Evaluation of the pharmacokinetic interaction and safety of ubrogepant coadministered with acetaminophen or nonsteroidal anti-inflammatory drugs: A randomized trial

Background: Ubrogepant is a novel, oral calcitonin gene–related peptide receptor antagonist approved by the US Food and Drug Administration for acute treatment of migraine with or without aura in adults. Objectives: To assess potential pharmacokinetic (PK) drug–drug interactions in healthy participants and inform the safety and tolerability of ubrogepant alone and in combination with acetaminophen or nonsteroidal anti-inflammatory drugs (NSAIDs) in healthy participants and participants with migraine. Methods: Two phase 1, three-way crossover studies randomized healthy adults to 100 mg ubrogepant alone, 1000 mg acetaminophen or 500 mg naproxen alone, and 100 mg ubrogepant plus 1000 mg acetaminophen or 500 mg naproxen. Geometric mean ratios (GMRs) and 90% confidence intervals were calculated based on statistical comparison of maximum plasma drug concentration ( C max) and area under the plasma drug concentration–time curve (AUC) for treatment in combination versus alone. Two phase 3 randomized trials included adults with migraine. Treatment-emergent adverse events (TEAEs) were evaluated. Results: Time to C max and terminal elimination half-life for all treatments were unchanged when coadministered. Ubrogepant C max and AUC increased by approximately 40% when coadministered with acetaminophen. Acetaminophen C max decreased by 24% (GMR = 0.76) when coadministered with ubrogepant. There were no significant PK interactions between ubrogepant and naproxen. TEAE rates in the acetaminophen and NSAID rescue medication groups were similar to ubrogepant alone. Conclusions: Coadministration of ubrogepant and acetaminophen resulted in a statistically significant increase in ubrogepant exposure and a decrease in acetaminophen C max; however, these changes were not clinically relevant. No statistically or clinically relevant changes in PK were associated with ubrogepant and naproxen coadministration. No safety concerns were identified for ubrogepant alone or in combination with acetaminophen or NSAIDs.

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Evaluation of Pharmacokinetic Interaction of Cilostazol with Metoclopramide after Oral Administration in Human

Current Drug Metabolism ◽

10.2174/1389200220666191105115805 ◽

2019 ◽

Vol 20 (11) ◽

pp. 924-928 ◽

Cited By ~ 1

Author(s):

Iram Kaukab ◽

Syed Nisar Hussain Shah ◽

Zelal Kharaba ◽

Ghulam Murtaza ◽

Abubaker Ali Saad ◽

...

Keyword(s):

High Performance ◽

Area Under The Curve ◽

Pharmacokinetic Interaction ◽

Plasma Drug Concentration ◽

Maximum Plasma ◽

Plasma Drug ◽

Two Phase ◽

Time Period ◽

Maximum Plasma Drug Concentration ◽

The Mean

Background: Metoclopramide is mainly metabolized by CYP2D6, CYP3A4, CYP2C19, and CYP1A2 enzymes, while cilostazol is also metabolized by CYP3A4, CYP2C19, and CYP1A2 enzymes. Aim: This study evaluates the effect of cilostazol on the pharmacokinetics of oral metoclopramide. Methods: This was a randomized, two-phase cross-over pharmacokinetic study separated by a 4-week wash-out time period, 12 healthy non-smoking volunteers received metoclopramide 20 mg as a single oral dose and after 4 weeks, cilostazol 100 mg twice daily for 4 days then with metoclopramide 20 mg on test day. Serial blood samples were analyzed by using a validated high-performance liquid chromatography-ultraviolet method to determine maximum plasma drug concentration (Cmax), time to reach (Tmax), and area under the curve (AUC0-∞) of metoclopramide. Results: Cilostazol increased the mean Cmax, AUC0-∞ and half-life (T1/2) of metoclopramide by 6%, 27% and by 0.79 %, respectively. In addition, Tmax of metoclopramide was delayed by cilostazol. Conclusion: The results showed delayed Tmax of metoclopramide by cilostazol, which could lead to the conclusion that cilostazol affects the absorption of metoclopramide. Both drugs when necessary to administer together must not be administered at the same time especially when given in gastroparesis patients.

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RP-HPLC METHOD DEVELOPMENT, VALIDATION, AND QUANTIFICATION OF LORNOXICAM IN LIPID NANOPARTICLE FORMULATIONS

International Journal of Pharmacy and Pharmaceutical Sciences ◽

10.22159/ijpps.2016v8i11.14256 ◽

2016 ◽

Vol 8 (11) ◽

pp. 152 ◽

Cited By ~ 2

Author(s):

Sandipan Dasgupta ◽

Sanjay Dey ◽

Paulomi Pal ◽

Bhaskar Mazumder

Keyword(s):

Drug Concentration ◽

High Speed ◽

Method Development ◽

Internal Standard ◽

Hplc Method ◽

Plasma Drug Concentration ◽

Maximum Plasma ◽

Plasma Drug ◽

Rp Hplc ◽

Lipid Nanoparticle

Objective: A simple, reliable, sensitive and validated reversed phase-high performance liquid chromatography (RP-HPLC) method was developed for quantification of lornoxicam (LX) in rat plasma.Methods: Solid lipid nanoparticle (SLN) and nanostructured lipid carriers (NLC) gel formulations containing lornoxicam were prepared using high-speed homogenization followed by ultra-sonication. Pharmacokinetic study of formulated LX loaded SLN and NLC were performed on Wister albino rats.Results: The chromatographic separation was performed on hypersil octadecylsilane (ODS)-18 column using a mobile phase of 10 mmol. Phosphate buffer (pH, 4.5) and acetonitrile (65:35 v/v). Elute was monitored at 377 nm with a flow rate of 1 ml/min. Calibration curve was linear over the concentration range of 25.38–2046.45 ng/ml. Retention times of LX and internal standard (piroxicam) were 9.3 and 10.2 min, respectively. Maximum plasma drug concentration, the area under the plasma drug concentration versus time curve and elimination half-life for LX loaded SLN gel were found 6381.51±971.27ng/ml, 19917.21±7111.24 ng h/ml and 7.27±1.21h and 8558.13±1564.08 ng/ml, 21317.99±4568.71 ng/ml and 6.22±2.16 h. respectively. In vivo in vitro correlation study, the fraction of drug dissolved from nanoparticle in pH 7.4 was plotted against the fraction of drug absorbed and a linear correlation (R2= 0.9987) was obtained.Conclusion: A novel simple, simple, sensitive, precise, rapid, accurate, and economical and reliable RP-HPLC method was developed and validated for the estimation of LX in rat plasma.

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Effect of Food on the Bioavailability of Stavudine in Subjects with Human Immunodeficiency Virus Infection

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.42.9.2295 ◽

1998 ◽

Vol 42 (9) ◽

pp. 2295-2298 ◽

Cited By ~ 16

Author(s):

Sanjeev Kaul ◽

Barbara Christofalo ◽

Ralph H. Raymond ◽

Michael B. Stewart ◽

Catherine M. Macleod

Keyword(s):

Human Immunodeficiency Virus ◽

Hiv Infection ◽

Drug Concentration ◽

Plasma Drug Concentration ◽

Maximum Plasma ◽

Fasting State ◽

Plasma Drug ◽

Cell Counts ◽

Concentration Time ◽

Immunodeficiency Virus

ABSTRACT A randomized, three-way crossover study was carried out to determine the effects of food ingestion on the pharmacokinetics of stavudine (d4T). Fifteen subjects with human immunodeficiency virus (HIV) infection and CD4+ cell counts of ≥200/μl received 70 mg of d4T in a fasting state or 1 h before or 5 min after a standardized high-fat breakfast. A 7- to 15-day washout period was included between treatments. Blood and urine were collected before and for 10 h after dosing, and plasma and urine d4T concentrations were determined with a validated radioimmunoassay. Plasma drug concentration-time data were analyzed with a noncompartmental model. The mean maximum plasma drug concentration (C max) and the time toC max (T max) for administration of d4T after a meal were significantly lower and longer (P = 0.0001 for both measures) than those observed in the fasting state, although the area under the concentration-time curve from time zero to infinity (AUC0–∞) was not significantly different. Neither of these parameters was significantly altered when d4T was taken 1 h before a meal. The bioavailability of d4T taken after a meal was 95% of that observed in the fasting state, and it was 97% when d4T was administered before a meal (P > 0.05 for both comparisons with the fasting state). The results of this study indicate that (i) ingestion of food does not affect the bioavailability of d4T and that patients with HIV infection can take it without regard to meals, and (ii) absorption is essentially complete within 1 h when d4T is administered in the fasted state.

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Comparative study of pharmacokinetics of two new fluoroquinolones, balofloxacin and grepafloxacin, in elderly subjects.

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.40.12.2824 ◽

1996 ◽

Vol 40 (12) ◽

pp. 2824-2828 ◽

Cited By ~ 18

Author(s):

O Kozawa ◽

T Uematsu ◽

H Matsuno ◽

M Niwa ◽

S Nagashima ◽

...

Keyword(s):

Drug Concentration ◽

The Elderly ◽

Plasma Drug Concentration ◽

Elderly Subjects ◽

Maximum Plasma ◽

Plasma Drug ◽

Urinary Recovery ◽

Time Curve ◽

Younger Adults ◽

Healthy Elderly

Comparative pharmacokinetics and tolerability were studied in healthy elderly volunteers for two new fluoroquinolones, balofloxacin (Q-35) and grepafloxacin (OPC-17116), the main excretion routes being the renal and hepatic routes, respectively. Both agents were well tolerated in elderly subjects. In comparison with previously reported data from healthy younger adults, the absorption of balofloxacin was slightly delayed and urinary excretion was delayed and diminished. As a significant linear correlation was observed between renal clearance of balofloxacin and creatinine clearance, the delayed and diminished urinary recovery was attributed to the reduced renal function of the elderly subjects enrolled in the study. The absorption of grepafloxacin was also delayed, and the maximum plasma drug concentration and area under the plasma drug concentration-time curve were increased in the elderly by 31 and 48%, respectively, over those in younger adults on the basis of dose normalized to body weight. The plasma terminal elimination half-life and urinary recovery remained unchanged. Decreases in distribution volume and total body clearance in the elderly were considered to be the primary factors contributing to these differences.

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Prospective observational study on the pharmacokinetic properties of the Irrua ribavirin regimen used in routine clinical practice in patients with Lassa fever in Nigeria

BMJ Open ◽

10.1136/bmjopen-2020-036936 ◽

2020 ◽

Vol 10 (4) ◽

pp. e036936

Author(s):

Cyril Erameh ◽

Osahogie Edeawe ◽

Peter Akhideno ◽

Gloria Eifediyi ◽

Till F Omansen ◽

...

Keyword(s):

Clinical Practice ◽

Research Ethics ◽

Drug Concentration ◽

Health Research ◽

Systemic Disease ◽

Lassa Fever ◽

Plasma Drug Concentration ◽

Maximum Plasma ◽

Plasma Drug ◽

Maximum Plasma Drug Concentration

IntroductionLassa fever (LF) is a severe and often fatal systemic disease in humans and affects a large number of countries in West Africa. Treatment options are limited to supportive care and the broad-spectrum antiviral agent ribavirin. However, evidence for ribavirin efficacy in patients with LF is poor and pharmacokinetic (PK) data are not available.Irrua Specialist Teaching Hospital (ISTH) developed an intravenous ribavirin regimen different to the WHO recommendation. Apart from a lower total daily dose the drug is usually administered once per day which reduces the exposure of personnel to patients with LF. The aim of this study is to characterise the PK of the Irrua ribavirin regimen.Methods and analysisThis prospective, observational clinical study will assess PK properties of the Irrua ribavirin regimen on routinely ribavirin-treated patients with LF at ISTH, a referral hospital serving 19 local governmental areas in a LF endemic zone in Nigeria. Participants will be adults with PCR-confirmed LF. The primary objective is to describe classical PK parameters for ribavirin (maximum plasma drug concentration, time to maximum plasma drug concentration, area under the plasma drug concentration vs time curve, half-life time T1/2, volume of distribution). Blood samples will be collected at 0.5, 1, 3, 5, 8, 12 and 24 hours after doses on day 1, day 4 and day 10 of ribavirin treatment. Ribavirin plasma concentrations will be determined using liquid chromatography coupled to tandem mass spectrometry.Ethics and disseminationThe study will be conducted in compliance with the protocol, the Declaration of Helsinki, Good Clinical Practice (GCP) and the Nigerian National Code for Health Research Ethics. The protocol has received approval by the Health Research Ethics Committee of ISTH. Results will be made available to LF survivors, their caregivers, the funders, LF research society and other researchers.Registration detailsISRCTN11104750

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Preparation and Pharmacokinetic Study of Daidzein Long-Circulating Liposomes

Nanoscale Research Letters ◽

10.1186/s11671-019-3164-y ◽

2019 ◽

Vol 14 (1) ◽

Cited By ~ 4

Author(s):

Qiao Wang ◽

Wenjin Liu ◽

Junjun Wang ◽

Hong Liu ◽

Yong Chen

Keyword(s):

Single Dose ◽

Drug Concentration ◽

Drug Loading ◽

Plasma Drug Concentration ◽

The Body ◽

Molar Ratio ◽

Terminal Phase ◽

Plasma Drug ◽

Ultrasonic Time ◽

Time Required

Abstract In this study, daidzein long-circulating liposomes (DLCL) were prepared using the ultrasonication and lipid film-hydration method. The optimized preparation conditions by the orthogonal design was as follows: 55 to 40 for the molar ratio of soybean phosphatidylcholine (SPC) to cholesterol, 1 to 10 for the mass ratio of daidzein to total lipid (SPC and cholesterol) (w:w), the indicated concentration of 5% DSPE-mPEG2000 (w:w), 50 °C for the hydration temperature, and 24 min for the ultrasonic time. Under these conditions, the encapsulation efficiency and drug loading of DLCL were 85.3 ± 3.6% and 8.2 ± 1.4%, respectively. The complete release times of DLCL in the medium of pH 1.2 and pH 6.9 increased by four- and twofold of that of free drugs, respectively. After rats were orally administered, a single dose of daidzein (30 mg/kg) and DLCL (containing equal dose of daidzein), respectively, and the MRT0−t (mean residence time, which is the time required for the elimination of 63.2% of drug in the body), t1/2 (the elimination half-life, which is the time required to halve the plasma drug concentration of the terminal phase), and AUC0−t (the area under the plasma drug concentration-time curve, which represents the total absorption after a single dose and reflects the drug absorption degree) of daidzein in DLCL group, increased by 1.6-, 1.8- and 2.5-fold as compared with those in the free group daidzein. Our results indicated that DLCL could not only reduce the first-pass effect of daidzein to promote its oral absorption, but also prolong its mean resident time to achieve the slow-release effect.

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Impact of Apixaban On a Large Panel of Routine or More Specific Coagulation Assays.

Blood ◽

10.1182/blood.v120.21.2275.2275 ◽

2012 ◽

Vol 120 (21) ◽

pp. 2275-2275

Author(s):

Jonathan Douxfils ◽

François Mullier ◽

Christian Chatelain ◽

Bernard Chatelain ◽

Dogné Jean-Michel

Keyword(s):

Atrial Fibrillation ◽

Drug Concentration ◽

Partial Thromboplastin Time ◽

Factor Xa ◽

Activated Partial Thromboplastin Time ◽

Plasma Drug Concentration ◽

Thrombin Time ◽

Plasma Drug ◽

Clotting Time

Abstract Abstract 2275 Introduction: Apixaban is direct factor-Xa inhibitor that reached the market for the prevention of venous thromboembolism in patients undergoing major orthopaedic surgery. It is also being evaluated in the reduction of recurrent ischemic events when added to antiplatelet therapy after an acute coronary syndrome and in the prevention of stroke in patients with non-valvular atrial fibrillation. Thanks to its predictable pharmacokinetic profile, biological monitoring is not required. Nevertheless, evaluation of plasma drug concentration may be valuable in specific situations such as recurrent thrombosis, bleedings, before urgent surgery, in case of bridging and in case of at least two risk factors among the following ones: drug interactions with caution, moderate renal impairment and moderate hepatic impairment; Monitoring may also be useful in infants, pregnant women or in extreme body weights, although no relevant data on drug levels associated with approximate therapeutic and harmful ranges are currently available. Material and Methods: Apixaban was spiked at increasing concentrations (0, 5, 10, 20, 50, 100, 200 and 500 ng/mL) in pooled citrated normal human platelet poor plasma (PPP) to measure Prothrombin Time (PT) and dilute PT with different thromboplastin, Thrombin Generation Assay (TGA) with different inducers and activity on different anti-Xa chromogenic assays. Activated Partial Thromboplastin Time with different reagents, Thrombin Time (TT), Ecarin Clotting Time (ECT) and Reptilase Time (RT), measurement of fibrinogen (Clauss method and PT-derived method) and antithrombin (anti-IIa and anti-Xa based chromogenic assays) were also tested. We also evaluated the impact of apixaban on assays used for the determination of lupus anticoagulant such as the DRVV-T.. (Screen and Confirm) as well as the PTT-LA.. and the Staclot-LA.. . Results and Discussion: As mentioned in previous studies, PT showed a weak sensitivity towards apixaban in comparison with the plasma range obtained in short pharmacokinetic studies. Indeed, the concentration needed to double the clotting time was 154 ng/mL with the most sensitive reagent while the mean Cmax obtained in a short PK study after one oral intake of 5 mg apixaban (dose given in atrial fibrillation) was 96 ng/mL. Therefore, the sensitivity of PT is not strong enough to allow accurate quantitative measurement of the plasma drug concentration (Table 1). Activated Partial Thromboplastin Time presented a better sensitivity but showed a plateau after 100 ng/mL reflecting the uselessness of this test for the quantification of apixaban. Thrombin Time, ECT and RT were logically not affected while DRVV-T.. showed a sensitivity of 205 ng/mL (Screen), which is once again not enough sensitive. On the opposite, chromogenic anti-Xa assays seemed to be very sensitive (Figure 2 and Table 1). Nevertheless, the relation was not always linear and some methodologies needed to be adapted to ensure a broader range of application. TGA (Figure 1) may be useful to assess the pharmacodynamics effects of apixaban on the coagulation process. Nevertheless, the turn around time and the lack of standardisation are currently limitations that restrict the use of this method. In the case of the exploration of an haemorrhagic event, specific tests such as RT, fibrinogen (Clauss and PT-derived method (dFib)), TT and clotting factor activity may be used. Apixaban did not interfere with these tests. Antithrombin determination if also of importance and chromogenic anti-IIa based assays should be used in face of patients treated with apixaban to avoid misdiagnosis since an overvaluation of 12% by 100 ng/mL was shown using one chromogenic anti-Xa based assay. Conclusion: PT may not be used as screening test to assess the risk of bleedings. A more specific and sensitive assay such as chromogenic anti-Xa assays using calibrators should be used to correctly assess the concentration of apixaban. Determination of lupus anticoagulant using DRVV-T.. and PTT-LA.. or Staclot LA.. as well as the determination of antithrombin using factor-Xa based chromogenic assays, were influenced by apixaban. Finally, standardization of the time between the last intake of apixaban and the sampling is mandatory. Figures: Disclosures: No relevant conflicts of interest to declare.

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