Is the Recommended Once-Daily Dose of Lamivudine Optimal in West African HIV-Infected Children?

Abstract

We aimed in this study to describe lamivudine concentration-time courses in treatment-naïve children after once-daily administration, to study the effects of body weight and age on lamivudine pharmacokinetics, and to simulate an optimized administration scheme. For this purpose, lamivudine concentrations were measured in 49 children after at least 2 weeks of didanosine-lamivudine-efavirenz treatment. A total of 148 plasma lamivudine concentrations were measured, and a population pharmacokinetic model was developed with NONMEM. The influence of individual characteristics was tested using a likelihood ratio test. Children were divided into two groups, according to their pharmacokinetic parameters, thanks to tree regression analysis. For each patient, the area under the curve was derived from estimated individual pharmacokinetic parameters. Different once-daily doses were simulated in each group, to obtain the same exposure in children as the mean effective exposure in adults (8.9 mg/liter ⅐ h). A two-compartment model in which the slope of distribution is assumed to be equal to the absorption rate constant adequately described the data. Parameter estimates were standardized for a mean standard body weight using an allometric model. Children were then divided into 2 groups according to body weight: CL/F was significantly higher in children weighing less than 17 kg (1.12 liters/h/kg) than in children over 17 kg (0.95 liters/h/kg; P ‫؍‬ 0.01). The target mean AUC of 8.9 mg/liters ⅐ h was obtained with a 10-mg/kg once-daily lamivudine (3TC) dose for children below 17 kg; the recommended dose of 8 mg/kg seems to be sufficient in children weighing more than 17 kg. These assumptions should be prospectively confirmed.According to the latest UNAIDS estimates, nearly 90% of the 2.5 million children infected by HIV around the world in 2007 were living in sub-Saharan Africa (21). Highly active antiretroviral therapy (HAART) has been shown to be effective in children from industrialized countries (22) and is feasible in developing countries (8, 10). The combination of didanosine (ddI), lamivudine (3TC), and efavirenz (EFV) once daily in adults showed a good antiretroviral efficacy and good long-term tolerability (9, 15). In children, the efficacy and tolerance of this ddI-3TC-EFV combination remain to be shown. The aims of the BURKINAME-ANRS 12103 trial were to estimate the pharmacokinetics of ddI, 3TC, and efavirenz given once daily in children from 30 months to 15 years or age and to evaluate the efficacy and tolerance of this drug combination.Lamivudine is rapidly absorbed following an oral dose and has a wide distribution due to its relatively low molecular mass (229 Da) and low plasma protein binding (Ͻ36%). The majority of lamivudine (approximately 70%) is eliminated unchanged in the urine over 24 h (13). Approximately 5 to 10% is metabolized to the pharmacologically inactive trans-sulfoxide metabolite, the majority of which is also excreted in the urine within 12 h after a single oral dose (13).The combination of didano...

Effect of Sorbitol on the Pharmacokinetic Profile of Lamivudine Oral Solution in Adults: An Open‐Label, Randomized Study

“…In some studies, children also received nevirapine suspension (162 mg of sorbitol/mL) or the prophylactic antibiotic trimethoprim‐sulfamethoxazole as a suspension (sorbitol amounts vary depending on the manufacturer). This interaction between lamivudine and sorbitol may also explain previous reports of lower exposures in younger/lower‐weight children compared with older/higher‐weight children17, 18, 19, 20 because younger children are more likely to be prescribed liquid medications for ease of swallowing.…”

Developmental Pharmacokinetic Changes of Lamivudine in Infants and Children

“…Our post hoc data yielded a mean apparent clearance and volume of distribution of 0.72 (95% confidence interval, 0.36–1.13) L/h/kg and 3.54 (2.09–5.57) L/h, respectively. Prior pediatric studies have reported apparent clearance means from 0.39 to 1.03 L/h/kg with apparent volume of distribution means from 2.29 to 4.31 L/kg 13 , 14 , 17 , 19 , 23 . Our study used a 1‐compartment model similar to prior studies in HIV‐infected adults using oral lamivudine 7 , 11 .…”

“…Intravenous dosing is more conducive to the development of a 2‐compartment model as absorption does not need to be considered and the PK of the separate compartments can be better characterized. Bouazza et al 19 used a 2‐compartment model for oral lamivudine dosing in children but had to fix the absorption constant to a value from the literature and assumed a model in which K a and the slope of the distribution phase (α) were equal. In a separate study, Bouazza et al 23 used a study design that incorporated once‐daily dosing with sampling out to 24 hours in some patients, thereby allowing for the fitting of a 2‐compartment model, but were still unable to estimate the variability of all parameters in the model.…”

24-Month adherence, tolerance and efficacy of once-a-day antiretroviral therapy with didanosine, lamivudine, and efavirenz in African HIV-1 infected children: ANRS 12103/12167

“…In our previous study, pharmacokinetic characteristics showed the low doses of Lamuvidine and Didanosine 7,8 . That could explain the virological failure occurring in this first year.…”

“…Once-a-day antiretroviral therapy may be an option regimen. This regimen may represent a significant advantage in terms of quality of life, adherence to long-term therapy, minimizing risk of treatment errors, and reduction of inappropriate prescriptions 5. Once-a-day combination with Didanosine, Lamivudine and Efavirenz was previously studied in Burkina Faso (ANRS 12103) [6][7][8] . Despite the satisfactory pharmacokinetics of DDI, 3TC and EFV, target DDI plasma concentrations were not always reached in some of the youngest children..…”