Population Pharmacokinetics of Abacavir in Plasma and Cerebrospinal Fluid

ABSTRACT The distribution of abacavir into the cerebrospinal fluid (CSF) was assessed by use of a population pharmacokinetic analysis. Plasma and CSF abacavir concentrations in 54 subjects were determined. The abacavir CSF/plasma ratio averaged 36% and increased throughout the dose interval. Abacavir penetrates into the CSF in adequate concentrations to inhibit local human immunodeficiency virus replication.

Download Full-text

Pyrimethamine pharmacokinetics in human immunodeficiency virus-positive patients seropositive for Toxoplasma gondii.

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.40.6.1360 ◽

1996 ◽

Vol 40 (6) ◽

pp. 1360-1365 ◽

Cited By ~ 23

Author(s):

J M Jacobson ◽

M Davidian ◽

P M Rainey ◽

R Hafner ◽

R H Raasch ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

Toxoplasma Gondii ◽

Drug Users ◽

Compartment Model ◽

Population Pharmacokinetic Analysis ◽

Pharmacokinetic Analysis ◽

Pharmacokinetic Parameters ◽

Population Pharmacokinetic ◽

Time Curve ◽

Immunodeficiency Virus

Pyrimethamine pharmacokinetics were studied in 11 human immunodeficiency virus (HIV)-positive patients who were seropositive for exposure to Toxoplasma gondii and were taking zidovudine (AIDS Clinical Trials Group Protocol 102). Pyrimethamine was administered at 50 mg daily for 3 weeks to achieve steady state, and pharmacokinetic profiles were determined after administration of the last dose. Noncompartmental and compartmental analyses were performed. Population pharmacokinetic analysis assuming a one-compartment model yielded the following estimates: area under the 24-h concentration-time curve, 42.7 +/- 12.3 micrograms.h/ml; halflife, 139 +/- 34 h; clearance, 1.28 +/- 0.41 liters/h; volume of distribution, 246 +/- 641; and absorption rate constant, 1.5 +/- 1.3 liters/h. These values are similar to those seen in subjects without HIV infection. Pyrimethamine pharmacokinetics did not differ significantly in those subjects who were intravenous drug users. Adverse effects were noted in 73% of those initially enrolled in this study, leading to discontinuation for 38%. No association was noted between pyrimethamine levels and the incidence of adverse events. No significant differences were seen in zidovudine pharmacokinetic parameters obtained from studies performed before and during treatment with pyrimethamine. In summary, pyrimethamine exhibited pharmacokinetics in HIV-infected patients that were similar to those in non-HIV-infected subjects and it did not alter the pharmacokinetics of zidovudine in these patients.

Download Full-text

Population Pharmacokinetics of Lamivudine in Human Immunodeficiency Virus-Exposed and -Infected Infants

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00332-07 ◽

2007 ◽

Vol 51 (12) ◽

pp. 4297-4302 ◽

Cited By ~ 23

Author(s):

Adriana H. Tremoulet ◽

Edmund V. Capparelli ◽

Parul Patel ◽

Edward P. Acosta ◽

Katherine Luzuriaga ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

Population Pharmacokinetic Analysis ◽

Pharmacokinetic Analysis ◽

Population Pharmacokinetic ◽

Individual Subject ◽

Final Model ◽

Interoccasion Variability ◽

Immunodeficiency Virus ◽

Hiv Exposed ◽

The Individual

ABSTRACT This study aimed to determine lamivudine disposition in infants and to construct an appropriate dose adjustment for age, given the widespread use of lamivudine for both the prevention of mother-to-child transmission of human immunodeficiency virus (HIV) and the treatment of HIV-infected infants. Using a pooled-population approach, the pharmacokinetics of lamivudine in HIV-exposed or -infected infants from four Pediatric AIDS Clinical Trials Group studies were assessed. Ninety-nine infants provided 559 plasma samples for measurement of lamivudine concentrations. All infants received combination antiretroviral therapy including lamivudine dosed at 2 mg/kg of body weight every 12 h (q12h) for the first 4 to 6 weeks of life and at 4 mg/kg q12h thereafter. Lamivudine's apparent clearance was 0.25 liter/h/kg at birth, doubling by 28 days. In the final model, age and weight were the only significant covariates for lamivudine clearance. While lamivudine is predominantly renally eliminated, the serum creatinine level was not an independent covariate in the final model, possibly because it was confounded by age. Inclusion of interoccasion variability for bioavailability improved the individual subject clearance prediction over the age range studies. Simulations based on the final model predicted that by the age of 4 weeks, 90% of infant lamivudine concentrations with the standard 2 mg/kg dose of lamivudine fell below the adult median concentration. This population pharmacokinetic analysis affirms that adjusting the dose of lamivudine from 2 mg/kg to 4 mg/kg q12 h at the age of 4 weeks for infants with normal maturation of renal function will provide optimal lamivudine exposure, potentially contributing to more successful therapy.

Download Full-text

A Population Pharmacokinetic Analysis of Nelfinavir Mesylate in Human Immunodeficiency Virus-Infected Patients Enrolled in a Phase III Clinical Trial

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.44.7.1832-1837.2000 ◽

2000 ◽

Vol 44 (7) ◽

pp. 1832-1837 ◽

Cited By ~ 25

Author(s):

Kimberley A. Jackson ◽

Sara E. Rosenbaum ◽

Bradley M. Kerr ◽

Yazdi K. Pithavala ◽

Geoffrey Yuen ◽

...

Keyword(s):

Clinical Trial ◽

Human Immunodeficiency Virus ◽

Population Pharmacokinetic Analysis ◽

Phase Iii ◽

Baseline Viral Load ◽

Accurate Estimation ◽

Pharmacokinetic Analysis ◽

Population Pharmacokinetic ◽

Phase Iii Clinical Trial ◽

Immunodeficiency Virus

ABSTRACT A population pharmacokinetic analysis was conducted on nelfinavir in patients infected with human immunodeficiency virus (HIV) who were enrolled in a phase III clinical trial. The data consisted of 509 plasma concentrations from 174 patients who received nelfinavir at a dose of 500 or 750 mg three times a day. The analysis was performed using nonlinear mixed-effect modeling as implemented in NONMEM (version 4.0; double precision). A one-compartment model with first-order absorption best described the data. The timing and small number of early postdose blood levels did not allow accurate estimation of volume of distribution (V/F) and the absorption rate constant (ka ). As a result, two models were used to analyze the data: model 1, in which oral clearance (CL/F),V/F, and ka were estimated, and model 2, in which V/F and ka were fixed to known values and only CL/F was estimated. Estimates of CL/F ranged from 41.9 to 45.1 liters/h, values in close agreement with previous studies. Neither body weight, age, sex, race, dose level, baseline viral load, metabolite-to-parent drug plasma concentration ratio, history of liver disease, nor elevated results of liver function tests appeared to be significant covariates for clearance. The only significant covariate-parameter relationship was concomitant use of fluconazole on CL/F, which was associated with a modest reduction in interindividual variability of CL/F. Patients who received concomitant therapy with fluconazole had a statistically significant reduction in nelfinavir CL/F of 26 to 30%. Since serious dose-limiting toxicity and concentration-related toxicities are not apparent for nelfinavir, this effect of fluconazole is unlikely to be of clinical significance.

Download Full-text

Dose evaluation of lamivudine in human immunodeficiency virus-infected children aged 5 months to 18 years based on a population pharmacokinetic analysis

British Journal of Clinical Pharmacology ◽

10.1111/bcp.13227 ◽

2017 ◽

Vol 83 (6) ◽

pp. 1287-1297 ◽

Cited By ~ 5

Author(s):

Esther J. H. Janssen ◽

Diane E. T. Bastiaans ◽

Pyry A. J. Välitalo ◽

Annemarie M. C. van Rossum ◽

Evelyne Jacqz-Aigrain ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

Population Pharmacokinetic Analysis ◽

Pharmacokinetic Analysis ◽

Population Pharmacokinetic ◽

Dose Evaluation ◽

Immunodeficiency Virus

Download Full-text

Metabolism of 3′-Azido-3′-Deoxythymidine and 3′-Fluoro-3′-Deoxythymidine in Combination in Human Immunodeficiency Virus Infected Lymphoblastoid Cells

Antiviral Chemistry and Chemotherapy ◽

10.1177/095632029200300306 ◽

1992 ◽

Vol 3 (3) ◽

pp. 165-170 ◽

Cited By ~ 5

Author(s):

S. Cox

Keyword(s):

Human Immunodeficiency Virus ◽

Virus Replication ◽

Cell Types ◽

Human Immunodeficiency Virus Replication ◽

Lymphoblastoid Cells ◽

Synergistic Inhibition ◽

Immunodeficiency Virus ◽

Deoxynucleoside Triphosphate ◽

The Individual

A combination of 3′-azido-3′-deoxythymidine (AZT) with 3′-fluoro-3′-deoxythymidine (FLT) has been shown previously to give synergistic inhibition of human immunodeficiency virus replication and greatly reduced cytotoxicity in vitro. The phosphorylation of the compounds, and their effect upon the natural deoxynucleoside triphosphate pools, were compared in CEM, H9, and HIV-infected H9 lymphoblastoid cells, both for the compounds when used alone and when combined together. Higher levels of FLT triphosphate than AZT triphosphate, and higher levels of AZT monophosphate than FLT monosphosphate, were formed in all cell types. Both compounds were phosphorylated most efficiently in CEM cells, whereas they were least efficiently phosphorylated in infected H9 cells. Owing to competition, the phosphorylation of both analogues was reduced when used in combination, compared to the phosphorylation of the separate compounds. The phosphorylation of the separate compounds was therefore at a maximum and was not increased by combining the compounds. The two compounds competed equally with each other for phosphorylation when used at a ratio of AZT: FLT of 5: 1. Both analogues severely reduced the deoxynucleoside triphosphate pools in uninfected and human immunodeficiency virus-infected H9 cells, but not in CEM cells. The effects of the two compounds were similar to those found when the compounds were combined, and thus H9 cells were shown to be much more sensitive to the effects of the analogues upon deoxynucleoside triphosphate pools than CEM cells were. Thus the synergistic combination of 3′-azido-3′-deoxythymidine and 3′-fluoro-3′-deoxythymidine was shown to have a similar metabolism and a similar effect upon cellular deoxynucleoside triphosphate pools to the individual compounds.

Download Full-text