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1.
Br J Clin Pharmacol ; 88(6): 2899-2908, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35001412

RESUMO

AIMS: Soticlestat, a first-in-class inhibitor of cholesterol 24-hydroxylase (also known as cytochrome P450 46A1), is currently in development for the treatment of developmental and epileptic encephalopathies. Here, we report safety, tolerability, pharmacokinetic and pharmacodynamic outcomes from a phase I, randomized, double-blind, placebo-controlled, multiple-rising-dose study of soticlestat in healthy adults. METHODS: Five cohorts of healthy subjects (n = 8 each, randomized 6:2 soticlestat:placebo) received oral soticlestat 100-600 mg once daily (QD) or 300 mg twice daily (BID) for 10-14 days. Serial blood and urine samples were obtained on days 1, 7 (blood only) and 14. RESULTS: Soticlestat in the dose range 100-400 mg/day for up to 14 days was generally well tolerated. In total, 45 treatment-emergent adverse events (TEAEs) were reported; most (91%) were transient and mild in intensity. Two subjects experienced TEAEs leading to discontinuation: one receiving soticlestat 600 mg QD reported a severe event of acute psychosis; another receiving 300 mg BID reported a mild event of confusional state. Steady-state exposure to soticlestat increased in a slightly greater than dose-proportional manner across the dose range 100-400 mg QD. Peak plasma concentrations were reached within 0.33-0.5 hour, and soticlestat elimination half-life was approximately 4 hours. Renal excretion of soticlestat was negligible. Soticlestat 100-400 mg QD reduced 24S-hydroxycholesterol levels by 46.8 (coefficient of variation [CV%] -9.2) to -62.7% (CV% -7.3) at steady state; values of enzymatic inhibition were compatible with antiepileptic effects observed in preclinical models. CONCLUSION: The pharmacokinetic and pharmacodynamic profiles of soticlestat characterized here provided a data-driven rationale for clinical trial dose selection.


Assuntos
Piperidinas , Piridinas , Adulto , Relação Dose-Resposta a Droga , Método Duplo-Cego , Voluntários Saudáveis , Humanos
2.
Invest New Drugs ; 39(2): 488-498, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33089874

RESUMO

Pevonedistat (TAK-924/MLN4924) is an investigational small-molecule inhibitor of the NEDD8-activating enzyme that has demonstrated preclinical and clinical activity across solid tumors and hematological malignancies. Here we report the results of a phase I trial characterizing the mass balance, pharmacokinetics, and clearance pathways of [14C]-pevonedistat in patients with advanced solid tumors (NCT03057366). In part A (n = 8), patients received a single 1-h intravenous infusion of [14C]-pevonedistat 25 mg/m2. In part B (n = 7), patients received pevonedistat 25 or 20 mg/m2 on days 1, 3, and 5 in combination with, respectively, docetaxel 75 mg/m2 or carboplatin AUC5 plus paclitaxel 175 mg/m2 on day 1 every 3 weeks. Following the single dose of [14C]-pevonedistat 25 mg/m2 in part A, there was a parallel log-linear decline in plasma and whole blood pevonedistat concentration, with systemic exposure of unchanged pevonedistat representing 41% of drug-related material (i.e., unchanged pevonedistat and its metabolites). The mean terminal half-life of pevonedistat and drug-related material in plasma was 8.4 and 15.6 h, respectively. Pevonedistat distributed preferentially in whole blood with a mean whole-blood-to-plasma ratio for pevonedistat AUC∞ of 40.8. By 1 week post dose, the mean recovery of administered radioactivity was 94% (41% in urine and 53% in feces). The pevonedistat safety profile during both study parts was consistent with previous clinical experience, with no new safety signals observed. In part B, pevonedistat in combination with docetaxel or carboplatin plus paclitaxel was generally well tolerated. ClinicalTrials.gov identifier: NCT03057366 .


Assuntos
Ciclopentanos/farmacocinética , Inibidores Enzimáticos/farmacocinética , Proteína NEDD8/antagonistas & inibidores , Pirimidinas/farmacocinética , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica , Área Sob a Curva , Ciclopentanos/uso terapêutico , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/uso terapêutico , Feminino , Meia-Vida , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias/tratamento farmacológico , Pirimidinas/uso terapêutico , Compostos Radiofarmacêuticos
3.
Eur Urol ; 78(2): 184-192, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32273183

RESUMO

BACKGROUND: External beam radiotherapy (EBRT) with neoadjuvant/adjuvant androgen deprivation therapy (ADT) is an established treatment option to prolong survival for patients with intermediate- and high-risk prostate cancer (PCa). Relugolix, an oral gonadotropin-releasing hormone (GnRH) receptor antagonist, was evaluated in this clinical setting in comparison with degarelix, an injectable GnRH antagonist. OBJECTIVE: To evaluate the safety and efficacy of relugolix to achieve and maintain castration. DESIGN, SETTING, AND PARTICIPANTS: A phase 2 open-label study was conducted in 103 intermediate-risk PCa patients undergoing primary EBRT and neoadjuvant/adjuvant ADT between June 2014 and December 2015. INTERVENTION: Patients randomly assigned (3:2) to 24-wk treatment with either daily oral relugolix or 4-wk subcutaneous depot degarelix (reference control). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary endpoint was the rate of effective castration (testosterone <1.73nmol/l) in relugolix patients between 4 and 24 wk of treatment. Secondary endpoints included rate of profound castration (testosterone <0.7nmol/l), prostate-specific antigen (PSA) levels, prostate volume, quality of life (QoL) assessed using the Aging Males' Symptoms scale, and the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life (30-item EORTC core questionnaire [EORTC QLQ-C30] and 25-item EORTC prostate cancer module [EORTC QLQ-PR25]) questionnaires, and safety. No formal statistical comparisons with degarelix were planned. RESULTS AND LIMITATIONS: Castration rates during treatment were 95% and 82% with relugolix and 89% and 68% with degarelix for 1.73 and 0.7nmol/l thresholds, respectively. Median time to castration in the relugolix arm was 4 d. During treatment, PSA levels and prostate volumes were reduced in both groups. Three months after discontinuing treatment, 52% of men on relugolix and 16% on degarelix experienced testosterone recovery (statistical significance of differences not tested). Mean and median QoL scores improved following treatment discontinuation. The most common adverse event was hot flush (relugolix 57%; degarelix 61%). Lack of blinding was a potential limitation. CONCLUSIONS: Relugolix achieved testosterone suppression to castrate levels within days and maintained it over 24 wk with a safety profile consistent with its mechanism of action. PATIENT SUMMARY: Oral once-daily relugolix may be a novel oral alternative to injectable androgen deprivation therapies.


Assuntos
Hormônio Liberador de Gonadotropina/antagonistas & inibidores , Compostos de Fenilureia/administração & dosagem , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/radioterapia , Pirimidinonas/administração & dosagem , Administração Oral , Idoso , Humanos , Masculino , Terapia Neoadjuvante , Neoplasias da Próstata/patologia , Medição de Risco
4.
Br J Clin Pharmacol ; 85(11): 2568-2579, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31355467

RESUMO

AIMS: A population pharmacokinetic (PK) analysis was conducted to quantify the impact of patient-specific and concurrent medication factors on pevonedistat PK. METHODS: Data were pooled from 6 clinical studies consisting of 335 patients with solid tumours or haematological malignancies administered pevonedistat alone or in combination with azacitidine, docetaxel, carboplatin + paclitaxel, or gemcitabine. Model development and covariate analysis followed standard methods. Parameters and bootstrap 95% confidence intervals were estimated using nonlinear mixed-effects modelling. The final model was evaluated using visual predictive checks and other goodness-of-fit criteria. RESULTS: A linear 2-compartment model best described pevonedistat PK. The final model included the effect of body surface area (BSA) on clearance (CL and Q) and volume of distribution of pevonedistat, effect of concomitantly administered carboplatin + paclitaxel on CL, and effect of albumin on Q. Race, sex, age, tumour type (haematological vs solid), mild or moderate renal impairment (creatinine clearance ≥30 mL/min), or mild hepatic impairment, had no impact on pevonedistat PK. CONCLUSIONS: The clinical PK profile of pevonedistat is comparable in patients with solid tumours or haematological malignancies. All PK parameters exhibited ≥20% change over the observed BSA range (1.38-3 m2 ) with CL ranging from 75.5 to 208% of the reference value, with simulations supporting BSA-based dosing to minimize interindividual variability in drug exposures. Concurrent administration of carboplatin + paclitaxel decreased pevonedistat CL by approximately 44%, while coadministration with azacitidine, gemcitabine or docetaxel did not alter pevonedistat CL. No other factors were identified as influencing pevonedistat PK.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Ciclopentanos/farmacocinética , Drogas em Investigação/farmacocinética , Neoplasias Hematológicas/tratamento farmacológico , Pirimidinas/farmacocinética , Padrão de Cuidado , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Variação Biológica da População , Ensaios Clínicos como Assunto , Ciclopentanos/administração & dosagem , Interações Medicamentosas , Drogas em Investigação/administração & dosagem , Feminino , Neoplasias Hematológicas/sangue , Humanos , Masculino , Taxa de Depuração Metabólica , Pessoa de Meia-Idade , Pirimidinas/administração & dosagem , Valores de Referência , Adulto Jovem
5.
Blood ; 131(13): 1415-1424, 2018 03 29.
Artigo em Inglês | MEDLINE | ID: mdl-29348128

RESUMO

Pevonedistat (TAK-924/MLN4924) is a novel inhibitor of NEDD8-activating enzyme (NAE) with single-agent activity in relapsed/refractory acute myeloid leukemia (AML). We performed a phase 1b study of pevonedistat (PEV) with azacitidine (AZA) based on synergistic activity seen preclinically. Primary objectives included safety and tolerability, and secondary objectives included pharmacokinetics (PK) and disease response. Patients ≥60 years with treatment-naive AML (unfit for standard induction therapy) received PEV 20 or 30 mg/m2 IV on days 1, 3, and 5 combined with fixed-dose AZA (75 mg/m2 IV/subcutaneously) on days 1 to 5, 8, and 9, every 28 days. The most common treatment-emergent adverse events were constipation (48%), nausea (42%), fatigue (42%), and anemia (39%). In total, 11 deaths were observed and considered unrelated to study therapy by the investigators. Transient elevations in aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were dose limiting. The recommended phase 2 dose (RP2D) of PEV in this combination is 20 mg/m2 PEV PK was not altered by the addition of AZA. Overall response rate (ORR) based on an intent-to-treat analysis was 50% (20 complete remissions [CRs], 5 complete remission with incomplete peripheral count recovery, 7 partial remissions [PRs]), with an 8.3-month median duration of remission. In patients receiving ≥6 cycles of therapy (n = 23, 44%), ORR was 83%. In patients with TP53 mutations, the composite CR/PR rate was 80% (4/5). Two of these patients stayed on study for >10 cycles. Baseline bone marrow blast percentage or cytogenetic/molecular risk did not influence ORR. This study was registered at www.clinicaltrials.gov as #NCT01814826.


Assuntos
Azacitidina/administração & dosagem , Ciclopentanos/administração & dosagem , Inibidores Enzimáticos/administração & dosagem , Leucemia Mieloide Aguda/tratamento farmacológico , Proteínas de Neoplasias/antagonistas & inibidores , Pirimidinas/administração & dosagem , Enzimas de Conjugação de Ubiquitina/antagonistas & inibidores , Idoso , Idoso de 80 Anos ou mais , Azacitidina/efeitos adversos , Ciclopentanos/efeitos adversos , Inibidores Enzimáticos/efeitos adversos , Feminino , Humanos , Leucemia Mieloide Aguda/enzimologia , Leucemia Mieloide Aguda/mortalidade , Leucemia Mieloide Aguda/patologia , Masculino , Pessoa de Meia-Idade , Proteínas de Neoplasias/metabolismo , Pirimidinas/efeitos adversos , Fatores de Risco , Enzimas de Conjugação de Ubiquitina/metabolismo
6.
Clin Cancer Res ; 22(1): 34-43, 2016 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-26561559

RESUMO

PURPOSE: Evaluate the safety, pharmacokinetic profile, pharmacodynamic effects, and antitumor activity of the first-in-class investigational NEDD8-activating enzyme (NAE) inhibitor pevonedistat (TAK-924/MLN4924) in patients with relapsed/refractory lymphoma or multiple myeloma. EXPERIMENTAL DESIGN: Patients with relapsed/refractory myeloma (n = 17) or lymphoma (n = 27) received intravenous pevonedistat 25 to 147 mg/m(2) on days 1, 2, 8, 9 (schedule A; n = 27) or 100 to 261 mg/m(2) on days 1, 4, 8, 11 (schedule B; n = 17) of 21-day cycles. RESULTS: Maximum tolerated doses were 110 mg/m(2) (schedule A) and 196 mg/m(2) (schedule B). Dose-limiting toxicities included febrile neutropenia, transaminase elevations, muscle cramps (schedule A), and thrombocytopenia (schedule B). Common adverse events included fatigue and nausea. Common grade ≥3 events were anemia (19%; schedule A), and neutropenia and pneumonia (12%; schedule B). Clinically significant myelosuppression was uncommon. There were no treatment-related deaths. Pevonedistat pharmacokinetics exhibited a biphasic disposition phase and approximate dose-proportional increases in systemic exposure. Consistent with the short mean elimination half-life of approximately 8.5 hours, little-to-no drug accumulation in plasma was seen after multiple dosing. Pharmacodynamic evidence of NAE inhibition included increased skin levels of CDT-1 and NRF-2 (substrates of NAE-dependent ubiquitin ligases), and increased NRF-2-regulated gene transcript levels in whole blood. Pevonedistat-NEDD8 adduct was detected in bone marrow aspirates, indicating pevonedistat target engagement in the bone marrow compartment. Three lymphoma patients had partial responses; 30 patients achieved stable disease. CONCLUSIONS: Pevonedistat demonstrated anticipated pharmacodynamic effects in the clinical setting, a tolerable safety profile, and some preliminary evidence that may be suggestive of the potential for activity in relapsed/refractory lymphoma.


Assuntos
Antineoplásicos/uso terapêutico , Ciclopentanos/uso terapêutico , Linfoma/tratamento farmacológico , Terapia de Alvo Molecular , Mieloma Múltiplo/tratamento farmacológico , Pirimidinas/uso terapêutico , Ubiquitinas/antagonistas & inibidores , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/farmacologia , Biomarcadores , Ciclopentanos/farmacologia , Esquema de Medicação , Monitoramento de Medicamentos , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Linfoma/diagnóstico , Linfoma/metabolismo , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Mieloma Múltiplo/diagnóstico , Mieloma Múltiplo/metabolismo , Proteína NEDD8 , Recidiva Local de Neoplasia , Pirimidinas/farmacologia , Retratamento , Resultado do Tratamento
7.
Clin Cancer Res ; 22(4): 847-57, 2016 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-26423795

RESUMO

PURPOSE: To determine the dose-limiting toxicities (DLTs) and maximum tolerated dose (MTD) of the investigational NEDD8-activating enzyme (NAE) inhibitor pevonedistat (TAK-924/MLN4924) and to investigate pevonedistat pharmacokinetics and pharmacodynamics in patients with advanced nonhematologic malignancies. EXPERIMENTAL DESIGN: Pevonedistat was administered via 60-minute intravenous infusion on days 1 to 5 (schedule A, n = 12), or days 1, 3, and 5 (schedules B, n = 17, and C, n = 19) of 21-day cycles. Schedule B included oral dexamethasone 8 mg before each pevonedistat dose. Dose escalation proceeded using a Bayesian continual reassessment method. Tumor response was assessed by RECIST 1.0. RESULTS: Schedule A MTD was 50 mg/m(2); based on the severity of observed hepatotoxicity, this schedule was discontinued. Schedules B and C MTDs were 50 and 67 mg/m(2), respectively. DLTs on both these schedules included hyperbilirubinemia and elevated aspartate aminotransferase. There were no grade ≥ 3 treatment-related serious adverse events reported on schedules B or C. Twenty-three (74%) evaluable patients on schedules B and C had stable disease. Intermittent dexamethasone use did not significantly influence pevonedistat pharmacokinetics. NAE inhibition by pevonedistat was demonstrated in multiple tumor types via IHC detection of pevonedistat-NEDD8 adduct and accumulation of Cullin-RING ligase substrates CDT1 and NRF2 in tumor biopsies. CONCLUSIONS: Pevonedistat was generally well tolerated on a day 1, 3, 5 schedule every 3 weeks with an MTD between 50 mg/m(2) and 67 mg/m(2). DLTs were predominantly hepatic enzyme elevations. Pharmacodynamic studies demonstrated that pevonedistat inhibited NAE in tumors.


Assuntos
Antineoplásicos/uso terapêutico , Ciclopentanos/uso terapêutico , Neoplasias/tratamento farmacológico , Pirimidinas/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/toxicidade , Ciclopentanos/toxicidade , Feminino , Humanos , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Neoplasias/patologia , Pirimidinas/toxicidade , Resultado do Tratamento , Carga Tumoral/efeitos dos fármacos , Enzimas Ativadoras de Ubiquitina/antagonistas & inibidores
8.
J Clin Endocrinol Metab ; 100(12): 4579-87, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26502357

RESUMO

CONTEXT: TAK-385 is a highly selective, oral, nonpeptide GnRH antagonist being investigated as a possible prostate cancer treatment. OBJECTIVE: The objectives were to evaluate safety, tolerability, pharmacokinetics, and pharmacodynamics of TAK-385 on LH and testosterone. DESIGN, SETTING, AND PARTICIPANTS: This was a three-part, randomized, double-blind, placebo-controlled, phase 1 dose-escalation study in 176 healthy male UK volunteers. INTERVENTIONS: Part 1, single doses of TAK-385 (0 [placebo], 80, 120, 180, or 360 mg). Part 2, 14-day TAK-385 (0, 20, 40, 80, or 180 mg) daily. Part 3, 28-day TAK-385 (40 [with loading dose], 60, 80, or 160 mg) or placebo daily. Parts 2 and 3 included men aged 40-75 years. MAIN OUTCOME MEASURES: Main outcome measures included plasma concentrations of TAK-385, LH, and testosterone. RESULTS: Oral TAK-385 was readily absorbed, and steady state was reached in ≤ 14 days. Food reduced TAK-385 systemic exposure by 47-52%. Mean serum testosterone levels declined ≤ 6 hours after TAK-385 administration. Loading doses up to 360 mg on day 1 or 360 mg on day 1 followed by 240 mg on day 2 reduced the time to achieve castrate testosterone levels from ≥ 7 to <3 days. TAK-385 doses ≥ 80 mg/d achieved sustained medical castration and trough TAK-385 concentrations >4 ng/mL. After discontinuation of TAK-385 on day 28, testosterone levels normalized in most subjects in ≤ 28 days. Common adverse events included bradycardia, headache, and hot flush (all grade ≤ 2). CONCLUSIONS: Oral TAK-385 (40-180 mg/d) was well tolerated and effectively lowered testosterone in healthy men. Planned phase 2 doses in men with hormone-sensitive prostate cancer are 80 and 120 mg/d.


Assuntos
Castração/métodos , Hormônio Liberador de Gonadotropina/antagonistas & inibidores , Compostos de Fenilureia/uso terapêutico , Neoplasias da Próstata/tratamento farmacológico , Pirimidinonas/uso terapêutico , Adulto , Idoso , Relação Dose-Resposta a Droga , Método Duplo-Cego , Interações Alimento-Droga , Humanos , Hormônio Luteinizante/sangue , Masculino , Pessoa de Meia-Idade , Compostos de Fenilureia/efeitos adversos , Compostos de Fenilureia/farmacocinética , Pirimidinonas/efeitos adversos , Pirimidinonas/farmacocinética , Testosterona/sangue , Resultado do Tratamento , Adulto Jovem
9.
Nicotine Tob Res ; 17(1): 106-13, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25145377

RESUMO

INTRODUCTION: Varenicline has been shown to significantly reduce craving and several aspects of smoking reinforcement in clinical trials, compared with placebo. This is the first report describing the concentration-effect relationship of varenicline on relief of craving. METHODS: The pharmacokinetics (PK) and pharmacodynamics (PD) of a single 2mg dose of varenicline were investigated in 40 smokers in a randomized, crossover study comparing the effect of varenicline with placebo on ameliorating abstinence-and cue-induced craving and withdrawal symptoms. Subjects were asked to complete self-reported questionnaires (Smoking Urges Scale and Minnesota Nicotine Withdrawal Scale [MNWS]) and blood samples were simultaneously collected for measurement of varenicline concentrations. Only the data from the 4-hr postdose abstinence period (just prior to the cue session) were analyzed. Data were described by a 2-compartment PK model and a linear PD model with first-order onset/offset rate constants describing the placebo response "kinetics." Response was described as the net effect of the baseline, placebo, and drug responses. RESULTS: Varenicline significantly decreased mean craving score when compared with placebo and the magnitude of this response was related to varenicline concentration. The time-course and magnitude of both placebo and varenicline craving response were characterized by a large degree of unexplained variability. Simulations were used to illustrate the expected craving response over time and its associated random variability after chronic dosing. CONCLUSIONS: Craving reduction is associated with increased varenicline concentrations. The relatively rapid onset of this effect within 4 hr postdose suggests that, smokers may experience some craving relief after acute administration of varenicline.


Assuntos
Benzazepinas/farmacologia , Fissura/efeitos dos fármacos , Nicotina/efeitos adversos , Agonistas Nicotínicos/farmacologia , Quinoxalinas/farmacologia , Abandono do Hábito de Fumar/métodos , Fumar/tratamento farmacológico , Adolescente , Adulto , Benzazepinas/sangue , Benzazepinas/farmacocinética , Estudos Cross-Over , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Agonistas Nicotínicos/sangue , Agonistas Nicotínicos/farmacocinética , Quinoxalinas/sangue , Quinoxalinas/farmacocinética , Inquéritos e Questionários , Vareniclina
10.
Clin Pharmacokinet ; 49(12): 799-816, 2010 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-21053991

RESUMO

Varenicline tartrate (Chantix®/Champix®) is a selective partial agonist of the α(4)ß(2) nicotinic acetylcholine receptor and is approved as an aid to smoking cessation. The usual oral dosage in adults is 1 mg twice daily for 12 weeks, with an initial titration week. Several clinical pharmacology studies have characterized the pharmacokinetics of varenicline in adult smokers aged 18-55 years, elderly smokers and nonsmokers aged ≥ 65 years, adolescent smokers aged 12-17 years and subjects with impaired renal function. Varenicline exhibits linear pharmacokinetics following single- and multiple-dose administration of up to 3 mg/day. After oral administration absorption is virtually complete and systemic availability is high. Oral bioavailability is not affected by food or time-of-day dosing; maximum plasma drug concentrations typically occur within 3-4 hours after dosing. Protein binding of varenicline is low (≤ 20%) and independent of age and renal function. Varenicline is almost exclusively excreted unchanged in urine, primarily through glomerular filtration, with some component of active tubular secretion via human organic cation transporter, hOCT-2. Varenicline does not undergo significant metabolism and is not metabolized by hepatic microsomal cytochrome P450 (CYP) enzymes. Consistent with an elimination half-life of ∼24 hours, steady-state conditions are reached within 4 days of repeat dosing. There are no remarkable differences between smokers and nonsmokers in metabolism or excretion of varenicline. In vitro, varenicline does not inhibit nor induce the activity of the major CYP enzymes. No clinically meaningful pharmacokinetic drug interactions are observed when varenicline is coadministered with the narrow therapeutic index drugs warfarin or digoxin, the smoking cessation therapies bupropion or transdermal nicotine, and the renally secreted drugs cimetidine or metformin. An integrated model-based analysis of varenicline pharmacokinetics across several studies in adult smokers further showed that renal function was the clinically important factor leading to interindividual variability in systemic exposure to varenicline. Although no dose adjustment is required for subjects with mild to moderate renal impairment, a dose reduction to 1 mg/day is indicated for subjects with severe renal insufficiency. After accounting for renal function, there was no apparent effect of age, sex or race on varenicline pharmacokinetics. Varenicline pharmacokinetics in adolescents were generally comparable to those in adults; the bodyweight effect, which resulted in greater exposure in individuals of smaller body size (weighing ≤ 55 kg), was adequately offset by administration of half the dose recommended in adults. (It is, however, important to note that varenicline is currently not approved for use in smokers aged under 18 years). Exposure-response analyses relating individual-specific drug exposure to clinical responses consistently showed that the end-of-treatment abstinence rate in adult smokers increased linearly with increasing varenicline exposure; the 1 mg twice-daily dose regimen was reliably associated with greater exposure and an increased probability of achieving a stable quit within 1 year from the start of treatment. Nausea was the single most frequently reported adverse event in varenicline clinical trials, with an incidence that was sex-related and increased with varenicline exposure. In all, the predictable pharmacokinetic properties and straightforward dispositional profile of varenicline simplify its use in clinical practice.


Assuntos
Benzazepinas/farmacologia , Agonistas Nicotínicos/farmacologia , Quinoxalinas/farmacologia , Abandono do Hábito de Fumar/métodos , Adolescente , Adulto , Fatores Etários , Idoso , Animais , Benzazepinas/efeitos adversos , Benzazepinas/farmacocinética , Disponibilidade Biológica , Interações Medicamentosas , Meia-Vida , Humanos , Pessoa de Meia-Idade , Agonistas Nicotínicos/efeitos adversos , Agonistas Nicotínicos/farmacocinética , Quinoxalinas/efeitos adversos , Quinoxalinas/farmacocinética , Vareniclina , Adulto Jovem
11.
Br J Clin Pharmacol ; 68(5): 669-81, 2009 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-19916991

RESUMO

AIMS: To characterize the population pharmacokinetics of varenicline and identify factors leading to its exposure variability in adult smokers. METHODS: Data were pooled from nine clinical studies consisting of 1878 subjects. Models were developed to describe concentration-time profiles across individuals. Covariates were assessed using a full model approach; parameters and bootstrap 95% confidence intervals (CI) were estimated using nonlinear mixed effects modelling. RESULTS: A two-compartment model with first-order absorption and elimination best described varenicline pharmacokinetics. The final population parameter estimates (95% CI) were: CL/F, 10.4 l h(-1) (10.2, 10.6); V(2)/F, 337 l (309, 364); V(3)/F, 78.1 l (61.9, 98.9); Q/F, 2.08 l h(-1) (1.39, 3.79); K(a), 1.69 h(-1) (1.27, 2.00); and A(lag), 0.43 h (0.37, 0.46). Random interindividual variances were estimated for K(a)[70% coefficient of variation (CV)], CL/F (25% CV), and V(2)/F (50% CV) using a block covariance matrix. Fixed effect parameters were precisely estimated [most with % relative standard error < 10 and all with % relative standard error < 25], and a visual predictive check indicated adequate model performance. CL/F decreased from 10.4 l h(-1) for a typical subject with normal renal function (CLcr = 100 ml min(-1)) to 4.4 l h(-1) for a typical subject with severe renal impairment (CLcr = 20 ml min(-1)), which corresponds to a 2.4-fold increase in daily steady-state exposure. Bodyweight was the primary predictor of variability in volume of distribution. After accounting for renal function, there was no apparent effect of age, gender or race on varenicline pharmacokinetics. CONCLUSIONS: Renal function is the clinically important factor leading to interindividual variability in varenicline exposure. A dose reduction to 1 mg day(-1), which is half the recommended dose, is indicated for subjects with severe renal impairment.


Assuntos
Benzazepinas/farmacocinética , Taxa de Filtração Glomerular/efeitos dos fármacos , Agonistas Nicotínicos/farmacocinética , Quinoxalinas/farmacocinética , Receptores Nicotínicos/efeitos dos fármacos , Insuficiência Renal/induzido quimicamente , Adulto , Relação Dose-Resposta a Droga , Humanos , Modelos Biológicos , Dinâmica não Linear , Fumar , Abandono do Hábito de Fumar , Vareniclina , Adulto Jovem
13.
J Clin Pharmacol ; 47(11): 1421-9, 2007 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-17962429

RESUMO

This study investigated the effect of varenicline on the pharmacokinetics and pharmacodynamics of a single dose of warfarin in 24 adult smokers and compared these findings with data generated using human in vitro systems. Subjects were randomized to receive varenicline 1 mg twice a day or placebo for 13 days and then switched to the alternative treatment after a 1-week washout period. A single dose of warfarin 25 mg was given on day 8 of each treatment period, and serial blood samples were collected over 144 hours postdose. Pharmacokinetic parameters for both (R)- and (S)-warfarin and international normalized ratio (INR) values were determined. Varenicline was assessed as an inhibitor and inducer of human cytochrome P450 activities using liver microsomes and hepatocytes, respectively. Consistent with the in vitro data, no alteration in human pharmacokinetics of warfarin enantiomers was observed with varenicline treatment. The 90% confidence intervals for the ratios of area under the concentration-time curve from zero hours to infinity and peak plasma concentrations were completely contained within 80% to 125%. Warfarin pharmacodynamic parameters, maximum INR, and the area under the prothrombin (INR)-time curve, were also unaffected by steady-state varenicline. Concomitant administration of varenicline and warfarin was well tolerated. Consequently, warfarin can be safely administered with varenicline without the need for dose adjustment.


Assuntos
Anticoagulantes/farmacocinética , Benzazepinas/farmacocinética , Quinoxalinas/farmacocinética , Abandono do Hábito de Fumar , Varfarina/farmacocinética , Adolescente , Adulto , Células Cultivadas , Inibidores das Enzimas do Citocromo P-450 , Sistema Enzimático do Citocromo P-450/metabolismo , Método Duplo-Cego , Feminino , Hepatócitos/enzimologia , Humanos , Coeficiente Internacional Normatizado , Masculino , Microssomos Hepáticos/enzimologia , Pessoa de Meia-Idade , Fumar/sangue , Fumar/tratamento farmacológico , Fatores de Tempo , Vareniclina
14.
J Clin Pharmacol ; 46(12): 1439-48, 2006 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-17101743

RESUMO

Varenicline is a novel and selective alpha4beta2 nicotinic acetylcholine receptor partial agonist developed for smoking cessation. The primary objectives of this double-blind, placebo-controlled, dose-escalation study were to determine the pharmacokinetics, safety, and tolerability of multiple oral doses of varenicline given as tablets once (1 mg, 2 mg, and 3 mg) or twice (1 mg) daily to healthy adult smokers. Within each dose level, 8 subjects were randomized to varenicline and 4 subjects to placebo. Varenicline was well tolerated at doses up to and including 2 mg daily. Dose-proportional increases in maximum observed plasma concentrations and area under the plasma concentration-time curve from time zero to the end of the dosing interval values were observed between the 1-mg and 2-mg daily doses of varenicline. Once- and twice-daily dosing resulted, on average, in an approximate 2- and 3-fold increase in varenicline systemic exposure, respectively, compared with single dose. There was no evidence of concentration- or time-dependent changes in the pharmacokinetics of varenicline upon repeat dosing.


Assuntos
Benzazepinas/farmacocinética , Quinoxalinas/farmacocinética , Receptores Nicotínicos/metabolismo , Prevenção do Hábito de Fumar , Administração Oral , Adolescente , Adulto , Área Sob a Curva , Benzazepinas/administração & dosagem , Benzazepinas/efeitos adversos , Cotinina/sangue , Relação Dose-Resposta a Droga , Método Duplo-Cego , Esquema de Medicação , Feminino , Meia-Vida , Cefaleia/induzido quimicamente , Humanos , Hipotensão Ortostática/induzido quimicamente , Masculino , Taxa de Depuração Metabólica , Pessoa de Meia-Idade , Náusea/induzido quimicamente , Nicotina/sangue , Pacientes Desistentes do Tratamento , Quinoxalinas/administração & dosagem , Quinoxalinas/efeitos adversos , Fumar/metabolismo , Abandono do Hábito de Fumar/métodos , Comprimidos , Vareniclina , Vômito/induzido quimicamente
15.
J Clin Pharmacol ; 46(11): 1234-40, 2006 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-17050788

RESUMO

Varenicline is a novel selective alpha4beta2 nicotinic acetylcholine partial agonist developed for smoking cessation. This study investigated the single- and multiple-dose pharmacokinetics, safety, and tolerability of varenicline in elderly (> or = 65 years) smokers. Twenty-four elderly smokers with normal renal function for their age (estimated creatinine clearance > or = 70 mL/min) received varenicline 1 mg once daily (n = 8) or placebo (n = 4) for 7 days, or 1 mg twice daily (n = 8) or placebo (n = 4) for 6 days with a single dose on day 7 in a double-blind, parallel group and placebo-controlled design. There was no evidence of concentration- or time-dependent changes in varenicline pharmacokinetics upon repeat dosing. Once- and twice-daily dosing was associated with an approximate 2-fold and 3-fold increase, respectively, in systemic exposure to varenicline. Varenicline was well tolerated; all adverse events reported were mild to moderate in intensity. Thus, no dose adjustment is necessary based on age alone.


Assuntos
Benzazepinas/efeitos adversos , Benzazepinas/farmacocinética , Quinoxalinas/efeitos adversos , Quinoxalinas/farmacocinética , Administração Oral , Idoso , Benzazepinas/administração & dosagem , Relação Dose-Resposta a Droga , Método Duplo-Cego , Esquema de Medicação , Feminino , Humanos , Masculino , Quinoxalinas/administração & dosagem , Receptores Nicotínicos/metabolismo , Abandono do Hábito de Fumar/métodos , Vareniclina
16.
J Clin Pharmacol ; 46(9): 991-8, 2006 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-16920893

RESUMO

Varenicline is a novel and selective alpha4beta2 nicotinic receptor partial agonist that is under development for smoking cessation. The primary objectives of this double-blind, placebo-controlled, single-dose, dose-escalation study were to determine the clinical pharmacology of single doses of varenicline in healthy smokers and nonsmokers under fed and fasted conditions and to determine the clinical pharmacology of varenicline administered in the morning and in the evening to smokers. Within each subject group, 4 subjects were randomized to varenicline and 2 subjects to placebo. Subjects received one single oral administration of varenicline or placebo: 6 doses (0.01, 0.03, 0.1, 0.3, 1.0, and 3.0 mg) were investigated in nonsmokers and 7 doses in smokers (0.01, 0.03, 0.1, 0.3, 1.0, 3.0, and 10.0 mg). Varenicline was well tolerated after single doses up to 3.0 mg in smokers and 1.0 mg in nonsmokers. Nausea and vomiting at doses above 3.0 mg in smokers and 1.0 mg in nonsmokers were dose limiting. Systemic exposure to varenicline and pharmacokinetic variability were similar between smokers and nonsmokers. Coadministration with food, smoking restriction, and time-of-day dosing did not affect the pharmacokinetics of varenicline.


Assuntos
Benzazepinas/farmacocinética , Saúde , Agonistas Nicotínicos/farmacocinética , Quinoxalinas/farmacocinética , Receptores Nicotínicos/metabolismo , Fumar , Administração Oral , Adolescente , Adulto , Benzazepinas/administração & dosagem , Benzazepinas/efeitos adversos , Benzazepinas/sangue , Relação Dose-Resposta a Droga , Método Duplo-Cego , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Agonistas Nicotínicos/administração & dosagem , Agonistas Nicotínicos/efeitos adversos , Agonistas Nicotínicos/sangue , Quinoxalinas/administração & dosagem , Quinoxalinas/efeitos adversos , Quinoxalinas/sangue , Vareniclina
17.
Int J Oncol ; 23(2): 401-9, 2003 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-12851689

RESUMO

In order to examine the intracellular locus of the folic acid (PteGlu)-enhanced synergies of trimetrexate (TMQ) plus the thymidylate synthase (TS) inhibitor, raltitrexed (RTX), and TMQ plus the glycinamide ribonucleotide formyltransferase (GARFT) inhibitor, AG2034, comprehensive protection studies with thymidine (dThd) and hypoxanthine (HX) were conducted in a 96-well plate cell growth inhibition (sulforhodamine B) assay. Current modeling techniques were extended to characterize these protection patterns involving multiple-agent interaction. Wild-type human ileocecal HCT-8 cells and DW2, a subline deficient in folylpoly-gamma-glutamate synthetase (FPGS) were individually treated for 96 h with TMQ, AG2034 and a 1:1 mixture of TMQ:AG2034 or with TMQ, RTX, and a 1:1 mixture of TMQ:RTX in the presence of PteGlu (2.3 or 40 micro M) and the protection agents (10 micro M dThd and/or 100 micro M HX). Drug treatments were randomly assigned to wells. Both isobols and 3-dimensional concentration-effect surfaces were used to assess the nature and the intensity of drug interactions. The structural Hill model was fitted to data with weighted non-linear regression for most cases. A so-called 'double Hill' model was sometimes more appropriate when a plateau in the middle of the concentration-effect curve was found. In HCT-8 and DW2 cells at 2.3 and 40 micro M PteGlu, inhibition of DHFR by TMQ induced antithymidylate and antipurine effects; AG2034 and RTX selectively inhibited de novo purine or thymidine synthesis, respectively. dThd protection increased the PteGlu-enhancement of the TMQ + AG2034 synergy, whereas HX protection increased the PteGlu-enhancement of the TMQ + RTX synergy. The PteGlu-enhanced synergies of TMQ + AG2034 and TMQ + RTX occur primarily through inhibition of purine synthesis and inhibition of thymidylate synthesis, respectively. These results further substantiate the hypothesis that the nonpolyglutamylatable DHFR inhibitor, TMQ, acts as a modulator by decreasing the protection by PteGlu of cells against the polyglutamylatable AG2034 and RTX.


Assuntos
Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/metabolismo , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Ácido Fólico/farmacologia , Hipoxantina/farmacologia , Timidina/farmacologia , Antineoplásicos/farmacologia , Neoplasias do Ceco/tratamento farmacológico , Neoplasias do Ceco/metabolismo , Divisão Celular/efeitos dos fármacos , Resistência a Múltiplos Medicamentos , Sinergismo Farmacológico , Inibidores Enzimáticos/farmacologia , Glutamatos/efeitos adversos , Hematínicos/farmacologia , Humanos , Hidroximetil e Formil Transferases/antagonistas & inibidores , Hipoxantina/metabolismo , Neoplasias do Íleo/tratamento farmacológico , Neoplasias do Íleo/metabolismo , Peptídeo Sintases/deficiência , Fosforribosilglicinamido Formiltransferase , Pirimidinas/efeitos adversos , Quinazolinas/farmacologia , Tiofenos/farmacologia , Timidina/metabolismo , Timidilato Sintase/antagonistas & inibidores , Trimetrexato/efeitos adversos , Células Tumorais Cultivadas
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