scholarly journals Clinical and Pharmacokinetic Data Support Once-Daily Low-Dose Boosted Saquinavir (1,200 Milligrams Saquinavir with 100 Milligrams Ritonavir) in Treatment-Naive or Limited Protease Inhibitor-Experienced Human Immunodeficiency Virus-Infected Patients

2007 ◽  
Vol 51 (6) ◽  
pp. 2035-2042 ◽  
Author(s):  
Ana Marin-Niebla ◽  
Luis Fernando Lopez-Cortes ◽  
Rosa Ruiz-Valderas ◽  
Pompeyo Viciana ◽  
Rosario Mata ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Protease Inhibitor ◽  
Virological Failure ◽  
Low Dose ◽  
Pharmacokinetic Data ◽  
Time Curve ◽  
Once Daily ◽  
Intention To Treat ◽  
Immunodeficiency Virus ◽  
Treatment Naïve

ABSTRACT We evaluated the plasma and intracellular pharmacokinetics, clinical efficacy, and safety of once-daily low-dose boosted saquinavir (SQVr; 1,200 of saquinavir [SQV] with 100 mg of ritonavir) plus two nucleotide reverse transcriptase inhibitors in treatment-naive or limited protease inhibitor (PI)-experienced human immunodeficiency virus (HIV)-infected patients. A prospective study without entry restrictions on the plasma HIV-RNA (VL) or CD4 cell count was carried out. Plasma and intracellular SQV levels were measured by high-performance liquid chromatography. Efficacy was evaluated by an intention-to-treat analysis; treatment failure was defined as virological failure (a VL of >50 copies/ml after 24 weeks or a confirmed rebound to >50 copies/ml) or interruption for any reason. A total of 151 patients were included in the study (106 of them either had never received PI or had no previous virological failure on PIs) and could be characterized as follows: previous C3 stage, 28.9%; injection-drug users, 69.1%; subjects with chronic viral hepatitis, 53%; and subjects with cirrhosis, 10%. The median baseline CD4 level was 184/μl, and the median VL was 4.8 log10 copies/ml. Median C max, area under the concentration-time curve from 0 to 24 h, and C min plasma and intracellular SQV levels were 3,672 and 10,105 ng/ml, 34,283 and 99,535 ng·h/ml, and 359 and 1,062 ng/ml, respectively. The efficacy as determined by intention to treat at 52 weeks was 69.7% (96% in the on-treatment analysis), with similar results regardless of the baseline VL and CD4 counts. Only five patients had virological failure despite adequate C min levels, but with a poor adherence (the only variable related to virological failure). Adverse events caused the withdrawal of the treatment in four patients (2.6%). In conclusion, given the pharmacokinetic profile, efficacy, and tolerability of this regimen, once-daily low-dose SQVr may be considered a treatment option in treatment-naive or limited PI-experienced HIV-infected patients, with the additional benefit of being currently the least-expensive PI-based regimen available.

scholarly journals Steady-State Pharmacokinetics of Abacavir in Plasma and Intracellular Carbovir Triphosphate following Administration of Abacavir at 600 Milligrams Once Daily and 300 Milligrams Twice Daily in Human Immunodeficiency Virus-Infected Subjects

2009 ◽  
Vol 53 (4) ◽  
pp. 1532-1538 ◽  
Author(s):  
Graeme Moyle ◽  
Marta Boffito ◽  
Carl Fletcher ◽  
Chris Higgs ◽  
Phillip E. Hay ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
High Performance ◽  
Pharmacokinetic Parameters ◽  
Virologic Suppression ◽  
Open Label ◽  
Time Curve ◽  
Mixed Effect ◽  
Once Daily ◽  
Immunodeficiency Virus ◽  
And Gender

ABSTRACT Abacavir (ABC) is administered either at 600 mg once daily (ABC 600 mg QD) or 300 mg twice daily (ABC 300 mg BID) in anti-human immunodeficiency virus (anti-HIV) combination therapy. Although ABC plasma pharmacokinetics following each regimen has been well defined, no study has directly compared the regimens with respect to pharmacokinetics of ABC's active intracellular anabolite, carbovir-triphosphate (CBV-TP). In an open-label, two-period, crossover study, 34 HIV-infected male and female subjects stabilized on antiretroviral regimens containing either ABC 600 mg QD or ABC 300 mg BID received their usual doses on days −1 and 1 and then switched regimens for days 2 to 11. Serial blood samples collected on days 1 and 11 were assayed for plasma ABC and intracellular CBV-TP concentrations using validated high-performance liquid chromatography-tandem mass spectrometry methods. Pharmacokinetic parameters were calculated using noncompartmental methods. Analysis of variance with a mixed-effect model was performed for treatment and gender comparisons. In 27 evaluable subjects, the regimens provided bioequivalent ABC daily areas under the concentration-time curve from 0 to 24 h (AUC0-24) and comparable CBV-TP concentrations at the end of the dosing interval (C τ). As expected, ABC QD resulted in 109% higher ABC maximum concentrations of drug in plasma (C max) than did ABC BID. ABC QD also resulted in 32% higher CBV-TP AUC0-24 and 99% higher CBV-TP C max than did ABC BID. Females had a 38% higher weight-adjusted ABC AUC0-24 and 81% higher weight-adjusted CBV-TP AUC0-24 than did males. Virologic suppression was maintained during regimen switch, and no tolerability differences between regimens were observed. In conclusion, this study showed that ABC 600 mg QD and ABC 300 mg BID regimens led to similar intracellular CBV-TP C τ values, thus providing pharmacokinetic support for the interchangeability of these two regimens. Women had higher intracellular CBV-TP exposure than did men.

scholarly journals Is the Recommended Dose of Efavirenz Optimal in Young West African Human Immunodeficiency Virus-Infected Children?

2009 ◽  
Vol 53 (10) ◽  
pp. 4407-4413 ◽  
Author(s):  
Déborah Hirt ◽  
Saik Urien ◽  
Mathieu Olivier ◽  
Hélène Peyrière ◽  
Boubacar Nacro ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Body Weight ◽  
Plasma Concentrations ◽  
Individual Characteristics ◽  
Population Pharmacokinetic ◽  
Ratio Test ◽  
Time Curve ◽  
Once Daily ◽  
Concentration Time ◽  
Immunodeficiency Virus

ABSTRACT We aimed in this study to describe efavirenz concentration-time courses in treatment-naïve children after once-daily administration to study the effects of age and body weight on efavirenz pharmacokinetics and to test relationships between doses, plasma concentrations, and efficacy. For this purpose, efavirenz concentrations in 48 children were measured after 2 weeks of didanosine-lamivudine-efavirenz treatment, and samples were available for 9/48 children between months 2 and 5 of treatment. Efavirenz concentrations in 200 plasma specimens were measured using a validated high-performance liquid chromatography method. A population pharmacokinetic model was developed with NONMEM. The influence of individual characteristics was tested using a likelihood ratio test. The estimated minimal and maximal concentrations of efavirenz in plasma (C min and C max, respectively) and the area under the concentration-time curve (AUC) were correlated to the decrease in human immunodeficiency virus type 1 RNA levels after 3 months of treatment. The threshold C min (and AUC) that improved efficacy was determined. The target minimal concentration of 4 mg/liter was considered for toxicity. An optimized dosing schedule that would place the highest percentage of children in the interval of effective and nontoxic concentrations was simulated. The pharmacokinetics of efavirenz was best described by a one-compartment model with first-order absorption and elimination. The mean apparent clearance and volume of distribution for efavirenz were 0.211 liter/h/kg and 4.48 liters/kg, respectively. Clearance decreased significantly with age. When the recommended doses were given to 46 of the 48 children, 19% (44% of children weighing less than 15 kg) had C mins below 1 mg/liter. A significantly higher percentage of children with C mins of >1.1 mg/liter or AUCs of >51 mg/liter·h than of children with lower values had viral load decreases greater than 2 log10 copies/ml after 3 months of treatment. Therefore, to optimize the percentage of children with C mins between 1.1 and 4 mg/liter, children should receive the following once-daily efavirenz doses: 25 mg/kg of body weight from 2 to 6 years, 15 mg/kg from 6 to 10 years, and 10 mg/kg from 10 to 15 years. These assumptions should be prospectively confirmed.

scholarly journals Safety and Pharmacokinetics of Once-Daily Regimens of Soft-Gel Capsule Saquinavir plus Minidose Ritonavir in Human Immunodeficiency Virus-Negative Adults

2000 ◽  
Vol 44 (10) ◽  
pp. 2672-2678 ◽  
Author(s):  
J. Michael Kilby ◽  
Greg Sfakianos ◽  
Nick Gizzi ◽  
Peggy Siemon-Hryczyk ◽  
Eric Ehrensing ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Combined Therapy ◽  
Treatment Options ◽  
Control Group ◽  
Post Dose ◽  
Time Curve ◽  
Once Daily ◽  
Treatment Regimens ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT Human immunodeficiency virus type 1 (HIV-1) protease inhibitors have dramatically improved treatment options for HIV infection, but frequent dosing may impact adherence to highly active antiretroviral treatment regimens (HAART). Previous studies demonstrated that combined therapy with ritonavir and saquinavir allows a decrease in frequency of saquinavir dosing to twice daily. In this study, we evaluated the safety and pharmacokinetics of combining once-daily doses of the soft-gel capsule (SGC) formulation of saquinavir (saquinavir-SGC) and minidose ritonavir. Forty-four healthy HIV-negative volunteers were randomized into groups receiving once-daily doses of saquinavir-SGC (1,200 to 1,800 mg) plus ritonavir (100 to 200 mg) or a control group receiving only saquinavir-SGC (1,200 mg) three times daily. Saquinavir-SGC alone and saquinavir-SGC–ritonavir combinations were generally well tolerated, and there were no safety concerns. Addition of ritonavir (100 mg) to saquinavir-SGC (1,200 to 1,800 mg/day) increased the area under the concentration-time curve (AUC) for saquinavir severalfold, and the intersubject peak concentration in plasma and AUC variability were reduced compared to those achieved with saquinavir-SGC alone (3,600 mg/day), while trough saquinavir levels (24 h post-dose) were substantially higher than the 90% inhibitory concentration calculated from HIV-1 clinical isolates. Neither increasing the saquinavir-SGC dose to higher than 1,600 mg nor increasing ritonavir from 100 to 200 mg appeared to further enhance the AUC. These results suggest that an all once-daily HAART regimen, utilizing saquinavir-SGC plus a more tolerable low dose of ritonavir, may be feasible. Studies of once-daily saquinavir-SGC (1,600 mg) in combination with ritonavir (100 mg) in HIV-infected patients are underway.

scholarly journals Indinavir Pharmacokinetics and Parmacodynamics in Children with Human Immunodeficiency Virus Infection

2000 ◽  
Vol 44 (3) ◽  
pp. 752-755 ◽  
Author(s):  
Giorgio Gatti ◽  
Alessandra Vigano' ◽  
Natascia Sala ◽  
Stefano Vella ◽  
Matteo Bassetti ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Dosage Regimen ◽  
Renal Toxicity ◽  
Significant Negative Correlation ◽  
Pharmacokinetic Parameters ◽  
Pharmacokinetic Data ◽  
Time Curve ◽  
Number Of Patients ◽  
Immunodeficiency Virus ◽  
The Difference

ABSTRACT The indinavir dosage regimen currently used for human immunodeficiency virus (HIV)-infected children is not based on pharmacokinetic data obtained in the target patient population. The purpose of our study was to characterize indinavir pharmacokinetics and pharmacodynamics in HIV-infected children. Eleven children (age range, 9.0 to 13.6 years; weight range, 21.7 to 56.0 kg) receiving indinavir (500 mg/m2 every 8 h) in combination with lamivudine and stavudine were studied. The correlation of indinavir pharmacokinetic parameters and demographic parameters was evaluated. Also, the pharmacodynamic relationship between parameters of indinavir exposure and parameters of renal toxicity and immunologic recovery was studied. The area under the indinavir concentration-time curve (AUC) and patient body surface area (BSA) showed a significant negative correlation (r = 0.73; P = 0.012). Patients with smaller BSA had excessive indinavir AUC compared to adults. On the other hand, the median minimum drug concentration in plasma (C min) was lower than that reported for adults. The maximum indinavir concentration in serum was higher in patients with renal toxicity (5 out of 11 children), but the difference was not statistically significant (15.3 ± 8.2 versus 9.8 ± 4.4 mg/liter; P = 0.19). There was a trend toward higher immunologic efficacy in patients with greater indinavir exposure: the time-averaged AUC of the percentage of CD4+ lymphocytes over the baseline value for patients with indinavir C min > 95% inhibitory concentration (IC95) was higher than in patients withC min < IC95(P = 0.068). Our study suggests that a dose reduction may be appropriate for children with small BSA and that a 6-h dosage regimen may be indicated for a substantial percentage of patients. Due to the low number of patients enrolled in this study, our results should be confirmed by a larger study.

scholarly journals Rifampin Reduces Concentrations of Trimethoprim and Sulfamethoxazole in Serum in Human Immunodeficiency Virus-Infected Patients

2001 ◽  
Vol 45 (11) ◽  
pp. 3238-3241 ◽  
Author(s):  
Esteban Ribera ◽  
Leonor Pou ◽  
Antoni Fernandez-Sola ◽  
Francisco Campos ◽  
Rosa M. Lopez ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
High Performance Liquid Chromatography ◽  
High Performance ◽  
Parent Drug ◽  
Time Curve ◽  
Once Daily ◽  
Concentration Time ◽  
Antituberculosis Treatment ◽  
Immunodeficiency Virus ◽  
Before And After

ABSTRACT To determine whether rifampin reduces concentrations of trimethoprim (TMP) and sulfamethoxazole (SMX) in serum of human immunodeficiency virus (HIV)-infected persons, levels of these agents were determined by high-performance liquid chromatography before and after more than 12 days of standard antituberculosis treatment for 10 patients who had been taking one double-strength tablet of co-trimoxazole once daily for more than 1 month. Statistically significant, 47 and 23% decreases in TMP and SMX mean areas under the concentration-time curve from 0 to 24 h (AUC0–24), respectively, were observed after administration of rifampin.N-Acetyl-SMX profiles without and with rifampin were similar. The steady-state AUC0–24 metabolite/parent drug ratio increased by 32% with rifampin administration. Our study shows that rifampin reduces profiles of TMP and SMX in serum of HIV-infected patients.

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.

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