scholarly journals Pharmacokinetics and Safety of S/GSK1349572, a Next-Generation HIV Integrase Inhibitor, in Healthy Volunteers

2009 ◽  
Vol 54 (1) ◽  
pp. 254-258 ◽  
Author(s):  
Sherene Min ◽  
Ivy Song ◽  
Julie Borland ◽  
Shuguang Chen ◽  
Yu Lou ◽  
...  
Keyword(s):  
Single Dose ◽  
Steady State ◽  
Multiple Dose ◽  
Geometric Mean ◽  
Integrase Inhibitor ◽  
Single Dose Study ◽  
Once Daily ◽  
Dosing Interval ◽  
Dose Study

ABSTRACT S/GSK1349572 is a novel integrase inhibitor with potent in vitro anti-HIV activity, an in vitro resistance profile different from those of other integrase inhibitors, and favorable preclinical safety and pharmacokinetics (PK). Randomized, double-blind, placebo-controlled single-dose and multiple-dose, dose escalation studies evaluated the PK, safety, and tolerability of S/GSK1349572 for healthy subjects. In the single-dose study, two cohorts of 10 subjects each (8 active, 2 receiving placebo) received suspension doses of 2, 5, 10, 25, 50, and 100 mg in an alternating panel design. In the multiple-dose study, three cohorts of 10 subjects each (8 active, 2 receiving placebo) received suspension doses of 10, 25, and 50 mg once daily for 10 days. A cytochrome P450 3A (CYP3A) substudy with midazolam was conducted with the 25-mg dose. Laboratory testing, vital signs, electrocardiograms (ECGs), and PK sampling were performed at regular intervals. S/GSK1349572 was well tolerated. Most adverse events (AEs) were mild, with a few moderate AEs reported. Headache was the most common AE. No clinically significant laboratory trends or ECG changes were noted. PK was linear over the dosage range studied. The steady-state geometric mean area under the concentration-time curve over a dosing interval (AUC0-τ) and maximum concentration of the drug in plasma (C max) ranged from 16.7 μg·h/ml (coefficient of variation [CV], 15%) and 1.5 μg/ml (CV, 24%) at a 10-mg dose to 76.8 μg·h/ml (CV, 19%) and 6.2 μg/ml (CV, 15%) at a 50-mg dose, respectively. The geometric mean steady-state concentration at the end of the dosing interval (C τ) with a 50-mg dose was 1.6 μg/ml, approximately 25-fold higher than the protein-adjusted 90% inhibitory concentration (0.064 μg/ml). The half-life was approximately 15 h. S/GSK1349572 had no impact on midazolam exposure, indicating that it does not modulate CYP3A activity. The PK profile suggests that once-daily, low milligram doses will achieve therapeutic concentrations.

An in Vivo Single- and Multiple-Dose Study of Several Marketed Brands of Conventional and Controlled-Release Theophylline

1984 ◽  
Vol 18 (2) ◽  
pp. 147-153 ◽  
Author(s):  
Jeffrey A. Kotzan ◽  
Joseph V. Vallner ◽  
James T. Stewart ◽  
Irwin L. Honigberg ◽  
W.J. Brown
Keyword(s):  
Single Dose ◽  
Controlled Release ◽  
Multiple Dose ◽  
Healthy Adult ◽  
Dosage Forms ◽  
Adult Males ◽  
Single Dose Study ◽  
Multiple Dose Study ◽  
Dose Study ◽  
Release Tablet

In a single-dose study, 18 healthy adult males consumed each of six dosage forms of theophylline. A conventional-release tablet, a syrup, and four competing brands of controlled-release theophylline were studied. Serial serum samples were obtained and analyzed via high pressure liquid chromatography (HPLC). After achieving steady state, 15 healthy adult males consumed each of five dosage forms of theophylline in a multiple-dose study. Serial blood samples were obtained between 0 and 72 hours and subjected to analysis with HPLC. The results indicated that the controlled-release products were not bioequivalent, although they achieved longer time-to-peak values than did the immediate-release syrup and the conventional-release tablet. A single sustained-release product was uniquely different on most pharmacokinetic parameters when compared with the remaining three controlled-release products. In general, the dosage form variation exceeded the individual subject variation on the single-dose study, but the opposite was true for the multiple-dose study.

Preclinical toxicology of a novel polymeric antitumour agent: HPMA copolymerdoxorubicin (PK1)

1998 ◽  
Vol 17 (2) ◽  
pp. 93-104 ◽  
Author(s):  
R Duncan ◽  
J K Coatsworth ◽  
S Burtles
Keyword(s):  
Single Dose ◽  
Multiple Dose ◽  
Clinical Chemistry ◽  
Testicular Atrophy ◽  
Phase I Clinical Trials ◽  
Polymer Backbone ◽  
Single Dose Study ◽  
Blood Samples ◽  
Multiple Dose Study ◽  
Dose Study

N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer-doxorubicin (PK1) is a novel polymeric anticancer agent containing doxorubicin (approximately 8 wt%) bound to the polymer backbone via a Gly-Phe-Leu-Gly peptidyl linker. The approximate LD50 of PK1 in MF1 mice after a single i.v. injection was 63 mg/kg (doxorubicin-equivalent). Single doses of PK1 were administered to MF1 mice at 22.5 or 45 mg/kg and blood samples taken on days 3, 7 and 14 for haematological examination and clinical chemistry. At day 14 all animals were sacrificed for necropsy. In a multiple dose study, PK1 was administered i.v. to MF1 mice or Wistar rats (20 animals per group) weekly for five consecutive weeks at doses of 12.0 or 22.5 mg/kg (mice) or 3 and 5 mg/kg (rats). After 31 days 10 animals from each group were sacrificed for necropsy and the remainder were sacrificed after 59 days. Blood samples were taken 3 days after administration of each dose and at the end of the experiment, and urine samples were collectedonthe day prior to sacrifice.Mortality inthe single dose mouse and multiple dose rat studies was low. In the multiple dose mouse study 4/10 animals were killed in extremis before the scheduled day 31 and all animals died before day 37. PK1 induced a reduction in WBC and platelets in rats and mice shortly after treatment and RBC at later times, and in the single dose study alanine and aspartate aminotransferase levels were elevated at higher doses. Liver damage was seen only in rat tissue during histological examination. Other histological changes induced by PK1 include thymic and testicular atrophy, bone marrow depletion gastrointestinal tract changes and in the multiple dose study an increase in nuclear size in the proximal tubules of the kidney (although no changes in urine were seen). Recovery from these effects was seen in rats at 59 days. A PK1 dose of 20 mg/m2 (doxorubicin equivalent) was recommended as a safe dose for the start of Phase I clinical trials.

scholarly journals Safety, Tolerability, and Pharmacokinetics of PA-824 in Healthy Subjects

2009 ◽  
Vol 53 (9) ◽  
pp. 3720-3725 ◽  
Author(s):  
Ann M. Ginsberg ◽  
Martino W. Laurenzi ◽  
Doris J. Rouse ◽  
Karl D. Whitney ◽  
Melvin K. Spigelman
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Single Dose ◽  
Healthy Subjects ◽  
Multiple Dose ◽  
Pharmacokinetic Parameters ◽  
Blood Levels ◽  
Drug Resistant ◽  
Single Dose Study ◽  
Multiple Dose Study ◽  
Dose Study

ABSTRACT PA-824 is a novel antibacterial agent that has shown in vitro activity against both drug-sensitive and drug-resistant Mycobacterium tuberculosis. The compound's MIC is between 0.015 and 0.25 μg/ml for drug-sensitive strains and between 0.03 and 0.53 μg/ml for drug-resistant strains. In addition, it is active against nonreplicating anaerobic Mycobacterium tuberculosis. The safety, tolerability, and pharmacokinetics of PA-824 were evaluated in two escalating-dose clinical studies, one a single-dose study and the other a multiple-dose study (up to 7 days of daily dosing). In 58 healthy subjects dosed with PA-824 in these studies, the drug candidate was well tolerated, with no significant or serious adverse events. In both studies, following oral administration PA-824 reached maximal plasma levels in 4 to 5 h independently of the dose. Maximal blood levels averaged approximately 3 μg/ml (1,500-mg dose) in the single-dose study and 3.8 μg/ml (600-mg dose) in the multiple-dose study. Steady state was achieved after 5 to 6 days of daily dosing, with an accumulation ratio of approximately 2. The elimination half-life averaged 16 to 20 h. Overall, PA-824 was well tolerated following oral doses once daily for up to 7 days, and pharmacokinetic parameters were consistent with a once-a-day regimen. The results of these studies, combined with the demonstrated activity of PA-824 against drug-sensitive and multidrug-resistant Mycobacterium tuberculosis, support the investigation of this novel compound for the treatment of tuberculosis.

scholarly journals Lack of Effect of Efavirenz on the Pharmacokinetics of Tipranavir-Ritonavir in Healthy Volunteers

2009 ◽  
Vol 53 (11) ◽  
pp. 4840-4844 ◽  
Author(s):  
C. J. L. la Porte ◽  
J. P. Sabo ◽  
L. Béïque ◽  
D. W. Cameron
Keyword(s):  
Steady State ◽  
Multiple Dose ◽  
Healthy Adult ◽  
Geometric Mean ◽  
Plasma Concentrations ◽  
Open Label ◽  
Multiple Dose Study ◽  
Chromatography Tandem Mass Spectrometry ◽  
Liquid Chromatography Tandem Mass ◽  
Dose Study

ABSTRACT Previously it has been shown that tipranavir-ritonavir (TPV/r) does not affect efavirenz (EFV) plasma concentrations. This study investigates the effect of steady-state EFV on steady-state TPV/r pharmacokinetics. This was a single-center, open-label, multiple-dose study of healthy adult female and male volunteers. TPV/r 500/200 mg twice a day (BID) was given with food for 24 days. After dosing with TPV/r for 10 days, EFV 600 mg once a day was added to the regimen. Intensive pharmacokinetic (PK) sampling was done on days 10 and 24. Validated bioanalytical high-pressure liquid chromatography-tandem mass spectrometry methods were used to determine plasma tipranavir (TPV), ritonavir (RTV), and EFV concentrations. Thirty-four subjects were entered into the study, and 16 subjects completed it. The geometric mean ratios (90% confidence intervals) for TPV and RTV area under the curves, C maxs, and C mins comparing TPV/r alone and in combination with EFV were 0.97 (0.87 to 1.09), 0.92 (0.81 to 1.03), and 1.19 (0.93 to 1.54) for TPV and 1.03 (0.78 to 1.38), 0.92 (0.65 to 1.30), and 1.04 (0.72 to 1.48) for RTV. Frequently observed adverse events were diarrhea, headache, dizziness, abnormal dreams, and rash. EFV had no effect on the steady-state PK of TPV or RTV, with the exception of a 19% increase in the TPV C min, which is not clinically relevant. TPV/r can be safely coadministered with EFV and without the need for a dose adjustment.

Single and Multiple-Dose Kinetics of Ofloxacin in Patients on Continuous Ambulatory Peritoneal Dialysis (CAPD)

1989 ◽  
Vol 9 (4) ◽  
pp. 267-272 ◽  
Author(s):  
J. Passlick ◽  
R. Wonner ◽  
E. Keller ◽  
L. Essers ◽  
B. Grabensee
Keyword(s):  
Single Dose ◽  
Peritoneal Dialysis ◽  
Continuous Ambulatory Peritoneal Dialysis ◽  
Multiple Dose ◽  
Serum Levels ◽  
Time Interval ◽  
Single Dose Study ◽  
Multiple Dose Study ◽  
Dose Study ◽  
Stage Renal Disease

To evaluate the pharmacokinetics of ofloxacin, a novel quinolon antibiotic, in patients with end-stage renal disease (ESRO) on continuous ambulatory peritoneal dialysis (CAPO), we investigated 6 patients in a single-dose study and 9 patients in a multiple-dose study, all without peritonitis. In the single-dose study, patients received 200 mg ofloxacin orally. Serum concentrations (Cmax) peaked at 3.1 ± 0.3 mg/L (x ± SEM), 1.6 ± 0.5 h after p. 0. administration of the drug. Elimination half-life ( t112) was 26.8 ± 2.5 h. Peritoneal clearance accounted for 10% of the total body clearance. After 5- h dwell time, ofloxacin concentrations in the dialysate were 1.5 ± 0.2 mg/L, which is above the MIC90 for most bacteria responsible for peritonitis in patients on CAPO. In the multiple dose study, 200 mg ofloxacin were administered twice, with a time interval of 12 h, followed by 200 mg for 9 days every morning. Mean trough serum levels were 2.6 ± 1.0 mg/L, mean peak concentrations were 4.1 ± 1.7 mg/L. Mean ofloxacin concentrations in the peritoneal effluent were 1.9 ± 0.9 mg/L. It is concluded that an oral loading dose of 400 mg on the first day and a maintenance dose of 200 mg ofloxacin/day does not lead to significant accumulation, even though the elimination by the peritoneal route is only small. The proposed dosing regimen could be an adequate therapy of peritonitis and exit-site infections in patients on CAPO since levels reached in the dialysate effluent are bactericidal. The clinical usefulness in the treatment of peritonitis has to be proven in further studies.

scholarly journals Pharmacokinetics of Bismuth following Oral Administration of Wei Bi Mei in Healthy Chinese Volunteers

2020 ◽  
Vol 2020 ◽  
pp. 1-6
Author(s):  
Lingye Zhang ◽  
Juan Liu ◽  
Fandong Meng ◽  
Yingying Guan ◽  
Yongjun Wang ◽  
...  
Keyword(s):  
Helicobacter Pylori ◽  
Single Dose ◽  
Inductively Coupled Plasma ◽  
Peak Concentration ◽  
Multiple Dose ◽  
Single Dose Study ◽  
Quadruple Therapy ◽  
Dose Study ◽  
The Mean ◽  
Healthy Chinese

Background. Bismuth-containing quadruple therapy achieves higher eradication rate of Helicobacter pylori. High level of bismuth in blood may result in damage of many organs. Wei Bi Mei is a new bismuth-containing drug combining chemicals and Chinese medicine portions. The present research is to study the pharmacokinetics of bismuth to evaluate the safety and rational use of Wei Bi Mei granules. Material and Methods. Seven healthy Chinese adult subjects were enrolled in this research, which included a single-dose study and a multiple-dose study. Wei Bi Mei granules were administered orally to the subjects at corresponding time. Blood and urine were collected. All samples were analyzed by inductively coupled plasma mass spectrometry (ICP-MS). Results. For single-dose Wei Bi Mei granules administration, the mean time to peak concentration (tmax) of bismuth was 2.29 ± 0.76 h, and the mean peak concentration (Cmax) of bismuth was 0.85 ± 0.55 ng/mL. For multiple-dose Wei Bi Mei granules administration, the Cmax was 2.25 ± 1.18 ng/mL at day two, and the volume of distribution (Vd) was (22.97 ± 9.82) × 103 L. The urinary excretion of bismuth was the fastest during the first two days, with a mean excretion rate of 3.84 ± 1.23 ng/h. The bismuth concentration in urine was significantly reduced at day 16. Conclusion. Bismuth has a washout period of approximately two months. The concentration of bismuth in blood was far less than the “safe level.” Thus, Wei Bi Mei is a highly safe therapeutic medicine, with a good clinical application value. Wei Bi Mei should be recommended more widely for use in bismuth-containing quadruple therapy for the treatment of Helicobacter pylori infection.

scholarly journals Pharmacokinetics, safety and tolerability of L-3-n-butylphthalide tablet after single and multiple oral administrations in healthy Chinese volunteers

2015 ◽  
Vol 51 (3) ◽  
pp. 525-531 ◽  
Author(s):  
Meng Wang ◽  
Quan-ying Zhang ◽  
Wen-yan Hua ◽  
Ming Huang ◽  
Wen-jia Zhou ◽  
...  
Keyword(s):  
Single Dose ◽  
Multiple Dose ◽  
Compartmental Analysis ◽  
Pharmacokinetic Parameters ◽  
Double Blind ◽  
Single Dose Study ◽  
Multiple Dose Study ◽  
Dose Study ◽  
Repeated Doses ◽  
Healthy Chinese

L-3-n-butylphthalide (L-NBP) is a naturally occurring antioxidant, which can be used for the treatment of acute ischemic stroke and vascular dementia. This study evaluated the safety, tolerability and pharmacokinetics of L-NBP tablets in healthy Chinese volunteers. This was a single-center, randomized, double-blind, placebo-controlled, single- and multiple-dose study. Subjects were assigned to receive a single dose of L-NBP tablet at either 80, 160, 320, or 480 mg (n=40), or multiple doses of 160 mg twice daily for 7 days (n=12). Plasma samples were analyzed with LC-MS/MS. Pharmacokinetic parameters of L-NBP were calculated using non-compartmental analysis with WinNonlin software. Statistical analysis was performed using SPSS software. All adverse events (AEs) were mild and of limited duration; AEs in this study occurred less frequently and more mildly than AEs listed for the DL-NBP soft capsule. No serious adverse event (SAE), death or withdrawal from the study was observed. In the single-dose study, Cmax was reached at about 1 h, and the mean t1/2 was approximately 13.76 h. Area under curve (AUC) and Cmax increased with dose escalation, but dose proportionality was not observed over the range of 160 to 480 mg. In the multiple-dose study, the steady-state was reached within 3 days with slight accumulation. In summary, the L-NBP tablet was well tolerated in healthy Chinese subjects. Slight accumulation appeared after repeated doses.

A pharmacokinetic evaluation of single and multiple doses of extended-release hydrocodone bitartrate in subjects experiencing surgical or osteoarthritic pain

2015 ◽  
Vol 11 (5) ◽  
pp. 405 ◽  
Author(s):  
Cynthia Y. Robinson, PhD ◽  
Christopher M. Rubino, PharmD ◽  
Stephen J. Farr, PhD
Keyword(s):  
Single Dose ◽  
Steady State ◽  
Extended Release ◽  
Venous Blood ◽  
Plasma Concentrations ◽  
Immediate Release ◽  
Pharmacokinetic Parameters ◽  
Single Dose Study ◽  
Dosing Interval ◽  
Osteoarthritic Pain

Objectives: To assess the single-dose and steady-state pharmacokinetics of a single-entity hydrocodone extended-release (ER) formulation in patients enrolled in two separate phase 2 clinical studies.Setting: Both studies were multicenter clinical studies.Subjects and interventions: In study 1, 115 subjects with postsurgical pain (bunionectomy) received single doses of 10, 20, 30, or 40 mg hydrocodone-ER, 10 mg hydrocodone/325 mg acetaminophen immediate-release (IR), or placebo. In study 2, 37 subjects with osteoarthritic pain received doses of 10, 20, 30, or 40 mg of hydrocodone-ER twice-daily for 7 days. Venous blood samples were taken periodically up to 24 hours postdosing after the single dose (study 1) or after 7 days of dosing (study 2) and were assayed for concentrations of hydrocodone and its major metabolites.Main outcome measures: Standard pharmacokinetic parameters were estimated by noncompartmental analysis methods.Results: Following a single dose of hydrocodone-ER, Tmax was prolonged to approximately 6 hours at all dose levels of hydrocodone-ER compared with 2.9 hours for the IR formulation. All doses of hydrocodone-ER formulations provided prolonged and sustained release of hydrocodone throughout the 12-hour dosing interval with reduced peak-to-trough fluctuation at steady state compared with hydrocodone/acetaminophen-IR comparator. Both single-dose and steady-state mean Cmax and AUClast values showed reasonable dose-proportionality. Norhydrocodone and hydromorphone plasma concentrations were 32-38 percent and <2.1 percent, respectively, of hydrocodone concentrations in both studies.Conclusions: The sustained plasma concentrations of hydrocodone support twice-daily dosing with a 12-hour dosing interval.

scholarly journals Pharmacokinetics of Prednisolone at Steady State in Young Patients With Systemic Lupus Erythematosus on Prednisone Therapy: An Open-Label, Single-Dose Study

2011 ◽  
Vol 33 (10) ◽  
pp. 1524-1536 ◽  
Author(s):  
Anna Carmela P. Sagcal-Gironella ◽  
Catherine M.T. Sherwin ◽  
Rommel G. Tirona ◽  
Michael J. Rieder ◽  
Hermine I. Brunner ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Single Dose ◽  
Steady State ◽  
Lupus Erythematosus ◽  
Young Patients ◽  
Systemic Lupus ◽  
Open Label ◽  
Single Dose Study ◽  
Prednisone Therapy ◽  
Dose Study

scholarly journals Results of a Doravirine-Atorvastatin Drug-Drug Interaction Study

2016 ◽  
Vol 61 (2) ◽  
Author(s):  
Sauzanne Khalilieh ◽  
Ka Lai Yee ◽  
Rosa I. Sanchez ◽  
Ilias Triantafyllou ◽  
Li Fan ◽  
...  
Keyword(s):  
Single Dose ◽  
Drug Interactions ◽  
Geometric Mean ◽  
Cancer Resistance ◽  
Serious Adverse Events ◽  
Fixed Sequence ◽  
Once Daily ◽  
Relevant Effect ◽  
Hiv 1

ABSTRACT Doravirine is a novel, highly potent, nonnucleoside reverse transcriptase inhibitor that is administered once daily and that is in development for the treatment of HIV-1 infection. In vitro and clinical data suggest that doravirine is unlikely to cause significant drug-drug interactions via major drug-metabolizing enzymes or transporters. As a common HIV-1 infection comorbidity, hypercholesterolemia is often treated with statins, including the commonly prescribed atorvastatin. Atorvastatin is subject to drug-drug interactions with cytochrome P450 3A4 (CYP3A4) inhibitors. Increased exposure due to CYP3A4 inhibition may lead to serious adverse events (AEs), including rhabdomyolysis. Furthermore, atorvastatin is a substrate for breast cancer resistance protein (BCRP), of which doravirine may be a weak inhibitor; this may increase atorvastatin exposure. The potential of doravirine to affect atorvastatin pharmacokinetics was investigated in a two-period, fixed-sequence study in healthy individuals. In period 1, a single dose of atorvastatin at 20 mg was administered followed by a 72-h washout. In period 2, doravirine at 100 mg was administered once daily for 8 days, with a single dose of atorvastatin at 20 mg concomitantly being administered on day 5. Sixteen subjects were enrolled, and 14 completed the trial; 2 discontinued due to AEs unrelated to the treatment. The atorvastatin area under the curve from time zero to infinity was similar with and without doravirine (geometric mean ratio [GMR] for doravirine-atorvastatin/atorvastatin, 0.98; 90% confidence interval [CI], 0.90 to 1.06), while the maximum concentration decreased by 33% (GMR for doravirine-atorvastatin/atorvastatin, 0.67; 90% CI, 0.52 to 0.85). These changes were deemed not to be clinically meaningful. Both of the study drugs were generally well tolerated. Doravirine had no clinically relevant effect on atorvastatin pharmacokinetics in healthy subjects, providing support for the coadministration of doravirine and atorvastatin.

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