scholarly journals Effect of Tipranavir-Ritonavir on Pharmacokinetics of Raltegravir

2009 ◽  
Vol 53 (7) ◽  
pp. 2752-2755 ◽  
Author(s):  
William D. Hanley ◽  
Larissa A. Wenning ◽  
Allison Moreau ◽  
James T. Kost ◽  
Eric Mangin ◽  
...  
Keyword(s):  
Geometric Mean ◽  
Study Drug ◽  
Integrase Inhibitor ◽  
Phase Iii ◽  
Open Label ◽  
Time Curve ◽  
Period 2 ◽  
Adverse Experiences ◽  
Immunodeficiency Virus

ABSTRACT Raltegravir (RAL) is a novel and potent human immunodeficiency virus type 1 integrase inhibitor that is predominantly metabolized via glucuronidation. The protease inhibitor combination tipranavir (TPV) at 500 mg and ritonavir (RTV) at 200 mg (TPV-RTV) has inhibitory and inductive effects on metabolic enzymes, which includes the potential to induce glucuronosyltransferase. Because RAL may be coadministered with TPV-RTV, there is the potential for the induction of RAL metabolism. Consequently, we assessed the effect of TPV-RTV on the pharmacokinetics of RAL and the safety and tolerability of this combination. Eighteen healthy adults were enrolled in this open-label study. The participants received RAL at 400 mg twice daily for 4 days (period 1) and TPV-RTV twice daily for 7 days (period 2), followed immediately by 400 mg RAL with TPV-RTV twice daily for 4 days (period 3). Under steady-state conditions, the RAL concentration at 12 h (C 12) was decreased when RAL was administered with TPV-RTV (geometric mean ratio [GMR], 0.45; 90% confidence interval [CI] 0.31, 0.66; P = 0.0021); however, the area under the concentration-time curve from time zero to 12 h (GMR, 0.76; 90% CI, 0.49, 1.19; P = 0.2997) and the maximum concentration in serum (GMR, 0.82; 90% CI, 0.46, 1.46; P = 0.5506) were not substantially affected. There were no serious adverse experiences or discontinuations due to study drug-related adverse experiences, and RAL coadministered with TPV-RTV was generally well tolerated. Although the RAL C 12 was decreased with TPV-RTV in this study, favorable efficacy data collected in phase III studies substantiate that TPV-RTV may be coadministered with RAL without dose adjustment.

scholarly journals Effect of Fluoxetine on Pharmacokinetics of Ritonavir

1998 ◽  
Vol 42 (12) ◽  
pp. 3107-3112 ◽  
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.

scholarly journals Pharmacokinetics of Indinavir Combined with Low-Dose Ritonavir in Human Immunodeficiency Virus Type 1-Infected Children

2004 ◽  
Vol 48 (5) ◽  
pp. 1904-1907 ◽  
Author(s):  
A. S. Bergshoeff ◽  
P. L. A. Fraaij ◽  
A. M. C. van Rossum ◽  
G. Verweel ◽  
L. H. Wynne ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Low Dose ◽  
Geometric Mean ◽  
Time Curve ◽  
Minimum Concentration ◽  
Concentration Time ◽  
Immunodeficiency Virus

ABSTRACT So far, no pediatric doses for indinavir combined with ritonavir have been defined. This study evaluated the pharmacokinetics of 400 mg of indinavir/m2 combined with 125 mg of ritonavir/m2 every 12 h (q12h) in 14 human immunodeficiency virus type 1-infected children. The area under the concentration-time curve from 0 to 24 h and the minimum concentration of drug in serum for indinavir were similar to those for 800 mg of indinavir-100 mg of ritonavir q12h in adults, while the maximum concentration of drug in serum was slightly decreased, with geometric mean ratios (90% confidence intervals in parentheses) of 1.1 (0.87 to 1.3), 0.96 (0.60 to 1.5), and 0.80 (0.68 to 0.94), respectively.

scholarly journals Minimal Effects of Ritonavir and Efavirenz on the Pharmacokinetics of Raltegravir

2008 ◽  
Vol 52 (12) ◽  
pp. 4338-4343 ◽  
Author(s):  
Marian Iwamoto ◽  
Larissa A. Wenning ◽  
Amelia S. Petry ◽  
Martine Laethem ◽  
Marina De Smet ◽  
...  
Keyword(s):  
Maximum Concentration ◽  
Geometric Mean ◽  
Plasma Concentrations ◽  
Strand Transfer ◽  
Time Curve ◽  
Period 2 ◽  
Immunodeficiency Virus ◽  
Transfer Inhibitor ◽  
Hiv 1

ABSTRACT Raltegravir is a novel human immunodeficiency virus type 1 (HIV-1) integrase strand transfer inhibitor with potent in vitro activity against HIV-1 (95% inhibitory concentration = 31 nM in 50% human serum). The possible effects of ritonavir and efavirenz on raltegravir pharmacokinetics were separately examined. Two clinical studies of healthy subjects were conducted: for ritonavir plus raltegravir, period 1, 400 mg raltegravir; period 2, 100 mg ritonavir every 12 h for 16 days with 400 mg raltegravir on day 14; for efavirenz plus raltegravir, period 1, 400 mg raltegravir; period 2, 600 mg efavirenz once daily for 14 days with 400 mg raltegravir on day 12. In the presence of ritonavir, raltegravir pharmacokinetics were weakly affected: the plasma concentration at 12 h (C 12 h) geometric mean ratio (GMR) (90% confidence interval [CI]) was 0.99 (0.70, 1.40), area under the concentration-time curve from zero to infinity (AUC0 - ∞) was 0.84 (0.70, 1.01), and maximum concentration of drug in serum (C max) was 0.76 (0.55, 1.04). In the presence of efavirenz, raltegravir pharmacokinetics were moderately to weakly reduced: C 12 h GMR (90% CI) was 0.79 (0.49, 1.28); AUC0- ∞ was 0.64 (0.52, 0.80); and C max was 0.64 (0.41, 0.98). There were no substantial differences in the time to maximum concentration of drug in plasma or the half-life. Plasma concentrations of raltegravir were not substantially affected by ritonavir. Though plasma concentrations of raltegravir were moderately to weakly reduced by efavirenz, the degree of this reduction was not clinically meaningful. No dose adjustment is required for raltegravir with coadministration with ritonavir or efavirenz.

scholarly journals Minimal Pharmacokinetic Interaction between the Human Immunodeficiency Virus Nonnucleoside Reverse Transcriptase Inhibitor Etravirine and the Integrase Inhibitor Raltegravir in Healthy Subjects

2008 ◽  
Vol 52 (12) ◽  
pp. 4228-4232 ◽  
Author(s):  
Matt S. Anderson ◽  
Thomas N. Kakuda ◽  
William Hanley ◽  
Jutta Miller ◽  
James T. Kost ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Reverse Transcriptase ◽  
Geometric Mean ◽  
Transcriptase Inhibitor ◽  
Strand Transfer ◽  
Open Label ◽  
Nonnucleoside Reverse Transcriptase Inhibitor ◽  
Adverse Experiences ◽  
Immunodeficiency Virus ◽  
Reverse Transcriptase Inhibitor

ABSTRACT Etravirine, a next-generation nonnucleoside reverse transcriptase inhibitor, and raltegravir, an integrase strand transfer inhibitor, have separately demonstrated potent activity in treatment-experienced, human immunodeficiency virus (HIV)-infected patients. An open-label, sequential, three-period study with healthy, HIV-seronegative subjects was conducted to assess the two-way interaction between etravirine and raltegravir for potential coadministration to HIV-infected patients. In period 1, 19 subjects were administered 400 mg raltegravir every 12 h (q12 h) for 4 days, followed by a 4-day washout; in period 2, subjects were administered 200 mg etravirine q12 h for 8 days; and in period 3, subjects were coadministered 400 mg raltegravir and 200 mg etravirine q12 h for 4 days. There was no washout between periods 2 and 3. Doses were administered with a moderate-fat meal. Etravirine had only modest effects on the pharmacokinetics of raltegravir, while raltegravir had no clinically meaningful effect on the pharmacokinetics of etravirine. For raltegravir coadministered with etravirine relative to raltegravir alone, the geometric mean ratio (GMR) and 90% confidence interval (CI) were 0.90 and 0.68 to 1.18, respectively, for the area under the concentration curve from 0 to 12 h (AUC0-12), 0.89 and 0.68 to 1.15, respectively, for the maximum concentration of drug in serum (C max), and 0.66 and 0.34 to 1.26, respectively, for the trough drug concentration (C 12); the GMR (90% CI) for etravirine coadministered with raltegravir relative to etravirine alone was 1.10 (1.03, 1.16) for AUC0-12, 1.04 (0.97, 1.12) for C max, and 1.17 (1.10, 1.26) for C 12. All drug-related adverse clinical experiences were mild and generally transient in nature. No grade 3 or 4 adverse experiences or discontinuations due to adverse experiences occurred. Coadministration of etravirine and raltegravir was generally well tolerated; the data suggest that no dose adjustment for either drug is necessary.

scholarly journals Effects of Etravirine on the Pharmacokinetics of the Integrase Inhibitor S/GSK1265744

2012 ◽  
Vol 57 (1) ◽  
pp. 277-280 ◽  
Author(s):  
Susan L. Ford ◽  
Elizabeth Gould ◽  
Shuguang Chen ◽  
Yu Lou ◽  
Etienne Dumont ◽  
...  
Keyword(s):  
Plasma Concentration ◽  
Healthy Subjects ◽  
Geometric Mean ◽  
Integrase Inhibitor ◽  
Cross Resistance ◽  
Hiv Integrase ◽  
Integrase Inhibitors ◽  
Open Label ◽  
Dosing Interval ◽  
Period 2

ABSTRACTHIV integrase inhibitors such as raltegravir and elvitegravir halt HIV progression, but treatment-emergent resistance and cross-resistance have been observed. The nonnucleoside reverse transcriptase inhibitor etravirine (ETR) may be used in combination with integrase inhibitors in patients with drug resistance. This single-center, open-label, two-period, single-sequence crossover study evaluated the effects of ETR coadministration on the pharmacokinetic profile of S/GSK1265744, an investigational integrase inhibitor in phase 2 studies. Healthy subjects received 30 mg of S/GSK1265744 alone once daily for 10 days (period 1) and in combination with 200 mg of ETR twice daily for 14 days (period 2). Serial plasma samples for pharmacokinetic analyses were collected on day 10 during period 1 and on day 14 during period 2. All treatments were well tolerated. Etravirine had no effects on S/GSK1265744 geometric mean ratios of the area under the curve from time zero until the end of the dosing interval (1.01; 90% confidence interval [CI], 0.956 to 1.06), of the maximum observed plasma concentration (1.04; 90% CI, 0.987 to 1.09), or of the plasma concentration at the end of the dosing interval (0.999; 90% CI, 0.942 to 1.06). Etravirine pharmacokinetics (PK) parameters observed following coadministration with S/GSK1265744 were in the range of historical values reported for ETR alone in healthy subjects. These results indicate that 30 mg of S/GSK1265744 for 10 days as monotherapy followed by an additional 14 days in combination with ETR was well tolerated in healthy subjects and that no dose adjustment of S/GSK1265744 is required when it is coadministered with ETR.

scholarly journals Lack of a Significant Drug Interaction between Raltegravir and Tenofovir

2008 ◽  
Vol 52 (9) ◽  
pp. 3253-3258 ◽  
Author(s):  
Larissa A. Wenning ◽  
Evan J. Friedman ◽  
James T. Kost ◽  
Sheila A. Breidinger ◽  
Jon E. Stek ◽  
...  
Keyword(s):  
Healthy Subjects ◽  
Peak Plasma ◽  
Geometric Mean ◽  
Integrase Inhibitor ◽  
Substantial Effect ◽  
Open Label ◽  
Time Curve ◽  
Once Daily ◽  
Hiv 1

ABSTRACT Raltegravir is a novel human immunodeficiency virus type 1 (HIV-1) integrase inhibitor with potent in vitro activity (95% inhibitory concentration of 31 nM in 50% human serum). This article reports the results of an open-label, sequential, three-period study of healthy subjects. Period 1 involved raltegravir at 400 mg twice daily for 4 days, period 2 involved tenofovir disoproxil fumarate (TDF) at 300 mg once daily for 7 days, and period 3 involved raltegravir at 400 mg twice daily plus TDF at 300 mg once daily for 4 days. Pharmacokinetic profiles were also determined in HIV-1-infected patients dosed with raltegravir monotherapy versus raltegravir in combination with TDF and lamivudine. There was no clinically significant effect of TDF on raltegravir. The raltegravir area under the concentration time curve from 0 to 12 h (AUC0-12) and peak plasma drug concentration (C max) were modestly increased in healthy subjects (geometric mean ratios [GMRs], 1.49 and 1.64, respectively). There was no substantial effect of TDF on raltegravir concentration at 12 h postdose (C 12) in healthy subjects (GMR [TDF plus raltegravir-raltegravir alone], 1.03; 90% confidence interval [CI], 0.73 to 1.45), while a modest increase (GMR, 1.42; 90% CI, 0.89 to 2.28) was seen in HIV-1-infected patients. Raltegravir had no substantial effect on tenofovir pharmacokinetics: C 24, AUC, and C max GMRs were 0.87, 0.90, and 0.77, respectively. Coadministration of raltegravir and TDF does not change the pharmacokinetics of either drug to a clinically meaningful degree. Raltegravir and TDF may be coadministered without dose adjustments.

scholarly journals Pharmacokinetics of Indinavir and Ritonavir Administered at 667 and 100 Milligrams, Respectively, Every 12 Hours Compared with Indinavir Administered at 800 Milligrams Every 8 Hours in Human Immunodeficiency Virus-Infected Patients

2004 ◽  
Vol 48 (11) ◽  
pp. 4200-4208 ◽  
Author(s):  
Frank S. Rhame ◽  
Sandy L. Rawlins ◽  
Richard A. Petruschke ◽  
Tara A. Erb ◽  
Gregory A. Winchell ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Lower Bound ◽  
Geometric Mean ◽  
Fold Increase ◽  
Open Label ◽  
Time Curve ◽  
Minimum Concentration ◽  
Mean Values ◽  
Immunodeficiency Virus ◽  
Primary Hypothesis

ABSTRACT Human immunodeficiency virus (HIV) patients on nucleoside or nucleotide reverse transcriptase inhibitors with HIV RNA at <1,000 copies/ml were randomized in an open-label study to administration of combined indinavir/ritonavir (IDV/RTV) at 667/100 mg every 12 h (q12h) or IDV alone at 800 mg q8h to determine the regimens' pharmacokinetics. On day 14, plasma IDV and RTV levels were determined over 24 h. Noncompartmental pharmacokinetics (minimum concentration of drug in serum [C min], area under the concentration-time curve from 0 to 24 h [AUC0-24], and maximum concentration of drug in serum [C max]) were expressed as geometric mean values with 90% confidence intervals (CI). The primary hypothesis was that the lower bound of the protocol-specified 90% CI for the geometric mean C min ratio of the combination compared to IDV alone regimen would be ≥2. Twenty-seven patients were enrolled, and 24 (15 male; average age, 42 years) completed the study. The C min, AUC0-24, and C max for IDV/RTV compared to IDV alone were 1,511 versus 250 nM, 119,557 versus 77,034 nM · h, and 10,428 versus 10,407 nM, respectively. Corresponding relationships for IDV/RTV compared to IDV alone were a 6.0-fold increase in C min (90% CI, 4.0, 9.3), an increase in AUC0-24 (1.5-fold, 90% CI, 1.2, 2.0), and no increase in C max. Adverse events were similar and generally mild, with no cases of nephrolithiasis. The geometric mean ratio of IDV C min for IDV/RTV compared to IDV was at least 2 by a lower bound of the 90% CI, satisfying the primary hypothesis. The C max was not increased, suggesting an IDV/RTV 667/100-mg toxicity profile may be similar to that of unboosted IDV.

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 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 Structural-Functional Analysis of 2,1,3-Benzoxadiazoles and Their N-oxides As HIV-1 Integrase Inhibitors

Acta Naturae ◽  
2013 ◽  
Vol 5 (1) ◽  
pp. 63-72 ◽  
Author(s):  
S. P. Korolev ◽  
O. V. Kondrashina ◽  
D. S. Druzhilovsky ◽  
A. M. Starosotnikov ◽  
M. D. Dutov ◽  
...  
Keyword(s):  
Integrase Inhibitor ◽  
Integrase Inhibitors ◽  
Mechanism Of Inhibition ◽  
Immunodeficiency Virus ◽  
Pharmacokinetic Properties ◽  
Nitro Derivatives ◽  
Derivatives Of ◽  
Anti Hiv ◽  
Hiv 1

Human immunodeficiency virus type 1 integrase is one of the most attractive targets for the development of anti-HIV-1 inhibitors. The capacity of a series of 2,1,3-benzoxadiazoles (benzofurazans) and their N-oxides (benzofuroxans) selected using the PASS software to inhibit the catalytic activity of HIV-1 integrase was studied in the present work. Only the nitro-derivatives of these compounds were found to display inhibitory activity. The study of the mechanism of inhibition by nitro-benzofurazans/benzofuroxans showed that they impede the substrate DNA binding at the integrase active site. These inhibitors were also active against integrase mutants resistant to raltegravir, which is the first HIV-1 integrase inhibitor approved for clinical use. The comparison of computer-aided estimations of the pharmacodynamic and pharmacokinetic properties of the compounds studied and raltegravir led us to conclude that these compounds show promise and need to be further studied as potential HIV-1 integrase inhibitors.

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