Pre-dosing plasma concentrations and beta-adrenoceptor blocking effects during repeated once daily dosing with 160 mg sustained-release propranolol (Inderal LA) and 16/260 oxprenolol Oros to healthy volunteers.

ABSTRACT Once-daily (QD) fosamprenavir (FPV) at 1,400 mg boosted with low-dose ritonavir (RTV) at 200 mg is effective when it is used in combination regimens for the initial treatment of human immunodeficiency virus infection. Whether a lower RTV boosting dose (i.e., 100 mg QD) could ensure sufficient amprenavir (APV) concentrations with improved safety/tolerability is unknown. This randomized, two 14-day-period, crossover pharmacokinetic study compared the steady-state plasma APV concentrations, safety, and tolerability of FPV at 1,400 mg QD boosted with either 100 mg or 200 mg of RTV QD in 36 healthy volunteers. Geometric least-square (GLS) mean ratios and the associated 90% confidence intervals (CIs) were estimated for plasma APV maximum plasma concentrations (C max), the area under the plasma concentration-time curve over the dosing period (AUC0-τ), and trough concentrations (C τ) during each dosing period. Equivalence between regimens (90% CIs of GLS mean ratios, 0.80 to 1.25) was observed for the plasma APV AUC0-τ (GLS mean ratio, 0.90 [90% CI, 0.84 to 0.96]) and C max (0.97 [90% CI, 0.91 to 1.04]). The APV C τ was 38% lower with RTV at 100 mg QD than with RTV at 200 mg QD (GLS mean ratio, 0.62 [90% CI, 0.55 to 0.69]) but remained sixfold higher than the protein-corrected 50% inhibitory concentration for wild-type virus, with the lowest APV C τ observed during the 100-mg QD period being nearly threefold higher. The GLS mean APV C τ was 2.5 times higher than the historical C τ for unboosted FPV at 1,400 mg twice daily. Fewer clinical adverse drug events and smaller increases in triglyceride levels were observed with the RTV 100-mg QD regimen. Clinical trials evaluating the efficacy and safety of FPV at 1,400 mg QD boosted by RTV at 100 mg QD are now under way with antiretroviral therapy-naïve patients.

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Effect of Rifampicin on S-ketamine and S-norketamine Plasma Concentrations in Healthy Volunteers after Intravenous S-ketamine Administration

Anesthesiology ◽

10.1097/aln.0b013e318218a881 ◽

2011 ◽

Vol 114 (6) ◽

pp. 1435-1445 ◽

Cited By ~ 32

Author(s):

Ingeborg Noppers ◽

Erik Olofsen ◽

Marieke Niesters ◽

Leon Aarts ◽

René Mooren ◽

...

Keyword(s):

Healthy Volunteers ◽

Plasma Concentrations ◽

Area Under The Curve ◽

Compartmental Analysis ◽

Placebo Treatment ◽

Drug Infusion ◽

Once Daily ◽

Cyp Enzymes ◽

Arterial Plasma ◽

Male Subjects

Background Low-dose ketamine is used as analgesic for acute and chronic pain. It is metabolized in the liver to norketamine via cytochrome P450 (CYP) enzymes. There are few human data on the involvement of CYP enzymes on the elimination of norketamine and its possible contribution to analgesic effect. The aim of this study was to investigate the effect of CYP enzyme induction by rifampicin on the pharmacokinetics of S-ketamine and its major metabolite, S-norketamine, in healthy volunteers. Methods Twenty healthy male subjects received 20 mg/70 kg/h (n = 10) or 40 mg/70 kg/h (n = 10) intravenous S-ketamine for 2 h after either 5 days oral rifampicin (once daily 600 mg) or placebo treatment. During and 3 h after drug infusion, arterial plasma concentrations of S-ketamine and S-norketamine were obtained at regular intervals. The data were analyzed with a compartmental pharmacokinetic model consisting of three compartments for S-ketamine, three sequential metabolism compartments, and two S-norketamine compartments using the statistical package NONMEM® 7 (ICON Development Solutions, Ellicott City, MD). Results Rifampicin caused a 10% and 50% reduction in the area-under-the-curve of the plasma concentrations of S-ketamine and S-norketamine, respectively. The compartmental analysis indicated a 13% and 200% increase in S-ketamine and S-norketamine elimination from their respective central compartments by rifampicin. Conclusions : A novel observation is the large effect of rifampicin on S-norketamine concentrations and indicates that rifampicin induces the elimination of S-ketamine's metabolite, S-norketamine, probably via induction of the CYP3A4 and/or CYP2B6 enzymes.

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Comparative Clinical Pharmacokinetics and Pharmacodynamics of Investigational Once-Daily Sustained-Release (SR) Vildagliptin 100 mg Tablet Formulation with Conventional 50 mg Twice-Daily Regimen in Healthy Indian Males

International Journal of Current Science Research and Review ◽

10.47191/ijcsrr/v4-i5-19 ◽

2021 ◽

Vol 04 (05) ◽

Author(s):

Alok Pote ◽

Keyword(s):

Sustained Release ◽

Multiple Dose ◽

Patient Adherence ◽

Plasma Concentrations ◽

Tablet Formulation ◽

Daily Regimen ◽

Post Dose ◽

Clinical Pharmacokinetics ◽

Once Daily ◽

Concentration Time

Background- Among the gliptins, vildagliptin is the only therapy requiring twice-daily dosing and thus adversely impacts patient adherence. To reduce dosing frequency, we developed a once-daily sustained-release (SR) vildagliptin 100 mg tablet formulation with potential to furnish comparable dipeptidyl peptidase-4 (DPP-4) inhibition coverage to the conventional twice-daily regimen. Objective- The current study compares the pharmacokinetic (PK) and pharmacodynamic (PD) characteristics of investigational once-daily SR vildagliptin 100 mg tablet formulation with the twice-daily dosage of marketed product, Galvus® in healthy Indian adult males after single and multiple-dose administration. Methods- Single and multiple-dose PK-PD assessment was conducted in separate clinical studies enrolling thirty-six healthy subjects under fed-condition. Each study was a randomized, open-label, two treatment, two-period, crossover design. Drug plasma concentrations were quantified by validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) method. DPP-4 inhibition was estimated in the fluorescence-based assay. PK parameters were calculated from the plasma concentration-time curve employing Phoenix® WinNonlin® software. Formulation safety was evaluated by monitoring adverse events. Results- SR vildagliptin 100 mg tablet resulted in peak-less, nearly steady drug concentration-time profile. Thus, its mean PK characteristics after single [Cmax (147.7), AUC(0-24) (1645.04), Tmax (5.29 hr), t1/2 (4.61 hr)] and multiple-dose [Cmaxss (163.59), AUCss (0-24) (1815.36), and Tmaxss (4.65 hrs), t1/2ss (3.71 hr)] administrations were significantly distinct from the Galvus® twice-daily regimen. SR vildagliptin 100 mg tablet demonstrated more than 80% DPP-4 inhibition profile for approximately 23 hrs in both the studies which was comparable to Galvus® twice-daily regimen. Conclusions- Investigational SR vildagliptin 100 mg tablet formulation was found to be safe and well-tolerated. Its ability to provide nearly 80% DPP-4 inhibition coverage over 23 hrs post-dose may reduce the additional pill burden in patients on conventional twice-daily regimen.

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Evaluation of the Pharmacokinetic Drug–Drug Interaction between Micronized Fenofibrate and Pitavastatin in Healthy Volunteers

Pharmaceutics ◽

10.3390/pharmaceutics12090869 ◽

2020 ◽

Vol 12 (9) ◽

pp. 869

Author(s):

Hae Won Lee ◽

Woo Youl Kang ◽

Wookjae Jung ◽

Mi-Ri Gwon ◽

Kyunghee Cho ◽

...

Keyword(s):

Adverse Events ◽

Healthy Volunteers ◽

Combined Treatment ◽

Plasma Concentrations ◽

Lipid Lowering ◽

Fenofibric Acid ◽

Serious Adverse Events ◽

Once Daily ◽

Pharmacokinetic Interactions ◽

Micronized Fenofibrate

Dyslipidemia is a major risk factor for development of atherosclerosis and cardiovascular disease (CVD). Effective lipid-lowering therapies has led to CVD risk reduction. This study evaluated the possible pharmacokinetic interactions between fenofibrate, a peroxisome proliferators-activated receptors α agonist, and pitavastatin, a 3-hydoxy-3-methylglutaryl-coenzyme A reductase inhibitor, in healthy Korean subjects. The study design was an open-label, randomized, multiple-dose, three-period, and six-sequence crossover study with a 10-day washout in 24 healthy volunteers. It had three treatments: 160 mg of micronized fenofibrate once daily for 5 days; 2 mg of pitavastatin once daily for 5 days; and 160 mg of micronized fenofibrate with 2 mg of pitavastatin for 5 days. Serial blood samples were collected at scheduled intervals for up to 48 h after the last dose in each period to determine the steady-state pharmacokinetics of both drugs. Plasma concentrations of fenofibric acid and pitavastatin were measured using a validated high-performance liquid chromatography with the tandem mass spectrometry method. A total of 24 subjects completed the study. Pitavastatin, when co-administered with micronized fenofibrate, had no effect on the Cmax,ss and AUCτ,ss of fenofibric acid. The Cmax,ss and AUCτ,ss of pitavastatin were increased by 36% and 12%, respectively, when co-administered with fenofibrate. Combined treatment with pitavastatin and micronized fenofibrate was generally well tolerated without serious adverse events. Our results demonstrated no clinically significant pharmacokinetic interactions between micronized fenofibrate and pitavastatin when 160 mg of micronized fenofibrate and 2 mg of pitavastatin are co-administered. The treatments were well tolerated during the study, with no serious adverse events.

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Chrono-Pharmacological Study of Once Daily Curative Dose of a Low Molecular Weight Heparin (200IU antiXa/kg of Dalteparin) in Ten Healthy Volunteers

Thrombosis and Haemostasis ◽

10.1055/s-0038-1649794 ◽

1995 ◽

Vol 74 (02) ◽

pp. 660-666 ◽

Cited By ~ 15

Author(s):

P Mismetti ◽

J Reynaud ◽

B Tardy-Poncet ◽

S Laporte-Simitsidis ◽

M Scully ◽

...

Keyword(s):

Molecular Weight ◽

Healthy Volunteers ◽

Low Molecular Weight Heparin ◽

Pharmacological Study ◽

Area Under The Curve ◽

Factor Xa ◽

Similar Efficacy ◽

Low Molecular Weight ◽

Thrombin Time ◽

Once Daily

SummaryLow molecular weight heparin (LMWH) is currently prescribed for the treatment of deep vein thrombosis at the dose of 100 IU antiXa/kg twice daily or at a dose of 175 IU antiXa/kg once daily with a similar efficacy. We decided to study the chrono-pharmacology of curative dose of LMWH once daily administrated according to the one previously described with unfractionated heparin (UFH).Ten healthy volunteers participated in an open three-period crossover study according to three 24 h cycles, separated by a wash-out interval lasting 7 days: one control cycle without injection, two cycles with subcutaneous injection of 200 IU antiXa/kg of Dalteparin (Fragmin®) at 8 a.m. or at 8 p.m. Parameters of heparin activity were analysed as maximal values and area under the curve.Activated partial thromboplastin time (APTT), thrombin time (TT), prothrombin time (PT) and tissue factor pathway inhibitor (TFPI) were higher after 8 p.m. injection than after 8 a.m. injection (p <0.05) while no chrono-pharmacological variation of anti factor Xa (AXa) activity was observed. Thus the biological anticoagulant effect of 200 IU antiXa/kg of Dalteparin seems to be higher after an evening injection than after a morning injection.A chrono-therapeutic approach with LMWH, as prescribed once daily, deserves further investigation since our results suggest that a preferential injection time may optimise the clinical efficacy of these LMWH.

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Pharmacokinetics and Effects on Fibrinolytic and Coagulation Parameters of Two Doses of Recombinant Tissue-Type Plasminogen Activator in Healthy Volunteers

Thrombosis and Haemostasis ◽

10.1055/s-0038-1661592 ◽

1986 ◽

Vol 56 (01) ◽

pp. 001-005 ◽

Cited By ~ 53

Author(s):

M Verstraete ◽

C A P F Su ◽

P Tanswell ◽

W Feuerer ◽

D Collen

Keyword(s):

Healthy Volunteers ◽

Plasminogen Activator ◽

Degradation Products ◽

Plasma Concentrations ◽

State Level ◽

Compartment Model ◽

Tissue Type ◽

Maximum Plasma ◽

Tissue Type Plasminogen Activator ◽

Type Plasminogen Activator

SummaryPharmacokinetics and pharmacological effects of two intravenous doses of recombinant tissue-type plasminogen activator (rt-PA) (40 and 60 mg over 90 min) were determined in healthy volunteers. Mean maximum plasma concentrations were 1080 and 1560 ng/ml respectively. The steady state level during subsequent maintenance infusion of 30 mg over 6 h was 250 ng/ml. The pharmacokinetics of rt-PA showed a bi-exponential disappearance from plasma consistent with a 2-compartment model of t½α = 5.7 min, a t½β = 1.3 h and a total clearance of 380 ml/min.Mean fibrinogen levels at the end of the infusions of 40 mg or 60 mg rt-PA over 90 min, measured in thawed plasma samples collected on citrate/aprotinin, decreased to 74% and 57% of the preinfusion values respectively. Plasminogen fell to 55% and 48%, and α2-antiplasmin to 28% and 18% of initial values. No further decrease of these parameters was observed during the infusion of 30 mg rt-PA over 6 h. Only 2% of the preinfusion fibrinogen levels could be recovered as fibrinogen-fibrin degradation products. This moderate extent of systemic fibrinogenolysis is much less than that reported for therapeutic i.v. infusions of streptokinase.

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Bioequivalence Study of Once Daily PMR Compared to Twice Daily Cilostazol IR Tablets in Healthy Volunteers

Case Medical Research ◽

10.31525/ct1-nct03864666 ◽

2019 ◽

Author(s):

Keyword(s):

Healthy Volunteers ◽

Bioequivalence Study ◽

Once Daily

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Pharmacokinetics of Plasma Doravirine Once Daily Over 72 Hours Following Drug Intake Cessation in Healthy Volunteers

Case Medical Research ◽

10.31525/ct1-nct03894124 ◽

2019 ◽

Author(s):

Keyword(s):

Healthy Volunteers ◽

Drug Intake ◽

Once Daily

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Nimodipine pharmacokinetics after intraventricular injection of sustained-release nimodipine for subarachnoid hemorrhage

Journal of Neurosurgery ◽

10.3171/2019.9.jns191366 ◽

2021 ◽

Vol 134 (1) ◽

pp. 95-101 ◽

Cited By ~ 2

Author(s):

R. Loch Macdonald ◽

Daniel Hänggi ◽

Poul Strange ◽

Hans Jakob Steiger ◽

J Mocco ◽

...

Keyword(s):

Subarachnoid Hemorrhage ◽

Sustained Release ◽

Aneurysmal Subarachnoid Hemorrhage ◽

External Ventricular Drain ◽

Plasma Concentrations ◽

Intraventricular Injection ◽

World Federation ◽

Maximum Plasma ◽

Clinical Trial Registration ◽

Sustained Release Formulation

OBJECTIVEThe objective of this study was to measure the concentration of nimodipine in CSF and plasma after intraventricular injection of a sustained-release formulation of nimodipine (EG-1962) in patients with aneurysmal subarachnoid hemorrhage (SAH).METHODSPatients with SAH repaired by clip placement or coil embolization were randomized to EG-1962 or oral nimodipine. Patients were classified as grade 2–4 on the World Federation of Neurosurgical Societies grading scale for SAH and had an external ventricular drain inserted as part of their standard of care. Cohorts of 12 patients received 100–1200 mg of EG-1962 as a single intraventricular injection (9 per cohort) or they remained on oral nimodipine (3 per cohort). Plasma and CSF were collected from each patient for measurement of nimodipine concentrations and calculation of maximum plasma and CSF concentration, area under the concentration-time curve from day 0 to 14, and steady-state concentration.RESULTSFifty-four patients in North America were randomized to EG-1962 and 18 to oral nimodipine. Plasma concentrations increased with escalating doses of EG-1962, remained stable for 14 to 21 days, and were detectable at day 30. Plasma concentrations in the oral nimodipine group were more variable than for EG-1962 and were approximately equal to those occurring at the EG-1962 800-mg dose. CSF concentrations of nimodipine in the EG-1962 groups were 2–3 orders of magnitude higher than in the oral nimodipine group, in which nimodipine was only detected at low concentrations in 10% (21/213) of samples. In the EG-1962 groups, CSF nimodipine concentrations were 1000 times higher than plasma concentrations.CONCLUSIONSPlasma concentrations of nimodipine similar to those achieved with oral nimodipine and lasting for 21 days could be achieved after a single intraventricular injection of EG-1962. The CSF concentrations from EG-1962, however, were at least 2 orders of magnitude higher than those with oral nimodipine. These results supported a phase 3 study that demonstrated a favorable safety profile for EG-1962 but yielded inconclusive efficacy results due to notable differences in clinical outcome based on baseline disease severity.Clinical trial registration no.: NCT01893190 (ClinicalTrials.gov).

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