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

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.

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Joint Population Pharmacokinetic Analysis of Zidovudine, Lamivudine, and Their Active Intracellular Metabolites in HIV Patients

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01487-10 ◽

2011 ◽

Vol 55 (7) ◽

pp. 3423-3431 ◽

Cited By ~ 15

Author(s):

C. Bazzoli ◽

H. Bénech ◽

E. Rey ◽

S. Retout ◽

D. Salmon ◽

...

Keyword(s):

Compartment Model ◽

Population Pharmacokinetic Analysis ◽

Pharmacokinetic Analysis ◽

Pharmacokinetic Parameters ◽

Population Pharmacokinetic ◽

Intracellular Metabolites ◽

Drug Concentrations ◽

The Mean ◽

Intracellular Concentrations ◽

Apparent Bioavailability

ABSTRACTThe population pharmacokinetic parameters of zidovudine (AZT), lamivudine (3TC), and their active intracellular metabolites in 75 naïve HIV-infected patients receiving an oral combination of AZT and 3TC twice daily as part of their multitherapy treatment in the COPHAR2-ANRS 111 trial are described. Four blood samples per patient were taken after 2 weeks of treatment to measure drug concentrations at steady state. Plasma AZT and 3TC concentrations were measured in 73 patients, and among those, 62 patients had measurable intracellular AZT-TP and 3TC-TP concentrations. For each drug, a joint population pharmacokinetic model was developed and we investigated the influence of different covariates. We then studied correlations between the mean plasma and intracellular concentrations of each drug. A one-compartment model with first-order absorption and elimination best described the plasma AZT concentration, with an additional compartment for intracellular AZT-TP. A similar model but with zero-order absorption was found to adequately described concentrations of 3TC and its metabolite 3TC-TP. The half-lives of AZT and 3TC were 0.81 h (94.8%) and 2.97 h (39.2%), respectively, whereas the intracellular half-lives of AZT-TP and 3TC-TP were 10.73 h (69%) and 21.16 h (44%), respectively. We found particularly a gender effect on the apparent bioavailability of AZT, as well as on the mean plasma and intracellular concentrations of AZT, which were significantly higher in females than in males. Relationships between mean plasma drug and intracellular metabolite concentrations were also highlighted both for AZT and for 3TC. Simulation with the model of plasma and intracellular concentrations for once- versus twice-daily regimens suggested that a daily dosing regimen with double doses could be appropriate.

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Didanosine Population Pharmacokinetics in West African Human Immunodeficiency Virus-Infected Children Administered Once-Daily Tablets in Relation to Efficacy after One Year of Treatment

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01187-08 ◽

2009 ◽

Vol 53 (10) ◽

pp. 4399-4406 ◽

Cited By ~ 8

Author(s):

Déborah Hirt ◽

Christophe Bardin ◽

Serge Diagbouga ◽

Boubacar Nacro ◽

Hervé Hien ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

Viral Load ◽

Compartment Model ◽

Volume Of Distribution ◽

Wilcoxon Test ◽

Population Pharmacokinetic ◽

Time Curve ◽

Drug Concentrations ◽

Immunodeficiency Virus ◽

One Year

ABSTRACT Our objective was to study didanosine pharmacokinetics in children after the administration of tablets, the only formulation available in Burkina Faso for which data are missing, and to establish relationships between doses, plasma drug concentrations, and treatment effects (efficacy/toxicity). Didanosine concentrations were measured for 40 children after 2 weeks and for 9 children after 2 to 5 months of treatment with a didanosine-lamivudine-efavirenz combination. A population pharmacokinetic model was developed with NONMEM. The link between the maximal concentration of the drug in plasma (C max), the area under the concentration-time curve (AUC), and the decrease in human immunodeficiency virus (HIV) type 1 RNA levels after 12 months of treatment was evaluated. The threshold AUC that improved efficacy was determined by the use of a Wilcoxon test for HIV RNA, and an optimized dosing schedule was simulated. Didanosine pharmacokinetics was best described by a one-compartment model with first-order absorption and elimination. The apparent clearance and volume of distribution were higher for tablets, probably due to a lower bioavailability with tablets than with pediatric powder. The decrease in the viral load after 12 months of treatment was significantly correlated with the didanosine AUC and C max (P ≤ 0.02) during the first weeks of treatment. An AUC of >0.60 mg/liter·h was significantly linked to a greater decrease in the viral load (a decrease of 3 log10 versus 2.4 log10 copies/ml; P = 0.03) than that with a lower AUC. A didanosine dose of 360 mg/m2 administered as tablets should be a more appropriate dose than 240 mg/m2 to improve efficacy for these children. However, data on adverse events with this dosage are missing.

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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.

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Integrated Population Pharmacokinetic Analysis of Voriconazole in Children, Adolescents, and Adults

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.05761-11 ◽

2012 ◽

Vol 56 (6) ◽

pp. 3032-3042 ◽

Cited By ~ 80

Author(s):

Lena E. Friberg ◽

Patanjali Ravva ◽

Mats O. Karlsson ◽

Ping Liu

Keyword(s):

Pediatric Population ◽

Compartment Model ◽

Population Pharmacokinetic Analysis ◽

Pharmacokinetic Analysis ◽

Population Pharmacokinetic ◽

Parameter Estimates ◽

Loading Dose ◽

Time Curve ◽

Individual Parameter ◽

Dosing Regimens

ABSTRACTTo further optimize the voriconazole dosing in the pediatric population, a population pharmacokinetic analysis was conducted on pooled data from 112 immunocompromised children (2 to <12 years), 26 immunocompromised adolescents (12 to <17 years), and 35 healthy adults. Different maintenance doses (i.e., 3, 4, 6, 7, and 8 mg/kg of body weight intravenously [i.v.] every 12 h [q12h]; 4 mg/kg, 6 mg/kg, and 200 mg orally q12h) were evaluated in these children. The adult dosing regimens (6 mg/kg i.v. q12h on day 1, followed by 4 mg/kg i.v. q12h, and 300 mg orally q12h) were evaluated in the adolescents. A two-compartment model with first-order absorption and mixed linear and nonlinear (Michaelis-Menten) elimination adequately described the voriconazole data. Larger interindividual variability was observed in pediatric subjects than in adults. Deterministic simulations based on individual parameter estimates from the final model revealed the following. The predicted total exposure (area under the concentration-time curve from 0 to 12 h [AUC0-12]) in children following a 9-mg/kg i.v. loading dose was comparable to that in adults following a 6-mg/kg i.v. loading dose. The predicted AUC0-12s in children following 4 and 8 mg/kg i.v. q12h were comparable to those in adults following 3 and 4 mg/kg i.v. q12h, respectively. The predicted AUC0-12in children following 9 mg/kg (maximum, 350 mg) orally q12h was comparable to that in adults following 200 mg orally q12h. To achieve voriconazole exposures comparable to those of adults, dosing in 12- to 14-year-old adolescents depends on their weight: they should be dosed like children if their weight is <50 kg and dosed like adults if their weight is ≥50 kg. Other adolescents should be dosed like adults.

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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.

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Tolerance and Pharmacokinetic Interactions of Rifabutin and Clarithromycin in Human Immunodeficiency Virus-Infected Volunteers

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.42.3.631 ◽

1998 ◽

Vol 42 (3) ◽

pp. 631-639 ◽

Cited By ~ 53

Author(s):

Richard Hafner ◽

James Bethel ◽

Maureen Power ◽

Bernard Landry ◽

Mary Banach ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

Combination Therapy ◽

Single Agent ◽

Pharmacokinetic Analysis ◽

Pharmacokinetic Parameters ◽

Time Curve ◽

Concentration Time ◽

Pharmacokinetic Interactions ◽

Immunodeficiency Virus ◽

Gastrointestinal Adverse Events

ABSTRACT This study evaluated the tolerance and potential pharmacokinetic interactions between clarithromycin (500 mg every 12 h) and rifabutin (300 mg daily) in clinically stable human immunodeficiency virus-infected volunteers with CD4 counts of <200 cells/mm3. Thirty-four subjects were randomized equally to either regimen A or regimen B. On days 1 to 14, subjects assigned to regimen A received clarithromycin and subjects assigned to regimen B received rifabutin, and then both groups received both drugs on days 15 to 42. Of the 14 regimen A and the 15 regimen B subjects who started combination therapy, 1 subject in each group prematurely discontinued therapy due to toxicity, but 19 of 29 subjects reported nausea, vomiting, and/or diarrhea. Pharmacokinetic analysis included data for 11 regimen A and 14 regimen B subjects. Steady-state pharmacokinetic parameters for single-agent therapy (day 14) and combination therapy (day 42) were compared. Regimen A resulted in a mean decrease of 44% (P = 0.003) in the clarithromycin area under the plasma concentration-time curve (AUC), while there was a mean increase of 57% (P = 0.004) in the AUC of the clarithromycin metabolite 14-OH-clarithromycin. Regimen B resulted in a mean increase of 99% (P = 0.001) in the rifabutin AUC and a mean increase of 375% (P < 0.001) in the AUC of the rifabutin metabolite 25-O-desacetyl-rifabutin. The usefulness of this combination for prophylaxis of Mycobacterium avium infections is limited by frequent gastrointestinal adverse events. Coadministration of clarithromycin and rifabutin results in significant bidirectional pharmacokinetic interactions. The resulting increase in rifabutin levels may explain the increased frequency of uveitis observed with concomitant use of these drugs.

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Population Pharmacokinetics of Abacavir in Plasma and Cerebrospinal Fluid

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.49.6.2504-2506.2005 ◽

2005 ◽

Vol 49 (6) ◽

pp. 2504-2506 ◽

Cited By ~ 38

Author(s):

Edmund V. Capparelli ◽

Scott L. Letendre ◽

Ronald J. Ellis ◽

Parul Patel ◽

Diane Holland ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

Cerebrospinal Fluid ◽

Population Pharmacokinetics ◽

Virus Replication ◽

Dose Interval ◽

Population Pharmacokinetic Analysis ◽

Pharmacokinetic Analysis ◽

Human Immunodeficiency Virus Replication ◽

Population Pharmacokinetic ◽

Immunodeficiency Virus

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.

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Population Pharmacokinetic Analysis of Isoniazid, Acetylisoniazid, and Isonicotinic Acid in Healthy Volunteers

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01244-15 ◽

2015 ◽

Vol 59 (11) ◽

pp. 6791-6799 ◽

Cited By ~ 16

Author(s):

Kok-Yong Seng ◽

Kim-Hor Hee ◽

Gaik-Hong Soon ◽

Nicholas Chew ◽

Saye H. Khoo ◽

...

Keyword(s):

Isonicotinic Acid ◽

Compartment Model ◽

Hepatic Function ◽

Population Pharmacokinetic Analysis ◽

Pharmacokinetic Analysis ◽

Pharmacokinetic Parameters ◽

Population Pharmacokinetic ◽

Mixed Effects Modeling ◽

Two Compartment Model

ABSTRACTIn this study, we aimed to quantify the effects of theN-acetyltransferase 2 (NAT2) phenotype on isoniazid (INH) metabolismin vivoand identify other sources of pharmacokinetic variability following single-dose administration in healthy Asian adults. The concentrations of INH and its metabolites acetylisoniazid (AcINH) and isonicotinic acid (INA) in plasma were evaluated in 33 healthy Asians who were also given efavirenz and rifampin. The pharmacokinetics of INH, AcINH, and INA were analyzed using nonlinear mixed-effects modeling (NONMEM) to estimate the population pharmacokinetic parameters and evaluate the relationships between the parameters and the elimination status (fast, intermediate, and slow acetylators), demographic status, and measures of renal and hepatic function. A two-compartment model with first-order absorption best described the INH pharmacokinetics. AcINH and INA data were best described by a two- and a one-compartment model, respectively, linked to the INH model. In the final model for INH, the derived metabolic phenotypes for NAT2 were identified as a significant covariate in the INH clearance, reducing its interindividual variability from 86% to 14%. The INH clearance in fast eliminators was 1.9- and 7.7-fold higher than in intermediate and slow eliminators, respectively (65 versus 35 and 8 liters/h). Creatinine clearance was confirmed as a significant covariate for AcINH clearance. Simulations suggested that the current dosing guidelines (200 mg for 30 to 45 kg and 300 mg for >45 kg) may be suboptimal (3 mg/liter ≤Cmax≤ 6 mg/liter) irrespective of the acetylator class. The analysis established a model that adequately characterizes INH, AcINH, and INA pharmacokinetics in healthy Asians. Our results refine the NAT2 phenotype-based predictions of the pharmacokinetics for INH.

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Population Pharmacokinetic Analysis of Isoniazid among Pulmonary Tuberculosis Patients from China

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01736-19 ◽

2020 ◽

Vol 64 (3) ◽

Author(s):

Wei Jing ◽

Zhaojing Zong ◽

Bohao Tang ◽

Jing Wang ◽

Tingting Zhang ◽

...

Keyword(s):

Compartment Model ◽

Population Pharmacokinetic Analysis ◽

Slow Acetylators ◽

Pharmacokinetic Analysis ◽

Population Pharmacokinetic ◽

Time Curve ◽

Tuberculosis Patients ◽

Two Compartment Model ◽

Acetylator Status ◽

Liquid Chromatography Tandem Mass

ABSTRACT The blood concentration of isoniazid (INH) is evidently affected by polymorphisms in N-acetyltransferase 2 (NAT2), an enzyme that is primarily responsible for the trimodal (i.e., fast, intermediate, and slow) INH elimination. The pharmacokinetic (PK) variability, driven largely by NAT2 activity, creates a challenge for the deployment of a uniform INH dosage in tuberculosis (TB) patients. Although acetylator-specific INH dosing has long been suggested, well-recognized dosages according to acetylator status remain elusive. In this study, 175 blood samples were collected from 89 pulmonary TB patients within 0.5 to 6 h after morning INH administration. According to their NAT2 genotypes, 32 (36.0%), 38 (42.7%), and 19 (21.3%) were fast, intermediate, and slow acetylators, respectively. The plasma INH concentration was detected by liquid chromatography-tandem mass spectrometry. Population pharmacokinetic (PPK) analysis was conducted using NONMEM and R software. A two-compartment model with first-order absorption and elimination well described the PK parameters of isoniazid. Body weight and acetylator status significantly affected the INH clearance rate. The dosage simulation targeting three indicators, including the well-recognized efficacy-safety indicator maximum concentration in serum (Cmax; 3 to 6 μg/ml), the reported area under the concentration-time curve from 0 h to infinity (AUC0–∞; ≥10.52 μg·h/ml), and the 2-h INH serum concentrations (≥2.19 μg/ml), was associated with the strongest early bactericidal activity. The optimal dosages targeting the different indicators varied from 700 to 900 mg/day, 500 to 600 mg/day, and 300 mg/day for the rapid, intermediate, and slow acetylators, respectively. Furthermore, a PPK model for isoniazid among Chinese tuberculosis patients was established for the first time and suggested doses of approximately 800 mg/day, 500 mg/day, and 300 mg/day for fast, intermediate, and slow acetylators, respectively, after a trade-off between efficacy and the occurrence of side effects.

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