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1.
Pharmaceutics ; 16(5)2024 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-38794263

RESUMO

INTRODUCTION: Docetaxel, a taxane used in the treatment of solid tumours, exerts pharmacological activity when in its unbound form. We report a sensitive assay to quantify unbound docetaxel after oral administration of docetaxel plus encequidar (oDox+E). Unbound drug quantification is important due to its direct correlation with drug-related toxicity and therapeutic efficacy. We improve on the sensitivity of current assay methods and demonstrate the utility of the assay on a novel formulation of oral docetaxel. METHODS: Ultrafiltration followed by high-performance liquid chromatography and tandem mass spectrometry (HPLC-MS/MS) was utilized. Long-term stability, precision, accuracy, and recovery experiments were conducted to validate the assay. Additionally, patient samples from a Phase I dose-escalation pharmacokinetic study were analyzed using the developed assay. RESULTS: The assay method exhibited long-term stability with an observed change between 0.8 and 6.9% after 131 days of storage at -60 °C. Precision and accuracy quality controls met the FDA acceptance criteria. An average recovery of 88% was obtained. Patient sample analysis demonstrated successful implementation of the assay. CONCLUSION: A validated sensitive assay was developed with an LLOQ of 0.084 ng/mL using 485 µL of human plasma. The sensitivity of the assay allowed quantification of unbound docetaxel concentrations in an early-phase oDox+E clinical study to compare it against IV docetaxel using pharmacokinetic modelling. Successful development of oDox+E represents an opportunity to replace the current IV docetaxel regimen with an oral regimen with lower cost, decreased side effects, and improve patient quality of life and experience.

2.
Artigo em Inglês | MEDLINE | ID: mdl-38814342

RESUMO

PURPOSE: To determine the bioavailability, safety, and tolerability of a single dose of oral docetaxel plus encequidar (oDox + E) and compare its pharmacokinetic exposure with current standard of care IV docetaxel. INTRODUCTION: Docetaxel is a taxane widely used as an anti-neoplastic agent. Due to low oral bioavailability secondary to gut P-glycoprotein (P-gp) efflux, its current use is limited to intravenous administration. Oral docetaxel may provide a less resource intensive, more convenient, and tolerable alternative. Encequidar is a first in class, minimally absorbed, oral gut-specific P-gp inhibitor. We tested whether oDox + E can achieve comparable pharmacokinetic exposure to IV docetaxel. METHODS: A multicentre, phase I open-label, pharmacokinetic trial was undertaken to determine the bioavailability, safety, and tolerability of a single dose of oDox + E (at 75 mg/m2 + 15 mg, 150 mg/m2 + 15 mg, and 300 mg/m2 + 15 mg) in metastatic prostate cancer (mPC) patients compared to standard of care IV docetaxel as prescribed by their oncologists. The 15 mg of Encequidar at each dose level was given one hour prior to oral docetaxel. RESULTS: 11 patients were enrolled; 9 patients completed the study. Oral docetaxel exposure increased with dose, achieving the highest at 300 mg/m2 oDox + E (with AUC0 - infinity of 1343.3 ± 443.0 ng.h/mL compared to the IV docetaxel AUC0 - infinity of 2000 ± 325 ng.h/mL) and became non-linear at 300 mg/m2. The mean absolute bioavailability of oDox + E across all 3 dose levels was 16.14% (range: 8.19-25.09%). No patient deaths, dose limiting toxicity, treatment-related serious adverse event or grade 4 toxicity were observed. Maximal tolerated dose was not reached. CONCLUSION: oDox + E has a safe and tolerable adverse event profile in patients with metastatic prostate cancer. The increase in oral bioavailability of oDox + E suggests a multi-dose oDox + E regimen could theoretically achieve exposures comparable with standard of care IV docetaxel. Further development to examine the optimal multiple dose regimen of oDox + E is warranted. TRIAL REGISTRATION NUMBER: U1111-1173-5473.

3.
Trials ; 25(1): 336, 2024 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-38773523

RESUMO

BACKGROUND: Symptoms of anxiety and depression are common in patients with terminal illness and multiple challenges exist with timely and effective care in this population. Several centres have reported that one dose of the serotonergic psychedelic psilocybin, combined with therapeutic support, improves these symptoms for up to 6 months in this patient group. Drawing upon related therapeutic mechanisms, 3,4-methylenedioxymethamphetamine (MDMA)-assisted therapy may have the potential to achieve similar, positive mental health outcomes in this group. Preliminary evidence also supports the tolerability of MDMA-assisted therapy for anxiety and depression in advanced-stage cancer. METHODS: Up to 32 participants with advanced-stage cancer and associated depression and anxiety will be randomised in a 1:1 ratio into one of two blinded parallel treatment arms. The intervention group will receive 120 mg (+ 60 mg optional supplemental dose) MDMA-assisted therapy. The psychoactive control group will receive 20 mg oral (+ 10 mg optional supplemental dose) methylphenidate-assisted therapy. For each medication-assisted therapy session, participants will undergo two 90-min therapeutic support sessions in the week preceding, and one 90-min support session the day after the experimental session. A battery of measures (mood, anxiety, quality of life, mystical experience, spiritual wellbeing, attitudes towards death, personality traits, holistic health and wellbeing, connectedness, demoralisation, expectations, qualitative data and safety measures) will be assessed at baseline and through to the end of the protocol. Participants will be followed up until either 12 months post-randomisation or death, whichever occurs first. DISCUSSION: This study will examine the effect of MDMA-assisted therapy on symptoms of anxiety and depression in advanced-stage cancer. Potential therapeutic implications include establishing the safety and effectiveness of a novel treatment that may relieve mental suffering in patients with life-threatening illness. TRIAL REGISTRATION: Trial registered on Australian New Zealand Clinical Trials Registry. REGISTRATION NUMBER: ACTRN12619001334190p. Date registered: 30/09/2019. URL: https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=378153&showOriginal=true&isReview=true.


Assuntos
Afeto , Ansiedade , Alucinógenos , N-Metil-3,4-Metilenodioxianfetamina , Neoplasias , Ensaios Clínicos Controlados Aleatórios como Assunto , Humanos , N-Metil-3,4-Metilenodioxianfetamina/efeitos adversos , N-Metil-3,4-Metilenodioxianfetamina/administração & dosagem , Neoplasias/psicologia , Neoplasias/complicações , Ansiedade/psicologia , Método Duplo-Cego , Afeto/efeitos dos fármacos , Alucinógenos/administração & dosagem , Alucinógenos/efeitos adversos , Alucinógenos/uso terapêutico , Resultado do Tratamento , Depressão/psicologia , Depressão/terapia , Depressão/tratamento farmacológico , Qualidade de Vida , Metilfenidato/uso terapêutico , Metilfenidato/efeitos adversos , Metilfenidato/administração & dosagem , Fatores de Tempo , Masculino , Estadiamento de Neoplasias
4.
Artigo em Inglês | MEDLINE | ID: mdl-38504032

RESUMO

The development of optimized dosing regimens plays a crucial role in oncology drug development. This study focused on the population pharmacokinetic modelling and simulation of docetaxel, comparing the pharmacokinetic exposure of oral docetaxel plus encequidar (oDox + E) with the standard of care intravenous (IV) docetaxel regimen. The aim was to evaluate the feasibility of oDox + E as a potential alternative to IV docetaxel. The article demonstrates an approach which aligns with the FDA's Project Optimus which aims to improve oncology drug development through model informed drug development (MIDD). The key question answered by this study was whether a feasible regimen of oDox + E existed. The purpose of this question was to provide an early GO / NO-GO decision point to guide drug development and improve development efficiency. METHODS:  A stepwise approach was employed to develop a population pharmacokinetic model for total and unbound docetaxel plasma concentrations after IV docetaxel and oDox + E administration. Simulations were performed from the final model to assess the probability of target attainment (PTA) for different oDox + E dose regimens (including multiple dose regimens) in relation to IV docetaxel using AUC over effective concentration (AUCOEC) metric across a range of effective concentrations (EC). A Go / No-Go framework was defined-the first part of the framework assessed whether a feasible oDox + E regimen existed (i.e., a PTA ≥ 80%), and the second part defined the conditions to proceed with a Go decision. RESULTS:  The overall population pharmacokinetic model consisted of a 3-compartment model with linear elimination, constant bioavailability, constant binding mechanics, and a combined error model. Simulations revealed that single dose oDox + E regimens did not achieve a PTA greater than 80%. However, two- and three-dose regimens at 600 mg achieved PTAs exceeding 80% for certain EC levels. CONCLUSION:  The study demonstrates the benefits of MIDD using oDox + E as a motivating example. A population pharmacokinetic model was developed for the total and unbound concentration in plasma of docetaxel after administration of IV docetaxel and oDox + E. The model was used to simulate oDox + E dose regimens which were compared to the current standard of care IV docetaxel regimen. A GO / NO-GO framework was applied to determine whether oDox + E should progress to the next phase of drug development and whether any conditions should apply. A two or three-dose regimen of oDox + E at 600 mg was able to achieve non-inferior pharmacokinetic exposure to current standard of care IV docetaxel in simulations. A Conditional GO decision was made based on this result and further quantification of the "effective concentration" would improve the ability to optimise the dose regimen.

5.
Int Psychogeriatr ; 36(1): 43-50, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36876332

RESUMO

OBJECTIVES: The number of older adults suffering from schizophrenia is increasing. Despite this, less than 1% of published studies about schizophrenia focus on those older than 65 years. Research indicates these individuals may age differently from the general population due to lifestyle, medication factors, and effects of the disease itself. We aimed to analyze whether schizophrenia was associated with a younger age at first assessment for social care as a proxy measure for accelerated aging. DESIGN: We analyzed the effect of schizophrenia diagnosis, demographics, mood, comorbidities, falls, cognition, and substance use on age at first assessment for social care using linear regression. PARTICIPANTS: We used data from 168,780 interRAI Home Care and Long-Term Care Facility (HC; LTCF) assessments completed from July 2013 to June 2020. RESULTS: When corrected for confounding factors, schizophrenia contributed to age at first assessment being 5.5 years younger (p = 0.0001 Cohen's D = 1.0) than in people free from schizophrenia. Its effect on age at first assessment was second only to smoking. People suffering from schizophrenia also required a higher level of care (long-term care facility rather than home care). People suffering from schizophrenia had significantly higher rates of diabetes mellitus and chronic obstructive pulmonary disease but otherwise had lower rates of comorbidity than people free from schizophrenia who required care. CONCLUSIONS: Aging with schizophrenia is associated with needing increased social care at a younger age. This has implications for social spending and developing policies to decrease frailty in this population.


Assuntos
Diabetes Mellitus , Esquizofrenia , Humanos , Idoso , Esquizofrenia/epidemiologia , Envelhecimento , Comorbidade , Diabetes Mellitus/epidemiologia , Casas de Saúde
6.
Arch Gerontol Geriatr ; 105: 104852, 2023 02.
Artigo em Inglês | MEDLINE | ID: mdl-36375272

RESUMO

BACKGROUND: Modifiable risk factors affect 40% of dementia risk thus creating an opportunity for prevention or delay. The risk factor life-course model of dementia prevention by the Lancet Commission has yet to be tested in the general populations. We aimed to assess the model's assumptions in a large national dataset of older adults assessed for support services. METHODS: The interRAI assessment is a comprehensive evidence-based tool encompassing 236 items that is mandatory in New Zealand (NZ) for older adults providing a standardized national dataset. We tested the Lancet model of dementia prevention in a sample of 66,638 participants who underwent an interRAI assessment during the period 2013-2018. There were 59% female interviewees; mean age was 82 years (range: 65-107). Our cross-sectional dataset analysis was performed in using a logistic regression model with diagnosis of dementia as the primary outcome. RESULTS: The Lancet prevention model was supported in part. Hypertension, Hearing Impairment and past or present Depression increase risk of dementia. Age - increased risk demonstrated until 85 years; Gender - females at increased risk; BMI - initial effect of high BMI increases risk of dementia. However, exercise, diabetes, vision impairment and smoking as modifiable factors were not associated with dementia risk as predicted by the Lancet model. CONCLUSIONS: Limitations of the dataset analysed may have affected our findings. Nevertheless, important modifiable factors are herein confirmed as increasing dementia risk. BMI, hypertension, hearing impairment and depression are risks confirmed in the older NZ population lending credibility to prevention efforts targeted at these variables.


Assuntos
Demência , Exercício Físico , Humanos , Feminino , Idoso , Idoso de 80 Anos ou mais , Masculino , Estudos Transversais , Fatores de Risco , Demência/epidemiologia , Demência/prevenção & controle
8.
Aging Clin Exp Res ; 33(3): 513-520, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32488471

RESUMO

BACKGROUND: Centenarians escapers are those who reached 100 years of age without the diagnosis of any of the common age-related diseases and exploring their characteristics will inform about successful ageing. No previous study has examined centenarians free of common chronic diseases amongst New Zealand centenarians. METHODS: Retrospective observational cross-sectional review of a national dataset determining the prevalence of depression, dementia, diabetes and hypertension, smoking, physical activity and social relationships among older adults (aged 60-99 years) and centenarians. Participants were all older New Zealanders living independently in the community who completed the international Residential Assessment Instrument-Home Care (interRAI-HC) assessment during the study's 5-year period (July 2013-June 2018). RESULTS: The assessments of 292 centenarians (mean age 101.03, SD 1.27 years) and 103,377 elderly (mean age 81.7, SD 5.7 years) were analysed. Compared to the elderly, centenarians were more likely to be female (74.7%, compared with 59.3% elderly, p < 0.001). Centenarians free of common chronic diseases did not differ from other centenarians on any of the analysed variables. Reduction in smoking rates and steady high rates of social engagement were associated with reaching a centenarian status free of common chronic diseases compared with older adults. CONCLUSIONS: Not smoking and being socially engaged throughout older age were associated with being a centenarian free of common chronic diseases. This study adds to our understanding the complexities of attaining exceptional longevity.


Assuntos
Envelhecimento , Longevidade , Idoso , Idoso de 80 Anos ou mais , Estudos Transversais , Feminino , Humanos , Estudos Retrospectivos , Fumar
9.
Hum Psychopharmacol ; 35(3): e2731, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32250509

RESUMO

Postpartum depression (PPD) is a severe disorder that adversely impacts both mothers and infants. It is associated with significant morbidity and mortality and reported prevalence is 11.5% (Ko, Rockhill, Tong, Morrow, & Farr. (2017). MMWR Morbidity and Mortality Weekly Report, 66(6), 153-158). Although PPD's fundamental pathophysiology remains to be fully illuminated, the influence of changes in perinatal hormones such as allopregnanolone (an endogenous progesterone metabolite) are most promising avenues of research. Conventional treatments for PPD are aligned with treatment strategies for depressive disorders. Brexanolone is a small molecule, neuroactive steroid GABAA receptor allosteric modulator consisting of synthetic allopregnanolone and a solubilizing agent. In early 2019, brexanolone received approval in the United States for the treatment of PPD. Brexanolone is only available through a restricted program and is costly. Animal models demonstrate that progesterone prevents depression-like behaviors. However, studies of progesterone's effects in women suffering from PPD are few and inconclusive. We hypothesize that orally dosed progesterone will increase concentrations of allopregnanolone in the central nervous system, which should relieve symptoms of PPD.


Assuntos
Depressão Pós-Parto/tratamento farmacológico , Progesterona/administração & dosagem , Progesterona/uso terapêutico , Administração Oral , Esquema de Medicação , Feminino , Humanos
10.
N Z Med J ; 129(1433): 37-40, 2016 Apr 22.
Artigo em Inglês | MEDLINE | ID: mdl-27349159

RESUMO

AIMS: We previously reported that passage of the 2013 Psychoactive Substances Act (PSA), which limited retail availability of synthetic cannabinoids (SCs), was followed by reduced numbers of presentations to one psychiatric emergency service. This analysis examined national trends in hospital presentations associated with use of SCs, and how these changed after passage of laws in 2011, 2013 and 2014, that altered SC availability. METHODS: Analysis of 2011-2015 Ministry of Health dataset of patients presenting to hospital associated with use of SCs. The relationship between changes in hospital presentations and the 3 legislative changes was evaluated using time series models. RESULTS: Monthly hospital presentations peaked in mid-2011, 2013 and 2014. Steep declines in numbers of presentations occurred after law changes between August and September 2011 (current SCs removed from sale), July and August 2013 (reduced number of SC retail outlets), and May and June 2014 (all SCs banned). The 2013 reduction in supply was associated with mean monthly presentations decreasing by 10.6 (95% CI 1.5, 19.7; p=0.023). Patients were predominantly young males, and presented with a range of emotional, psychotic and behavioural symptoms. CONCLUSIONS: Law changes that reduced SC availability were associated with reduced harms (hospitalisation) associated with use of SCs.


Assuntos
Canabinoides/provisão & distribuição , Controle de Medicamentos e Entorpecentes/legislação & jurisprudência , Feminino , Humanos , Masculino , Nova Zelândia , Inquéritos e Questionários
11.
N Z Med J ; 128(1414): 15-8, 2015 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-26117386

RESUMO

AIMS: Use of synthetic cannabinoids is associated with a range of mental health harms. The 2013 Psychoactive Substances Act (PSA) was intended to limit retail availability of synthetic cannabinoids which had acceptable safety profiles. We evaluated numbers and clinical characteristics of patients presenting with mental health harms associated with use of synthetic cannabinoids for three months before and after implementation of the PSA on 18July 2013. METHODS: Retrospective audit of case notes of patients presenting to an emergency psychiatric service (EPS) in Dunedin. RESULTS: In the three months post-PSA, there was a 42% reduction in EPS contacts and 52% reduction in patient presentations, compared with the three months pre-PSA. Patient demographics (predominantly young males with prior contact with mental health services), presenting symptoms (mood and psychotic symptoms and suicidality), and management and disposition were identical in both periods. CONCLUSIONS: The decrease in mental health harms, as measured by frequency of EPS contacts, appeared to be due to reduced retail availability of synthetic cannabinoids rather that reduced toxicity of available products.


Assuntos
Sintomas Comportamentais/prevenção & controle , Canabinoides , Drogas Desenhadas , Indóis , Naftalenos , Retirada de Medicamento Baseada em Segurança , Adulto , Sistemas de Notificação de Reações Adversas a Medicamentos/estatística & dados numéricos , Sintomas Comportamentais/induzido quimicamente , Sintomas Comportamentais/epidemiologia , Canabinoides/química , Canabinoides/farmacologia , Drogas Desenhadas/química , Drogas Desenhadas/farmacologia , Serviços de Emergência Psiquiátrica/estatística & dados numéricos , Feminino , Humanos , Indóis/química , Indóis/farmacologia , Masculino , Auditoria Médica , Saúde Mental/estatística & dados numéricos , Naftalenos/química , Naftalenos/farmacologia , Nova Zelândia , Avaliação de Resultados em Cuidados de Saúde , Estudos Retrospectivos , Retirada de Medicamento Baseada em Segurança/métodos , Retirada de Medicamento Baseada em Segurança/organização & administração
13.
J Palliat Med ; 15(4): 400-3, 2012 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-22468772

RESUMO

Depression is highly prevalent in patients with advanced cancer, commonly affecting quality of life. Considering the response delay with conventional antidepressants and the short life expectancy for these patients, treatments for Major Depressive Disorder (MDD) with faster onset of action are desirable. In this case report, a female patient with metastatic ovarian cancer presented rapid and sustained response to intramuscular (IM) injections of ketamine (1mg/kg). Over a course of six treatments, her mood response was identical on each occasion and provided remission of her depressive symptoms. Pain was also improved, although for a shorter duration. These findings support the use of IM ketamine as a possible antidepressant option for this population.


Assuntos
Anestésicos Dissociativos/uso terapêutico , Transtorno Depressivo Maior/tratamento farmacológico , Ketamina/uso terapêutico , Neoplasias/tratamento farmacológico , Dor/tratamento farmacológico , Adulto , Anestésicos Dissociativos/administração & dosagem , Transtorno Depressivo Maior/etiologia , Transtorno Depressivo Maior/psicologia , Progressão da Doença , Transtorno Distímico , Feminino , Humanos , Injeções Intramusculares , Ketamina/administração & dosagem , Neoplasias/complicações , Neoplasias/psicologia , Dor/etiologia , Medição da Dor , Psicometria , Qualidade de Vida/psicologia , Estatística como Assunto
14.
Eur J Clin Pharmacol ; 68(4): 415-8, 2012 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-22037562

RESUMO

PURPOSE: This study describes the pharmacokinetics, safety, and tolerability of ribavirin in hemodialysis-dependent patients. METHODS: Six adult patients (4 male, 2 female) were recruited from a hemodialysis clinic where they were receiving regular hemodialysis sessions. Patients received a single oral 400-mg dose of ribavirin (2 × 200-mg capsules) after an overnight fast. A 4-h hemodialysis session was performed between 6 and 10 h post-dose. Plasma and urinary concentrations of ribavirin were determined using validated high-performance liquid chromatography/tandem mass spectrometric methods. RESULTS: Single oral doses of ribavirin 400 mg were safe and well tolerated in this population. Urinary excretion of ribavirin over 48 h was minimal (0.6 mg: approximately 0.14% of the dose). The mean amount removed during the 4-h hemodialysis session (9.6 mg) represented approximately 2.4% of the dose. CONCLUSIONS: Ribavirin hemodialysis clearance (CLhd = 74.5 ml/min) represented approximately 50% of the renal clearance (CLr) measured in subjects with normal renal function (CLr = 129 ml/min).


Assuntos
Antivirais/farmacocinética , Falência Renal Crônica/metabolismo , Adulto , Antivirais/sangue , Antivirais/urina , Feminino , Humanos , Falência Renal Crônica/terapia , Masculino , Pessoa de Meia-Idade , Diálise Renal , Ribavirina/sangue , Ribavirina/farmacocinética , Ribavirina/urina
15.
Pediatr Cardiol ; 32(4): 433-41, 2011 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-21259004

RESUMO

This study aimed to assess the efficacy and tolerability of atorvastatin in Tanner stage (TS) 1 patients ages 6 to 10 years and TS ≥ 2 patients ages 10 to <18 years with genetically confirmed heterozygous familial hypercholesterolemia (HeFH) and a low density lipoprotein cholesterol (LDL-C) level of 4 mmol/l (155 mg/dl) or higher. In this open-label, 8-week study, 15 TS 1 children were treated initially with atorvastatin 5 mg/day and 24 TS ≥ 2 children with 10 mg/day. Doses were doubled at week 4 if the LDL-C target (<3.35 mmol/l [130 mg/dl]) was not achieved. The efficacy variables were the percentage change from baseline in LDL-C, total cholesterol (TC), triglycerides (TG), high density lipoprotein cholesterol (HDL-C), very low density lipoprotein cholesterol (VLDL-C), and apolipoprotein (Apo) A-I and Apo B. Safety evaluations included clinical monitoring, subject-reported adverse events (AEs), vital signs, and clinical laboratory tests. The mean values for LDL-C, TC, VLDL-C, and Apo B decreased by week 2 among all TS 1 and TS ≥ 2 patients, whereas TG, HDL-C, and Apo A-I varied considerably from week to week. After 8 weeks, the mean reduction in LDL-C was -40.7% ± 8.4 for the TS 1 children and -39.7% ± 10.3 for the TS ≥ 2 children. For the TS 1 patients, the mean reductions were -34.1% ± 6.9 for TC and -6.0% ± 32.1 for TG. The corresponding changes for the TS ≥ 2 patients were -35.6% ± 9.5 for TC and -21.1% ± 29.7 for TG. Four patients experienced mild to moderate treatment-related AEs. No serious AEs or discontinuations were reported. Overall, no difference in safety or tolerability was observed between the younger and older cohorts. Across the range of exposures after atorvastatin 5 to 10 mg (TS 1) or atorvastatin 10 to 20 mg (TS ≥ 2) doses for 8 weeks, clinically meaningful reductions in LDL-C, TC, VLDL-C, and Apo were observed with atorvastatin in pediatric patients who had HeFH. Atorvastatin also was well tolerated in this population.


Assuntos
HDL-Colesterol/sangue , LDL-Colesterol/sangue , Tolerância a Medicamentos , Ácidos Heptanoicos/uso terapêutico , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Hiperlipoproteinemia Tipo II/tratamento farmacológico , Pirróis/uso terapêutico , Adolescente , Atorvastatina , Criança , HDL-Colesterol/efeitos dos fármacos , LDL-Colesterol/efeitos dos fármacos , Relação Dose-Resposta a Droga , Feminino , Seguimentos , Ácidos Heptanoicos/administração & dosagem , Heterozigoto , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/administração & dosagem , Hiperlipoproteinemia Tipo II/sangue , Hiperlipoproteinemia Tipo II/genética , Masculino , Pirróis/administração & dosagem , Estudos Retrospectivos , Resultado do Tratamento
16.
J Clin Pharmacol ; 51(5): 731-8, 2011 May.
Artigo em Inglês | MEDLINE | ID: mdl-20484616

RESUMO

Dexrazoxane is approved as a cardioprotective agent for use in female patients with breast cancer who are receiving doxorubicin. The effect of renal insufficiency on elimination is not known. The pharmacokinetics of dexrazoxane 150 mg/m(2), given as a 15-minute constant-rate intravenous infusion, were assessed in 24 men and women with varying degrees of renal function in a single-dose, open-label, parallel-group study. Blood and urine samples were measured by a validated liquid chromatography/mass spectrometry assay. Dexrazoxane pharmacokinetic parameters were derived by standard noncompartmental methods. The effect of kidney function and effect of body surface area on the pharmacokinetics of dexrazoxane were analyzed using linear and nonlinear regression in the SPSS statistical program. Dexrazoxane clearance is decreased in subjects with kidney dysfunction. Compared with normal subjects (creatinine clearance [CL(CR)] >80 mL/min), mean area under the concentration curve from time 0 to infinity (AUC(0-inf)) was 2-fold greater in subjects with moderate (CL(CR) 30-50 mL/min) to severe (CL(CR) <30 mL/min) renal dysfunction. Modeling demonstrated that equivalent exposure (AUC(0-inf)) could be achieved if dosing were reduced by 50% in subjects with CL(CR) less than 40 mL/min compared with control subjects (CL(CR) >80 mL/min). Modeling study results suggested that equivalent exposure could be achieved if dosing was halved in subjects with CL(CR) less than 40 mL/min compared with controls.


Assuntos
Fármacos Cardiovasculares/farmacocinética , Rim/metabolismo , Razoxano/farmacocinética , Insuficiência Renal/metabolismo , Adulto , Idoso , Área Sob a Curva , Superfície Corporal , Fármacos Cardiovasculares/administração & dosagem , Fármacos Cardiovasculares/sangue , Fármacos Cardiovasculares/urina , Cromatografia Líquida de Alta Pressão , Creatinina/sangue , Feminino , Meia-Vida , Humanos , Infusões Intravenosas , Kentucky , Rim/fisiopatologia , Modelos Lineares , Masculino , Taxa de Depuração Metabólica , Pessoa de Meia-Idade , Modelos Biológicos , Dinâmica não Linear , Razoxano/administração & dosagem , Razoxano/sangue , Razoxano/urina , Insuficiência Renal/fisiopatologia , Espectrometria de Massas em Tandem , Adulto Jovem
17.
Clin Cancer Res ; 8(8): 2480-7, 2002 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-12171873

RESUMO

PURPOSE: High-dose IFNalpha-2b therapy (HDI) is the standard of adjuvant therapy for patients with high-risk melanoma, but toxicities of this regimen have limited its application. IFNs affect cytochrome P450 (CYP) enzymes, which metabolize many endogenous (e.g., steroids, fatty acids) and exogenous (e.g., drugs) substrates. No systematic studies have been performed to evaluate the effect of HDI on CYP enzymes. A significant inhibitory effect of HDI on CYP enzymes would increase the potential for adverse drug reactions and altered homeostasis through effects on hormone metabolism. METHODS: To evaluate the potential effect of HDI on CYP enzymes, 17 patients with high-risk melanoma were treated with HDI, and CYP enzyme activity was measured by administration of selectively metabolized probe drugs over time (days -6, +1, +26, and +52 of HDI). Probe drugs and/or metabolites were quantified and used to derive indexes of enzyme activity. RESULTS: The results indicate that HDI differentially impairs CYP-mediated metabolism, having no effect on some enzymes (CYP2E1) and substantial effects on others (CYP1A2; median 60% decrease). A significant association was found between the magnitude of CYP inhibition and the occurrence of side effects including fever and neurological toxicity, which may form a novel basis of the underlying pathophysiology of some IFNalpha-2b-induced toxicity. CONCLUSION: These data suggest that strategies to minimize the impairment of CYP enzymes could alter the toxicity profile of HDI and augment its therapeutic utility, and that recognition of these potential interactions is important in the therapeutic application of IFNs.


Assuntos
Sistema Enzimático do Citocromo P-450/metabolismo , Interferon-alfa/farmacocinética , Quimioterapia Adjuvante , Citocromo P-450 CYP1A2/metabolismo , Citocromo P-450 CYP2D6/metabolismo , Citocromo P-450 CYP2E1/metabolismo , Humanos , Interferon alfa-2 , Modelos Logísticos , Melanoma/tratamento farmacológico , Melanoma/cirurgia , Isoformas de Proteínas , Proteínas Recombinantes , Fatores de Tempo
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