ABSTRACT
OBJECTIVES: Guideline-issuing groups differ regarding the recommendation that patients with stage I colon cancer receive surveillance colonoscopy after cancer-directed surgery. This observational comparative effectiveness study was conducted to evaluate the association between surveillance colonoscopy and colon cancer-specific mortality in early stage patients. METHODS: This was a retrospective cohort study of the Surveillance, Epidemiology, and End Results database combined with Medicare claims. Surveillance colonoscopy was assessed as a time-varying exposure up to 5 years after cancer-directed surgery with the following groups: no colonoscopy, one colonoscopy, and ≥ 2 colonoscopies. Inverse probability of treatment weighting was used to balance covariates. The time-dependent Cox regression model was used to obtain inverse probability of treatment weighting-adjusted hazard ratios (HRs), with 95% confidence intervals (CIs) for 5- and 10-year colon cancer, other cancer, and noncancer causes of death. RESULTS: There were 8,783 colon cancer cases available for analysis. Overall, compared with patients who received one colonoscopy, the no colonoscopy group experienced an increased rate of 10-year colon cancer-specific mortality (HR = 1.63; 95% CI 1.31-2.04) and noncancer death (HR = 1.36; 95% CI 1.25-1.49). Receipt of ≥ 2 colonoscopies was associated with a decreased rate of 10-year colon cancer-specific death (HR = 0.60; 95% CI 0.45-0.79), other cancer death (HR = 0.68; 95% CI 0.53-0.88), and noncancer death (HR = 0.69; 95% CI 0.62-0.76). Five-year cause-specific HRs were similar to 10-year estimates. DISCUSSION: These results support efforts to ensure that stage I patients undergo surveillance colonoscopy after cancer-directed surgery to facilitate early detection of new and recurrent neoplastic lesions.
Subject(s)
Carcinoma/surgery , Colonic Neoplasms/surgery , Neoplasm Recurrence, Local/diagnosis , Age Factors , Aged , Aged, 80 and over , Carcinoma/mortality , Carcinoma/pathology , Cause of Death , Colonic Neoplasms/mortality , Colonic Neoplasms/pathology , Comparative Effectiveness Research , Disease Management , Female , Humans , Information Storage and Retrieval , Male , Medicare , Neoplasm Grading , Neoplasm Staging , Proportional Hazards Models , SEER Program , United StatesABSTRACT
BACKGROUND: Addition of CDK4/6 inhibitors (CDK4/6i) to endocrine therapy significantly increased progression-free survival, leading to their approval and incorporation into the metastatic breast cancer treatment paradigm. With these inhibitors being routinely used for patients with advanced estrogen receptor-positive (ER+) breast cancer, resistance to these agents and its impact on subsequent therapy needs to be understood. Considering the central role of ER in driving the growth of ER+ breast cancers, and thus endocrine agents being a mainstay in the treatment paradigm, the effects of prior CDK4/6i exposure on ER signaling and the relevance of ER-targeted therapy are important to investigate. The objective of this study was to evaluate the anti-tumor activity of elacestrant, a novel oral selective estrogen receptor degrader (SERD), in preclinical models of CDK4/6i resistance. METHODS: Elacestrant was evaluated as a single agent, and in combination with alpelisib or everolimus, in multiple in vitro models and patient-derived xenografts that represent acquired and "de novo" CDK4/6i resistance. RESULTS: Elacestrant demonstrated growth inhibition in cells resistant to all three approved CDK4/6i (palbociclib, abemaciclib, ribociclib) in both ESR1 wild-type and mutant backgrounds. Furthermore, we demonstrated that elacestrant, as a single agent and in combination, inhibited growth of patient-derived xenografts that have been derived from a patient previously treated with a CDK4/6i or exhibit de novo resistance to CDK4/6i. While the resistant lines demonstrate distinct alterations in cell cycle modulators, this did not affect elacestrant's anti-tumor activity. In fact, we observe that elacestrant downregulates several key cell cycle players and halts cell cycle progression in vitro and in vivo. CONCLUSIONS: We demonstrate that breast cancer tumor cells continue to rely on ER signaling to drive tumor growth despite exposure to CDK4/6i inhibitors. Importantly, elacestrant can inhibit this ER-dependent growth despite previously reported mechanisms of CDK4/6i resistance observed such as Rb loss, CDK6 overexpression, upregulated cyclinE1 and E2F1, among others. These data provide a scientific rationale for the evaluation of elacestrant in a post-CDK4/6i patient population. Additionally, elacestrant may also serve as an endocrine backbone for rational combinations to combat resistance.
Subject(s)
Breast Neoplasms/metabolism , Cyclin-Dependent Kinase 4/antagonists & inhibitors , Cyclin-Dependent Kinase 6/antagonists & inhibitors , Drug Resistance, Neoplasm , Protein Kinase Inhibitors/pharmacology , Receptors, Estrogen/metabolism , Tetrahydronaphthalenes/pharmacology , Animals , Antineoplastic Agents , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Breast Neoplasms/drug therapy , Breast Neoplasms/pathology , Cell Cycle Proteins/metabolism , Cell Line, Tumor , Cell Proliferation/drug effects , Disease Models, Animal , Female , Humans , Mice , Models, Biological , Molecular Targeted Therapy , Xenograft Model Antitumor AssaysABSTRACT
OBJECTIVE: To ascertain the role of patient age as an influencing factor in the pharmacokinetics of anagrelide and to clarify whether different dosing is required in young (18 - 50 years) vs. elderly (≥ 65 years) patients with essential thrombocythemia (ET). METHOD: This Phase II, multicenter, open-label study compared the pharmacokinetics, pharmacodynamics and tolerability of anagrelide and its active metabolite, 3-hydroxy-anagrelide, in young and elderly patients with ET. Three days prior to pharmacokinetic assessment, patients divided their normal daily anagrelide into a structured twice-daily dosing (BID) schedule. Serial blood samples were obtained for pharmacokinetic and pharmacodynamic analysis over a 12-h dosing interval. Anagrelide and 3-hydroxy-anagrelide plasma concentrations were normalized to a common dose (1 mg BID) to control for dosing differences between patients. Patients were monitored routinely for adverse events (AEs) and vital signs. RESULTS: A total of 24 patients (12 young; 12 elderly) completed the study. The dose-normalized anagrelide maximum observed plasma concentration (Cmax) and area under the plasma concentration vs. time curve over one dosing interval (AUCτ), were higher in elderly patients compared with young patients (Cmax: 3.63 vs. 2.66 ng/ml; p = 0.09, AUCτ: 10.3 vs. 6.4 ng×h/ml; p = 0.01). In contrast, the dose-normalized 3-hydroxy-anagrelide Cmax and AUCτ were lower in the elderly patients when compared with young patients (Cmax: 4.19 vs. 7.26 ng/ml; p = 0.02, AUCτ: 17.4 vs. 27.6 ng×h/ml; p = 0.03). No significant difference was observed in the geometric mean terminal half-life (t1/2) of anagrelide in elderly and young patients (1.4 vs. 1.3 h, respectively; p = 0.38), whereas the geometric mean t1/2 of 3-hydroxy-anagrelide was significantly longer in the elderly patients compared with the young patients (3.5 vs. 2.7 h, respectively; p = 0.01). There were no significant differences in platelet count or vital signs between the age groups. Anagrelide was well tolerated; there were no serious AEs or AEs that led to withdrawal from the study. CONCLUSIONS: To conclude, the differences observed in anagrelide and 3-hydroxy-anagrelide pharmacokinetics do not justify using a different dosing regimen in young vs. elderly patients with ET.
Subject(s)
Hematologic Agents/pharmacokinetics , Quinazolines/pharmacokinetics , Thrombocythemia, Essential/drug therapy , Thrombopoiesis/drug effects , Adolescent , Adult , Age Factors , Aged , Area Under Curve , Biotransformation , Europe , Female , Half-Life , Hematologic Agents/administration & dosage , Hematologic Agents/adverse effects , Hematologic Agents/blood , Humans , Hydroxylation , Male , Metabolic Clearance Rate , Middle Aged , Models, Biological , Platelet Count , Quinazolines/administration & dosage , Quinazolines/adverse effects , Quinazolines/blood , Thrombocythemia, Essential/blood , Thrombocythemia, Essential/diagnosis , Treatment Outcome , Young AdultABSTRACT
INTRODUCTION/BACKGROUND: This first-in-human, phase 1 study aimed to characterize the safety, tolerability, maximum tolerated dose (MTD), pharmacokinetic (PK) profile, and antitumor activity of RAD140, an oral selective androgen receptor (AR) modulator (SARM). PATIENTS AND METHODS: This dose-escalation study with a 3 + 3 design and PK expansion cohort enrolled postmenopausal women with ER+/HER2- metastatic breast cancer (mBC). Serum sex hormone-binding globulin (SHBG) and prostate-specific antigen (PSA) were used as surrogate markers of AR engagement. RESULTS: Twenty-two (21 AR+) heavily pretreated mBC patients were enrolled. Dose levels included 50 mg (n = 6), 100 mg (n = 13), and 150 mg (n = 3) once daily (QD). Most frequent (> 10%) treatment-emergent adverse events (TEAEs) were elevated AST (59.1%), ALT (45.5%), and total blood bilirubin (27.3%), and vomiting, dehydration, and decreased appetite and weight (27.3% each). Grade 3/4 TEAEs occurred in 16 (72.7%) patients and included elevations in AST/ALT and hypophosphatemia (22.7% each). Treatment-related TEAEs occurred in 17 per 22 patients (77.3%); 7 (31.8%) were Grade 3; none were Grade 4. The half-life (t1/2) of 44.7 hours supported QD dosing. At the MTD of 100 mg/day, 1 patient with an ESR1 mutation at baseline had a partial response. Overall, clinical benefit rate at 24 weeks was 18.2%, and median progression-free survival was 2.3 months. SHBG decreased in 18 per 18 patients, and PSA increased in 16 per 20 patients. Paired baseline and on-treatment tumor biopsies demonstrated AR engagement. CONCLUSION: RAD140 is a novel oral AR-targeted agent for the treatment of AR+/ER+/HER2- mBC with an acceptable safety profile and preliminary evidence of target engagement and antitumor activity.
Subject(s)
Antineoplastic Agents/therapeutic use , Breast Neoplasms/drug therapy , Breast Neoplasms/metabolism , Nitriles/therapeutic use , Oxadiazoles/therapeutic use , Administration, Oral , Aged , Breast Neoplasms/pathology , Disease-Free Survival , Dose-Response Relationship, Drug , ErbB Receptors , Female , Humans , Maximum Tolerated Dose , Middle Aged , Neoplasm MetastasisABSTRACT
Video 1Video presentation of a single session EUS-guided cholecystoduodenostomy and gastrojejunostomy.
ABSTRACT
BACKGROUND AND OBJECTIVE: Abaloparatide, an anabolic osteoporosis treatment administered by subcutaneous (SC) injection, increases bone mineral density (BMD) and reduces fracture risk in postmenopausal women with osteoporosis. The abaloparatide-solid Microstructured Transdermal System [abaloparatide-sMTS (Kindeva, St Paul, MN, USA)], which delivers abaloparatide intradermally, is in development to provide an alternative method for abaloparatide delivery. The objective of this study was to evaluate the ability of subjects to self-administer abaloparatide-sMTS, based on pharmacokinetic and pharmacodynamic markers. METHODS: In this single-arm, open-label, Phase 1b study, 22 healthy postmenopausal women aged 50-85 years with low BMD were trained to self-administer abaloparatide-sMTS 300 µg once daily to the thigh for 5 min for 29 days. The primary endpoint was systemic exposure to abaloparatide. Secondary endpoints included percent change from baseline in serum procollagen type I N-terminal propeptide (s-PINP), patient experience, and safety. RESULTS: All 22 subjects completed the study. At baseline, mean age was 65.2 years, mean total hip T-score was - 1.32, and mean lumbar spine T-score was - 1.98. On Day 1, the median time to reach maximum concentration (Tmax) for abaloparatide-sMTS was 0.33 h and geometric mean (CV %) maximum concentration (Cmax) and area under the concentration-time curve from time 0 to the time of the last quantifiable concentration (AUC0-t) were 447 (38.0) pg/mL and 678 (45.3) pg·h/mL, respectively; the pharmacokinetic profile was similar on Days 15 and 29. Median percentage change in s-PINP was 45.4% and 64.4% at Days 15 and 29, respectively. The most common adverse events (AEs) were application site erythema, pain, and swelling, which were mostly of mild or moderate severity. No AEs led to study drug withdrawal and no serious AEs were reported. The success rate for self-administration at first application was 99.7%, and subject acceptability was high (~ 4.5 on a 5-point Likert Scale). CONCLUSIONS: Subjects successfully self-administered abaloparatide-sMTS, which provided a consistent pharmacokinetic profile over 29 days and produced s-PINP increases from baseline similar to that observed in the pivotal trial with abaloparatide-SC. Observed patient experience along with the clinical data support continued clinical development of abaloparatide-sMTS. TRIAL REGISTRATION NUMBER: NCT04366726, Date of registration 04/29/2020, retrospectively registered.
Osteoporosis is a serious health condition that causes more than 2 million fractures in the USA annually. Treatment options for osteoporosis include drugs that prevent bone resorption and anabolic agents that build new bone. Bone anabolic agents, such as abaloparatide, have been shown to increase bone mineral density and reduce the risk of fracture in postmenopausal women with osteoporosis. Currently, all bone anabolic agents are delivered by subcutaneous injection. However, some patients do not like injectable treatments, which can negatively impact patients' adherence to prescribed medication. In this study, we describe a novel mode of administration, the abaloparatide-solid Microstructured Transdermal System (abaloparatide-sMTS), which is applied to the thigh for 5 min and delivers abaloparatide intradermally. The study showed that this new method delivered abaloparatide into the blood as effectively as subcutaneous injections and demonstrated signs of activity in the body. Study participants were satisfied with abaloparatide-sMTS and found it easy to use. The most common side effects were skin related, including redness, pain, and swelling, which resolved shortly after dosing.
Subject(s)
Bone Density Conservation Agents/therapeutic use , Bone Density/drug effects , Osteoporosis, Postmenopausal/drug therapy , Parathyroid Hormone-Related Protein/administration & dosage , Aged , Aged, 80 and over , Female , Humans , Injections, Subcutaneous , Lumbar Vertebrae/drug effects , Middle Aged , Peptide Fragments/blood , Procollagen/bloodABSTRACT
Metachromatic leukodystrophy (MLD) is a lysosomal storage disease caused by deficient arylsulfatase A (ASA) activity, which leads to neuronal sulfatide accumulation and motor and cognitive deterioration. Intrathecal delivery of a recombinant human ASA (TAK-611, formerly SHP611) is under development as a potential therapy for MLD. We used serum and cerebrospinal fluid (CSF) TAK-611 concentrations measured during the phase I/II trial of intrathecal TAK-611 to develop a pharmacokinetic (PK) model describing drug disposition. CSF data were well characterized by a two-compartment model in the central nervous system (CNS); a single central compartment described the serum data. Estimated parameters suggested rapid distribution of TAK-611 from CSF into the putative brain tissue compartment, with persistence in the brain between doses (median distributive and terminal half-lives in the CNS: 1.02 and 477 hours, respectively). This model provides a valuable basis for understanding the PK distribution of TAK-611 and for PK/pharmacodynamic analyses of functional outcomes.
Subject(s)
Brain/metabolism , Cerebroside-Sulfatase/administration & dosage , Leukodystrophy, Metachromatic/drug therapy , Models, Biological , Cerebroside-Sulfatase/pharmacokinetics , Child , Child, Preschool , Half-Life , Humans , Infant , Injections, Spinal , Tissue DistributionABSTRACT
Authors would like to correct the errors in table 2.
ABSTRACT
BACKGROUND AND OBJECTIVES: Advanced estrogen receptor-positive (ER+) breast cancer is currently treated with endocrine therapy. Elacestrant is a novel, nonsteroidal, selective estrogen receptor degrader with complex dose-related ER agonist/antagonist activity that is being developed as a treatment option for ER+ breast cancer. METHODS: Two first-in-human phase 1 studies of elacestrant in healthy postmenopausal women (Study 001/Study 004) were conducted to determine its pharmacokinetic and pharmacodynamic profile as well as its safety and maximum tolerated dose. RESULTS: In total, 140 postmenopausal subjects received at least one dose of study drug (114 received elacestrant and 26 received placebo). Single-ascending dose and multiple-ascending dose assessments showed that doses up to 1000 mg daily were safe and well tolerated, and the maximum tolerated dose was not reached. Oral administration of elacestrant had an absolute bioavailability of 10% and a mean half-life ranging from 27 to 47 h, reaching steady state after 5-6 days. Mean occupancy of the ER in the uterus after seven daily doses was 83% for 200 mg and 92% for 500 mg daily. The median ratio of elacestrant concentrations in the cerebral spinal fluid vs. plasma was 0.126% (500 mg dose) and 0.205% (200 mg dose). Most adverse events were related to the upper gastrointestinal tract. CONCLUSIONS: These data demonstrate that elacestrant has good bioavailability when administered orally with a half-life that supports once-daily administration. Engagement of the ER and some ability to cross the blood-brain barrier was demonstrated in addition to an acceptable safety profile.
Subject(s)
Postmenopause , Selective Estrogen Receptor Modulators/administration & dosage , Tetrahydronaphthalenes/administration & dosage , Administration, Oral , Aged , Biological Availability , Cohort Studies , Dose-Response Relationship, Drug , Female , Half-Life , Humans , Maximum Tolerated Dose , Middle Aged , Selective Estrogen Receptor Modulators/pharmacokinetics , Selective Estrogen Receptor Modulators/pharmacology , Tetrahydronaphthalenes/pharmacokinetics , Tetrahydronaphthalenes/pharmacologyABSTRACT
The case of a female presenting with Shiga toxin-producing Escherichia coli and hemolytic uremic syndrome highlights a severe neurologic complication that can be associated with these conditions.
ABSTRACT
INTRODUCTION: Although the colorectal cancer (CRC) mortality rate has significantly improved over the past several decades, many patients will have a recurrence following curative treatment. Despite this high risk of recurrence, adherence to CRC surveillance testing guidelines is poor which increases cancer-related morbidity and potentially, mortality. Several randomised controlled trials (RCTs) with varying surveillance strategies have yielded conflicting evidence regarding the survival benefit associated with surveillance testing. However, due to differences in study protocols and limitations of sample size and length of follow-up, the RCT may not be the best study design to evaluate this relationship. An observational comparative effectiveness research study can overcome the sample size/follow-up limitations of RCT designs while assessing real-world variability in receipt of surveillance testing to provide much needed evidence on this important clinical issue. The gap in knowledge that this study will address concerns whether adherence to National Comprehensive Cancer Network CRC surveillance guidelines improves survival. METHODS AND ANALYSIS: Patients with colon and rectal cancer aged 66-84 years, who have been diagnosed between 2002 and 2008 and have been included in the Surveillance, Epidemiology, and End Results-Medicare database, are eligible for this retrospective cohort study. To minimise bias, patients had to survive at least 12 months following the completion of treatment. Adherence to surveillance testing up to 5 years post-treatment will be assessed in each year of follow-up and overall. Binomial regression will be used to assess the association between patients' characteristics and adherence. Survival analysis will be conducted to assess the association between adherence and 5-year survival. ETHICS AND DISSEMINATION: This study was approved by the National Cancer Institute and the Institutional Review Board of the University of Central Florida. The results of this study will be disseminated by publishing in the peer-reviewed scientific literature, presentation at national/international scientific conferences and posting through social media.
Subject(s)
Colorectal Neoplasms , Aged , Aged, 80 and over , Colorectal Neoplasms/mortality , Colorectal Neoplasms/therapy , Florida , Humans , Medicare , Neoplasm Recurrence, Local , Retrospective Studies , SEER Program , Survival Analysis , United StatesABSTRACT
A recent phase 3 trial of prucalopride in children with functional constipation (SPD555-303 ClinicalTrials.gov Identifier: NCT01330381) reported negative efficacy results. Here, we developed a population pharmacokinetic (PK) model of prucalopride in children to assess prucalopride exposure in SPD555-303. An initial population PK model in children was developed based on sampled single-dose data from a phase 1 study (PRU-USA-12). This model was subsequently updated with sampled data from SPD555-303 and used to simulate plasma concentration-time profiles for children aged 6 months to 18 years who were treated once daily with prucalopride 0.02, 0.04, or 0.06 mg kg-1 (maximum dose, 2 mg). Simulated PK profiles were compared with those of adults at the recommended dose of 2 mg once daily. Data were available from 38 patients (median age, 8.5 years) in PRU-USA-12 and 137 patients (median age, 7.9 years) in SPD555-303. Mean (range) area under the plasma concentration-time curve (AUC) at steady state was 62.3 (40.5-82.7) ng mL-1 h (dose, 0.03 mg kg-1) in PRU-USA-12 and 100.3 (22.7-286.0) ng mL-1 h (dose, 0.04 mg kg-1; maximum, 2 mg) in SPD555-303. Prucalopride 0.04 mg kg-1 once daily in children produced similar maximum plasma concentrations and approximately 10% lower AUC compared with adults receiving 2 mg once daily. This population PK analysis indicates that the PK profile of prucalopride in children in SPD555-303 was similar to that observed in adults. The negative efficacy results of SPD555-303 cannot be explained by differences in prucalopride exposure between children and adults.
ABSTRACT
PURPOSE: Gastroesophageal reflux disease involves the reflux of gastric and/or duodenal content into the esophagus. Prokinetic therapies, such as the selective 5-hydroxytryptamine receptor 4 agonist revexepride, may aid gastric emptying. This Phase I study evaluated the pharmacokinetics and excretion pathways of [14C]revexepride in healthy individuals using a microtracer approach with accelerator mass spectrometry. PARTICIPANTS AND METHODS: Six healthy men received a single oral dose of 2 mg [14C]revexepride containing ~200 nCi of radioactivity; blood, urine, and fecal samples were collected over a 10-day period. RESULTS: Almost 100% of 14C was recovered: 38.2%±10.3% (mean ± standard deviation) was recovered in urine, and 57.3%±0.4% was recovered in feces. Blood cell uptake was low, based on the blood plasma total radioactivity ratio of 0.8. The mean revexepride renal clearance was 8.6 L/h, which was slightly higher than the typical glomerular filtration rate in healthy individuals. Time to reach maximal concentration was 1.75±1.17 hours (mean ± standard deviation). No safety signals were identified. CONCLUSION: This study demonstrated that revexepride had rapid and moderate-to-good oral absorption. Excretion of radioactivity was completed with significant amounts in feces and urine. Renal clearance slightly exceeded the typical glomerular filtration rate, suggesting the involvement of active transportation in the renal tubules.
Subject(s)
Benzofurans/pharmacokinetics , Mass Spectrometry/methods , Radiopharmaceuticals/pharmacokinetics , Absorption, Physiological , Adult , Benzofurans/analysis , Benzofurans/blood , Benzofurans/urine , Humans , Male , Radiopharmaceuticals/analysis , Radiopharmaceuticals/blood , Radiopharmaceuticals/urineABSTRACT
PURPOSE: Chronic constipation is a prevalent gastrointestinal disorder globally. It is often treated with medications such as laxatives. Newer therapies to improve gastric motility include the selective 5-hydroxytryptamine receptor-4 agonist prucalopride, which is licensed for the treatment of chronic constipation in adults. The aim of this study was to investigate the pharmacokinetic properties and excretion of prucalopride in healthy individuals, using a microtracer approach with (14)C radioactivity detection using liquid scintillation counting and accelerator mass spectrometry. METHODS: This was a single-period, open-label, nonrandomized absorption, metabolism, and excretion study of [(14)C]prucalopride. Participants were 6 healthy men aged 18 to 50 years. After screening, participants were administered a single dose of [(14)C]prucalopride succinate 2 mg (~200 nCi). Postadministration, urine, feces, and blood samples were collected over a 10-day period. Safety and adverse event data were also collected. FINDINGS: Almost 100% of the administered dose of radioactivity was recovered, with a mean (SD) of 84.2% (8.88%) recovered in urine and 13.3% (1.73%) recovered in feces. The mean blood-to-plasma concentration ratio of 1.9 indicated uptake of prucalopride into blood cells. The renal clearance of prucalopride was 17.0 (2.5) L/h, which is higher than the glomerular filtration rate in healthy individuals, suggesting active renal transport of prucalopride. Prucalopride was well tolerated, with no serious adverse events reported. IMPLICATIONS: Prucalopride was well absorbed and excreted mainly by the kidneys, including both passive and active transporter mechanisms. Quantitative recovery of the radioactive dose was achieved. Consistent with previous studies, prucalopride was generally well tolerated. ClinicalTrials.gov identifier: NCT01807000.
Subject(s)
Benzofurans/pharmacokinetics , Laxatives/pharmacokinetics , Administration, Oral , Adolescent , Adult , Benzofurans/administration & dosage , Benzofurans/adverse effects , Carbon Radioisotopes , Feces/chemistry , Healthy Volunteers , Humans , Intestinal Absorption , Laxatives/administration & dosage , Laxatives/adverse effects , Male , Middle Aged , Young AdultABSTRACT
BACKGROUND: The novel antiepileptic drug retigabine is the first selective M-current potassium channel opener for KCNQ2/3 and KCNQ3/5 channels. Retigabine undergoes phase II metabolism (N-glucuronidation, acetylation) exclusively and renal excretion. OBJECTIVE: Our objective was to evaluate the effects of age and sex on the pharmacokinetics of retigabine. METHODS: Healthy young (age range, 18-40 years) and elderly (age range, 66-81 years) white subjects (12 men and 12 women in each group) received a single 200-mg oral dose of retigabine. After dosing, blood was collected over a 72-hour period to determine plasma concentrations of retigabine and its acetylated metabolite, AWD21-360. Pharmacokinetics was compared for age group and sex by ANOVA. RESULTS: In young men, retigabine was rapidly absorbed, with the maximum concentration occurring within 2 hours, and was eliminated with an apparent clearance of 0.67 L x h(-1) x kg(-1) and a mean terminal half-life of 8.5 hours. Subjects were similarly exposed to AWD21-360. Compared with young men, young women had higher retigabine maximum concentration (56%) and exposure (20%) but similar clearance (0.68 L x h(-1) x kg(-1)); these differences were related to differences in body weight. Although maximum concentration was similar in elderly subjects, retigabine elimination was slower (30% lower apparent clearance normalized for weight), resulting in higher exposure (42%) and a longer half-life (30%). Because phase II metabolism is scarcely affected by age, these differences may be related to the known decline of renal function with age. CONCLUSIONS: Although there are no substantial sex-related differences in the disposition of retigabine, a relevant decrease in clearance resulting in higher exposure occurs in elderly patients. The results suggest that decline of renal function with age may account for some of the observed changes.
Subject(s)
Aging/metabolism , Anticonvulsants/pharmacokinetics , Carbamates/pharmacokinetics , Phenylenediamines/pharmacokinetics , Sex Characteristics , Adult , Aged , Aged, 80 and over , Anticonvulsants/blood , Area Under Curve , Carbamates/blood , Creatinine/blood , Female , Half-Life , Humans , Male , Phenylenediamines/blood , Reference ValuesABSTRACT
Retigabine, a first-in-class selective M-current potassium channel opener, is a novel antiepileptic compound currently in clinical development. The purpose of this randomized placebo-controlled study was to assess retigabine oral safety and pharmacokinetics in healthy male volunteers (N = 45). Subjects received one dose on day 1 and doses every 12 hours for the next 14 days. Fixed doses were given to the first four groups (200, 400, 500, and 600 mg per day). Titrated doses were given to group 5 in 100 mg increases every 4 days, achieving 700 mg per day on day 15. Serial blood samples were collected on days 1 and 15. Pharmacokinetic parameters were compared between days and among dose groups. After administration of a single dose, retigabine was rapidly absorbed, with maximum concentrations of 387 ng/ml (normalized to a 100 mg dose) occurring within 1.5 hours. Retigabine was eliminated with a mean terminal half-life of 8.0 hours and an apparent oral clearance of 0.70 L/h/kg in white subjects. In black subjects, retigabine clearance and volume of distribution were 25% and 30% lower, respectively, after normalizing by body weight, leading to higher exposure in this population. Retigabine's pharmocokinetics was linearly dose proportional. Steady-state pharmacokinetics was in agreement with single-dose pharmacokinetics, and the accumulation ratio was about 1.5. Retigabine and AWD21-360 trough evening concentrations were significantly lower (about 30% to 35%) than morning values. The titration regimen allowed for higher doses to be tolerated compared to the fixed-dose regimen. In conclusion, the pharmacokinetics of retigabine is linearly dose proportional for daily doses of 100 to 700 mg and is not modified on multiple administrations.
Subject(s)
Anticonvulsants/pharmacokinetics , Carbamates/pharmacokinetics , Phenylenediamines/pharmacokinetics , Acetylation , Adult , Anticonvulsants/administration & dosage , Anticonvulsants/adverse effects , Area Under Curve , Biotransformation , Carbamates/administration & dosage , Carbamates/adverse effects , Chromatography, High Pressure Liquid , Dose-Response Relationship, Drug , Double-Blind Method , Half-Life , Humans , Male , Mass Spectrometry , Phenylenediamines/administration & dosage , Phenylenediamines/adverse effects , Reproducibility of ResultsABSTRACT
Although anagrelide is widely used for the treatment of essential thrombocythemia (ET) in the USA and Europe, it is not licensed in Japan. Existing literature has reported differences in polymorphism and activity of CYP1A2 in Japanese and non-Japanese ethnic groups, which may alter anagrelide metabolism. We intended to identify the optimum dosage of anagrelide in treatment-naïve Japanese patients with ET and assess its long-term safety and efficacy. Twelve patients with ET and a platelet count of ≥ 80 × 10(4)/µL were enrolled. Anagrelide was administered at an initial dose of 0.5 mg/day (weeks 1-4), then increased to 1.0 mg/day (weeks 5-8). During the following maintenance (weeks 9-52) and continuation periods (weeks 53-104), the dose was adjusted according to patient safety data and to maintain target platelet counts (<60 × 10(4)/µL). Increasing the dose led to a decrease in mean platelet count, and target platelet counts were maintained in 11 patients. Adverse events were mild or moderate, and none led to discontinuation. This cohort of Japanese patients exhibited higher pharmacokinetic exposures of anagrelide and its active metabolite than those previously documented in non-Japanese patients. These differences were modest, suggesting specific dosing regimens for Japanese patients are not required.
Subject(s)
Platelet Aggregation Inhibitors/administration & dosage , Platelet Aggregation Inhibitors/pharmacokinetics , Quinazolines/administration & dosage , Quinazolines/pharmacokinetics , Thrombocythemia, Essential/drug therapy , Adult , Aged , Asian People , Female , Follow-Up Studies , Humans , Japan , Male , Middle Aged , Platelet Aggregation Inhibitors/adverse effects , Platelet Count , Quinazolines/adverse effects , Thrombocythemia, Essential/blood , Time FactorsABSTRACT
The pharmacokinetic parameters of tigecycline were assessed in subjects with severe renal impairment (creatinine clearance <30 mL/min, n = 6), subjects receiving hemodialysis (4 received tigecycline before and 4 received tigecycline after hemodialysis), and subjects with age-adjusted, normal renal function (n = 6) after administration of single 100-mg doses. Serial serum and urine samples were collected and assayed using validated liquid chromatography with tandem mass spectrometer (LC/MS/MS) methods. Concentration-time data were then analyzed using noncompartmental pharmacokinetic methods. Tigecycline renal clearance in subjects with normal renal function represented approximately 20% of total systemic clearance. Tigecycline clearance was reduced by approximately 20%, and area under the tigecycline concentration-time curve increased by approximately 30% in subjects with severe renal impairment. Tigecycline was not efficiently removed by dialysis; thus, it can be administered without regard to timing of hemodialysis. Based on these pharmacokinetic data, tigecycline requires no dosage adjustment in patients with renal impairment.
Subject(s)
Anti-Bacterial Agents/pharmacokinetics , Minocycline/analogs & derivatives , Renal Insufficiency/metabolism , Adult , Aged , Anti-Bacterial Agents/blood , Anti-Bacterial Agents/urine , Female , Humans , Kidney/metabolism , Male , Middle Aged , Minocycline/blood , Minocycline/pharmacokinetics , Minocycline/urine , Renal Dialysis , Renal Insufficiency/physiopathology , TigecyclineABSTRACT
Tigecycline belongs to a new class of tetracyclines, the glycylcyclines, less than 20% of which is metabolized in the liver. Twenty-five patients with cirrhosis with varying degrees of functional hepatic reserve (Child-Pugh A, n = 10; B, n = 10; C, n = 5) and 23 healthy adults, matched by age, sex, weight, and smoking habits, received 100 mg of tigecycline infused intravenously over 60 minutes. Serum and urine samples were collected up to 120 hours after dosing. Pharmacokinetic data were derived using noncompartmental methods. The most common treatment-emergent adverse events in healthy volunteers were nausea (56.5%), vomiting (21.7%), and headache (21.7%) and in the patients with cirrhosis, albuminuria (12%). Mean (± 1 SD) tigecycline clearance values were 29.8 ± 11.3 L/h in healthy subjects and 31.2 ± 13.9 L/h (Child-Pugh A), 22.1 ± 9.3 L/h (Child-Pugh B), and 13.5 ± 2.7 L/h (Child-Pugh C) in the patients. A single intravenous dose of tigecycline 100 mg was safe and well-tolerated in patients with cirrhosis with varying degrees of hepatic functional reserve. No adjustment of tigecycline maintenance dosage is warranted in patients with compensated or moderately decompensated cirrhosis; doses should be reduced by 50%, to 25 mg, every 12 hours in patients with severely decompensated disease.
Subject(s)
Anti-Bacterial Agents/pharmacokinetics , Liver Cirrhosis/complications , Minocycline/analogs & derivatives , Adult , Anti-Bacterial Agents/adverse effects , Case-Control Studies , Female , Humans , Infusions, Intravenous , Liver Cirrhosis/pathology , Male , Middle Aged , Minocycline/adverse effects , Minocycline/pharmacokinetics , Severity of Illness Index , TigecyclineABSTRACT
The pharmacokinetics of tigecycline was evaluated in 46 healthy young and elderly men and women. Except for the volumes of distribution at steady state (approximately 350 liters in women versus 500 liters in men), there were no significant differences in tigecycline pharmacokinetic parameters. Based on pharmacokinetics, no dosage adjustment is warranted based on age or sex.