Pharmacokinetics and Drug-Drug Interactions of Abacavir and Lamuvudine Co-administered With Antituberculosis Drugs in HIV-Positive Children Treated for Multidrug-Resistant Tuberculosis

Abstract

Given the high prevalence of multidrug-resistant (MDR)-TB in high HIV burden settings, it is important to identify potential drug-drug interactions between MDR-TB treatment and widely used nucleoside reverse transcriptase inhibitors (NRTIs) in HIV-positive children. Population pharmacokinetic models were developed for lamivudine (n = 54) and abacavir (n = 50) in 54 HIV-positive children established on NRTIs; 27 with MDR-TB (combinations of high-dose isoniazid, pyrazinamide, ethambutol, ethionamide, terizidone, fluoroquinolones, and amikacin), and 27 controls without TB. Two-compartment models with first-order elimination and transit compartment absorption described both lamivudine and abacavir pharmacokinetics, respectively. Allometric scaling with body weight adjusted for the effect of body size. Clearance was predicted to reach half its mature value ∼2 (lamivudine) and ∼3 (abacavir) months after birth, with completion of maturation for both drugs at ∼2 years. No significant difference was found in key pharmacokinetic parameters of lamivudine and abacavir when co-administered with routine drugs used for MDR-TB in HIV-positive children.

Pharmacokinetics and pharmacodynamics of anti-tuberculosis drugs: An evaluation of in vitro, in vivo methodologies and human studies

“…Thereby, pharmacometric approaches are increasingly used compared to conventional methods (two-stage approach, non-compartmental analysis) as they come with several advantages: pharmacometric models can handle sparse and/or imbalanced data. Thereby even PK data generated in routine TB care can be leveraged (van der Laan et al, 2021;Tietjen et al, 2022). Moreover, pharmacometric models allow to separate PK variability into different sources (e.g., within-patient, between patient, between dosing occasion, etc.,).…”

“…For TB, such approaches have specifically facilitated the evaluation of TB dosing regimens in children, where the impact of body weight and organ maturation is included (Zvada et al, 2014). Also, pharmacometric models have an important role in the evaluation of drug interactions, e.g., with anti-retroviral drugs (van der Laan et al, 2021) in the co-treatment of HIV and TB.…”

Pharmacokinetic and pharmacodynamic features of antiretroviral products

“…Психоневрологические расстройства чаще встречаются у афроамериканцев, чем у американцев европейского или латиноамериканского происхождения. Это может быть следствием более высокой распространенности генотипа CYP2B6 Т/Т, что приводит к более медленному метаболизму EFV и более высокой его концентрации в плазме [39]. Из других рисков НР следует отметить липодистрофию, которая может возникать у пациентов, получающих высокоактивную АРВТ на основе EFV.…”