Pharmacokinetics and Pharmacokinetic/Pharmacodynamic Relationships of Etravirine in HIV‐1‐Infected, Treatment‐Experienced Children and Adolescents in PIANO

Abstract

PIANO (NCT00665847) investigated etravirine pharmacokinetics, efficacy, and safety in children and adolescents. Treatment-experienced, HIV-1-infected patients (≥6 to <18 years) received etravirine 5.2 mg/kg twice daily (maximum 200 mg twice daily) plus background antiretrovirals. A population pharmacokinetic model was developed, and etravirine C and AUC were estimated. Relationships among intrinsic/extrinsic factors and etravirine pharmacokinetics and pharmacokinetics with pharmacodynamics were assessed. The best model describing etravirine pharmacokinetics consisted of a single compartment with sequential zero- and first-order absorption following a lag time. Interindividual variability terms were included on clearance (CL/F) and the first-order input rate constant (KA). The final model estimates (coefficient of variation, %) for CL/F and KA were 46.3 (11) L/h and 1.07 (34) h , respectively. Overall, median (range) estimated etravirine C and AUC were 287 (2-2276) ng/mL and 4560 (62-28,865) ng · h/mL, respectively. Exposure was slightly lower in adolescents vs children. Sex and adherence did not affect etravirine pharmacokinetics. Factors significantly affecting etravirine exposure were body weight (higher with lower weight), race (lower in Asians than in white or black patients), and the use of certain HIV protease inhibitors. Virologic response (<50 copies/mL at week 48) was lower in the lowest etravirine AUC quartile vs the upper 3 quartiles (41% vs 67% to 76%). Rash occurred more frequently in the highest quartile than in the lower 3 quartiles (52% versus 8% to 20%). Etravirine 5.2 mg/kg twice daily in treatment-experienced, HIV-1-infected children and adolescents provides comparable exposure to that in adults receiving etravirine 200 mg twice daily and is the recommended dose for children and adolescents.

Etravirine in treatment-experienced HIV-1-infected children 1 year to less than 6 years of age

“…Though rashes were reported in 46.2% of study participants in P1090, these events were grades 1 or 2 and none for which causality data were available were attributed to ETR. The risk of rash increases with increasing ETR exposure [ 8 ], thus the overall lower exposures in P1090 and small sample size may explain the lack of severe rashes in this study.…”

“…ETR was initially evaluated in six children in cohort I at a dose of 5.2 mg/kg twice daily based on data from the PIANO trial in children aged 6--17 years [ 8 ]. ETR exposures with this dose failed to meet the protocol-defined pharmacokinetics criteria, and thus the ETR starting dose was revised.…”

Clinical Pharmacokinetics and Pharmacodynamics of Etravirine: An Updated Review

“…Lower weight, Asian race, and adolescence were identified as negative predictors of etravirine exposure. An exposureresponse relationship was observed, with fewer participants achieving virologic suppression in the lower AUC 12 quartile (lowest AUC 12 quartile: ≤ 2704 ng•h/mL; virologic suppression: 41% vs. 67-76%) [34].…”

“…Subjects with hepatitis B virus co-infection had an 8.3% increase in etravirine CL/F, whereas those with hepatitis C virus co-infection had a 24% decrease in CL/F [24,33]. Etravirine PK exhibits relatively low interpatient variability (approximately 50% for CL/F); recent studies found approximately 13% and 5% of the interpatient variability in CL/F arises from concomitant ARVs and pharmacogenomics, respectively [34][35][36]. Steady-state PK parameters of etravirine in HIVpositive individuals are shown in Table 1.…”

“…The 5.2 mg/kg dose showed comparable exposures to adults receiving 200 mg twice daily and was selected for further pediatric development. Table 1 summarizes the etravirine PK parameters in pediatric and adolescent populations [12,34].…”