ABSTRACT
OBJECTIVE: To compare the effects of body weight-supported treadmill training and overground walking training when matched for task and dose (duration/frequency/intensity) on improving walking function, activity, and participation after stroke. DESIGN: Single-blind, pilot randomized controlled trial with three-month follow-up. SETTINGS: University and community settings. SUBJECTS: A convenience sample of participants (N = 20) at least six months post-stroke and able to walk independently were recruited. INTERVENTIONS: Thirty-minute walking interventions (body weight-supported treadmill training or overground walking training) were administered five times a week for two weeks. Intensity was monitored with the Borg Rating of Perceived Exertion Scale at five-minute increments to maintain a moderate training intensity. MAIN MEASURES: Walking speed (comfortable/fast 10-meter walk), walking endurance (6-minute walk), spatiotemporal symmetry, and the ICF Measure of Participation and ACTivity were assessed before, immediately after, and three months following the intervention. RESULTS: The overground walking training group demonstrated significantly greater improvements in comfortable walking speed compared with the body weight-supported treadmill training group immediately (change of 0.11 m/s vs. 0.06 m/s, respectively; p = 0.047) and three months (change of 0.14 m/s vs. 0.08 m/s, respectively; p = 0.029) after training. Only the overground walking training group significantly improved comfortable walking speed (p = 0.001), aspects of gait symmetry (p = 0.032), and activity (p = 0.003) immediately after training. Gains were maintained at the three-month follow-up (p < 0.05) for all measures except activity. Improvements in participation were not demonstrated. CONCLUSION: Overgound walking training was more beneficial than body weight-supported treadmill training at improving self-selected walking speed for the participants in this study.
Subject(s)
Exercise Therapy/methods , Stroke Rehabilitation , Walking/physiology , Aged , Body Weight , Exercise Test/instrumentation , Exercise Test/methods , Exercise Therapy/instrumentation , Female , Humans , Male , Middle Aged , Pilot ProjectsABSTRACT
WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: While recent publications have suggested the pharmacokinetics (PK) of vismodegib appear to be non-linear, there has not been a report describing the mechanisms of non-linearity. WHAT THIS STUDY ADDS: This study provides evidence that two separate processes, namely, solubility-limited absorption and concentration-dependent plasma protein binding, can explain the non-linear PK of vismodegib. This study provides quantitative results which can account for the lower than expected accumulation of vismodegib with continuous daily dosing. AIM: Vismodegib has demonstrated clinical activity in patients with advanced basal cell carcinoma. The pharmacokinetics (PK) of vismodegib are non-linear. The objective of this study was to determine whether vismodegib PK change following repeated dosing by administering a tracer intravenous (i.v.) dose of (14) C-vismodegib with single and multiple oral doses. METHODS: Healthy post menopausal female subjects (n= 6/group) received either a single or daily 150 mg vismodegib oral dose with a (14) C-labelled 10 µg i.v. bolus dose administered 2 h after the single or last oral dose (day 7). Plasma samples were assayed for vismodegib by LC-MS/MS and for (14) C-vismodegib by accelerator mass spectrometry. RESULTS: Following a single i.v. dose, mean clearance, volume of distribution and absolute bioavailability were 43.4 ml h(-1) , 16.4 l and 31.8%, respectively. Parallel concentration-time profiles following single oral and i.v. administration of vismodegib indicated elimination rate limited PK. Following i.v. administration at steady-state, mean clearance and volume of distribution were 78.5 ml h(-1) and 26.8 l, respectively. Comparison of i.v. PK parameters after single and multiple oral dosing showed similar half-life, increased clearance and volume of distribution (81% and 63% higher, respectively) and decreased bioavailability (77% lower) after repeated dosing. Relative to single dose, the unbound fraction of vismodegib increased 2.4-fold with continuous daily dosing. CONCLUSION: Vismodegib exhibited a long terminal half-life after oral and i.v. administration, moderate absolute bioavailability and non-linear PK after repeated dosing. Results from this study suggest that the non-linear PK of vismodegib result from two separate, non-linear processes, namely solubility limited absorption and high affinity, saturable plasma protein binding.
Subject(s)
Anilides/pharmacokinetics , Antineoplastic Agents/pharmacokinetics , Pyridines/pharmacokinetics , Anilides/administration & dosage , Antineoplastic Agents/administration & dosage , Biological Availability , Blood Proteins/metabolism , Chromatography, Liquid , Drug Administration Schedule , Female , Half-Life , Humans , Injections, Intravenous , Mass Spectrometry/methods , Middle Aged , Nonlinear Dynamics , Protein Binding , Pyridines/administration & dosage , Solubility , Tandem Mass Spectrometry , Tissue DistributionABSTRACT
Vemurafenib is a BRAF kinase inhibitor indicated for the treatment of patients with BRAFV600 mutation-positive unresectable or metastatic melanoma and Erdheim-Chester disease. This phase 1, open-label, single-arm study was designed to estimate absolute bioavailability of oral vemurafenib at steady state and to characterize the pharmacokinetics of a single intravenous microdose of 14 C-labeled vemurafenib in patients with BRAFV600 mutation-positive malignancies. Patients received oral vemurafenib 960 mg twice daily on days 1 through 28, with a single intravenous infusion of 14 C-labeled vemurafenib solution (3 mL, corresponding to a radioactive dose of 18.5 kBq and a vemurafenib dose of 20 µg) given on the morning of day 21, immediately following the morning dose of oral vemurafenib. A total of 6 patients were enrolled. Four patients who received 14 C-labeled vemurafenib infusion were included in the pharmacokinetic and bioavailability analyses. Geometric mean absolute bioavailability of oral vemurafenib at steady state, calculated as the ratio of dose-normalized area under the curve during the dosing interval (AUCτ ) following oral vemurafenib dose to dose-normalized AUC from time 0 extrapolated to infinity (AUC0-inf ) following vemurafenib intravenous dose, was 57.8%. The majority of radioactivity (geometric mean 41%) was recovered in feces, and a small proportion (geometric mean 1.4%) was recovered in urine. Treatment-emergent adverse events occurred in 5 of 6 (83%) patients and were all grade 1/2 in severity, except for 1 grade-4 anaphylactic reaction occurring during infusion of 14 C-labeled vemurafenib, which was thought to be related to the excipient polysorbate 80 in the intravenous formulation.
Subject(s)
Melanoma , Proto-Oncogene Proteins B-raf , Biological Availability , Humans , Melanoma/drug therapy , Melanoma/genetics , Melanoma/pathology , Mutation , Protein Kinase Inhibitors , Proto-Oncogene Proteins B-raf/genetics , Vemurafenib/adverse effectsABSTRACT
BACKGROUND: Central nervous system (CNS) metastasis is common in advanced melanoma patients. New treatment options have improved overall prognosis, but information is lacking for patients with CNS metastases. We investigated treatment patterns and survival outcomes in older melanoma patients with and without CNS metastases. METHODS: A retrospective analysis of SEER-Medicare, a population-based linked database, was undertaken in patients aged > 65 years with advanced melanoma diagnosed from 2004 to 2011 and followed until 2013. RESULTS: A total of 2522 patients were included. CNS metastases were present in 24.8% of patients at initial metastatic diagnosis; 16.5% developed CNS metastases during follow-up. Chemotherapy was the most common treatment regardless of CNS metastases. Overall survival (OS) was better for patients without CNS metastases (median, 9.5 months; 95% confidence interval [CI], 8.8-10.2) vs patients with CNS metastases (3.63 months; 95% CI, 3.4-3.9). Among patients with CNS metastases, median OS for targeted therapy, immunotherapy, and chemotherapy was 6 (95% CI, 2.5-9.6), 5.5 (95% CI, 3.8-7.5), and 4.5 (95% CI, 3.8-5.4) months, respectively, vs 2.4 (95% CI, 2.1-2.7) and 2.1 (95% CI, 1.8-2.7) months for local radiotherapy and no treatment, respectively. Stereotactic radiosurgery demonstrated higher OS vs whole-brain radiation therapy (median, 4.98 [95% CI, 3.5-7.5] vs 2.4 [95% CI, 2.1-2.7] months). CONCLUSION: Patients with CNS metastases from melanoma remain a population with high unmet medical need despite recent advances in treatment. Systemic treatments (eg, BRAF-targeted therapy and immunotherapy) and stereotactic radiosurgery demonstrated meaningful but modest improvements in OS. Further explorations of combinations of radiotherapy, BRAF-targeted therapies, and immunotherapies are needed.
Subject(s)
Central Nervous System Neoplasms/secondary , Melanoma/mortality , Melanoma/secondary , Skin Neoplasms/mortality , Aged , Aged, 80 and over , Central Nervous System Neoplasms/mortality , Central Nervous System Neoplasms/therapy , Confidence Intervals , Cranial Irradiation/mortality , Drug Therapy/mortality , Female , Humans , Immunotherapy/mortality , Male , Medicare , Melanoma/pathology , Melanoma/therapy , Molecular Targeted Therapy/mortality , Radiosurgery/mortality , Radiotherapy/mortality , Retrospective Studies , SEER Program , Skin Neoplasms/pathology , Skin Neoplasms/therapy , Time Factors , United StatesABSTRACT
The primary objective of this phase 1, open-label, multicenter, 3-period, fixed-sequence study was to evaluate the effect of multiple doses of vemurafenib on the pharmacokinetics of a single dose of digoxin, a probe P-glycoprotein (P-gp) substrate, in patients with BRAFV600 mutation-positive metastatic malignancy. Following a 28-day screening period, patients received a single oral dose of digoxin 0.25 mg on day 1 in period A, oral vemurafenib 960 mg twice daily for 21 days in period B (days 8-28), and a single oral dose of digoxin 0.25 mg on day 29 and vemurafenib 960 mg twice a day for 7 days (days 29-35) in period C. Log-transformed area under the concentration-time curve and peak concentration values for digoxin were compared between periods A (digoxin alone) and C (digoxin + vemurafenib) using an analysis of variance model. Twenty-six patients were evaluated for the primary pharmacokinetic analysis. The geometric mean ratio (period C/period A) of area under the curve to the last measurable concentration for digoxin was 1.82 (90%CI 1.63 to 2.02), and the geometric mean ratio of peak concentrations was 1.47 (90%CI 1.30 to 1.65); the 90%CIs were outside of the equivalence limits of 0.82 to 1.22, indicating an effect of vemurafenib on digoxin. Multiple oral doses of vemurafenib were generally well tolerated, with an adverse event profile similar to that previously seen in phase 2 and 3 studies of vemurafenib monotherapy. This study confirmed vemurafenib as an inhibitor of P-gp in vivo with a statistically significant drug-drug interaction with digoxin. Caution should be exercised when dosing vemurafenib concurrently with P-gp substrates.
ABSTRACT
PURPOSE: Vismodegib is a Hedgehog pathway inhibitor approved for the treatment of advanced basal cell carcinoma. Currently, the pharmacokinetics (PK) and safety of vismodegib in patients with hepatic dysfunction are unknown and are the objective of this study. METHODS: Patients with advanced solid malignancies and hepatic impairment were enrolled into one of four cohorts: normal [bilirubin (bili) < upper limit of normal (ULN)], mild (ULN < bili ≤ 1.5 × ULN), moderate (1.5 × ULN < bili ≤ 3×ULN), and severe (3 × ULN < bili < 10 × ULN) dysfunction. Patients received oral vismodegib 150 mg daily. Plasma PK samples on days 1, 3, 5, and 8 were collected. Vismodegib therapy was continued until disease progression, intolerable toxicity, or withdrawal of consent. RESULTS: Thirty-one patients were accrued: nine normal, eight mild, eight moderate, and six severe. Four patients experienced dose-limiting toxicity of hyperbilirubinemia on study: one in the moderate cohort and three in the severe cohort. Six patients died within 30 days after the last dose of vismodegib. All deaths were attributed to disease progression. Observed maximal and average steady-state concentrations and AUC of vismodegib at steady state (day 8) were similar across cohorts. Average AAG concentrations in patients with hepatic impairment were comparable to those of patients with normal hepatic function. CONCLUSIONS: Hepatic impairment does not appear to impact vismodegib PK, and therefore, dose adjustment is not necessary in this special population. The study was influenced by the high number of patients with hepatocellular carcinoma with advanced cirrhosis; rendering it difficult to draw any causal relationships between vismodegib exposure and the serious adverse events.
Subject(s)
Anilides/administration & dosage , Antineoplastic Agents/administration & dosage , Liver Diseases/physiopathology , Neoplasms/drug therapy , Pyridines/administration & dosage , Adult , Aged , Aged, 80 and over , Anilides/adverse effects , Anilides/pharmacokinetics , Antineoplastic Agents/adverse effects , Antineoplastic Agents/pharmacokinetics , Area Under Curve , Cohort Studies , Disease Progression , Dose-Response Relationship, Drug , Female , Humans , Male , Middle Aged , Neoplasms/pathology , Pyridines/adverse effects , Pyridines/pharmacokinetics , Severity of Illness Index , Time FactorsABSTRACT
PURPOSE: The Hedgehog pathway inhibitor vismodegib exhibits pH-dependent solubility, and in vitro studies have shown that vismodegib is a substrate of P-glycoprotein (P-gp) and is metabolized by cytochrome P450 (CYP) 2C9 and 3A4. The objective of this four-arm parallel study in healthy subjects was to evaluate the effect of the proton-pump inhibitor rabeprazole, the P-gp/CYP3A4 inhibitor itraconazole, and the CYP2C9 and 3A4 inhibitor fluconazole on vismodegib steady-state pharmacokinetics. METHODS: Cohorts included a control arm (n = 22), in which vismodegib 150 mg was administered once daily (QD) for 7 days, and 3 arms in which vismodegib was co-administered QD for 7 days with rabeprazole 20 mg (including a 4-day lead-in; n = 24); itraconazole 200 mg (n = 22); or fluconazole 400 mg (n = 22). RESULTS: Area under the vismodegib concentration-time curve from zero to 24 h (AUC0-24h) at steady state was lower with concomitant rabeprazole administration relative to vismodegib alone [geometric mean ratio (GMR), 86.2 (associated 90 % confidence interval [CI], 76.1, 97.7)]. There was no effect of itraconazole on steady-state exposure of vismodegib [GMR, 96.4 (90 % CI 84.9, 109.6)]. Co-administration with fluconazole increased vismodegib steady-state AUC0-24h [GMR, 130.9 (90 % CI 115.2, 148.7)]. Co-administration of rabeprazole, itraconazole, and fluconazole had similar effects on the exposure of unbound vismodegib and total vismodegib. CONCLUSION: The results of this study suggest that vismodegib can be administered with acid-reducing agents and P-gp and CYP inhibitors without the risk of a clinically meaningful pharmacokinetic drug-drug interaction. CLINICALTRIALS. GOV IDENTIFIER: NCT01772290.
Subject(s)
Anilides/pharmacokinetics , Fluconazole/pharmacology , Itraconazole/pharmacology , Pyridines/pharmacokinetics , Rabeprazole/pharmacology , ATP Binding Cassette Transporter, Subfamily B, Member 1/antagonists & inhibitors , ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism , Anilides/administration & dosage , Area Under Curve , Cytochrome P-450 CYP2C9 Inhibitors/administration & dosage , Cytochrome P-450 CYP2C9 Inhibitors/pharmacology , Cytochrome P-450 CYP3A Inhibitors/administration & dosage , Cytochrome P-450 CYP3A Inhibitors/pharmacology , Drug Interactions , Female , Fluconazole/administration & dosage , Humans , Hydrogen-Ion Concentration , Itraconazole/administration & dosage , Proton Pump Inhibitors/administration & dosage , Proton Pump Inhibitors/pharmacology , Pyridines/administration & dosage , Rabeprazole/administration & dosage , SolubilityABSTRACT
PURPOSE: The tyrosine kinase inhibitor imatinib mesylate inhibits the function of the Bcr-Abl oncoprotein associated with Philadelphia-positive chronic myelogenous leukemia (CML). Anagrelide suppresses megakaryocyte proliferation and differentiation. The objectives of this study were to investigate the feasibility and safety of imatinib mesylate and anagrelide combination therapy in patients with Ph-positive CML or chronic myeloproliferative disorders (MPD) with persistent thrombocythemia. METHODS: This study was a retrospective review of all available records of patients with chronic MPD presenting to the M.D. Anderson Cancer Center between October 1998 and May 2002, treated with imatinib mesylate combined with anagrelide. RESULTS: Of 22 patients identified, 18 had Ph-positive CML (chronic phase, 16 patients; accelerated phase, 2 patients), 1 had agnogenic myeloid metaplasia (AMM), 2 had essential thrombocythemia (ET) and 1 had MPD transformed into refractory anemia with excess blasts (RAEB). The median age was 57 years (range 26-82 years). The median dose of imatinib mesylate administered was 400 mg (range 300-800 mg) and the median dose of anagrelide was 1.5 mg (range 0.5-4.0 mg). Imatinib mesylate and anagrelide combination therapy was feasible and tolerable. Of the 18 patients with Ph-positive CML, 15 in chronic phase and 1 in accelerated phase achieved a complete hematologic response (CHR), and 9 of the 18 achieved cytogenetic response (complete in 8 patients). No responses were noted in patients with AMM, ET or MPD transformed into RAEB. CONCLUSIONS: The combination of imatinib mesylate and anagrelide was safe and was associated with an 89% CHR rate in patients with CML in chronic phase and persistent thrombocythemia.
Subject(s)
Enzyme Inhibitors/therapeutic use , Fibrinolytic Agents/therapeutic use , Myeloproliferative Disorders/drug therapy , Piperazines/therapeutic use , Pyrimidines/therapeutic use , Quinazolines/therapeutic use , Adult , Aged , Aged, 80 and over , Benzamides , Chronic Disease , Drug Therapy, Combination , Enzyme Inhibitors/adverse effects , Female , Fibrinolytic Agents/adverse effects , Humans , Imatinib Mesylate , Male , Medical Records Systems, Computerized , Middle Aged , Myeloproliferative Disorders/mortality , Piperazines/adverse effects , Pyrimidines/adverse effects , Quinazolines/adverse effects , Retrospective Studies , Survival AnalysisABSTRACT
INTRODUCTION: ATLAS compared bevacizumab plus erlotinib (B+E) with bevacizumab plus placebo (B+P) as maintenance therapy after first-line bevacizumab plus chemotherapy (B+C) for advanced non-small-cell lung cancer (NSCLC). Prespecified biomarkers were prospectively evaluated. METHODS: Tumor samples were analyzed for: epidermal growth factor receptor (EGFR) expression (immunohistochemistry [IHC]); EGFR gene copy number (fluorescence in-situ hybridization [FISH]); EGFR mutations (exon 19 deletions/L858R mutations); and KRAS mutations (exons 2/3). Progression-free survival (PFS) and overall survival (OS) were estimated. RESULTS: Of 743 patients randomized to receive maintenance treatment (after four cycles of B+C without progression), 190 (B+E) and 177 (B+P) were evaluable for biomarker status. Median PFS (from randomization) was 4.4 months (B+E) versus 3.7 months (B+P; hazard ratio [HR], 0.75; 95% confidence interval [CI], 0.57-0.99), which was numerically similar to the intent-to-treat PFS. PFS benefit of B+E was observed across most biomarker subgroups. EGFR IHC, EGFR FISH, and EGFR/KRAS mutation status were not predictive of outcome. B+E-treated patients with EGFR mutation-positive NSCLC had longer PFS compared with B+P-treated patients (HR, 0.44; 95% CI, 0.22-0.86; p = 0.0139). Patients with KRAS wild-type disease had significant PFS improvements with B+E, compared with B+P (HR, 0.66; 95% CI, 0.485-0.914; p = 0.0105). No OS benefit of B+E was observed. CONCLUSIONS: Patients with KRAS wild-type or EGFR mutation-positive NSCLC derived PFS benefits from B+E. However, EGFR IHC, EGFR FISH, and EGFR or KRAS mutation status were not strongly predictive of survival. A larger sample size would be needed to confirm the initial trends observed in this study.
Subject(s)
Antibodies, Monoclonal, Humanized/therapeutic use , Biomarkers, Tumor/metabolism , Carcinoma, Non-Small-Cell Lung/drug therapy , Lung Neoplasms/drug therapy , Quinazolines/therapeutic use , Adolescent , Adult , Aged , Angiogenesis Inhibitors/therapeutic use , Bevacizumab , Carcinoma, Non-Small-Cell Lung/metabolism , Carcinoma, Non-Small-Cell Lung/mortality , Disease-Free Survival , Drug Therapy, Combination , ErbB Receptors/antagonists & inhibitors , Erlotinib Hydrochloride , Female , Humans , Lung Neoplasms/metabolism , Lung Neoplasms/mortality , Male , Middle Aged , Protein Kinase Inhibitors/therapeutic use , Survival Rate/trends , United States/epidemiology , Vascular Endothelial Growth Factor A , Young AdultABSTRACT
PURPOSE: Vismodegib, a first-in-class oral hedgehog pathway inhibitor, is an effective treatment for advanced basal cell carcinoma. Based on in vitro data, a clinical drug-drug interaction (DDI) assessment of cytochrome P450 (CYP) 2C8 was necessary; vismodegib's teratogenic potential warranted a DDI study with oral contraceptives (OCs). METHODS: This single-arm, open-label study included two cohorts of patients with locally advanced or metastatic solid malignancies [Cohort 1: rosiglitazone 4 mg (selective CYP2C8 probe); Cohort 2: OC (norethindrone 1 mg/ethinyl estradiol 35 µg; CYP3A4 substrate)]. On Day 1, patients received rosiglitazone or OC. On Days 2-7, patients received vismodegib 150 mg/day. On Day 8, patients received vismodegib plus rosiglitazone or OC. The effect of vismodegib on rosiglitazone and OC pharmacokinetic parameters (primary objective) was evaluated through pharmacokinetic sampling over a 24-h period (Days 1 and 8). RESULTS: The mean ± SD vismodegib steady-state plasma concentration (Day 8, N = 51) was 20.6 ± 9.72 µM (range 7.93-62.4 µM). Rosiglitazone AUC(0-inf) and C(max) were similar with concomitant vismodegib [≤8% change in geometric mean ratios (GMRs); N = 24]. Concomitant vismodegib with OC did not affect ethinyl estradiol AUC(0-inf) and C(max) (≤5% change in GMRs; N = 27); norethindrone C(max) and AUC(0-inf) GMRs were higher (12 and 23%, respectively) with concomitant vismodegib. CONCLUSIONS: This DDI study in patients with cancer demonstrated that systemic exposure of rosiglitazone (a CYP2C8 substrate) or OC (ethinyl estradiol/norethindrone) is not altered with concomitant vismodegib. Overall, there appears to be a low potential for DDIs when vismodegib is co-administered with other medications.
Subject(s)
Anilides/pharmacology , Antineoplastic Agents/pharmacology , Contraceptives, Oral, Combined/pharmacokinetics , Neoplasms/drug therapy , Pyridines/pharmacology , Thiazolidinediones/pharmacokinetics , Aged , Anilides/administration & dosage , Anilides/pharmacokinetics , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/pharmacokinetics , Area Under Curve , Aryl Hydrocarbon Hydroxylases/drug effects , Aryl Hydrocarbon Hydroxylases/metabolism , Cohort Studies , Contraceptives, Oral, Combined/administration & dosage , Cytochrome P-450 CYP2C8 , Cytochrome P-450 CYP3A/metabolism , Drug Interactions , Ethinyl Estradiol/administration & dosage , Ethinyl Estradiol/pharmacokinetics , Female , Humans , Male , Middle Aged , Neoplasm Metastasis , Neoplasms/pathology , Norethindrone/administration & dosage , Norethindrone/pharmacokinetics , Pyridines/administration & dosage , Pyridines/pharmacokinetics , RosiglitazoneABSTRACT
PURPOSE: This study was designed to evaluate whether less frequent dosing [three times per week (TIW) or once weekly (QW)] of 150 mg vismodegib following a loading dose [150 mg once daily (QD) for 11 days] would result in similar safety, tolerability, and steady-state levels of total and unbound vismodegib as continuous QD dosing. EXPERIMENTAL DESIGN: Sixty-seven patients with advanced solid tumors were stratified by baseline plasma alpha 1-acid glycoprotein (AAG) levels and randomized to one of three vismodegib 150 mg regimens: QD (n = 23), TIW (n = 22), or QW (n = 22) for up to 42 days after an 11-day loading phase (150 mg QD). Total and unbound (dialyzed) plasma vismodegib concentrations were determined by LC-MS/MS. RESULTS: The most frequently reported adverse events were consistent with those in prior monotherapy trials, with similar incidence and severity regardless of dosing schedule. After the 150 mg QD loading phase, a concentration-dependent change in protein binding (3-fold increase in vismodegib fraction unbound) was observed at steady state compared with single dose. Mean total and unbound vismodegib steady-state concentrations were lower after TIW and QW than QD dosing, with an average intrasubject decrease of 50% and 80%, respectively, for unbound drug. Mechanism-based PK model simulations accurately and prospectively predicted the PK results. CONCLUSIONS: Vismodegib 150 mg TIW or QW failed to achieve unbound plasma concentrations previously associated with efficacy in patients with advanced basal cell carcinoma and medulloblastoma, even after a QD loading dose period. The 150 mg QD regimen is appropriate for vismodegib based on its clinical activity, tolerability, and favorable unbound concentrations.
Subject(s)
Anilides/administration & dosage , Anilides/pharmacokinetics , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/pharmacokinetics , Hedgehog Proteins/antagonists & inhibitors , Neoplasms/drug therapy , Pyridines/administration & dosage , Pyridines/pharmacokinetics , Anilides/adverse effects , Anilides/therapeutic use , Antineoplastic Agents/adverse effects , Dose-Response Relationship, Drug , Drug Administration Schedule , Female , Humans , Male , Neoplasms/pathology , Pyridines/adverse effects , Pyridines/therapeutic useABSTRACT
Skin infiltration with B-lymphocyte chronic lymphocytic leukemia (B-CLL) is rare. In contrast to Richters transformation of CLL or myeloid leukemias, skin involvement in CLL may be consistent with prolonged survival, as illustrated by the currently reported two cases. As in these patients, local therapy for skin disease may delay or obviate the need for systemic therapy in B-CLL.
Subject(s)
Leukemia, Lymphocytic, Chronic, B-Cell/pathology , Leukemic Infiltration , Skin Neoplasms/etiology , Humans , Male , Middle Aged , PrognosisABSTRACT
BACKGROUND: A phase II study of paclitaxel in patients with relapsed adult acute lymphocytic leukemia (ALL) was conducted. METHODS: Patients with relapsed ALL, no more than one prior salvage regimen, and no overt hepatic, renal, or cardiac dysfunction were eligible. Patients received paclitaxel 250 mg/m2 given as a continuous 24-h intravenous infusion repeated every 3-4 weeks. RESULTS: Eight patients received 13 courses of paclitaxel. One transient partial response was observed. The only severe extramedullary toxicities observed were Grade 3 myalgias and arthralgias. CONCLUSION: The study paclitaxel regimen was ineffective in refractory adult ALL.
Subject(s)
Antineoplastic Agents, Phytogenic/therapeutic use , Paclitaxel/therapeutic use , Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , Adolescent , Adult , Aged , Antineoplastic Agents, Phytogenic/administration & dosage , Antineoplastic Agents, Phytogenic/adverse effects , Dose-Response Relationship, Drug , Female , Humans , Male , Middle Aged , Neoplasm Recurrence, Local , Paclitaxel/administration & dosage , Paclitaxel/adverse effects , Treatment OutcomeABSTRACT
PURPOSE: Antifungal prophylaxis is an important component of induction therapy for patients with acute myeloid leukemia (AML). Azole antifungal agents are increasingly used in this context. In vitro assays were performed to assess whether cytochrome P450 (CYP450) enzymes were affected by combinations of cytarabine or idarubicin with itraconazole or caspofungin. METHODS: The high throughput microtiter assay was used to determine whether cytarabine, idarubicin and itraconazole or caspofungin were CYP450 isoenzyme substrates, inhibitors of CYP450 isoenzymes, and to determine potential CYP450 metabolism interactions between these agents. RESULTS: Idarubicin is a substrate for CYP450 2D6 and 2C9. Cytarabine is a substrate of CYP450 3A4. Idarubicin inhibits CYP450 2D6, and cytarabine, itraconazole, and caspofungin inhibit CYP450 3A4. Cytarabine metabolism was significantly decreased when combined with caspofungin or itraconazole. CONCLUSIONS: The inhibition of cytarabine metabolism may have important clinical implications. These in vitro findings warrant investigation with in vivo pharmacokinetic studies.