scholarly journals Posaconazole Tablet Pharmacokinetics: Lack of Effect of Concomitant Medications Altering Gastric pH and Gastric Motility in Healthy Subjects

2014 ◽  
Vol 58 (7) ◽  
pp. 4020-4025 ◽  
Author(s):  
Walter K. Kraft ◽  
Peter S. Chang ◽  
Marlou L. P. S. van Iersel ◽  
Hetty Waskin ◽  
Gopal Krishna ◽  
...  
Keyword(s):  
Healthy Volunteers ◽  
Gastric Motility ◽  
Maximum Concentration ◽  
Geometric Mean ◽  
Gastric Ph ◽  
Oral Suspension ◽  
Open Label ◽  
Time Curve ◽  
Concentration Time ◽  
Concomitant Medications

ABSTRACTPosaconazole oral suspension is an extended-spectrum triazole that should be taken with food to maximize absorption. A new posaconazole tablet formulation has demonstrated improved bioavailability over the oral suspension in healthy adults in a fasting state. This study evaluated the effects of concomitant medications altering gastric pH (antacid, ranitidine, and esomeprazole) and gastric motility (metoclopramide) on the pharmacokinetics of posaconazole tablets. This was a prospective open-label 5-way crossover study in 20 healthy volunteers. In each treatment period, a single 400-mg dose (4 100-mg tablets) of posaconazole was administered alone or with 20 ml antacid (2 g of aluminum hydroxide and 2 g of magnesium hydroxide), ranitidine (150 mg), esomeprazole (40 mg), or metoclopramide (15 mg). There was a ≥10-day washout between treatment periods. Posaconazole exposure, time to maximum concentration of drug in serum (Tmax), and apparent terminal half-life (t1/2) were similar when posaconazole was administered alone or with medications affecting gastric pH and gastric motility. Geometric mean ratios (90% confidence intervals [CIs]) of the area under the concentration-time curve from time zero to infinity (AUC0–inf) (posaconazole with medications affecting gastric pH and gastric motility versus posaconazole alone) were 1.03 (0.88–1.20) with antacid, 0.97 (0.84–1.12) with ranitidine, 1.01 (0.87–1.17) with esomeprazole, and 0.93 (0.79–1.09) with metoclopramide. Geometric mean ratios (90% CIs) of the maximum concentration of drug in serum (Cmax) were 1.06 (0.90–1.26) with antacid, 1.04 (0.88–1.23) with ranitidine, 1.05 (0.89–1.24) with esomeprazole, and 0.86 (0.73–1.02) with metoclopramide. In summary, in healthy volunteers, the pharmacokinetics of a single 400-mg dose of posaconazole tablets was not altered to a clinically meaningful extent when posaconazole was administered alone or with medications affecting gastric pH or gastric motility.

scholarly journals Pharmacokinetic Interactions between the Hormonal Emergency Contraception, Levonorgestrel (Plan B), and Efavirenz

2012 ◽  
Vol 2012 ◽  
pp. 1-4 ◽  
Author(s):  
Monica L. Carten ◽  
Jennifer J. Kiser ◽  
Awewura Kwara ◽  
Samantha Mawhinney ◽  
Susan Cu-Uvin
Keyword(s):  
Geometric Mean ◽  
Liver Function Tests ◽  
Open Label ◽  
Time Curve ◽  
Geometric Means ◽  
Concentration Time ◽  
Plan B ◽  
Effective Contraception ◽  
Grade 3 ◽  
Hiv Negative

Objectives. Compare the Plan B levonorgestrel (LNG) area under the concentration- time curve (AUC12) prior to and with efavirenz (EFV).Design. Prospective, open-label, single-arm, equivalence study.Methods. Healthy HIV-negative subjects underwent 12 hr intensive pharmacokinetic (PK) sampling following single dose LNG alone and after 14 days of EFV. Geometric means, Geometric Mean Ratios, and 90% confidence intervals (CI) are reported for PK Parameters.T-tests were utilized. Clinical parameters and liver function tests (LFTs) were assessed.Results. 24 women enrolled and 21 completed the study. With EFV, LNG AUC12was reduced 56% (95% CI: 49%, 62%) from 42.9 to 17.8 ng*hr/mL, and maximum concentration (Cmax⁡) was reduced 41% (95% CI: 33%, 50%) from 8.4 to 4.6 ng/mL. LNG was well tolerated with no grade 3 or 4 treatment-related toxicities.Conclusions. EFV significantly reduced LNG exposures. Higher LNG doses may be required with EFV. These results reinforce the importance of effective contraception in women taking EFV.

scholarly journals P78 Pharmacokinetics of intravenous and intranasal nalbuphine in infants

2019 ◽  
Vol 104 (6) ◽  
pp. e49.2-e49
Author(s):  
M Pfiffner ◽  
V Gotta ◽  
E Berger-Olah ◽  
M Pfister ◽  
P Vonbach
Keyword(s):  
Maximum Concentration ◽  
Opioid Analgesic ◽  
Wilcoxon Test ◽  
Noncompartmental Analysis ◽  
Open Label ◽  
Post Dose ◽  
Time Curve ◽  
Acute Setting ◽  
Non Invasive ◽  
Concentration Time

BackgroundNalbuphine is a mixed agonist-antagonist opioid analgesic agent frequently used in paediatrics, and licensed for parenteral use only. Intranasal delivery could be a safe, effective and non-invasive alternative, especially in infants in the acute setting. However, pharmacokinetic (PK) data for this route of administration is completely lacking. The aim of this study was to assess PK of nalbuphine in infants 1–3 months after single intravenous (0.05 mg/kg) and intranasal (0.1 mg/kg) application, respectively.MethodsWe conducted a prospective, single centre, open-label pharmacokinetic study in infants 1–3 months undergoing sepsis workup in the emergency unit. Included infants received alternating nalbuphine as 0.05 mg/kg intravenous bolus or as 0.1 mg/kg intranasal spray. PK samples were taken at 3 pre-defined time points (15, 30 and max. 240 min post-dose before discharge). Area under the concentration-time curve (AUC0-Tlast, and AUC0-infinity for i.v.) was calculated using noncompartmental analysis and was compared between groups using Wilcoxon test. Further parameters derived included maximum concentration (Cmax), time of maximum concentration (Tmax for i.n.) and terminal half-life (t1/2).ResultsA total of 31 patients were included in the analysis. Median age was 55 days [interquartile range 38–63] in the intranasal (N=20) and 42 [37–76] days in the iv group (N=11). Median AUC0-Tlast was 7.6 (5.4–10.4) mcg*h/L following intranasal versus 7.9 (6.0–14.7) mcg*h/L for iv administration (p=0.46). AUC0-Tlast (i.v.) covered 80 [68–83]% of AUC0-infinity. Median Cmax was 4.5 [3.5–5.6] mcg/L (i.n.) versus 6.5 [5.3–15.9] mcg/L (i.v.) (p=0.014), t1/22.4 [1.3–2.8] h (i.n.) versus 1.3 [1.1–1.5] h (i.v.) (p=0.021). Tmax occurred 37 [32–65] min after intranasal administration.ConclusionThis first PK study of intranasal nalbuphine in infants suggests that 0.1 mg/kg i.n. dosing provides similar exposure as 0.05 mg/kg i.v. in infants in terms of AUC, and hence intranasal bioavailability close to 50%.Disclosure(s)Nothing to disclose

scholarly journals Open-Label Crossover Study of Primaquine and Dihydroartemisinin-Piperaquine Pharmacokinetics in Healthy Adult Thai Subjects

2014 ◽  
Vol 58 (12) ◽  
pp. 7340-7346 ◽  
Author(s):  
Borimas Hanboonkunupakarn ◽  
Elizabeth A. Ashley ◽  
Podjanee Jittamala ◽  
Joel Tarning ◽  
Sasithon Pukrittayakamee ◽  
...  
Keyword(s):  
Crossover Study ◽  
Hospital Admissions ◽  
Geometric Mean ◽  
Radical Cure ◽  
Open Label ◽  
Time Curve ◽  
Content Type ◽  
Concentration Time ◽  
Pharmacokinetic Assessment ◽  
Adult Volunteers

ABSTRACTDihydroartemisinin-piperaquine is an artemisinin-based combination treatment (ACT) recommended by the WHO for uncomplicatedPlasmodium falciparummalaria, and it is being used increasingly for resistant vivax malaria where combination with primaquine is required for radical cure. The WHO recently reinforced its recommendations to add a single dose of primaquine to ACTs to reduceP. falciparumtransmission in low-transmission settings. The pharmacokinetics of primaquine and dihydroartemisinin-piperaquine were evaluated in 16 healthy Thai adult volunteers in a randomized crossover study. Volunteers were randomized to two groups of three sequential hospital admissions to receive 30 mg (base) primaquine, 3 tablets of dihydroartemisinin-piperaquine (120/960 mg), and the drugs together at the same doses. Blood sampling was performed over 3 days following primaquine and 36 days following dihydroartemisinin-piperaquine dosing. Pharmacokinetic assessment was done with a noncompartmental approach. The drugs were well tolerated. There were no statistically significant differences in dihydroartemisinin and piperaquine pharmacokinetics with or without primaquine. Dihydroartemisinin-piperaquine coadministration significantly increased plasma primaquine levels; geometric mean ratios (90% confidence interval [CI]) of primaquine combined versus primaquine alone for maximum concentration (Cmax), area under the concentration-time curve from 0 h to the end of the study (AUC0–last), and area under the concentration-time curve from 0 h to infinity (AUC0–∞) were 148% (117 to 187%), 129% (103 to 163%), and 128% (102 to 161%), respectively. This interaction is similar to that described recently with chloroquine and may result in an enhanced radical curative effect. (This study has been registered at ClinicalTrials.gov under registration no. NCT01525511.)

scholarly journals Pharmacokinetics and Absorption of Posaconazole Oral Suspension under Various Gastric Conditions in Healthy Volunteers

2008 ◽  
Vol 53 (3) ◽  
pp. 958-966 ◽  
Author(s):  
Gopal Krishna ◽  
Allen Moton ◽  
Lei Ma ◽  
Matthew M. Medlock ◽  
James McLeod
Keyword(s):  
Proton Pump ◽  
Gastric Motility ◽  
Nutritional Supplement ◽  
Gastric Ph ◽  
High Fat ◽  
Time Curve ◽  
Concentration Time ◽  
Dosing Frequency ◽  
Randomized Crossover Study ◽  
Fat Meal

ABSTRACT A four-part, randomized, crossover study with healthy subjects evaluated the effects of gastric pH, the dosing frequency and prandial state, food consumption timing, and gastric motility on the absorption of posaconazole. In part 1, a single dose (SD) of posaconazole (400 mg) was administered alone or with an acidic beverage or a proton pump inhibitor (PPI), or both. In part 2, posaconazole (400 mg twice daily and 200 mg four times daily) was administered for 7 days with and without a nutritional supplement (Boost). In part 3, an SD of posaconazole (400 mg) was administered while the subjects were fasting and before, during, and after a high-fat meal. In part 4, an SD of posaconazole (400 mg) and the nutritional supplement were administered alone, with metoclopramide, and with loperamide. Compared to the results obtained with posaconazole alone, administration with an acidic beverage increased the posaconazole maximum concentration in plasma (C max) and the area under the concentration-time curve (AUC) by 92% and 70%, respectively, whereas a higher gastric pH decreased the posaconazole C max and AUC by 46% and 32%, respectively. Compared to the results obtained with posaconazole alone, posaconazole at 400 mg or at 200 mg plus the nutritional supplement increased the posaconazole C max and AUC by 65% and 66%, respectively, and by up to 137% and 161%, respectively. Administration before a high-fat meal increased the C max and the AUC by 96% and 111%, respectively, while administration during and after the meal increased the C max and the AUC by up to 339% and 387%, respectively. Increased gastric motility decreased the C max and the AUC by 21% and 19%, respectively. Strategies to maximize posaconazole exposure in patients with absorption difficulties include administration with or after a high-fat meal, with any meal or nutritional supplement, with an acidic beverage, or in divided doses and the avoidance of proton pump inhibitors.

scholarly journals Phase I Study Assessing the Pharmacokinetic Profile, Safety, and Tolerability of a Single Dose of Ceftazidime-Avibactam in Hospitalized Pediatric Patients

2016 ◽  
Vol 60 (10) ◽  
pp. 6252-6259 ◽  
Author(s):  
John S. Bradley ◽  
Jon Armstrong ◽  
Antonio Arrieta ◽  
Raafat Bishai ◽  
Shampa Das ◽  
...  
Keyword(s):  
Single Dose ◽  
Phase I ◽  
Pediatric Patients ◽  
Geometric Mean ◽  
Open Label ◽  
Serious Adverse Events ◽  
Time Curve ◽  
Age Cohorts ◽  
Concentration Time ◽  
Systemic Antibiotic Therapy

ABSTRACTThis study aimed to investigate the pharmacokinetics (PK), safety, and tolerability of a single dose of ceftazidime-avibactam in pediatric patients. A phase I, multicenter, open-label PK study was conducted in pediatric patients hospitalized with an infection and receiving systemic antibiotic therapy. Patients were enrolled into four age cohorts (cohort 1, ≥12 to <18 years; cohort 2, ≥6 to <12 years; cohort 3, ≥2 to <6 years; cohort 4, ≥3 months to <2 years). Patients received a single 2-h intravenous infusion of ceftazidime-avibactam (cohort 1, 2,000 to 500 mg; cohort 2, 2,000 to 500 mg [≥40 kg] or 50 to 12.5 mg/kg [<40 kg]; cohorts 3 and 4, 50 to 12.5 mg/kg). Blood samples were collected to describe individual PK characteristics for ceftazidime and avibactam. Population PK modeling was used to describe characteristics of ceftazidime and avibactam PK across all age groups. Safety and tolerability were assessed. Thirty-two patients received study drug. Mean plasma concentration-time curves, geometric mean maximum concentration (Cmax), and area under the concentration-time curve from time zero to infinity (AUC0–∞) were similar across all cohorts for both drugs. Six patients (18.8%) reported an adverse event, all mild or moderate in intensity. No deaths or serious adverse events occurred. The single-dose PK of ceftazidime and avibactam were comparable between each of the 4 age cohorts investigated and were broadly similar to those previously observed in adults. No new safety concerns were identified. (This study has been registered at ClinicalTrials.gov under registration no. NCT01893346.)

scholarly journals Comparative Pharmacokinetics of Voriconazole Administered Orally as either Crushed or Whole Tablets

2006 ◽  
Vol 51 (3) ◽  
pp. 877-880 ◽  
Author(s):  
E. S. Dodds Ashley ◽  
A. K. Zaas ◽  
A. F. Fang ◽  
B. Damle ◽  
J. R. Perfect
Keyword(s):  
Maximum Concentration ◽  
Fungal Infections ◽  
Random Sequence ◽  
Systemic Absorption ◽  
Open Label ◽  
Time Curve ◽  
Comparative Pharmacokinetic ◽  
Crushed Tablet ◽  
Concentration Time ◽  
Clinical Scenarios

ABSTRACT Voriconazole is a triazole antifungal agent used to treat serious, invasive fungal infections including aspergillosis and candidemia. Limitations with existing formulations of voriconazole including restricted utility in patients with renal dysfunction (intravenous preparation) and the unavailability of an oral suspension in some countries make the administration of crushed tablets desirable in many clinical scenarios. However, concerns that this approach may alter the systemic absorption of voriconazole exist. Therefore, an open-label, randomized, two-way crossover comparative pharmacokinetic (PK) study using healthy volunteers was performed to compare these methods of tablet administration. In a random sequence, subjects received voriconazole tablets either crushed or whole. The voriconazole dose was 400 mg every 12 h for 1 day orally followed by 200 mg every 12 h orally for 5.5 days. Study periods were separated by 7 days. PK parameters were determined by the noncompartmental method. An equivalence approach with no-effect boundaries of 80 to 125% was used to assess bioequivalence. Twenty healthy subjects (10 males; aged 20 to 43 years) were enrolled in and completed the study. The adjusted mean areas under the plasma concentration-time curve from 0 to τ, where τ equals 12 h, for the crushed and whole tablet groups were 9,793 and 11,164 ng · h/ml, respectively (ratio, 87.72; 90% confidence interval [CI], 80.97, 95.04). The ratio of the maximum concentration of drug in serum for the crushed tablet versus whole tablet arms was 94.94 (90% CI, 86.51, 104.22). The only difference noted between groups was a slightly faster time to maximum concentration of drug in serum when subjects received crushed tablets, 0.5 h versus 1.5 h (90% CI, −0.75, −0.25). Treatment-related adverse events occurred in 12 subjects receiving whole tablets and 9 subjects receiving crushed tablets; all were mild. The administration of crushed voriconazole tablets is bioequivalent to whole-tablet administration.

scholarly journals Effect of a Nutritional Supplement on Posaconazole Pharmacokinetics following Oral Administration to Healthy Volunteers

2006 ◽  
Vol 50 (5) ◽  
pp. 1881-1883 ◽  
Author(s):  
Angela Sansone-Parsons ◽  
Gopal Krishna ◽  
Angela Calzetta ◽  
David Wexler ◽  
Bhavna Kantesaria ◽  
...  
Keyword(s):  
Oral Administration ◽  
Crossover Study ◽  
Healthy Volunteers ◽  
Maximum Concentration ◽  
Nutritional Supplement ◽  
Healthy Adults ◽  
Time Curve ◽  
Fasted State ◽  
Concentration Time ◽  
Randomized Crossover Study

ABSTRACT We conducted a randomized, crossover study in healthy adults to examine the effects of a nutritional supplement (Boost Plus) on posaconazole pharmacokinetics. In this study, coadministration of posaconazole with Boost Plus increased the maximum concentration of posaconazole in serum and area under the concentration-time curve from 0 to 72 h values 3.4- and 2.6-fold, respectively, compared to those for the fasted state.

scholarly journals Atogepant and sumatriptan: no clinically relevant drug–drug interactions in a randomized, open-label, crossover trial

2021 ◽  
Author(s):  
Ramesh Boinpally ◽  
Abhijeet Jakate ◽  
Matthew Butler ◽  
Antonia Periclou
Keyword(s):  
Plasma Concentration ◽  
Crossover Trial ◽  
Peak Plasma ◽  
Peak Plasma Concentration ◽  
Geometric Mean ◽  
Open Label ◽  
Time Curve ◽  
Concentration Time ◽  
Pharmacokinetic Interactions ◽  
Randomized Crossover Study

Aim: To evaluate pharmacokinetic interactions of atogepant with sumatriptan, an open-label, randomized, crossover study was conducted. Patients & methods: Thirty healthy adults received atogepant 60 mg, sumatriptan 100 mg, or coadministered drugs. Primary end point was geometric mean ratios (GMRs) and 90% CIs of interventions for area under the plasma concentration–time curve from time 0 to t (AUC0-t) or infinity (AUC0-∞) and peak plasma concentration (Cmax). Results: Atogepant GMRs for AUC0-t and AUC0-∞ versus with sumatriptan were within 90% CI 0.80–1.25, indicating no interaction; atogepant Cmax was reduced by 22% (GMR: 0.78; 90% CI: 0.69–0.89) with sumatriptan. Sumatriptan GMRs for AUC0-t, AUC0-∞ and Cmax versus with atogepant were within 90% CI 0.80–1.25. Conclusion: Atogepant with sumatriptan had no clinically relevant pharmacokinetic interactions.

Bioequivalence Study of Rivastigmine 6 mg Capsules (Single Dose) in Healthy Volunteers

2017 ◽  
Vol 32 (6) ◽  
pp. 360-366
Author(s):  
Dhiraj Abhyankar ◽  
Ashish Shedage ◽  
Milind Gole ◽  
Preeti Raut
Keyword(s):  
Single Dose ◽  
Standard Deviation ◽  
Geometric Mean ◽  
Bioequivalence Study ◽  
Open Label ◽  
Time Curve ◽  
Healthy Men ◽  
Time Zero ◽  
Concentration Time ◽  
To Receive

Objective: To assess the bioequivalence of generic formulation of rivastigmine (test) and Exelon (reference). Methods: This randomized, open-label, 2-period, single-dose, 2-treatment, 2-sequence, crossover study was conducted in 40 healthy men under fed condition. Participants were randomized to receive a single dose of Exelon or rivastigmine capsule. Results: A total of 31 participants completed the study. Area under the concentration–time curve from time zero to time t (AUC0- t) and area under the concentration–time curve from time zero to infinity (AUC0-∞) for Exelon (mean [standard deviation], h·ng/mL) were 126.40 (56.95) and 129.46 (59.94), respectively, while they were 122.73 (43.46) and 125.08 (45.39) for rivastigmine. Geometric mean ratios of rivastigmine/Exelon were 99.17% for AUC0- t, 98.81% for AUC0-∞, and 105% for maximum observed plasma concentration ( Cmax). The 90% confidence intervals (CIs) were 94.14% to 104.46%, 93.77% to 104.12%, and 93.08% to 118.44%, respectively. Both formulations were well tolerated. Conclusion: The generic and reference formulations were bioequivalent, as the 90% CIs for Cmax, AUC0- t, and AUC0-∞ were within the range of 80% to 125%.

scholarly journals Effects of Food and Omeprazole on a Novel Formulation of Super Bioavailability Itraconazole in Healthy Subjects

2018 ◽  
Vol 62 (12) ◽  
Author(s):  
Julian Lindsay ◽  
Stuart Mudge ◽  
George R. Thompson
Keyword(s):  
Steady State ◽  
Maximum Concentration ◽  
Healthy Adults ◽  
Plasma Exposure ◽  
Open Label ◽  
Time Curve ◽  
Dosing Interval ◽  
Fasted State ◽  
Concentration Time ◽  
Bioavailability Study

ABSTRACT To address the limited bioavailability and intolerance of the conventional itraconazole (ITZ) formulations, a new formulation labeled super bioavailability (SUBA) itraconazole has been developed; however, the specific effects of food and gastric pH are unknown. This study evaluated the pharmacokinetic profile of SUBA itraconazole under fasting and fed conditions, as well as with the concomitant administration of a proton pump inhibitor. First, the effect of food was assessed in an open-label, randomized, crossover bioavailability study of 65-mg SUBA itraconazole capsules (2 65-mg capsules twice a day) in healthy adults (n = 20) under fasting and fed conditions to steady-state levels. Second, an open-label, two-treatment, fixed-sequence comparative bioavailability study in healthy adults (n = 28) under fasted conditions compared the pharmacokinetics of a single oral dose of SUBA itraconazole capsules (2 65-mg capsules/day) with and without coadministration of daily omeprazole delayed-release capsules (1 40-mg capsule/day) under steady-state conditions. In the fed and fasted states, SUBA itraconazole demonstrated similar concentrations at the end of the dosing interval, with modestly lower total and peak ITZ exposure being shown when it was administered under fed conditions than when it was administered in the fasted state, with fed state/fasted state ratios of 78.09% (90% confidence interval [CI], 74.49 to 81.86%) for the area under the concentration-time curve over the dosing interval (14,183.2 versus 18,479.8 ng · h/ml), 73.05% (90% CI, 69.01 to 77.33%) for the maximum concentration at steady state (1,519.1 versus 2,085.2 ng/ml), and 91.53% (90% CI, 86.41 to 96.96%) for the trough concentration (1,071.5 versus 1,218.5 ng/ml) being found. When dosed concomitantly with omeprazole, there was a 22% increase in the total plasma exposure of ITZ, as measured by the area under the concentration-time curve from time zero to infinity (P = 0.0069), and a 31% increase in the peak plasma exposure of ITZ, as measured by the maximum concentration (P = 0.0083).

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