scholarly journals Pharmacokinetic Interaction between Fosamprenavir-Ritonavir and Rifabutin in Healthy Subjects

2007 ◽  
Vol 52 (2) ◽  
pp. 534-538 ◽  
Author(s):  
Susan L. Ford ◽  
Ya-Chi Chen ◽  
Yu Lou ◽  
Julie Borland ◽  
Sherene S. Min ◽  
...  
Keyword(s):  
Steady State ◽  
Systemic Exposure ◽  
Pharmacokinetic Interaction ◽  
Concomitant Administration ◽  
Pharmacokinetic Parameters ◽  
Phosphate Ester ◽  
Open Label ◽  
Time Curve ◽  
Dosing Interval ◽  
Cyp3a4 Inhibitors

ABSTRACT Rifabutin (RFB) is administered for treatment of tuberculosis and Mycobacterium avium complex infection, including use for patients coinfected with human immunodeficiency virus (HIV). Increased systemic exposure to RFB and its equipotent active metabolite, 25-O-desacetyl-RFB (dAc-RFB), has been reported during concomitant administration of CYP3A4 inhibitors, including ritonavir (RTV), lopinavir, and amprenavir (APV); therefore, a reduction in the RFB dosage is recommended when it is coadministered with these protease inhibitors. Fosamprenavir (FPV), the phosphate ester prodrug of the HIV type 1 protease inhibitor APV, is administered either with or without RTV. A randomized, open-label, two-period, two-sequence, balanced, crossover drug interaction study was conducted with 22 healthy adult subjects to compare steady-state plasma RFB pharmacokinetic parameters during concomitant administration of FPV-RTV (700/100 mg twice a day [BID]) with a 75%-reduced RFB dose (150 mg every other day [QOD]) to the standard RFB regimen (300 mg once per day [QD]) by geometric least-squares mean ratios. Relative to results with RFB (300 mg QD), coadministration of dose-adjusted RFB with FPV-RTV resulted in an unchanged RFB area under the concentration-time curve for 0 to 48 h (AUC0-48) and a 14% decrease in the maximum concentration of drug in plasma (C max), whereas the AUC0-48 and C max of dAc-RFB were increased by 11- and 6-fold, respectively, resulting in a 64% increase in the total antimycobacterial AUC0-48. Relative to historical controls, the plasma APV AUC from 0 h to the end of the dosing interval (AUC0-τ) and C max were increased ∼35%, and the concentration at the end of the dosing interval at steady state was unchanged following coadministration of RFB with FPV-RTV. The safety profile of the combination of RFB and FPV-RTV was consistent with previously described events with RFB or FPV-RTV alone. Based on the results of this study, a reduction in the RFB dose by ≥75% (to 150 mg QOD or three times per week) is recommended when it is coadministered with FPV-RTV (700/100 mg BID).

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.

scholarly journals Pharmacokinetic Interaction between Maraviroc and Fosamprenavir-Ritonavir: an Open-Label, Fixed-Sequence Study in Healthy Subjects

2013 ◽  
Vol 57 (12) ◽  
pp. 6158-6164 ◽  
Author(s):  
Manoli Vourvahis ◽  
Anna Plotka ◽  
Laure Mendes da Costa ◽  
Annie Fang ◽  
Jayvant Heera
Keyword(s):  
Healthy Subjects ◽  
Geometric Mean ◽  
Active Form ◽  
Pharmacokinetic Interaction ◽  
Pharmacokinetic Parameters ◽  
Maximum Plasma ◽  
Open Label ◽  
Fixed Sequence ◽  
Dosing Interval ◽  
Period 2

ABSTRACTThis open-label, fixed-sequence, phase 1 study evaluated the pharmacokinetic interaction between maraviroc (MVC) and ritonavir-boosted fosamprenavir (FPV/r) in healthy subjects. In period 1, subjects received 300 mg of MVC twice daily (BID; cohort 1) or once daily (QD; cohort 2) for 5 days. In period 2, cohort 1 subjects received 700/100 mg of FPV/r BID alone on days 1 to 10 and then FPV/r at 700/100 mg BID plus MVC at 300 mg BID on days 11 to 20; cohort 2 subjects received FPV/r at 1,400/100 mg QD alone on days 1 to 10 and then FPV/r at 1,400/100 mg QD plus MVC at 300 mg QD on days 11 to 20. Pharmacokinetic parameters, assessed on day 5 of period 1 and on days 10 and 20 of period 2, included the maximum plasma concentration (Cmax), the concentration at end of dosing interval (Cτ), and the area under the curve over dosing interval (AUCτ). Safety and tolerability were also assessed. MVC geometric mean AUCτ,Cmax, andCτwere increased by 149, 52, and 374%, respectively, after BID dosing with FPV/r, and by 126, 45, and 80%, respectively, after QD dosing. Amprenavir (the active form of the prodrug fosamprenavir) and ritonavir exposures were decreased in the presence of MVC with amprenavir AUCτ,Cmax, andCτdecreased by 34 to 36% in the presence of FPV/r plus maraviroc BID and by 15 to 30% with FPV/r plus MVC QD both compared to FPV/r alone. The overall all-causality adverse-event (AE) incidence rate was 96.4%; all AEs were of mild or moderate severity. Commonly reported treatment-related AEs (>20% of patients overall) included diarrhea, fatigue, abdominal discomfort, headache, and nausea. No serious AEs or deaths occurred. In summary, maraviroc exposure increased in the presence of FPV/r, whereas MVC coadministration decreased amprenavir and ritonavir exposures. MVC dosed at 300 mg BID with FPV/r is not recommended due to concerns of lower amprenavir exposures; however, no dose adjustment is warranted with MVC at 150 mg BID in combination with FPV/r based on the available clinical data. MVC plus FPV/r was generally well tolerated; no new safety signals were detected.

Clinically Significant Pharmacokinetic Interaction between Colchicine and Ritonavir in Healthy Volunteers

2013 ◽  
Vol 5 ◽  
pp. CMT.S10561 ◽  
Author(s):  
Suman Wason ◽  
Jennifer L. DiGiacinto ◽  
Matthew W. Davis
Keyword(s):  
Healthy Volunteers ◽  
Multiple Dose ◽  
Plasma Concentrations ◽  
Pharmacokinetic Interaction ◽  
Concomitant Administration ◽  
Study Data ◽  
Open Label ◽  
Time Curve ◽  
Clinically Significant ◽  
Cyp3a4 Enzyme

Colchicine is a substrate for cytochrome 3A4 (CYP3A4) enzyme and P-glycoprotein efflux transporter (P-gp); consequently, concomitant administration with drugs that inhibit these have the potential to cause clinically significant increases in colchicine plasma concentrations and precipitate adverse events. Ritonavir, a protease inhibitor, elicits potent CYP3A4 and P-gp inhibitory activity. In this open-label, nonrandomized, one-sequence, two-period study, 24 healthy volunteers received a single 0.6-mg dose of colchicine alone and together with multiple-dose ritonavir (100 mg twice daily for 4 days) to evaluate drug-drug interactions. Serial blood samples were collected for the determination of colchicine plasma concentrations. Standard pharmacokinetic parameter values were calculated along with 90% confidence intervals (ie, area under the concentration-time curve plasma from time zero to the time of last quantifiable concentration [AUC0-t and AUC0-∞], maximum drug concentration [Cmax]) for colchicine alone and colchicine combined with multiple-dose ritonavir. The mean Cmax and AUC0-t were significantly increased (170% and 245%, respectively) when colchicine was coadministered with ritonavir as compared with colchicine alone. Study data confirm the need for a dose adjustment (approximately 50% reduction) when colchicine is coadministered with strong CYP3A/P-gp inhibitors.

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).

scholarly journals 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

2015 ◽  
Vol 59 (7) ◽  
pp. 3816-3822 ◽  
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.

Ritonavir-Enhanced Pharmacokinetics of Nelfinavir/M8 during Rifampin Use

2003 ◽  
Vol 37 (4) ◽  
pp. 521-525 ◽  
Author(s):  
Alina S Bergshoeff ◽  
Tom FW Wolfs ◽  
Sibyl PM Geelen ◽  
David M Burger
Keyword(s):  
Steady State ◽  
Protease Inhibitor ◽  
Highly Active Antiretroviral Therapy ◽  
Adult Population ◽  
Plasma Concentrations ◽  
Pharmacokinetic Interaction ◽  
Male Infant ◽  
Pharmacokinetic Parameters ◽  
Time Curve ◽  
Highly Active

OBJECTIVE: To describe a case of successful protease inhibitor–based highly active antiretroviral therapy (HAART) concomitant with rifampin. CASE SUMMARY: In a 7-month-old male infant with tuberculosis and HIV-1 infection, tuberculosis therapy including rifampin and HAART containing the protease inhibitor nelfinavir 40 mg/kg every 8 hours was started. Intensive steady-state pharmacokinetic sampling from baseline to 8 hours revealed very low plasma concentrations of nelfinavir: area under the plasma concentration–time curve (AUC0–24) <10% of adult population values for 750 mg every 8 hours and nonquantifiable concentrations of nelfinavir's principal metabolite (M8). Nelfinavir 40 mg/kg every 8 hours was then substituted with nelfinavir 30 mg/kg twice daily plus ritonavir 400 mg/m2 twice daily. Intensive steady-state (0–12 h) pharmacokinetic sampling was repeated. Nelfinavir concentrations had improved, but remained low when compared with adult population values of 1250 mg every 12 hours: AUC0–24 21.9 versus 47.6 mg/L•h (46%) and 12-hour trough level (C12) 0.25 versus 0.85 mg/L (29%). However, concentrations of M8 considerably exceeded population values: AUC0–24 57.5 versus 13.6 mg/L•h (443%) and C12 1.35 versus 0.28 mg/L (482%). Since M8 concentrations were highly elevated, pharmacokinetic parameters for (nelfinavir + M8) were used rather than those for nelfinavir alone. Thus, AUC0–24 (nelfinavir + M8) and C12 (nelfinavir + M8) comprised 130% and 142%, respectively of the adult population values. This, in addition to good clinical response and tolerability, favored continuation of the regimen. CONCLUSIONS: In an infant, nelfinavir-containing HAART was successfully used with rifampin after the addition of ritonavir. Ritonavir resolved the pharmacokinetic interaction between rifampin and nelfinavir by boosting nelfinavir and, especially, M8 concentrations. More research is needed to confirm these results.

scholarly journals Pharmacokinetic Interaction between Zidovudine and Trimethoprim/sulphamethoxazole in HIV-1 Infected Children

2000 ◽  
Vol 11 (5) ◽  
pp. 254-258 ◽  
Author(s):  
Shannon Dallas ◽  
Stanley E Read ◽  
Susan King ◽  
Gideon Koren ◽  
Reina Bendayan
Keyword(s):  
Half Life ◽  
Statistical Significance ◽  
Pharmacokinetic Interaction ◽  
Pharmacokinetic Analysis ◽  
Pharmacokinetic Parameters ◽  
Open Label ◽  
Time Curve ◽  
Number Of Patients ◽  
Glucuronide Metabolite ◽  
Hiv 1

OBJECTIVE: To evaluate the effect of the antimicrobial agent trimethoprim/sulphamethoxazole (TMP/SMX) on the pharmacokinetic properties of the antiretroviral drug zidovudine (ZDV).DESIGN: This single dose, open label, crossover study involved the oral administration of ZDV (150 mg/m2) alone and in combination with oral TMP/SMX (2.5 mg/kg) on two separate occasions. Serial blood samples (0 to 8 h) were collected, and concentrations of ZDV and its glucuronide metabolite were quantified using a radioimmunoassay. ZDV pharmacokinetics were determined by noncompartmental analysis.PATIENTS AND SETTING: Six HIV-1 infected children aged four months to five years were recruited from the HIV clinic at The Hospital for Sick Children, Toronto, Ontario. Only three patients completed both study phases and were included in the pharmacokinetic analysis.MAIN RESULTS: With TMP/SMX therapy, no statistically significant changes were observed in ZDV pharmacokinetic parameters. However, there was a trend towards increased ZDV half-life and area under the concentration versus time curve, as well as decreased apparent oral clearance. Similarly, a trend towards an increased half-life of the ZDV-glucuronide metabolite was also observed.CONCLUSION: The changes in ZDV pharmacokinetics in the presence of TMP/SMX did not reach statistical significance, most likely due to the limited number of patients involved. Despite the limited data, a possible interaction between ZDV and TMP/SMX in young HIV-1 infected children should be considered, and patients may require close clinical monitoring.

An Evaluation of the Potential for Pharmacokinetic Interaction between Tramadol and Cytochrome P450 2D6 Inhibitor Promethazine

2014 ◽  
Vol 989-994 ◽  
pp. 1041-1043
Author(s):  
Ping Liu ◽  
Liang Sun ◽  
Jian Zhang ◽  
Rui Chen Guo
Keyword(s):  
Single Dose ◽  
Plasma Concentration ◽  
Pharmacokinetic Interaction ◽  
Apparent Volume ◽  
Volume Of Distribution ◽  
Pharmacokinetic Parameters ◽  
Maximum Plasma ◽  
Open Label ◽  
Tramadol Hydrochloride ◽  
Time Curve

In this single-center, randomized, open-label, 3-way crossover study, subjects received each of the following: a single dose of Tramadol Hydrochloride Injection (THI) 35 mg, a single dose of Promethazine Hydrochloride Injection (PHI) 45 mg, and single dose of Compound Tramadol Hydrochloride Injection (CTHI) 80mg. Blood was collected and plasma was analyzed for the pharmacokinetic parameters (maximum plasma concentration [Cmax], time to Cmax [Tmax], area under the plasma concentration-time curve, plasma elimination half-life, clearance, and apparent volume of distribution) of Tramadol and Promethazine. In general, several pharmacokinetic interactions were observed between Tramadol and Promethazine in the present study.

scholarly journals Herb-Drug Interaction betweenEchinacea purpureaand Darunavir-Ritonavir in HIV-Infected Patients

2010 ◽  
Vol 55 (1) ◽  
pp. 326-330 ◽  
Author(s):  
José Moltó ◽  
Marta Valle ◽  
Cristina Miranda ◽  
Samandhy Cedeño ◽  
Eugenia Negredo ◽  
...  
Keyword(s):  
High Performance ◽  
Geometric Mean ◽  
Echinacea Purpurea ◽  
The Body ◽  
Pharmacokinetic Parameters ◽  
Root Extract ◽  
Open Label ◽  
Fixed Sequence ◽  
Time Curve ◽  
Sequence Study

ABSTRACTThe aim of this open-label, fixed-sequence study was to investigate the potential ofEchinacea purpurea, a commonly used botanical supplement, to interact with the boosted protease inhibitor darunavir-ritonavir. Fifteen HIV-infected patients receiving antiretroviral therapy including darunavir-ritonavir (600/100 mg twice daily) for at least 4 weeks were included.E. purpurearoot extract capsules were added to the antiretroviral treatment (500 mg every 6 h) from days 1 to 14. Darunavir concentrations in plasma were determined by high-performance liquid chromatography immediately before and 1, 2, 4, 6, 8, 10, and 12 h after a morning dose of darunavir-ritonavir on days 0 (darunavir-ritonavir) and 14 (darunavir-ritonavir plus echinacea). Individual darunavir pharmacokinetic parameters were calculated by noncompartmental analysis and compared between days 0 and 14 with the geometric mean ratio (GMR) and its 90% confidence interval (CI). The median age was 49 (range, 43 to 67) years, and the body mass index was 24.2 (range, 18.7 to 27.5) kg/m2. Echinacea was well tolerated, and all participants completed the study. The GMR for darunavir coadministered with echinacea relative to that for darunavir alone was 0.84 (90% CI, 0.63-1.12) for the concentration at the end of the dosing interval, 0.90 (90% CI, 0.74-1.10) for the area under the concentration-time curve from 0 to 12 h, and 0.98 (90% CI, 0.82-1.16) for the maximum concentration. In summary, coadministration ofE. purpureawith darunavir-ritonavir was safe and well tolerated. Individual patients did show a decrease in darunavir concentrations, although this did not affect the overall darunavir or ritonavir pharmacokinetics. Although no dose adjustment is required, monitoring darunavir concentrations on an individual basis may give reassurance in this setting.

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.

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