Bioequivalence and safety of a novel fentanyl transdermal matrix system compared with a transdermal reservoir system

Objectives: Fentanyl is a potent synthetic opioid used for the management of chronic pain. A newer transdermal matrix system was developed and compared with a reservoir system used in the United States.Setting: An open-label, single-center, randomized, two-period crossover study was conducted to evaluate the bioequivalence of the transdermal matrix system to the transdermal reservoir system. Seventy-four subjects completed treatment with both the reservoir system (100 μg/h) and the matrix system (100 μg/h), each applied for 72 hours. After application of the first system, subjects completed a 9-day washout and then crossed over to receive the other system for another 72 hours.Main outcome measure: Blood samples for the determination of serum fentanyl concentrations were taken in each treatment period for up to 120 hours following application.Results: The ratios of geometric means for maximum fentanyl concentration (Cmax) and area under the concentration-time curve (AUClast and AUC∞ ) were 106 percent, 110 percent, and 110 percent, respectively. The 90% confidence intervals for the ratios of the geometric means were contained within the bioequivalence criteria of 80-125 percent. The matrix system adhered well to skin. Systemic and topical safety profiles were comparable between treatments.Conclusions: The transdermal fentanyl matrix system adhered well, was well tolerated, and produced systemic exposures of fentanyl that were bioequivalent to the reservoir system.

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

Infectious Diseases in Obstetrics and Gynecology ◽

10.1155/2012/137192 ◽

2012 ◽

Vol 2012 ◽

pp. 1-4 ◽

Cited By ~ 45

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.

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Lack of Effect of Simultaneously Administered Didanosine Encapsulated Enteric Bead Formulation (Videx EC) on Oral Absorption of Indinavir, Ketoconazole, or Ciprofloxacin

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.46.2.385-391.2002 ◽

2002 ◽

Vol 46 (2) ◽

pp. 385-391 ◽

Cited By ~ 30

Author(s):

Bharat D. Damle ◽

Vanaja Mummaneni ◽

Sanjeev Kaul ◽

Catherine Knupp

Keyword(s):

Oral Absorption ◽

Historical Data ◽

Point Estimate ◽

Open Label ◽

Time Curve ◽

Geometric Means ◽

Point Estimates ◽

Concentration Time ◽

Crossover Studies ◽

Post Hoc

ABSTRACT Didanosine formulation that contains a buffer to prevent it from acid-mediated degradation can result in a significant decrease in the oral absorption of certain drugs because of interactions with antacids. An enteric formulation of didanosine is unlikely to cause such drug interactions because it lacks antacids. This study was undertaken to determine whether the enteric bead formulation of didanosine (Videx EC) influences the bioavailability of indinavir, ketoconazole, and ciprofloxacin, three drugs that are representative of a broader class of drugs affected by interaction with antacids. Healthy subjects of either gender were enrolled in three separate open-label, single-dose, two-way crossover studies. Subjects were randomized to treatment A (800 mg of indinavir, 200 mg of ketoconazole, or 750 mg of ciprofloxacin) or treatment B (same dose of indinavir, ketoconazole, or ciprofloxacin, but with 400 mg of didanosine as an encapsulated enteric bead formulation). A lack of interaction was concluded if the 90% confidence interval (CI) of the ratio of the geometric means of log-transformed C max and AUC0-∞ values (i.e., values for the area under the concentration-time curve from time zero to infinity) of indinavir, ketoconazole, and ciprofloxacin were contained entirely between 0.75 and 1.33. For indinavir (n = 23), the point estimate (90% CI; minimum, maximum) of the ratios of C max and AUC0-∞ values were 0.99 (0.91, 1.06) and 0.96 (0.91, 1.02), respectively. In the ketoconazole study, 3 of 24 subjects showed anomalous absorption of ketoconazole (i.e., an ∼8-fold-lower AUC compared to historical data), which was the reference treatment. A post hoc analysis performed after these three subjects were excluded indicated that the point estimates (90% CI) of the ratios of Cmax and AUC0-∞ values were 0.99 (0.86, 1.14) and 0.97 (0.85, 1.10), respectively. For ciprofloxacin (n = 16), the point estimate (90% CI) of the ratios of C max and AUC0-∞ values were 0.92 (0.79, 1.07) and 0.91 (0.76, 1.08), respectively. All three studies clearly indicated a lack of interaction. The T max and t 1/2 for indinavir, ketoconazole, and ciprofloxacin were similar between treatments. Our results showed that the lack of interaction of didanosine encapsulated enteric bead formulation with indinavir, ketoconazole, and ciprofloxacin indicates that this enteric formulation of didanosine can be concomitantly administered with drugs whose bioavailability is known to be reduced by interaction with antacids.

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Effect of Fluoxetine on Pharmacokinetics of Ritonavir

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.42.12.3107 ◽

1998 ◽

Vol 42 (12) ◽

pp. 3107-3112 ◽

Cited By ~ 23

Author(s):

Daniele Ouellet ◽

Ann Hsu ◽

Jiang Qian ◽

Janet E. Lamm ◽

John H. Cavanaugh ◽

...

Keyword(s):

Rate Constant ◽

Elimination Rate ◽

Potential Interaction ◽

Elimination Rate Constant ◽

Open Label ◽

Time Curve ◽

Blood Samples ◽

Immunodeficiency Virus

ABSTRACT The potential interaction between fluoxetine, a known inhibitor of cytochrome P-450 isoform 2D6 (CYP2D6), and ritonavir, a human immunodeficiency virus type 1 protease inhibitor, was evaluated in this open-label study. Sixteen male and female subjects ranging in age from 18 to 40 years completed the study. Subjects received single doses of 600 mg of ritonavir on days 1 and 10. On study days 3 to 10, all subjects received 30 mg of fluoxetine every 12 h for a total of 16 consecutive doses. Serial blood samples for determination of ritonavir concentrations in plasma were collected after the administration of ritonavir on days 1 and 10. A limited number of blood samples for determination of fluoxetine and norfluoxetine concentrations were collected after administration of the morning dose on day 10. A statistically significant increase (19%) in the ritonavir area under the concentration-time curve (AUC) was observed with concomitant fluoxetine administration, with individual changes ranging from −12 to +56%. The change in the ritonavir AUC with concomitant fluoxetine administration was positively correlated with the norfluoxetine 24-h AUC (AUC24) (r 2 = 0.42), the norfluoxetine/fluoxetine AUC24 ratio (r 2 = 0.53), and the fluoxetine elimination rate constant (r 2 = 0.65), with larger increases in the ritonavir AUC tending to occur with higher norfluoxetine concentrations and higher fluoxetine elimination rate constants. The effect of fluoxetine appeared to be larger in subjects with the CYP2D6 wt/wt genotype. There was little or no effect on the time to maximum drug concentration (C max) in serum, C max, and the elimination rate constant of ritonavir with concomitant fluoxetine administration. Considering the magnitude of the change observed, no ritonavir dose adjustment is recommended during concomitant fluoxetine administration.

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Effect of the Hepatitis C Virus Protease Inhibitor Telaprevir on the Pharmacokinetics of Amlodipine and Atorvastatin

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00653-11 ◽

2011 ◽

Vol 55 (10) ◽

pp. 4569-4574 ◽

Cited By ~ 53

Author(s):

Jee Eun Lee ◽

Rolf van Heeswijk ◽

Katia Alves ◽

Frances Smith ◽

Varun Garg

Keyword(s):

Hepatitis C Virus ◽

Hepatitis C ◽

Protease Inhibitor ◽

Inhibitory Effect ◽

Least Square ◽

Open Label ◽

Time Curve ◽

Protease Inhibitor Telaprevir ◽

Single Sequence

ABSTRACTTelaprevir is a hepatitis C virus protease inhibitor that is both a substrate and an inhibitor of CYP3A. Amlodipine and atorvastatin are both substrates of CYP3A and are among the drugs most frequently used by patients with hepatitis C. This study was conducted to examine the effect of telaprevir on atorvastatin and amlodipine pharmacokinetics (PK). This was an open-label, single sequence, nonrandomized study involving 21 healthy male and female volunteers. A coformulation of 5 mg amlodipine and 20 mg atorvastatin was administered on day 1. Telaprevir was taken with food as a 750-mg dose every 8 h from day 11 until day 26, and a single dose of the amlodipine-atorvastatin combination was readministered on day 17. Plasma samples were collected for determination of the PK of telaprevir, amlodipine, atorvastatin,ortho-hydroxy atorvastatin, andpara-hydroxy atorvastatin. When administration with telaprevir was compared with administration without telaprevir, the least-square mean ratios (90% confidence limits) for amlodipine were 1.27 (1.21, 1.33) for the maximum drug concentration in serum (Cmax) and 2.79 (2.58, 3.01) for the area under the concentration-time curve from 0 h to infinity (AUC0-∞); for atorvastatin, they were 10.6 (8.74, 12.9) for theCmaxand 7.88 (6.84, 9.07) for the AUC0-∞. Telaprevir significantly increased exposure to amlodipine and atorvastatin, consistent with the inhibitory effect of telaprevir on the CYP3A-mediated metabolism of these agents.

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Bray–Liebhafsky oscillatory reaction in a continuous-flow stirred tank reactor as the matrix system for determination of tyrosine

Reaction Kinetics Mechanisms and Catalysis ◽

10.1007/s11144-021-02130-5 ◽

2022 ◽

Author(s):

Luka Negrojević ◽

Aleksandar Lončar ◽

Jelena Maksimović ◽

Slobodan Anić ◽

Željko Čupić ◽

...

Keyword(s):

Continuous Flow ◽

Stirred Tank ◽

Oscillatory Reaction ◽

Matrix System ◽

Stirred Tank Reactor ◽

Tank Reactor ◽

The Matrix

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

American Journal of Alzheimer s Disease & Other Dementias® ◽

10.1177/1533317517712890 ◽

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%.

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Pharmacokinetic Interactions between BMS-626529, the Active Moiety of the HIV-1 Attachment Inhibitor Prodrug BMS-663068, and Ritonavir or Ritonavir-Boosted Atazanavir in Healthy Subjects

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.04914-14 ◽

2015 ◽

Vol 59 (7) ◽

pp. 3816-3822 ◽

Cited By ~ 12

Author(s):

Li Zhu ◽

Matthew Hruska ◽

Carey Hwang ◽

Vaishali Shah ◽

Michael Furlong ◽

...

Keyword(s):

Healthy Subjects ◽

Systemic Exposure ◽

Open Label ◽

Time Curve ◽

Once Daily ◽

Viral Attachment ◽

Cyp3a4 Substrate ◽

Cyp3a4 Inhibitors ◽

To Receive ◽

Hiv 1

ABSTRACTBMS-663068 is a prodrug of BMS-626529, a first-in-class attachment inhibitor that binds directly to HIV-1 gp120, preventing initial viral attachment and entry into host CD4+T cells. This open-label, multiple-dose, four-sequence, crossover study addressed potential two-way drug-drug interactions following coadministration of BMS-663068 (BMS-626529 is a CYP3A4 substrate), atazanavir (ATV), and ritonavir (RTV) (ATV and RTV are CYP3A4 inhibitors). Thirty-six healthy subjects were randomized 1:1:1:1 to receive one of four treatment sequences with three consecutive treatments: BMS-663068 at 600 mg twice daily (BID), BMS-663068 at 600 mg BID plus RTV at 100 mg once daily (QD), ATV at 300 mg QD plus RTV at 100 mg QD (RTV-boosted ATV [ATV/r]), or BMS-663068 at 600 mg BID plus ATV at 300 mg QD plus RTV at 100 mg QD. Compared with the results obtained by administration of BMS-663068 alone, coadministration of BMS-663068 with ATV/r increased the BMS-626529 maximum concentration in plasma (Cmax) and the area under the concentration-time curve in one dosing interval (AUCtau) by 68% and 54%, respectively. Similarly, coadministration of BMS-663068 with RTV increased the BMS-626529Cmaxand AUCtauby 53% and 45%, respectively. Compared with the results obtained by administration of ATV/r alone, ATV and RTV systemic exposures remained similar following coadministration of BMS-663068 with ATV/r. BMS-663068 was generally well tolerated, and there were no adverse events (AEs) leading to discontinuation, serious AEs, or deaths. Moderate increases in BMS-626529 systemic exposure were observed following coadministration of BMS-663068 with ATV/r or RTV. However, the addition of ATV to BMS-663068 plus RTV did not further increase BMS-626529 systemic exposure. ATV and RTV exposures remained similar following coadministration of BMS-663068 with either ATV/r or RTV. BMS-663068 was generally well tolerated alone or in combination with either RTV or ATV/r.

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Analysis of the results of thermal treatment of single crystals of silicon doped with boron impurity

Theory and practice of metallurgy ◽

10.34185/tpm.1.2019.10 ◽

2019 ◽

Vol 1 (1) ◽

pp. 77-80

Author(s):

Panchenko O ◽

Chervony I

Keyword(s):

Heat Treatment ◽

Single Crystals ◽

Self Control ◽

Matrix System ◽

Electric Resistance ◽

Technological Parameters ◽

The Matrix ◽

Specific Electric Resistance ◽

Silicon Doped

Two groups of plastins of single-crystals of silicon doped with boron, were preliminary grown by the method of Chochralsky and thermally treat. Got values of specific electric resistance at different terms realizations of heat treatment served as a weekend by data. On the basis of the obtained experimental data were conducted: analysis of variance of the matrix system, estimation of results on the criterion of Cochren and Student. Built mathematical models. Determination of values of optimal technological parameters allowed objectively, taking into account influence of factors, to educe the maximum-possible circle of values for the receipt of necessary results. For basis accepted the change of temperature of heat treatment and time of self-control. All got experimental job performances are recreated and real at the construction of matrix of planning.

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Effect of Varying Amounts of a Liquid Nutritional Supplement on the Pharmacokinetics of Posaconazole in Healthy Volunteers

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00889-09 ◽

2009 ◽

Vol 53 (11) ◽

pp. 4749-4752 ◽

Cited By ~ 38

Author(s):

Gopal Krishna ◽

Lei Ma ◽

Donna Vickery ◽

Xin Yu ◽

Irene Wu ◽

...

Keyword(s):

Healthy Volunteers ◽

Clinical Laboratory ◽

Phase 1 ◽

Vital Signs ◽

Nutritional Supplement ◽

Relative Bioavailability ◽

Open Label ◽

Time Curve ◽

Physical Examinations ◽

To Receive

ABSTRACT The aim of this single-center, phase 1, randomized, 5 by 5 crossover, open-label study was to determine the effects of varying amounts of a nutritional supplement (Boost Plus) on the pharmacokinetics of posaconazole in 30 healthy volunteers. After an overnight fast, subjects were administered a single dose of 400 mg posaconazole oral suspension alone or following Boost Plus (8 fluid ounces [oz] [240 ml], 4 oz [120 ml], 2 oz [60 ml], or 1 oz [30 ml]). Subjects were randomized to receive all five treatments in different sequences, with a 14-day washout between treatments. Primary pharmacokinetic variables—area under the concentration-time curve from time zero to the time of the final quantifiable sample (AUCtf), maximum observed plasma concentration (C max), time to C max (T max), and relative bioavailability—were assessed up to 5 days postdose. Safety assessments included testing for adverse events, clinical laboratory tests, measurement of vital signs, physical examinations, and electrocardiograms. Posaconazole bioavailability increased almost linearly with increasing amounts of Boost Plus. Based on log-transformed data, the relative bioavailabilities (AUCs) of posaconazole were 35% (fasting), 48% (1 oz), 60% (2 oz), and 77% (4 oz) of the level reached in the presence of 8 oz Boost Plus, whereas T max was unaffected. Compared with the levels reached under fasting conditions, posaconazole C max and AUC values increased 3.5- and 2.9-fold, respectively, when given with 8 oz Boost Plus. Single doses of posaconazole at 400 mg alone and with 1, 2, 4, or 8 oz Boost Plus were safe and well tolerated in healthy subjects.

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