Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 7 de 7
Filtrar
1.
Int J Clin Pharmacol Ther ; 56(5): 231-238, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29633699

RESUMO

OBJECTIVE: Gabapentin immediate release (GBP-IR), gabapentin gastric retentive (GBP-GR), and the prodrug gabapentin enacarbil extended release formulation (GEn) have been approved for management of postherpetic neuralgia (PHN) in adults. This is the first pharmacokinetic (PK) comparison of all three formulations using FDA-recommended doses for PHN. MATERIALS: This study compared the steady-state PK of GBP-IR 600 mg t.i.d., GBP-GR 1,800 mg q.d., and GEn 600 mg b.i.d. in healthy adults. METHODS: The open-label study consisted of a 3-day lead-in of escalating doses of GBP-IR, 5 days of treatment with each formulation (GPB-IR, GPB-GR, and GEn), and a 7-day taper period on 600 mg GEn q.d.. Plasma concentrations were collected on day 5 for each formulation. PK parameters were estimated from plasma concentration data. RESULTS: 14 healthy subjects (7 men, 7 women; mean (SD) age, 46.8 (7.60) years; mean (SD) body mass index, 26.7 (1.7) kg/m2) received all doses and completed the study. GBP-GR resulted in substantially (~ 4-fold) higher peak-to-trough ratio and percent fluctuation compared to GEn. GEn resulted in more sustained and less fluctuating daily exposure relative to GBP-IR, particularly at the end of 24 hours of dosing. In contrast, gabapentin fluctuation from GBP-IR consisted of 3 distinct peaks. After dose normalization, gabapentin exposure with GEn was ~ 2.2-fold and ~ 1.4-fold higher compared to GBP-GR and GBP-IR, respectively. All treatments were well tolerated. CONCLUSION: GEn requires less frequent dosing compared with GBP-IR and fluctuates less with sustained gabapentin exposure throughout the day. These PK differences may have clinically relevant implications.
.


Assuntos
Aminas/farmacocinética , Analgésicos/farmacocinética , Ácidos Cicloexanocarboxílicos/farmacocinética , Ácido gama-Aminobutírico/farmacocinética , Administração Oral , Adulto , Aminas/administração & dosagem , Aminas/sangue , Aminas/química , Analgésicos/administração & dosagem , Analgésicos/sangue , Analgésicos/química , Disponibilidade Biológica , Ácidos Cicloexanocarboxílicos/administração & dosagem , Ácidos Cicloexanocarboxílicos/sangue , Ácidos Cicloexanocarboxílicos/química , Preparações de Ação Retardada , Composição de Medicamentos , Monitoramento de Medicamentos , Feminino , Gabapentina , Voluntários Saudáveis , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Biológicos , Equivalência Terapêutica , Ácido gama-Aminobutírico/administração & dosagem , Ácido gama-Aminobutírico/sangue , Ácido gama-Aminobutírico/química
2.
Antimicrob Agents Chemother ; 59(8): 4379-86, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-25870056

RESUMO

Solithromycin, a new macrolide and the first fluoroketolide, is in late-stage clinical development and, like older macrolides, is primarily metabolized and excreted through liver-dependent mechanisms. This study evaluated the safety and pharmacokinetics of solithromycin in patients with chronic liver disease. This open-label, multiple-dose study in subjects with hepatic impairment and in healthy control subjects (matched for age, weight, and sex) enrolled 8 Child-Pugh class A (mild), 8 class B (moderate), and 8 class C (severe) patients and 9 healthy controls. Subjects (n = 33) received one 800-mg dose on day 1 followed by once-daily doses of 400 mg on days 2 through 5. The most commonly reported adverse events were mild diarrhea and mild headache, and no significant differences were noted between hepatically impaired subjects and healthy controls. The pharmacokinetics of plasma solithromycin in subjects with mild and moderate impairment was similar to that in control subjects. In subjects with severe impairment, total exposure to solithromycin at steady state (area under the plasma concentration-time curve [AUC0-tau]) was decreased compared to that in control subjects, which may have been related to the higher body mass index of individuals in this group. No greater accumulation was noted in any hepatically impaired cohort on day 5 compared to that in control subjects. No decrease in dosage is therefore needed when administering solithromycin to patients with mild, moderate, or severe hepatic impairment. Solithromycin was well tolerated in this patient population, and no significant differences in safety, compared to healthy controls, were noted.


Assuntos
Hepatopatias/tratamento farmacológico , Macrolídeos/efeitos adversos , Macrolídeos/farmacocinética , Triazóis/efeitos adversos , Triazóis/farmacocinética , Adulto , Idoso , Área Sob a Curva , Índice de Massa Corporal , Estudos de Casos e Controles , Feminino , Humanos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Hepatopatias/metabolismo , Masculino , Pessoa de Meia-Idade
3.
Am J Ther ; 18(1): 2-8, 2011 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-20864883

RESUMO

Morphine sulfate and naltrexone hydrochloride extended release capsules (EMBEDA®, King Pharmaceuticals®, Inc., Bristol, TN), indicated for the management of chronic, moderate to severe pain, contain extended release morphine pellets with a sequestered naltrexone core (MS-sNT). If the product is tampered with by crushing, naltrexone, a µ-opioid antagonist, is intended for release to mitigate morphine-induced subjective effects. The primary end point of this randomized 2-way crossover study in healthy fasted volunteers was evaluation of morphine bioequivalence between MS-sNT (treatment A) and morphine sulfate extended release capsules (KADIAN®, treatment B). Morphine pharmacokinetics were assessed predose to 72 hours postdose of single 100-mg doses of treatment A or B. Analysis of variance of ln-transformed ratios of least squares mean of the area under the concentration time curve (AUC) from time 0 to last measurable concentration (AUC0-t) and AUC from time 0 to infinity (AUCinf) and maximum serum concentration (Cmax) for treatments A versus B were performed. Ratios and 90% confidence intervals for least squares mean for AUC0-t (102.2%; 98.6-105.9%), AUCinf (97.4%; 91.2-104.1%), and Cmax (93.8%; 82.4-106.7%) indicated bioequivalence between the 2 formulations. When subjects who vomited during the 12-hour dosing interval were excluded, the confidence interval for AUC0-t and AUCinf fell within the 80%-125% range, but the lower limit for Cmax was 76.9%.


Assuntos
Analgésicos Opioides/farmacocinética , Morfina/farmacocinética , Naltrexona/farmacocinética , Adulto , Analgésicos Opioides/administração & dosagem , Área Sob a Curva , Disponibilidade Biológica , Biotransformação , Cápsulas , Química Farmacêutica , Estudos Cross-Over , Preparações de Ação Retardada , Método Duplo-Cego , Combinação de Medicamentos , Jejum/metabolismo , Feminino , Meia-Vida , Humanos , Masculino , Pessoa de Meia-Idade , Morfina/administração & dosagem , Naltrexona/administração & dosagem , Equivalência Terapêutica , Adulto Jovem
4.
J Clin Pharmacol ; 56(9): 1130-40, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-26865195

RESUMO

Cabozantinib is a tyrosine kinase inhibitor approved for the treatment of patients with progressive, metastatic medullary thyroid cancer. Two clinical pharmacology studies were conducted to characterize single-dose pharmacokinetics (PK) of cabozantinib in renally or hepatically impaired subjects. Study 1 enrolled 10 subjects, each with mild or moderate impairment of renal function; 12 healthy subjects were matched to the moderate group for age, sex, and body mass index (BMI). Study 2 enrolled 8 males each with mild or moderate hepatic impairment; 10 healthy males were matched to the moderate group for age, BMI, and ethnicity. All subjects received one 60 mg cabozantinib oral capsule dose followed by PK sampling over 21 days. Plasma concentration and protein binding were determined by liquid chromatography tandem mass spectrometry and equilibrium dialysis, respectively. PK parameters were computed using noncompartmental methods. Geometric least squared mean (LSM) ratios for plasma cabozantinib AUC0-∞ for impaired to normal organ function cohorts were (1) approximately 30% and 6% higher in subjects with mild and moderate renal impairment, respectively, and (2) approximately 81% and 63% higher in subjects with mild and moderate hepatic impairment, respectively. The percentage of unbound drug was slightly higher in both moderately impaired cohorts. No deaths or discontinuations due to adverse events occurred in either study. Cabozantinib should be used with caution in subjects with mild or moderate renal impairment. Subjects with mild or moderate hepatic impairment administered cabozantinib should be monitored closely for potential treatment-emergent drug toxicity that may necessitate a dose hold or reduction.


Assuntos
Anilidas/sangue , Hepatopatias/sangue , Piridinas/sangue , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Insuficiência Renal/sangue , Idoso , Anilidas/efeitos adversos , Anilidas/farmacocinética , Área Sob a Curva , Estudos de Coortes , Feminino , Humanos , Hepatopatias/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Piridinas/efeitos adversos , Piridinas/farmacocinética , Insuficiência Renal/tratamento farmacológico , Resultado do Tratamento
5.
J Clin Pharmacol ; 52(5): 747-56, 2012 May.
Artigo em Inglês | MEDLINE | ID: mdl-21593282

RESUMO

Although contraindicated, coingestion of alcohol and opioids by patients or drug abusers is a major health concern because of dangerous additive and potentially life-threatening sedative and respiratory effects. In addition, alcohol has been shown to disrupt the extended-release characteristics of certain extended-release opioid formulations, releasing a hazardous amount of opioid over a short time period. Morphine sulfate and naltrexone hydrochloride extended release capsules (MS-sNT), which contain naltrexone sequestered in each pellet core, are indicated for management of chronic, moderate to severe pain. Sequestered naltrexone is designed for release upon product tampering (crushing) to potentially mitigate morphine-induced subjective effects. This open-label, single-dose, 4-way crossover, pharmacokinetic drug interaction study compared the relative bioavailability of morphine and naltrexone when MS-sNT is administered (under fasting conditions) with increasing doses of alcohol. Thirty-two healthy, opioid-naive adults were randomized to MS-sNT administered with 240 mL of 4%, 20%, or 40% alcohol or water. No drug interaction was found between morphine in MS-sNT and 4% or 20% alcohol. Administration with 40% alcohol did not affect overall morphine exposure but was associated with a 2-fold increase in C(max) and reduction of t(max) from 9 to 4 hours versus MS-sNT taken with water. Naltrexone sequestering was successful in all treatment arms and not affected by coadministration with alcohol over the dose range tested.


Assuntos
Consumo de Bebidas Alcoólicas/metabolismo , Analgésicos Opioides/farmacocinética , Etanol/administração & dosagem , Morfina/farmacocinética , Naltrexona/farmacocinética , Antagonistas de Entorpecentes/farmacocinética , Adulto , Consumo de Bebidas Alcoólicas/sangue , Analgésicos Opioides/administração & dosagem , Analgésicos Opioides/sangue , Analgésicos Opioides/química , Análise de Variância , Área Sob a Curva , Cápsulas , Estudos Cross-Over , Preparações de Ação Retardada , Combinação de Medicamentos , Interações Medicamentosas , Etanol/sangue , Feminino , Humanos , Masculino , Taxa de Depuração Metabólica , Modelos Biológicos , Morfina/administração & dosagem , Morfina/sangue , Morfina/química , Naltrexona/administração & dosagem , Naltrexona/sangue , Naltrexona/química , Antagonistas de Entorpecentes/administração & dosagem , Antagonistas de Entorpecentes/sangue , Antagonistas de Entorpecentes/química , Adulto Jovem
6.
Drugs R D ; 11(3): 259-75, 2011 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-21902287

RESUMO

BACKGROUND: Opioid analgesics can be abused by crushing followed by solubilization and intravenous injection to attain rapid absorption. Morphine sulfate and naltrexone hydrochloride extended release capsules (EMBEDA, MS-sNT), indicated for management of chronic, moderate to severe pain, contain pellets of morphine sulfate with a sequestered naltrexone core. Should product tampering by crushing occur, the sequestered naltrexone is intended for release to reduce morphine-induced subjective effects. OBJECTIVE: This study compared self-reports of high, euphoria, and drug-liking effects of intravenous morphine alone versus intravenous morphine combined with naltrexone in a clinical simulation of intravenous abuse of crushed MS-sNT. METHODS: This single-center, randomized, double-blind, crossover study characterized subjective effects of naltrexone administered intravenously at the same ratio to morphine present in MS-sNT. Subjects were male and had used prescription opioids five or more times within the previous 12 months to get 'high' but were not physically dependent on opioids. The primary outcome was the response to the Drug Effects Questionnaire (DEQ) question #5, "How high are you now?" (100 mm Visual Analog Scale [VAS]). The secondary outcome was the response to a Cole/Addiction Research Center Inventory (ARCI) Stimulation-Euphoria modified scale. Additional outcomes included response to VAS drug liking, the remaining DEQ questions, and pupillometry. RESULTS: Administration of intravenous naltrexone following intravenous morphine diminished mean high (29.8 vs 85.2 mm), Cole/ARCI Stimulation-Euphoria (13.7 vs 27.8 mm), and drug-liking (38.9 vs 81.4 mm) scores (all p < 0.0001) compared with intravenous morphine alone. No serious adverse events occurred as a result of the tested ratio of naltrexone to morphine. CONCLUSIONS: Results in this study population suggest that naltrexone added to morphine in the 4% ratio within MS-sNT mitigates the high, euphoria, and drug liking of morphine alone, potentially reducing the attractiveness for product tampering. Assessment of the true clinical significance of these findings will require further study.


Assuntos
Analgésicos Opioides/farmacologia , Morfina/farmacologia , Naltrexona/farmacologia , Transtornos Relacionados ao Uso de Opioides/tratamento farmacológico , Analgésicos Opioides/efeitos adversos , Analgésicos Opioides/farmacocinética , Estudos Cross-Over , Método Duplo-Cego , Combinação de Medicamentos , Interações Medicamentosas , Euforia/efeitos dos fármacos , Humanos , Injeções Intravenosas , Masculino , Morfina/administração & dosagem , Morfina/efeitos adversos , Morfina/farmacocinética , Naltrexona/administração & dosagem , Naltrexona/efeitos adversos , Naltrexona/farmacocinética , Antagonistas de Entorpecentes/administração & dosagem , Antagonistas de Entorpecentes/efeitos adversos , Antagonistas de Entorpecentes/farmacocinética , Transtornos Relacionados ao Uso de Opioides/metabolismo , Dor/tratamento farmacológico , Medição da Dor/efeitos dos fármacos , Transtornos Relacionados ao Uso de Substâncias/tratamento farmacológico , Transtornos Relacionados ao Uso de Substâncias/metabolismo , Adulto Jovem
7.
Adv Ther ; 27(11): 846-58, 2010 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-20949341

RESUMO

INTRODUCTION: Morphine sulfate and naltrexone hydrochloride extended release capsules, indicated for chronic moderate-to-severe pain, contain extended-release morphine pellets with a sequestered naltrexone core. If pellets are tampered by crushing, naltrexone is released to reduce morphine-induced effects that appeal to opioid abusers. The primary objective of this study was to assess single-dose relative bioavailability of morphine when morphine sulfate and naltrexone hydrochloride extended release capsules were taken under fed and fasting conditions and when pellets were sprinkled on apple sauce. METHODS: This was a single-center, randomized, open-label study in 36 healthy adult volunteers. Subjects took a 100-mg morphine sulfate and naltrexone hydrochloride extended release capsule intact with 240 mL water, under fed and fasted conditions, and when the capsule was opened and pellets were sprinkled over apple sauce and consumed without chewing; each treatment was separated by a 14-day washout. Plasma samples were collected just before dosing through 72 hours postdose for pharmacokinetic analyses of morphine, and through 168 hours postdose for naltrexone and its major metabolite 6-ß-naltrexol. RESULTS: Morphine bioavailability was similar for all treatments. There was a lack of sprinkle effect (sprinkle vs. whole, fasted); 90% confidence intervals (CIs) of ratios of log-transformed least squares means for area under the plasma concentration-time curve (AUC) and peak plasma concentration (C(max)) fell within 80%-125% boundaries. For the food effect, 90% CIs were within the boundaries for AUC, but C(max) was reduced and time to C(max) was delayed by 2.5 hours under fed conditions. Naltrexone remained sequestered under all treatment conditions with only trace systemic exposure. CONCLUSION: Results indicated that morphine sulfate and naltrexone hydrochloride extended release capsules can be administered without regard to meals, and contents can be sprinkled over apple sauce and consumed without chewing by patients with difficulty swallowing.


Assuntos
Comportamento Alimentar , Interações Alimento-Droga , Morfina/farmacologia , Naltrexona/farmacocinética , Adulto , Área Sob a Curva , Disponibilidade Biológica , Estudos Cross-Over , Preparações de Ação Retardada , Gorduras na Dieta , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Jejum , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Morfina/administração & dosagem , Naltrexona/administração & dosagem
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA