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

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 didanosinelamivudine-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 ⅐ h was significantly linked to a greater decrease in the viral load (a decrease of 3 log 10 versus 2.4 log 10 copies/ml; P ‫؍‬ 0.03) than that with a lower AUC. A didanosine dose of 360 mg/m 2 administered as tablets should be a more appropriate dose than 240 mg/m 2 to improve efficacy for these children. However, data on adverse events with this dosage are missing.According to the latest UNAIDS estimates, 2.5 million children around the world were living with human immunodeficiency virus (HIV) in 2007. Nearly 90% of them were living in sub-Saharan Africa (33). Highly active antiretroviral therapy (HAART) has been shown to be effective for children from industrialized countries (34) and is feasible in developing countries (10, 13). Since compliance is essential for individual efficacy (36), once-daily administration of HAART could decrease treatment failure, especially for children from developing countries. The once-a-day combination of didanosine (ddI), lamivudine (3TC), and efavirenz (EFV) has been successfully used for adults (11,12,25,26). It improves compliance, antiretroviral efficacy (25), and long-term tolerance (11,12,26). For children, the once-daily administration of HAART is recommended in the United States and possibly in Europe, but the efficacy and tolerance of this ddI-3TC-EFV combination remain to be shown. ddI is susceptible to acid hydrolysis when administered orally; an estimated 10% of ddI is degraded every 2 min at pH 3.0 or below (22). Another limitation of ddI is its poor solubility at low pH values (pK a ϭ 9.1). As a result, one oral dosage formulation contains buffers to prevent the degradation of the drug in the gastro...

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..…”

HIV-Antiretroviral Therapy Induced Liver, Gastrointestinal, and Pancreatic Injury

“…The patient's condition started improving following liver transplantation and replacement of efavirenz with raltegravir [67]. Bilirubin levels did not affect the rate of hepatotoxicity in another study [35]. Grade 3 hyperbilirubinemia/liver toxicity was also observed with nevirapine [21].…”

“…Among other NRTIs, the development of rash led to zidovudine and stavudine substitution [30] and the development of pruritis led to didanosine substitution [35] in other studies.…”

Analysis of in vivo absorption of didanosine tablets in male adult dogs by HPLC

“…Some reports describe simultaneous determination of HIV drugs by HPLC with tandem mass spectrometry in plasma. This methodology can be used for pharmacological research and clinical purposes in rats [16] , [17] and humans [18] , [19] , [20] , [21] . In another study, Yan et al [5] developed a rapid and efficient HPLC–tandem mass spectrometry coupled with SPE for determining didanosine concentrations in maternal rat plasma, amniotic fluid, placental and fetal tissue samples.…”