Steady‐State Pharmacokinetics of Emtricitabine and Tenofovir Disoproxil Fumarate Administered Alone and in Combination in Healthy Volunteers

Blum, Martin; Chittick, Gregory E.; Begley, John; Zong, Jian

doi:10.1177/0091270007300951

Cited by 73 publications

(66 citation statements)

References 22 publications

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“…Moreover, these half-lives are comparable to those for children (9.3 to 11.7 h for 2-to 17-year-old children) (17) and adults (10.5 h in the Blum et al study, 9.4 h in the Zhong et al study, and 8.3 h in the Ramanathan et al study) (4,15,18).…”

Section: Discussionsupporting

confidence: 59%

Population Pharmacokinetics of Emtricitabine in Human Immunodeficiency Virus Type 1-Infected Pregnant Women and Their Neonates

Hirt

Urien

Rey

et al. 2009

Antimicrob Agents Chemother

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The objectives of this study were to evaluate emtricitabine (FTC) pharmacokinetics in pregnant women and their neonates and to determine the optimal prophylactic dose for neonates after birth to prevent mother-tochild transmission of human immunodeficiency virus (HIV). A total of 38 HIV-infected pregnant women were administered tenofovir disoproxyl fumarate (300 mg)-FTC (200 mg) tablets-two tablets at the initiation of labor and one daily for 7 days postpartum. By pair, 11 maternal, one cord blood, and two neonatal FTC concentrations were measured using a high-performance liquid chromatography-tandem mass spectrometry validated method and analyzed by a population approach. Model and mean estimates (interpatient variability) were a two-compartment model for mothers, with an absorption rate constant of 0.54 h ؊1 (61%), apparent elimination and intercompartmental clearances of 23.2 (17%) and 6.04 liters ⅐ h ؊1 , and apparent central and peripheral volumes of 127 and 237 liters, respectively; an effect compartment linked to maternal circulation for cord blood and a neonatal compartment disconnected, after delivery, with a 10.6-h half-life (30%). After the 400-mg FTC administration, the median population area under the concentration-time curve and the minimal and maximal plasma FTC concentrations in pregnant women were 14.3 mg ⅐ liter ؊1 ⅐ h and 1.68 and 0.076 mg/liter, respectively. At delivery, median (range) predicted maternal and cord blood FTC concentrations were, respectively, 1.16 (0.14 to 1.99) and 0.72 (0.05 to 1.19) mg ⅐ liter ؊1 . We concluded that the 400-mg FTC administration in pregnant women produces higher exposition than does the 200-mg administration in other adults, at steady state. FTC was shown to have good placental transfer (80%). Administering 1 mg FTC/kg as soon as possible after birth or 2 mg/kg 12 h after birth should produce neonatal concentrations comparable to the concentrations observed in adults.To prevent mother-to-child transmission of human immunodeficiency virus (HIV) during delivery, a single-dose administration of nevirapine (NVP) administered at the start of labor is the most common antiretroviral regimen used in resourcelimited settings, as recommended by the World Health Organization in the Antiretroviral Drugs for Treating Pregnant Women and Preventing HIV Infection in Infants report (http: //www.who.int/hiv/pub/guidelines/pmtctguidelines3.pdf). However, the use of the single-dose administration of NVP results in resistance mutations in 15 to 70% of women, at 4 to 6 weeks postpartum, compromising the success of subsequent treatments with NVP in mother and child (7,9). A recent clinical study suggests that adding a single dose of tenofovir disoproxyl fumarate (TDF) and emtricitabine (FTC) at delivery may reduce those resistances by half (6).FTC is a potent, once-daily-administered nucleoside reverse transcriptase inhibitor approved for the treatment of HIV in adults and children older than 3 months in combination with other antiretroviral agents. The physiological changes asso...

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Section: Discussionsupporting

confidence: 59%

Population Pharmacokinetics of Emtricitabine in Human Immunodeficiency Virus Type 1-Infected Pregnant Women and Their Neonates

Hirt

Urien

Rey

et al. 2009

Antimicrob Agents Chemother

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“…Interday and intraday coefficients of variation across the range of concentrations were less than 13%. Table 1 shows the pharmacokinetic (PK) parameters of each antiretroviral in blood plasma and IT over a 24-h period in Rag2 Ϫ/Ϫ ␥ c Ϫ/Ϫ mice and their comparison to human plasma (6). The PK of TFV, FTC, and L-870812 were evaluated by noncompartmental methods using WinNonlin (5.1; Pharsight, Mountain View, CA).…”

mentioning

confidence: 99%

Suppression of Human Immunodeficiency Virus Type 1 (HIV-1) Viremia with Reverse Transcriptase and Integrase Inhibitors, CD4 ⁺ T-Cell Recovery, and Viral Rebound upon Interruption of Therapy in a New Model for HIV Treatment in the Humanized Rag2 ^−/− γ _c ^−/− Mouse

Choudhary¹,

Rezk²,

Ince³

et al. 2009

J Virol

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“…Plasma protein binding correction k p ,18 lymph node penetration k l ,19 and variability in the susceptibility of wildtype virus in the population 3, 27, 28, 29…”

Section: Supporting Informationmentioning

confidence: 99%

A Mathematical Model to Predict HIV Virological Failure and Elucidate the Role of Lymph Node Drug Penetration

Sanche

Sheehan

Mésplède

et al. 2017

CPT Pharmacom & Syst Pharma

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Preventing virological failure following HIV treatment remains a difficult task that is further complicated by the emergence of drug resistance. We have developed a mathematical model able to explain and predict HIV virological outcomes for various compounds and patients' drug intake patterns. Compared to current approaches, this model considers, altogether, drug penetration into lymph nodes, a refined adherence representation accounting for the propensity for long drug holidays, population pharmacokinetic and pharmacodynamic variability, drug interaction, and crossresistance. In silico results are consistent with clinical observations for treatment with efavirenz, efavirenz in association with tenofovir DF and emtricitabine, or boosted darunavir. Our findings indicate that limited lymph node drug penetration can account for a large proportion of cases of virological failure and drug resistance. Since a limited amount of information is required by the model, it can be of use in the process of drug discovery and to guide clinical treatment strategies.

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Steady‐State Pharmacokinetics of Emtricitabine and Tenofovir Disoproxil Fumarate Administered Alone and in Combination in Healthy Volunteers

Cited by 73 publications

References 22 publications

Population Pharmacokinetics of Emtricitabine in Human Immunodeficiency Virus Type 1-Infected Pregnant Women and Their Neonates

Population Pharmacokinetics of Emtricitabine in Human Immunodeficiency Virus Type 1-Infected Pregnant Women and Their Neonates

Suppression of Human Immunodeficiency Virus Type 1 (HIV-1) Viremia with Reverse Transcriptase and Integrase Inhibitors, CD4 ⁺ T-Cell Recovery, and Viral Rebound upon Interruption of Therapy in a New Model for HIV Treatment in the Humanized Rag2 ^−/− γ _c ^−/− Mouse

A Mathematical Model to Predict HIV Virological Failure and Elucidate the Role of Lymph Node Drug Penetration

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Steady‐State Pharmacokinetics of Emtricitabine and Tenofovir Disoproxil Fumarate Administered Alone and in Combination in Healthy Volunteers

Cited by 73 publications

References 22 publications

Population Pharmacokinetics of Emtricitabine in Human Immunodeficiency Virus Type 1-Infected Pregnant Women and Their Neonates

Population Pharmacokinetics of Emtricitabine in Human Immunodeficiency Virus Type 1-Infected Pregnant Women and Their Neonates

Suppression of Human Immunodeficiency Virus Type 1 (HIV-1) Viremia with Reverse Transcriptase and Integrase Inhibitors, CD4 + T-Cell Recovery, and Viral Rebound upon Interruption of Therapy in a New Model for HIV Treatment in the Humanized Rag2 −/− γ c −/− Mouse

A Mathematical Model to Predict HIV Virological Failure and Elucidate the Role of Lymph Node Drug Penetration

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Suppression of Human Immunodeficiency Virus Type 1 (HIV-1) Viremia with Reverse Transcriptase and Integrase Inhibitors, CD4 ⁺ T-Cell Recovery, and Viral Rebound upon Interruption of Therapy in a New Model for HIV Treatment in the Humanized Rag2 ^−/− γ _c ^−/− Mouse