in each pouch, were able to keep the Lf concentration in the saliva at effective levels for at least 2 hr, while the pH of the saliva remained within the desired range. We concluded that the developed mucoadhesive tablet can improve the therapeutic efficacy of Lf and that it is suitable for further clinical research.


Assuntos
Antifúngicos/administração & dosagem , Antifúngicos/farmacologia , Candida/efeitos dos fármacos , Candidíase Bucal/tratamento farmacológico , Lactoferrina/administração & dosagem , Lactoferrina/farmacologia , Adesividade , Administração Bucal , Adulto , Candida/crescimento & desenvolvimento , Candidíase Bucal/microbiologia , Estudos Cross-Over , Preparações de Ação Retardada , Desenho de Fármacos , Feminino , Humanos , Concentração de Íons de Hidrogênio , Masculino , Testes de Sensibilidade Microbiana , Mucosa Bucal , Saliva/química , Comprimidos
8.
J Pharmacol Sci ; 102(4): 405-12, 2006 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-17170513

RESUMO

Determining the pharmacokinetics and safety of solifenacin succinate, a once-daily, oral antimuscarinic agent indicated for treatment of overactive bladder, in subjects with hepatic impairment. In this open-label study, 16 subjects (eight with moderate hepatic impairment [defined as a Child-Pugh score of 7 - 9], eight healthy) received a single oral 10 mg solifenacin dose. Blood and urine were collected for pharmacokinetic assessments. Pharmacokinetic parameters (primary: area under the plasma concentration-time curve from time 0 to infinity [AUC(0-infinity)] and maximum plasma concentration [C(max)]) and safety were evaluated for solifenacin and its metabolites. There were no clinically relevant differences in safety. Moderate hepatic impairment increased AUC(0-infinity) by 60%, and the mean elimination half-life of solifenacin and several of its metabolites was longer versus healthy subjects. Mean C(max) values were comparable between the groups. A single oral dose of solifenacin was well tolerated in hepatically impaired and healthy subjects; however, moderate hepatic impairment influenced solifenacin pharmacokinetics. In patients with mild hepatic impairment, solifenacin may be used without special caution; however, in patients with moderate hepatic impairment, doses greater than 5 mg are not recommended and the 5 mg dose should be used with caution.


Assuntos
Hepatopatias/metabolismo , Antagonistas Muscarínicos/farmacocinética , Quinuclidinas/farmacocinética , Tetra-Hidroisoquinolinas/farmacocinética , Administração Oral , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Área Sob a Curva , Feminino , Seguimentos , Meia-Vida , Humanos , Hepatopatias/patologia , Masculino , Taxa de Depuração Metabólica , Pessoa de Meia-Idade , Antagonistas Muscarínicos/administração & dosagem , Antagonistas Muscarínicos/efeitos adversos , Quinuclidinas/administração & dosagem , Quinuclidinas/efeitos adversos , Índice de Gravidade de Doença , Succinato de Solifenacina , Tetra-Hidroisoquinolinas/administração & dosagem , Tetra-Hidroisoquinolinas/efeitos adversos , Fatores de Tempo
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