Effect of dosing interval on pharmacokinetics of fentanyl pectin nasal spray from a crossover study

2015 ◽  
Vol 11 (2) ◽  
pp. 139 ◽  
Author(s):  
Cuiping Chen, PhD ◽  
Shay Bujanover, MD ◽  
Anita Gupta, DO, PharmD
Keyword(s):  
Nasal Spray ◽  
Pharmacokinetic Parameters ◽  
Open Label ◽  
Time Curve ◽  
Open Label Study ◽  
Concentration Time ◽  
The Difference ◽  
Multiple Dose Pharmacokinetics ◽  
The Right ◽  
Dosing Intervals

Objective: To evaluate the effects of different dosing intervals on multiple-dose pharmacokinetics, and safety and tolerability of fentanyl pectin nasal spray (FPNS).Methods: This was an open-label study in healthy volunteers. Five FPNS treatments (1 × 100 μg; 2 × 100 μg at 4-, 2-, and 1-hour intervals, and 8 × 100 μg consecutively) were administered to the right nostril, with a ≥3-day washout period. Blood samples were collected at predose and up to 1,440 minutes postdose. Plasma fentanyl concentrations were determined. Pharmacokinetic parameters—peak concentration (Cmax), time to Cmax (tmax), and area under the concentration-time curve (AUC)—were derived using noncompartmental method. For the two-dose regimens, pharmacokinetic parameters were compared between doses using a paired t-test with p < 0.05 as statistically significant.Results: Thirteen subjects were enrolled and 10 completed the study. Median tmax was 10-15 minutes across five regimens. Cmax post the second dose significantly increased for 1-hour (p < 0.0001) and 2-hour (p < 0.001) but not 4-hour intervals (p = 0.462). Cmax and AUC0-24 following 8 × 100 μg were approximately fivefold of those following 1 × 100 μg. Dizziness (11.9 percent) and somnolence (4.9 percent) were most common adverse events (AEs). 12.9 percent of patients discontinued due to AEs.Conclusions: FPNS exhibited consistently rapid tmax. When intervals between two doses were shorter, the difference in Cmax between the first and second dose was larger. All regimens of FPNS were well tolerated. Exposure reached a plateau after eight consecutive doses, suggesting potential limited absorption through the nasal mucosa.

scholarly journals Fosamprenavir plus Ritonavir Increases Plasma Ketoconazole and Ritonavir Exposure, while Amprenavir Exposure Remains Unchanged

2007 ◽  
Vol 51 (8) ◽  
pp. 2982-2984 ◽  
Author(s):  
Mary B. Wire ◽  
Charles H. Ballow ◽  
Julie Borland ◽  
Mark J. Shelton ◽  
Yu Lou ◽  
...  
Keyword(s):  
Steady State ◽  
Healthy Subjects ◽  
Open Label ◽  
Time Curve ◽  
Once Daily ◽  
Open Label Study ◽  
Label Study ◽  
Concentration Time

ABSTRACT Plasma ketoconazole (KETO), amprenavir (APV), and ritonavir (RTV) pharmacokinetics were evaluated in 15 healthy subjects after being treated with KETO at 200 mg once daily (QD), fosamprenavir (FPV)/RTV at 700/100 mg twice daily (BID), and then KETO at 200 mg QD plus FPV/RTV at 700/100 mg BID in this open-label study. The KETO area under the concentration-time curve at steady state was increased 2.69-fold with FPV/RTV. APV exposure was unchanged, and RTV exposure was slightly increased.

scholarly journals Lack of Effect of Zafirlukast on the Pharmacokinetics of Azithromycin, Clarithromycin, and 14-Hydroxyclarithromycin in Healthy Volunteers

1999 ◽  
Vol 43 (5) ◽  
pp. 1152-1155 ◽  
Author(s):  
Kevin W. Garey ◽  
Charles A. Peloquin ◽  
Paul G. Godo ◽  
Anne N. Nafziger ◽  
Guy W. Amsden
Keyword(s):  
Steady State ◽  
Healthy Subjects ◽  
High Performance ◽  
Pharmacokinetic Parameters ◽  
Steady State Concentration ◽  
Open Label ◽  
Time Curve ◽  
Data Analyses ◽  
Concentration Time ◽  
State Concentration

ABSTRACT This randomized, open-label, crossover study was conducted to investigate whether the coadministration of zafirlukast would affect the pharmacokinetics of azithromycin, clarithromycin, or 14-hydroxyclarithromycin (14-OHC). Twelve healthy subjects (six males and six females) received single 500-mg doses of azithromycin and clarithromycin with and without zafirlukast given to a steady-state concentration. Blood was collected prior to all macrolide doses and for 3 and 10 days after each clarithromycin and azithromycin dose, respectively. Serum was assayed for azithromycin, clarithromycin, and 14-OHC concentrations by validated high-performance liquid chromatography assay systems. Data analyses were done by noncompartmental and nonparametric methods. Analysis of the patients indicated that the addition of steady-state concentrations of zafirlukast did not significantly alter the pharmacokinetic parameters of or overall exposure (based on the area under the concentration-time curve) to azithromycin, clarithromycin, and 14-OHC. While zafirlukast is a known inhibitor of CYP3A4, it does not appear to exert a clinically or statistically significant pharmacokinetic effect on azithromycin, clarithromycin, or 14-OHC.

Oral Bioavailability of Nizatidine and Ranitidine Concurrently Administered with Antacid

1989 ◽  
Vol 17 (1) ◽  
pp. 62-67 ◽  
Author(s):  
J. P. Desager ◽  
C. Harvengt
Keyword(s):  
High Performance ◽  
Drug Application ◽  
Open Label ◽  
Time Curve ◽  
Open Label Study ◽  
Concentration Time ◽  
Neutralizing Capacity ◽  
Significant Difference ◽  
Student’S T ◽  
Student’S T Test

This four-way crossover open-label study on eight healthy subjects was designed to investigate the effect on bioavailability of orally administered nizatidine given concurrently with an antacid (magnesium hydroxide–aluminium hydroxide mixture). Ranitidine was used as a comparison. Subjects were hospitalized overnight for each drug application which was given as a single dose [nizatidine or ranitidine (300 mg) or antacid (20 ml) of a neutralizing capacity of 50 mmol hydrochloric acid]. Plasma nizatidine or ranitidine concentrations were measured by high performance liquid chromatography. No statistically significant difference occurred in the kinetic profile of nizatidine after antacid administration although it took longer to reach maximum concentration in plasma. The area under the concentration–time curve was also reduced (by ≤10%) and there was a longer lag between administration and absorption. Bioequivalence (Westlake test) for ranitidine in the presence or absence of antacid was confirmed (difference ≤12%). For nizatidine, with or without antacid, the value of the Westlake test was just above the limit for bioequivalence (21.4%), whereas the Student's t-test for related means (one-tailed distribution) gave P = 0.045. There was no clinically relevant nizatidine–antacid interaction at the doses used in this study.

scholarly journals Pharmacokinetics-Pharmacodynamics of CB-618 in Combination with Cefepime, Ceftazidime, Ceftolozane, or Meropenem: the Pharmacological Basis for a Stand-Alone β-Lactamase Inhibitor

2017 ◽  
Vol 61 (12) ◽  
Author(s):  
Paul G. Ambrose ◽  
Brian D. VanScoy ◽  
Michael Trang ◽  
Jennifer McCauley-Miller ◽  
Haley Conde ◽  
...  
Keyword(s):  
Infection Model ◽  
Time Curve ◽  
Content Type ◽  
Model Studies ◽  
Time Profiles ◽  
Concentration Time ◽  
The Right ◽  
Dosing Intervals ◽  
Lactamase Inhibitor

ABSTRACT A major challenge in treating patients is the selection of the “right” antibiotic regimen. Given that the optimal β-lactam/β-lactamase inhibitor pair is dependent upon the spectrum of β-lactamase enzymes produced and the frequency of resistance to the β-lactamase inhibitor, it might be useful if a stand-alone were available for the clinician to pair with the “right” β-lactam rather than only in a fixed combination. We describe herein a one-compartment in vitro infection model studies conducted to identify the magnitudes of the pharmacokinetic-pharmacodynamic (PK-PD) index for a β-lactamase inhibitor, CB-618, that would restore the activity of four β-lactam partner agents (cefepime, ceftazidime, ceftolozane, and meropenem) with various doses (1 or 2 g) and dosing intervals (8 or 12 h). The challenge panel included Klebsiella pneumoniae (n = 5), Escherichia coli (n = 2), and Enterobacter cloacae (n = 1) strains, which produced a wide variety of β-lactamase enzymes (AmpC, CTXM-15, KPC-2, KPC-3, FOX-5, OXA-1/30, OXA-48, SHV-1, SHV-11, SHV-27, and TEM-1). Free-drug human concentration-time profiles were simulated for each agent, and specimens were collected for drug concentration and bacterial density determinations. CB-618 restored the activity of each β-lactam partner. The magnitudes of the CB-618 ratio of the area under the concentration-time curve from 0 to 24 h to the MIC (i.e., the AUC/MIC ratio) associated with net bacterial stasis and 1- and 2-log10 CFU/ml reductions from baseline at 24 h were 11.2, 32.9, and 136.3, respectively. These data may provide a PK-PD basis for the development of a stand-alone β-lactamase inhibitor.

scholarly journals Investigation of the Interactions between Methadone and Elvitegravir-Cobicistat in Subjects Receiving Chronic Methadone Maintenance

2013 ◽  
Vol 57 (12) ◽  
pp. 6154-6157 ◽  
Author(s):  
R. Douglas Bruce ◽  
P. Winkle ◽  
J. M. Custodio ◽  
X. Wei ◽  
M. S. Rhee ◽  
...  
Keyword(s):  
Opioid Dependence ◽  
Methadone Maintenance ◽  
Pharmacokinetic Parameters ◽  
Pharmacokinetics And Pharmacodynamics ◽  
Open Label ◽  
Time Curve ◽  
Concentration Time ◽  
State Evaluation ◽  
Baseline Values ◽  
Historical Controls

ABSTRACTInteractions between HIV and opioid dependence therapies are known to occur. We sought to determine if such interactions occurred between methadone and elvitegravir boosted with cobicistat (EVG/COBI). We performed a within-subject open-label pharmacokinetic and pharmacodynamic study of 11 HIV-seronegative subjects stabilized on at least 2 weeks of methadone. Subjects underwent baseline and steady-state evaluation of the effect of elvitegravir 150 mg once a day (QD) boosted with 150 mg QD of cobicistat (EVG/COBI) on methadone pharmacokinetic parameters. Safety and pharmacodynamics were monitored throughout the study. Compared to baseline values, theR-methadone mean area under the concentration-time curve to the end of the dosing period (AUCtau) (5,550 versus 6,210 h · ng/ml) and mean maximum concentration of drug in serum (Cmax) (316 versus 337 ng/ml) did not significantly increase in the presence of EVG/COBI. Compared to baseline values, theS-methadone mean AUCtau(7,040 versus 7,540 h · ng/ml) and meanCmax(446 versus 452 ng/ml) did not significantly increase in the presence of EVG/COBI. The AUCtau,Cmax, andCtauof elvitegravir and cobicistat did not significantly differ from those of historical controls. Opioid withdrawal or overdose was not observed among subjects in this study. The addition of EVG/COBI to stabilized patients receiving methadone did not affect methadone pharmacokinetics and pharmacodynamics. These two agents can be safely coadministered.

scholarly journals Sequential Open-Label Study of the Safety, Tolerability, and Pharmacokinetic Interactions between Dihydroartemisinin-Piperaquine and Mefloquine in Healthy Thai Adults

2019 ◽  
Vol 63 (8) ◽  
Author(s):  
Borimas Hanboonkunupakarn ◽  
Rob W. van der Pluijm ◽  
Richard Hoglund ◽  
Sasithon Pukrittayakamee ◽  
Markus Winterberg ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Multidrug Resistant ◽  
Combination Therapies ◽  
Open Label ◽  
Time Curve ◽  
Open Label Study ◽  
Label Study ◽  
Content Type ◽  
Concentration Time ◽  
Pharmacokinetic Properties

ABSTRACT Artemisinin-based combination therapies (ACTs) have contributed substantially to the global decline in Plasmodium falciparum morbidity and mortality, but resistance to artemisinins and their partner drugs is increasing in Southeast Asia, threatening malaria control. New antimalarial compounds will not be generally available soon. Combining three existing antimalarials in the form of triple ACTs, including dihydroartemisinin (DHA)-piperaquine + mefloquine, is a potential treatment option for multidrug-resistant Plasmodium falciparum malaria. In a sequential open-label study, healthy Thai volunteers were treated with DHA-piperaquine (120 to 960 mg), mefloquine (500 mg), and DHA-piperaquine + mefloquine (120 to 960 mg + 500 mg), and serial symptom questionnaires, biochemistry, full blood counts, pharmacokinetic profiles, and electrocardiographic measurements were performed. Fifteen healthy subjects were enrolled. There was no difference in the incidence or severity of adverse events between the three treatment arms. The slight prolongation in QTc (QT interval corrected for heart rate) associated with DHA-piperaquine administration did not increase after administration of DHA-piperaquine + mefloquine. The addition of mefloquine had no significant effect on the pharmacokinetic properties of piperaquine. However, coadministration of mefloquine significantly reduced the exposures to dihydroartemisinin for area under the concentration-time curve (−22.6%; 90% confidence interval [CI], −33.1, −10.4; P = 0.0039) and maximum concentration of drug in serum (−29.0%; 90% CI, −40.6, −15.1; P = 0.0079). Mefloquine can be added safely to dihydroartemisinin-piperaquine in malaria treatment. (This study has been registered at ClinicalTrials.gov under identifier NCT02324738.)

scholarly journals Determination of Appropriate Weight-Based Cutoffs for Empiric Cefazolin Dosing Using Data from a Phase 1 Pharmacokinetics and Safety Study of Cefazolin Administered for Surgical Prophylaxis in Pediatric Patients Aged 10 to 12 Years

2015 ◽  
Vol 59 (7) ◽  
pp. 4173-4180 ◽  
Author(s):  
Michael L. Schmitz ◽  
Jeffrey L. Blumer ◽  
Wes Cetnarowski ◽  
Christopher M. Rubino
Keyword(s):  
Pediatric Patients ◽  
Phase 1 ◽  
Pharmacokinetic Parameters ◽  
Pharmacokinetic Data ◽  
Time Data ◽  
Surgical Prophylaxis ◽  
Open Label ◽  
Time Curve ◽  
Concentration Time ◽  
Few Data

ABSTRACTDespite over 40 years of worldwide usage, relatively few data have been published on the pharmacokinetics of cefazolin in pediatric surgical patients. The primary objectives of this study were to examine the pharmacokinetics and safety of cefazolin in children 10 to 12 years of age (inclusive) receiving 1 or 2 g of cefazolin, based on body weight. This multiple-center, open-label study enrolled pediatric patients electively scheduled for surgical procedures who required cefazolin as part of their routine clinical management. Patients weighing ≥25 to <50 kg received a 1-g dose, and patients weighing ≥50 to ≤85 kg received a 2-g dose. Postdose pharmacokinetic and safety assessments were conducted following drug administration. Cefazolin concentration-time data were analyzed by using both noncompartmental and population pharmacokinetics methods. Monte Carlo simulations were performed to identify appropriate weight-based cutoffs for the dosing of children aged 10 to 17 years of age. Twelve patients were enrolled in this study and provided the requisite pharmacokinetic data. In general, cefazolin was well tolerated. The mean cefazolin terminal elimination half-life, clearance, and area under the concentration-time curve from time zero to infinity in this population were 1.95 h, 0.804 ml/min/kg, and 607 mg · h/liter, respectively. Patients weighing 50 to 60 kg exhibited elevated cefazolin exposures. Observed pharmacokinetic parameters and simulation results indicated that a weight-based cutoff of 60 kg is predicted to provide cefazolin exposure consistent with that observed in normal, healthy adults at recommended doses for surgical prophylaxis. (This study has been registered at ClinicalTrials.gov under registration no. NCT01904357.)

Effect of Terbinafine on Theophylline Pharmacokinetics in Healthy Volunteers

1998 ◽  
Vol 42 (3) ◽  
pp. 695-697 ◽  
Author(s):  
Eric F. Trépanier ◽  
Anne N. Nafziger ◽  
Guy W. Amsden
Keyword(s):  
Healthy Volunteers ◽  
Multiple Dose ◽  
Treatment Phase ◽  
Pharmacokinetic Parameters ◽  
Noncompartmental Analysis ◽  
Open Label ◽  
Time Curve ◽  
Blood Samples ◽  
Concentration Time ◽  
Randomized Crossover Study

ABSTRACT Twelve healthy volunteers were enrolled in an open-label, randomized, crossover study. Subjects received single doses of theophylline (5 mg/kg) with and without multiple-dose terbinafine, and 11 blood samples were collected over 24 h. The study phases were separated by a 4-week washout period. Theophylline serum data were modeled via noncompartmental analysis. When the control phase (i.e., no terbinafine) was compared to the treatment phase (terbinafine), theophylline exposure (the area under the serum concentration-time curve from time zero to infinity) increased by 16% (P= 0.03), oral clearance decreased by 14% (P = 0.04), and half-life increased by 24% (P = 0.002). No significant changes in other theophylline pharmacokinetic parameters were evident.

scholarly journals Pharmacokinetics and Bioequivalence Study of Two Ciprofloxacin Hydrochloride Tablets in Chinese Healthy Volunteers Under Fasting and Fed Conditions: A Randomized, Open-Label, Two-Formulation, Two-Sequence, Two-Period, Single-Dose Crossover Study.

2020 ◽  
Author(s):  
Fei Qin ◽  
Gan-Mi Wang ◽  
Jin-Ying Huang ◽  
Jia-Rong Wu ◽  
Wen-Jie Song ◽  
...  
Keyword(s):  
Single Dose ◽  
Plasma Concentration ◽  
Oral Dose ◽  
Single Oral Dose ◽  
Pharmacokinetic Parameters ◽  
Open Label ◽  
Time Curve ◽  
Ciprofloxacin Hydrochloride ◽  
Concentration Time ◽  
Plasma Concentration Time Curve

Abstract BackgroundCiprofloxacin is a broad-spectrum fluoroquinolone antibiotic which is active against a wide range of Gram-positive and Gram-negative bacteria. The study mainly aimed to determine the bioequivalence of two branded ciprofloxacin hydrochloride tablets (250 mg) under the fasting and fed conditions.MethodsThe study was carried out in 48 healthy Chinese subjects under fasting and fed conditions with a randomized, open-label, two-formulation, two-sequence, two-period, single-dose crossover design. In each period of the study, the subjects were assigned to receive a single oral dose of 250 mg of ciprofloxacin hydrochloride. Blood samples were collected from an hour before dosing to 36 h after administration with 16 time points in total. The bioequivalence analysis was performed after ln-transformation of the ciprofloxacin pharmacokinetic parameters including maximum concentration (Cmax), area under the plasma concentration–time curve from time 0 to time t (AUC0-t), area under the plasma concentration-time curve from time 0 to infinity (AUC0-∞). Two formulations are considered bioequivalent if the 90% confidence intervals (CIs) for the test/reference geometric mean ratios (GMRs) for the ln-transformed pharmacokinetic parameters fall within the standard acceptance range of 80% – 125%. ResultsIn total of 48 subjects were enrolled in the fasting and fed studies, and one of the subjects was excluded before the administration. In the fasting study, the 90% CIs for the test/reference GMRs of the ln-transformed data for Cmax, AUC0–t, and AUC0–∞ were 85.41% to 100.97%, 95.40% to 100.27%, and 95.48% to 100.30%, respectively. For the fed study, the 90% CIs for the test/reference GMRs of the ln-transformed data for Cmax, AUC0–t, and AUC0–∞ were 90.15% to 113.75%, 99.10% to 103.77% and 99.11% to 103.80%, respectively. A total of 8 of 47 subjects experienced AEs in the fasting and fed studies.ConclusionsIn the study, the generic (test) product of ciprofloxacin hydrochloride 250 mg was bioequivalent to the innovator (reference) product after a single oral dose administration under the fasting and fed conditions. Both two brands of ciprofloxacin tablets were safe and well tolerated.Trial registrationThe clinical trial was registered at Center for the Drug Evaluation of the National Medical Products Administration (registration number: CTR20171152; date of registration：September 25, 2017; http://www.chinadrugtrials.org.cn/clinicaltrials.searchlistdetail.dhtml).

scholarly journals Voriconazole Pharmacokinetics and Safety in Immunocompromised Children Compared to Adult Patients

2010 ◽  
Vol 54 (8) ◽  
pp. 3225-3232 ◽  
Author(s):  
Claudia Michael ◽  
Uta Bierbach ◽  
Katrin Frenzel ◽  
Thoralf Lange ◽  
Nadezda Basara ◽  
...  
Keyword(s):  
Pediatric Patients ◽  
Fungal Infections ◽  
Adult Patients ◽  
European Medicines Agency ◽  
Pharmacokinetic Parameters ◽  
Time Curve ◽  
Entire Study ◽  
Interindividual Variations ◽  
Concentration Time ◽  
Days Of Therapy

ABSTRACT The aim of this study was to investigate the pharmacokinetics and safety of voriconazole after intravenous (i.v.) administration in immunocompromised children (2 to 11 years old) and adults (20 to 60 years old) who required treatment for the prevention or therapy of systemic fungal infections. Nine pediatric patients were treated with a dose of 7 mg/kg i.v. every 12 h for a period of 10 days. Three children and 12 adults received two loading doses of 6 mg/kg i.v. every 12 h, followed by a maintenance dose of 5 mg/kg (children) or 4 mg/kg (adults) twice a day during the entire study period. Trough voriconazole levels in blood over 10 days of therapy and regular voriconazole levels in blood for up to 12 h postdose on day 3 were examined. Wide intra- and interindividual variations in plasma voriconazole levels were noted in each dose group and were most pronounced in the children receiving the 7-mg/kg dose. Five (56%) of them frequently had trough voriconazole levels in plasma below 1 μg/ml or above 6 μg/ml. The recommended dose of 7 mg/kg i.v. in children provides exposure (area under the concentration-time curve) comparable to that observed in adults receiving 4 mg/kg i.v. The children had significantly higher C max values; other pharmacokinetic parameters were not significantly different from those of adults. Voriconazole exhibits nonlinear pharmacokinetics in the majority of children. Voriconazole therapy was safe and well tolerated in pediatric and adult patients. The European Medicines Agency-approved i.v. dose of 7 mg/kg can be recommended for children aged 2 to <12 years.

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