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

The aims of this study were to describe the pharmacokinetics of zidovudine (ZDV) and its biotransformation to its metabolite, 3*-azido-3*-deoxy-5*-glucuronylthymidine (G-ZDV), in HIV-infected children, to identify factors that influence the pharmacokinetics of ZDV, and to compare and evaluate the doses recommended by the World Health Organization (WHO) and the Food and Drug Administration (FDA). ZDV concentrations in 782 samples and G-ZDV concentrations in 554 samples from 247 children ranging in age from 0.5 to 18 years were retrospectively measured. A population pharmacokinetic model was developed with NONMEM software (version 6.2), and the pharmacokinetics of ZDV were best described by a one-compartment model with first-order absorption and elimination. The effect of body weight on the apparent elimination clearance and volume of distribution was significant. The mean population parameter estimates were as follows: absorption rate, 2.86 h ؊1 ; apparent elimination clearance, 89.7 liters · h ؊1 (between-subject variability, 0.701 liters · h ؊1 ); apparent volume of distribution, 229 liters (betweensubject variability, 0.807 liters); metabolic formation rate constant, 12.6 h ؊1 (between-subject variability, 0.352 h ؊1 ); and elimination rate constant of G-ZDV, 2.27 h ؊1 . On the basis of simulations with FDA and WHO dosing recommendations, the probabilities of observing efficient exposures (doses resulting in exposures of between 3 and 5 mg/liter · h) with less adverse events (doses resulting in exposures below 8.4 mg/liter · h) were higher when the FDA recommendations than when the WHO recommendations were followed. In order to improve the FDA recommendations, ZDV doses should be reconsidered for the weight band (WB) of 20 to 40 kg. The most appropriate doses should be decreased from 9 to 8 mg/kg of body weight twice a day (BID) for the WB from 20 to 29.9 kg and from 300 to 250 mg BID for the WB from 30 to 39.9 kg. The highest dose, 300 mg BID, should be started from body weights of 40 kg. Z idovudine (ZDV) was the first antiretroviral drug allowed by the Food and Drug Administration (FDA) and approved for the treatment of children with HIV infection (1). It was the most prescribed monotherapy in children and adults, and currently, ZDV-containing regimens are still recommended as first-line combination regimens for infants and children by the World Health Organization (WHO) (2). However, limited pharmacokinetic (PK) studies have been conducted in children (small size, narrow range of ages and/or body weight, single-dose regimen, and the doses administered were different from the last doses recommended) (3-11).Recommended dosing regimens have changed in recent years. Before 2009, the ZDV dosage was based on the body surface area (BSA). The recommended oral dose was 480 mg/m 2 /day given as 240 mg/m 2 twice daily (BID) or 160 mg/m 2 three times daily (TID) (12). The equivalent weight-based dose of 480 mg/m 2 /day for an average child with a BSA of 1 m 2 and a weight of 32 kg is approximately 15 mg/kg of body wei...

“…Bazzoli et al (30) found an effect of gender on CL/F, but no significant differences between administration route and gender were found in the present study.…”

Section: Discussioncontrasting

confidence: 40%

“…The stability of the model was improved when the value was fixed to 2.86 h Ϫ1 . This value was reported by Panhard et al (28) and used in another study (30).…”

Section: Zdv Population Pharmacokineticsmentioning

confidence: 67%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Population Pharmacokinetics Study of Recommended Zidovudine Doses in HIV-1-Infected Children

Fauchet

Tréluyer

Frange

et al. 2013

“…These data indicate that lamivudine or emtricitabine have a long enough intracellular half-life for reduction of viral resistance to NNRTI (1). Previously reported data for nevirapine in the prevention to mother-to-child transmission support these findings (2,3,13).…”

supporting

confidence: 78%

Presence of Lamivudine or Emtricitabine Is Associated with Reduced Emergence of Nonnucleoside Reverse Transcriptase Inhibitor Mutations in an Efavirenz-Based Intermittent Antiretroviral Treatment Regimen

Trancart

Charreau

Marchou

et al. 2012

Efavirenz concentrations were measured in 21 patients during an interruption cycle of the ANRS 106 Window trial. The median efavirenz concentrations in the patients 12 h, 3 days, and 7 days after discontinuation of the drug were 1,962 ng/ml, 416 ng/ml, and 112 ng/ml, respectively. The half-life ranged from 27 to 136 h. No relationship between efavirenz exposure and detection of nonnucleoside reverse transcriptase inhibitor (NNRTI) mutations was demonstrated. Patients who were treated by a lamivudine-or emtricitabine-based regimen had a lower risk of NNRTI mutation selection. The pharmacokinetics of efavirenz is characterized by a long half-life which raised the question of duration of monotherapy whenever an efavirenz-based antiretroviral regimen is stopped. The primary objective was to describe the rate of decrease in efavirenz concentrations during an interruption cycle in patients included in the intermittent arm of the ANRS 106 Window trial (11). Furthermore, we evaluated the relationship between these concentrations and the occurrence of new nonnucleoside reverse transcriptase inhibitor (NNRTI) mutations.Patients enrolled in the interruption arm and treated with efavirenz-based antiretroviral therapy (600 mg of efavirenz once a day [QD]) gave their informed consent to participate in this pharmacokinetic substudy.Efavirenz was stopped 7 days before the other combined drugs. Blood samples were drawn 12 h and 3, 7, and 10 days following efavirenz interruption. Following an 8-week-off therapy cycle, the HIV-1 RNA genotype was determined using population sequencing with a detection cutoff of Ͼ20%.Efavirenz was assayed by high-performance liquid chromatography (HPLC) with UV detection (lower limit of quantification [LLQ] of 50 ng/ml). Half-lives were calculated from the slope of the monoexponential decline of at least 3 graphs of log linear concentrations versus time, and the first concentration below the LLQ was set at LLQ/2. For comparison, the concentration at day 10 was extrapolated from the concentration at 12 h and the halflife, whenever the measured concentration was below the LLQ.All data are presented as median and range. Fisher's exact test was used to compare qualitative variables, and the Wilcoxon rank sum test was used to compare continuous variables. Factors related to the selection of NNRTI mutation were identified by univariate analysis. Comparisons were made using a two-sided alpha level of 0.05. Statistical analysis was performed with the use of SAS software version 9.1 (SAS Institute Inc., Cary, NC).Twenty-one patients (15 males with a median age of 39 years and median weight of 69 kg) participated in this substudy. The patients had a baseline median CD4 ϩ count of 649 cells/mm 3 (range, 435 to 1,151 cells/mm 3 ) with a median nadir of 252 cells/ mm 3 (range, 108 to 547 cells/mm 3 ) after a median duration of NNRTI therapy of 2.6 years (range, 1.9 to 3.1 years). At the beginning of this study, the 21 patients had Ͻ400 copies of HIV-1 RNA per ml and 19 (90%) had Ͻ50 copies of HIV-1 RNA per ml. C...

“…One study of ZDV-3TC-indinavir among 29 men and 4 women demonstrated approximately 2-fold higher ZDV-TP and 1.4-fold higher 3TC-TP levels in women (4). Other studies have shown similar results for ZDV-phosphates (10,38), but still others have shown opposite results for ZDV-phosphates (8). Given possible differences in NRTI response, there is an urgent need for additional comparisons of NRTI cellular pharmacology by sex.…”

mentioning

confidence: 79%

Effect of HIV-1 Infection and Sex on the Cellular Pharmacology of the Antiretroviral Drugs Zidovudine and Lamivudine

Rower

Meditz

Gardner

et al. 2012

ABSTRACTThe cellular pharmacology of zidovudine (ZDV) and lamivudine (3TC)in vivois not completely understood. This prospective longitudinal study investigated the relationship between HIV-1 serostatus, sex, race, and time on therapy with intracellular and plasma ZDV and 3TC concentrations. Of 20 HIV-seronegative and 23 HIV-seropositive volunteers enrolled, 16 (8 women) and 21 (5 women) completed all 12 study days, respectively. Volunteers began ZDV-3TC therapy (plus a third active drug in HIV-seropositive volunteers), and steady-state concentrations (Css) were determined after days 1, 3, 7, and 12. A repeated-measures mixed model was utilized. HIV-seronegative status was associated with 22% (95% confidence interval [CI], 0%, 50%) and 37% (15%, 67%) higherCssestimates compared to those of HIV-seropositive individuals for intracellular ZDV-TP and 3TC-TP levels, respectively. African-Americans had 36% (8%, 72%) higher ZDV-TP estimates than non-African-Americans. Sex was not associated with ZDV-TP or 3TC-TP (P> 0.19). Women had 36% (4%, 78%) higher plasma ZDV, but the effect was lessened when normalized by lean body weight (5% [−19%, 38%];P= 0.68). Plasma 3TC was 19% (0%, 41%) higher in HIV-seropositive volunteers and 22% (0%, 48%) higher in African American volunteers, but these effects were not significant when corrected for creatinine clearance (7% [−9%, 20%] and −5% [−26%, 12%] for HIV serostatus and race, respectively;P> 0.35). These results suggest that HIV-seropositive status decreases and African American race elevates the cellular triphosphates of ZDV and 3TC. This information extends knowledge of ZDV and 3TC cellular pharmacologyin vivoand provides new leads for future cellular pharmacology studies aimed at optimizing HIV prevention/treatment with these agents.