scholarly journals Didanosine reduces atevirdine absorption in subjects with human immunodeficiency virus infections.

1996 ◽  
Vol 40 (3) ◽  
pp. 767-771 ◽  
Author(s):  
G D Morse ◽  
M A Fischl ◽  
M J Shelton ◽  
M T Borin ◽  
M R Driver ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Human Immunodeficiency Virus Type ◽  
Maximum Concentration ◽  
Concurrent Administration ◽  
Time Curve ◽  
Concentration Time ◽  
Immunodeficiency Virus ◽  
Combination Regimens

Atevirdine is a nonnucleoside reverse transcriptase inhibitor with in vitro activity against human immunodeficiency virus type 1 and is currently in phase II clinical trials. Atevirdine is most soluble at a pH of < 2, and therefore, normal gastric acidity is most likely necessary for optimal bioavailability. Because of the rapid development of resistance in vitro, atevirdine is being evaluated in combination with didanosine and/or zidovudine in both two- and three-drug combination regimens. To examine the influence of concurrent didanosine (buffered tablet formulation) on the disposition of atevirdine, 12 human immunodeficiency virus type 1-infected subjects (mean CD4+ cell count, 199 cells per mm3; range, 13 to 447 cells/mm3) participated in a three-way, partially randomized, crossover, single-dose study to evaluate the pharmacokinetics of didanosine and atevirdine when each drug was given alone (treatments A and B, respectively) versus concurrently (treatment C). Concurrent administration of didanosine and atevirdine significantly reduced the maximum concentration of atevirdine in serum from 3.45 +/- 2.8 to 0.854 +/- 0.33 microM (P = 0.004). Likewise, the mean atevirdine area under the concentration-time curve from 0 to 24 h after administration of the combination was reduced to 6.47 +/- 2.2 microM.h (P = 0.004) relative to a value of 11.3 +/- 4.8 microM.h for atevirdine alone. Atevirdine had no statistically significant effect on the pharmacokinetic parameters of didanosine. Concurrent administration of single doses of atevirdine and didanosine resulted in a markedly lower maximum concentration of atevirdine in serum and area under the concentration-time curve, with a minimal effect on the disposition of didanosine. It is unknown whether an interaction of similar magnitude would occur under steady-state conditions; thus, combination regimens which include both atevirdine and didanosine should be designed so that their administration times are separated. Since the duration of the buffering effect of didanosine formulations is unknown, atevirdine should be given prior to didanosine.

scholarly journals Steady-State Pharmacokinetics of Amprenavir Coadministered with Ritonavir in Human Immunodeficiency Virus Type 1-Infected Patients

2003 ◽  
Vol 47 (1) ◽  
pp. 118-123 ◽  
Author(s):  
Cecile Goujard ◽  
Isabelle Vincent ◽  
Jean-Luc Meynard ◽  
Nathalie Choudet ◽  
Diane Bollens ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Steady State ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Time Curve ◽  
Concentration Time ◽  
Immunodeficiency Virus ◽  
The Mean ◽  
Hiv 1

ABSTRACT The protease inhibitor (PI) ritonavir is used as a strong inhibitor of cytochrome P450 3A4, which boosts the activities of coadministered PIs, resulting in augmented plasma PI levels, simplification of the dosage regimen, and better efficacy against resistant viruses. The objectives of the present open-label, multiple-dose study were to determine the steady-state pharmacokinetics of amprenavir administered at 600 mg twice daily (BID) and ritonavir administered at 100 mg BID in human immunodeficiency virus type 1 (HIV-1)-infected adults treated with different antiretroviral combinations including or not including a nonnucleoside reverse transcriptase inhibitor (NNRTI). Nineteen patients completed the study. The steady-state mean minimum plasma amprenavir concentration (C min,ss) was 1.92 μg/ml for patients who received amprenavir and ritonavir without an NNRTI and 1.36 μg/ml for patients who received amprenavir and ritonavir plus efavirenz. For patients who received amprenavir-ritonavir without an NNRTI, the steady-state mean peak plasma amprenavir concentration (C max,ss) was 7.12 μg/ml, the area under the concentration-time curve from 0 to 10 h (AUC0-10) was 32.06 μg · h/ml, and the area under the concentration-time curve over a dosing interval (12 h) at steady-state (AUCss) was 35.74 μg · h/ml. Decreases in the mean values of C min,ss (29%), C max,ss (42%), AUC0-10 (42%), and AUCss (40%) for amprenavir occurred when efavirenz was coadministered with amprenavir-ritonavir. No unexpected side effects were observed. As expected, coadministration of amprenavir with ritonavir resulted in an amprenavir C min,ss markedly higher than those previously reported for the marketed dose of amprenavir. When amprenavir-ritonavir was coadministered with efavirenz, amprenavir-ritonavir maintained a mean amprenavir C min,ss above the mean 50% inhibitory concentration of amprenavir previously determined for both wild-type HIV-1 isolates and HIV-1 strains isolated from PI-experienced patients. These data support the use of low-dose ritonavir to enhance the level of exposure to amprenavir and increase the efficacy of amprenavir.

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 Pharmacokinetics of the Protease Inhibitor Indinavir in Human Immunodeficiency Virus Type 1-Infected Children

2001 ◽  
Vol 45 (3) ◽  
pp. 701-705 ◽  
Author(s):  
David M. Burger ◽  
Annemarie M. C. van Rossum ◽  
Patricia W. H. Hugen ◽  
Marja H. Suur ◽  
Nico G. Hartwig ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Drug Exposure ◽  
Optimal Dose ◽  
Dose Increase ◽  
Time Curve ◽  
Concentration Time ◽  
Immunodeficiency Virus

ABSTRACT The objective of this study was to evaluate the pharmacokinetics of indinavir in human immunodeficiency virus-infected children as part of a prospective, open, uncontrolled, multicenter study in The Netherlands. Human immunodeficiency virus type 1-infected children were monitored over 6 months of treatment with zidovudine (120 mg/m2 every 8 h [q8h]), lamivudine (4 mg/kg of body weight q12h), and indinavir (33mg/kg of metabolic weight [MW] q8h). Four weeks after the start of treatment, the steady-state pharmacokinetics of indinavir were determined by high-pressure liquid chromatography. If patients had an indinavir area under the concentration-time curve (AUC) of below 10 or above 30 mg/liter · h, a dose increase or a dose reduction was made and pharmacokinetic measurements were repeated 4 weeks later. Nineteen patients started with the dose of 33 mg/kg of MW q8h. The median AUC (range) was 10.5 (2.8 to 51.0) mg/liter · h. The median AUC (range) in 17 children treated with 50 mg/kg of MW q8h was 20.6 (4.1 to 38.7) mg/liter · h. Finally, five patients had a dose increase to 67 mg/kg of MW q8h, resulting in a median AUC (range) of 36.6 (27.2 to 80.0) mg/liter · h. After 6 months of treatment, there were 11 children with an AUC of below 20 mg/liter · h, of whom 5 (45%) had a detectable viral load, while this was the case in none of the 11 children with an AUC of higher than 20 mg/liter · h. We conclude that the optimal dose of indinavir in children to obtain drug exposure similar to that observed in adult patients is 50 mg/kg of MW q8h, which approximates 600 mg/m2 q8h. It would even be better to adjust the indinavir dose based on an AUC of greater than 20 mg/liter · h.

scholarly journals If Taken 1 Hour before Indinavir (IDV), Didanosine Does Not Affect IDV Exposure, despite Persistent Buffering Effects

2001 ◽  
Vol 45 (1) ◽  
pp. 298-300 ◽  
Author(s):  
Mark J. Shelton ◽  
Haijing Mei ◽  
Ross G. Hewitt ◽  
Robin Defrancesco
Keyword(s):  
Human Immunodeficiency Virus ◽  
Maximum Concentration ◽  
Gastric Ph ◽  
Concurrent Administration ◽  
Time Curve ◽  
Time Zero ◽  
Concentration Time ◽  
Significant Difference ◽  
Immunodeficiency Virus ◽  
Buffering Effects

ABSTRACT Concurrent administration of indinavir and didanosine significantly reduces the level of exposure to indinavir, but it is unclear how soon after didanosine administration indinavir may be given safely. We compared indinavir pharmacokinetics and gastric pH in 12 human immunodeficiency virus-positive patients by use of 800 mg of indinavir alone versus 800 mg of indinavir administered 1 h after didanosine administration. Median gastric pH was significantly higher when indinavir was taken after didanosine administration; however, no significant difference in the maximum concentration in plasma or the area under the concentration-time curve from time zero to 8 h was observed. Indinavir may be taken with a light meal 1 h following the administration of 400 mg of didanosine.

scholarly journals Human immunodeficiency virus type-1 induces a regulatory B cell-like phenotype in vitro

2017 ◽  
Vol 15 (10) ◽  
pp. 917-933 ◽  
Author(s):  
Jacobo Lopez-Abente ◽  
Adrián Prieto-Sanchez ◽  
Maria-Ángeles Muñoz-Fernandez ◽  
Rafael Correa-Rocha ◽  
Marjorie Pion
Keyword(s):  
Human Immunodeficiency Virus ◽  
B Cell ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Regulatory B Cell ◽  
Immunodeficiency Virus

scholarly journals The Late-Domain-Containing Protein p6 Is the Predominant Phosphoprotein of Human Immunodeficiency Virus Type 1 Particles

2002 ◽  
Vol 76 (3) ◽  
pp. 1015-1024 ◽  
Author(s):  
Barbara Müller ◽  
Tilo Patschinsky ◽  
Hans-Georg Kräusslich
Keyword(s):  
Human Immunodeficiency Virus ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Metabolic Labeling ◽  
Immunodeficiency Virus ◽  
Infected Cells ◽  
A Minor ◽  
Hiv 1

ABSTRACT The Gag-derived protein p6 of human immunodeficiency virus type 1 (HIV-1) plays a crucial role in the release of virions from the membranes of infected cells. It is presumed that p6 and functionally related proteins from other viruses act as adapters, recruiting cellular factors to the budding site. This interaction is mediated by so-called late domains within the viral proteins. Previous studies had suggested that virus release from the plasma membrane shares elements with the cellular endocytosis machinery. Since protein phosphorylation is known to be a regulatory mechanism in these processes, we have investigated the phosphorylation of HIV-1 structural proteins. Here we show that p6 is the major phosphoprotein of HIV-1 particles. After metabolic labeling of infected cells with [ortho- 32P]phosphate, we found that phosphorylated p6 from infected cells and from virus particles consisted of several forms, suggesting differential phosphorylation at multiple sites. Apparently, phosphorylation occurred shortly before or after the release of p6 from Gag and involved only a minor fraction of the total virion-associated p6 molecules. Phosphoamino acid analysis indicated phosphorylation at Ser and Thr, as well as a trace of Tyr phosphorylation, supporting the conclusion that multiple phosphorylation events do occur. In vitro experiments using purified virus revealed that endogenous or exogenously added p6 was efficiently phosphorylated by virion-associated cellular kinase(s). Inhibition experiments suggested that a cyclin-dependent kinase or a related kinase, most likely ERK2, was involved in p6 phosphorylation by virion-associated enzymes.

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