Days Of Once-daily Administration Research Articles

Pharmacokinetics of single- and multiple-dose flumatinib in patients with chronic phase chronic myeloid leukemia.

Flumatinib is a novel, oral breakpoint cluster region-abelson (BCR-ABL) tyrosine kinase inhibitor that has demonstrated manageable safety and promising efficacy in patients with newly diagnosed chronic phase (CP) chronic myeloid leukemia (CML). This study evaluated the pharmacokinetic (PK) profiles of flumatinib mesylate tablets at a dose of 400 mg and 600 mg in patients with CML-CP. The study was registered at chictr.org Identifier (ChiCTR2100044700). In this open-label, pharmacokinetic study, eligible patients were administered a single-dose of flumatinib 400 mg or 600 mg on day 1, followed by 2-day washout and 8 consecutive days of once-daily administration. Serial plasma samples were assayed for flumatinib and its metabolites (N-demethylate metabolite M1 and amide-bond hydrolytic metabolite M3). Twenty-nine patients were assigned to flumatinib 400 mg (n=14) or 600 mg (n=15). Serum concentrations of flumatinib reached maximum measured plasma concentration (Cmax) at a median time of 2 hours after each single dose, and then eliminated slowly with a mean apparent terminal disposition half-life (t1/2) from 16.0 to 16.9 hours. Following single- and multiple-dose administration, flumatinib exposure (Cmax, area under the concentration-time curve from 0 to t hours (AUC0-t), area under the concentration-time curve from 0 hours to infinity (AUC0-∞)) increased in an approximately dose-proportional manner. There was approximately 4.1- and 3.4- fold drug accumulation at steady-state after multiple-dose administration at 400 mg and 600 mg, respectively. The drug-related AEs associated with both treatments were primarily low-grade and tolerable events. Analysis of PK parameters indicated that flumatinib exposure increased in an approximately dose-proportional manner. Further research needs to be conducted in a large sample-size study.

​Safety Evaluation of Andrographolide-nanosuspensions

Background: Andrographolide (ANDRO) is a hydrophobic drug, which faces the problem of limited absorption due to poor water solubility. The current research prepared andrographolide nanosuspensions (ANDRO-NS) and examined in vivo toxicity for mice. Methods: ANDRO-NS were prepared by anti-solvent precipitation method, transmission electron micrographs, granularity analysis and in vitro release were used to characterize the ANDRO-NS, we evaluate the safety of the ANDRO-NS by using the acute toxicity test, local irritation test and chronic toxicity test. Result: The particle size of ANDRO-NS was (568.51±13.74 nm). The LD50 for ANDRO-NS was 548.91 mg/kg after oral administration to KM mice with a 95% CI of 468.19-645.03 mg/kg. The white blood cell counts and hemoglobin levels for the experimental groups were lower than controls receiving only saline. Serum aspartate transaminase, creatinine and blood urea nitrogen levels were greater than controls after 7 and 14 days of once-daily administration. After 14 days of administration, the platelet counts as well asalanine transaminase levels were, in addition, Histological observations indicated that interstitial kidney tissues were wider than controls and showed episodic bleeding after 7 days of administration. The highest dose administered also resulted in the dilation and blood engorgement of the central hepatic veins with some severed hepatic cords. Mice receiving the lowest dose of ANDRO-NS we administered appeared healthy and similar to controls receiving saline only. Following 14 days of administration, we found significant vacuolar degeneration of renal tubular epithelial cells and glomerular atrophy for the high-dose group as well as edema and necrosis in liver cells. The medium-dose group displayed kidney interstitial tissue widening with scattered bleeding, inflammatory cell infiltration and hepatocyte edema. The low-dose group displayed dilated renal tubules and irregularly-arranged liver cells as well as bleeding in the hepatic sinusoids. Therefore, short-term administration of andrographolide suspensions resulted in inflammation and time- and dose-dependent toxic effects on the kidneys and liver.

GPR171 Agonist Reduces Chronic Neuropathic and Inflammatory Pain in Male, But Not Female Mice.

Chronic pain is a growing public health crisis that requires exigent and efficacious therapeutics. GPR171 is a promising therapeutic target that is widely expressed through the brain, including within the descending pain modulatory regions. Here, we explore the therapeutic potential of the GPR171 agonist, MS15203, in its ability to alleviate chronic pain in male and female mice using a once-daily systemic dose (10 mg/kg, i.p.) of MS15203 over the course of 5 days. We found that in our models of Complete Freund's Adjuvant (CFA)-induced inflammatory pain and chemotherapy-induced peripheral neuropathy (CIPN), MS15203 did not alleviate thermal hypersensitivity and allodynia, respectively, in female mice. On the other hand, MS15203 treatment decreased the duration of thermal hypersensitivity in CFA-treated male mice following 3 days of once-daily administration. MS15203 treatment also produced an improvement in allodynia in male mice, but not female mice, in neuropathic pain after 5 days of treatment. Gene expression of GPR171 and that of its endogenous ligand BigLEN, encoded by the gene PCSK1N, were unaltered within the periaqueductal gray (PAG) in both male and female mice following inflammatory and neuropathic pain. However, following neuropathic pain in male mice, the protein levels of GPR171 were decreased in the PAG. Treatment with MS15203 then rescued the protein levels of GPR171 in the PAG of these mice. Taken together, our results identify GPR171 as a GPCR that displays sexual dimorphism in alleviation of chronic pain. Further, our results suggest that GPR171 and MS15203 have demonstrable therapeutic potential in the treatment of chronic pain.

Pharmacokinetics of single and multiple oral doses of 5 mg linagliptin in healthy Chinese volunteers

To investigate the pharmacokinetic and safety profile of linagliptin after single and multiple doses in healthy Chinese volunteers. Men and women (n = 12) aged 18 - 45 years with body mass index 19 - 24 kg/m2 received a single 5-mg dose of linagliptin on Day 1, followed by 7-day washout and 6 consecutive days of once-daily administration. Vital signs, electrocardiogram, routine laboratory tests, urinalysis, and adverse events were recorded. Blood and urine analytes were measured by HPLC/MS/MS. Linagliptin was rapidly absorbed; median time to maximum concentration was 1.75 h for single dose and 1.5 h at steady-state. Maximum plasma drug concentration (Cmax) after single dose was 4.9 ng/ml (10.4 nM), with a geometric coefficient of variation (gCV) 46%. The corresponding geometric mean area under the plasma concentrationtime curve (AUC) was 71 ng×h ml-1 (150 nmol×h l-1, gCV 25%). At steady-state, Cmax and AUC were 6.7 ng/ml (14.1 nM, gCV 49%) and 96 nmol×h l-1 (204 nmol×h l-1, gCV 25%). An accumulation half-life of ~ 11.5 h (gCV 46.9%) was calculated. Renal excretion of linagliptin was low and < 8% of administered dose at steady-state (< 2% at Day 1). Single and multiple daily oral doses of 5 mg linagliptin were safe and well tolerated. No adverse events or clinically significant changes in laboratory tests, vital signs, or physical examination were reported. Linagliptin demonstrated a favorable safety profile in healthy Chinese volunteers, with a pharmacokinetic profile that was similar to that observed previously in subjects of Japanese, Caucasian, or African American origin.

Steady State is Reached within Two to Three Days of Once-daily Administration of Ultra-Long-acting Insulin Degludec

(IDeg), a new ultra-long-acting basal insulin, as a function of administration region. Twenty healthy subjects (17 males/3 females; mean age: 37 years, body mass index: 24.1 kg/m2) received single subcutaneous (s.c.) doses of IDeg (0.4 U/kg) in the thigh, the deltoid and the abdomen. Blood samples for pharmacokinetic assessment were taken up to 120 hours after injection, and the pharmacodynamic response was evaluatedduring a24-hour euglycaemic glucose clamp (Biostator; target blood glucose: 4.5 mmol/L). As observed with other insulin preparations, total exposure of IDeg (AUCIDeg,0e120h,SD) (area under the curve) was slightly greater (by 6e7%) after s.c. injection in the deltoid or the abdomen compared to the thigh. There was no difference between the deltoid and abdomen (Table 1). The glucose infusion rate (GIR) profiles were similar for the 3 s.c. injection regions: mean AUCGIR,0e24h,SD (coefficient of variation %) was 2572 (38), 2960 (43) and 2833 (42) mg/kg for thigh, deltoid and abdomen, respectively; mean GIRmax,SD was 2.7 (32), 3.0 (42) and 3.0 (37) mg/kg/min, respectively. The glucose-lowering effect extended beyond 24 hours in all subjects for all 3 s.c. injection regions. In conclusion, IDeg can be administered s.c. in the thigh, the deltoid or the abdomen with similar glucose-lowering effect from a clinical perspective.

The Clinical Pharmacology of Anastrozole

Anastrozole is a potent non-steroidal aromatase inhibitor that selectively inhibits aromatase. It is the first aromatase inhibitor approved by the US Food and Drug Administration as an adjuvant hormonal therapy in early-stage breast cancer. With most patients needing to take anastrozole for two to five years, it is important for physicians to understand the clinical pharmacology of anastrozole. Anastrozole has excellent oral bioavailability and is widely distributed throughout the body. It is extensively metabolised by the liver, with a half-life of 40–50 hours. Anastrozole is primarily excreted through the faecal route. Steady-state concentrations are achieved after seven days of once-daily administration. The standard dosage of anastrozole is 1mg/day orally. No dose adjustments are necessary based on hepatic or renal dysfunction. No significant drug–drug interaction has been reported with anastrozole use. This article is to summarise the existing knowledge of the pharmacokinetics of anastrozole.

Safety and pharmacokinetics of novel selective vascular endothelial growth factor receptor-2 inhibitor YN968D1 in patients with advanced malignancies

BackgroundYN968D1 (Apatinib) selectively inhibits phosphorylation of VEGFR-2 and tumor angiogenesis in mice model. The study was conducted to determine the maximum tolerated dose (MTD), safety profile, pharmacokinetic variables, and antitumor activity in advanced solid malignancies.MethodsThis dose-escalation study was conducted according to the Chinese State Food and Drug Administration (SFDA) recommendations in patients with advanced solid tumors to determine the MTD for orally administered apatinib. Doses of continuously administered apatinib were escalated from 250 mg. Treatment continued after dose-escalation phase until withdrawal of consent, intolerable toxicities, disease progression or death.ResultsForty-six patients were enrolled. Hypertension and hand-foot syndrome were the two dose-limiting toxicities noted at dose level of 1000 mg. MTD was determined to be 850 mg once daily. Pharmacokinetic analysis showed early absorption with a half-life of 9 hours. The mean half-life was constant over all dose groups. Steady-state conditions analysis suggested no accumulation during 56 days of once-daily administration. The most frequently observed drug-related adverse events were hypertension (69.5%, 29 grade 1-2 and 3 grade 3-4), proteinuria (47.8%, 16 grade 1-2 and 6 grade 3-4), and hand-foot syndrome (45.6%, 15 grade 1-2 and 6 grade 3-4). Among the thirty-seven evaluable patients, PR was noted in seven patients (18.9%), SD 24 (64.9%), with a disease control rate of 83.8% at 8 weeks.ConclusionsThe recommended dose of 750 mg once daily was well tolerated. Encouraging antitumor activity across a broad range of malignancies warrants further evaluation in selected populations.Trial registrationClinicalTrials.gov unique identifier: NCT00633490

Evaluation of the urodynamic and hemodynamic effects of orally administered phenylpropanolamine and ephedrine in female dogs

To compare the urodynamic and hemodynamic effects of different dosages of phenylpropanolamine and ephedrine and determine effective dosages in increasing urethral resistance in female dogs. 20 sexually intact female Beagles. Dogs were allocated into 4 groups and received phenylpropanolamine once, twice, or 3 times daily, or ephedrine twice daily, for 14 days. On days 0, 7, and 14, urethral pressure profiles were performed while dogs were anesthetized with propofol. Variables recorded included maximum urethral pressure, maximum urethral closure pressure, integrated pressure, functional profile length, anatomic profile length, plateau distance, distance before maximum urethral pressure, and maximum meatus pressure. Arterial and central venous pressures were measured before anesthetic induction and 10 and 35 minutes after induction. Administration of phenylpropanolamine once daily or ephedrine twice daily significantly increased maximum urethral pressure and maximum urethral closure pressure. Values for integrated pressure were significantly increased after 14 days of once-daily administration of phenylpropanolamine. Variables did not change significantly from day 7 to day 14. Diastolic and mean arterial blood pressures increased significantly during the treatment periods, and arterial pressure decreased during propofol infusion. Oral administration of phenylpropanolamine once daily or ephedrine twice daily increased urethral resistance in clinically normal dogs and may be recommended for management of urethral sphincter mechanism incompetence. Treatment efficacy may be assessed after 1 week. Dogs with concurrent cardiovascular disease should be monitored for blood pressure while receiving alpha-adrenergic agents because of the effects on diastolic and mean arterial pressure.

The Clinical Pharmacokinetics of Darifenacin

Darifenacin hydrobromide is a selective muscarinic M(3) receptor antagonist that is indicated for use in treatment of overactive bladder disorder. Darifenacin was found to have a short terminal elimination half-life after intravenous and immediate-release oral dosage forms (3-4 hours) but this increased with a prolonged-release (PR) formulation (14-16 hours). The absolute bioavailability of darifenacin from 7.5 and 15 mg PR tablets was estimated to be 15.4% and 18.6%, respectively. With repeated once-daily oral administration of the PR formulation, peak plasma concentrations of darifenacin are achieved approximately 7 hours post-dose. After oral administration, darifenacin is well absorbed from the gastrointestinal tract and very little unchanged drug (<2%) is recovered in the faeces. Steady state is achieved after 6 days of once-daily administration of the PR formulation. As expected, values of peak plasma concentration (C(max)) and area under the plasma concentration-time curve are dose dependent, although the increase in plasma concentrations is proportionally greater than the increase in dose owing to saturation of presystemic metabolism. From intravenous administration, it has been established that darifenacin possesses a moderate-to-high hepatic extraction ratio, with high plasma clearance (36-52 L/h) and a volume of distribution (165-276L) that exceeds total body water. It is highly protein bound (98%), primarily to alpha(1)-acid glycoprotein. Darifenacin is subject to extensive hepatic metabolism, with 3% of unchanged drug excreted in urine and faeces. Metabolism is mediated by hepatic cytochrome P450 2D6 and 3A4, the main metabolic routes being monohydroxylation in the dihydrobenzfuran ring, dihydrobenzfuran ring opening, and N-dealkylation of the pyrrolidine nitrogen. Several possibly important drug-drug interactions have been identified with darifenacin, including ketoconazole, erythromycin and fluconazole, each of which increases darifenacin mean C(max) by 9.52-, 2.28- and 1.88-fold, respectively. When given with imipramine, darifenacin causes 1.6-fold higher plasma concentrations of the antidepressant and its major metabolite. Moderate hepatic impairment, but not renal insufficiency, has been shown to increase plasma concentrations of the drug. The pharmacokinetic profile of darifenacin is not affected by food.

Clinical Pharmacokinetics of Telithromycin, the First Ketolide Antibacterial

Telithromycin is the first ketolide, which is a new class of antibacterial agents related to the macrolides that have structural modifications permitting dual binding to bacterial ribosomal RNA so that activity is retained against Streptococcus pneumoniae with macrolide-lincosamide-streptogramin(B) resistance. Clinical experience in infectious patients has shown that oral telithromycin 800mg once daily for 5-10 days is effective for the treatment of community-acquired upper and lower respiratory tract infections. Absorption of telithromycin in humans is estimated to be > or = 90%. Prior to entering the systemic circulation, telithromycin undergoes first-pass metabolism (mainly by the liver). Its absolute bioavailability is 57% and is unaffected by food. The volume of distribution of telithromycin after intravenous infusion is 2.9 L/kg. Telithromycin is 60-70% bound to serum proteins and has extensive diffusion into a range of target biological tissues, achieving concentrations above its minimum inhibitory concentration (MIC) against key respiratory pathogens throughout the dosing interval. After entering the systemic circulation, telithromycin is eliminated by multiple pathways (7% by biliary and/or intestinal excretion, 13% by renal excretion and 37% by hepatic metabolism). Telithromycin is metabolised via cytochrome P450 (CYP) 3A4 and non-CYP pathways. The identified metabolites show minimal antibacterial activity compared with the parent drug. In healthy subjects receiving telithromycin 800 mg once daily, the peak plasma concentration achieved is 2.27 microg/mL. Plasma concentrations of telithromycin show a biphasic decrease over time, with an initial disposition half-life of 2.9 hours and a terminal elimination half-life of approximately 10 hours after multiple dose administration. Steady-state plasma concentrations are achieved within 2-3 days of once-daily administration. Owing to elimination by multiple pathways there is a small increase in exposure when one of these elimination pathways is impaired, as indicated by the results of studies in special patient populations (e.g. those with hepatic or renal impairment). Dosage reductions may be recommended in patients with severe renal impairment. Inhibition of CYP3A4 by potent inhibitors such as itraconazole and ketoconazole results in a 54% and 95% increase in telithromycin area under the plasma concentration-time curve, respectively. The potential for telithromycin to inhibit the CYP3A4 pathway is similar to that of clarithromycin. The once-daily administration of telithromycin is likely to limit the potential for drug interactions and clinically significant increases in exposure. In phase III clinical trials, the telithromycin 800 mg once-daily dose has been shown to provide close to the maximum antimicrobial activity against S. pneumoniae, Haemophilus influenzae and Staphylococcus aureus in patients with community-acquired pneumonia. In conclusion, telithromycin has a well characterised and reproducible pharmacokinetic profile, with pharmacokinetic/pharmacodynamic relationships supporting an oral dosage regimen of 800 mg once daily.

Effect of intravenous and oral omeprazole on 24-hour intragastric acidity in duodenal ulcer patients

Nine patients with duodenal ulcer were on separate occasions given omeprazole, 20 mg orally, 10 mg intravenously (IV), and 40 mg IV once daily for 5 days. On day 1, the median reduction of 24-hour intragastric acidity was 42.2% for the 20-mg oral dose and 54.8% and 88.4% for the two IV doses, respectively, but the between-patient variability was considerable for all three doses. On day 5, the degree of reduction had increased for all three doses to a median value of 99.9% for the 20-mg oral dose and 95.7% and 99.9% for the two IV doses, respectively. Plasma omeprazole concentrations increased significantly from day 1 to day 5 only for the 20-mg oral and 40-mg IV doses. Thus, the increased pharmacological effect of omeprazole during repeated once daily administration can only partly be explained by increased plasma concentrations, suggesting that some additional factor(s) must influence the degree of reduction of 24-hour intragastric acidity. Thus, when determining the optimal dose of omeprazole for acid inhibition, the route and duration of administration must be taken into consideration; after 5 days of once-daily administration of doses as low as 10 mg IV and 20 mg orally are effective and dependable in reducing 24-hour intragastric acidity in patients with duodenal ulcer. However, a daily dose of 40 mg IV omeprazole is not sufficient to keep intragastric pH above 4 in all patients during the first day of treatment.