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Pharmacokinetics and Pharmacokinetic/Pharmacodynamic Relationships of Etravirine in HIV‐1‐Infected, Treatment‐Experienced Children and Adolescents in PIANO
Author(s) -
Kakuda Thomas N.,
Brochot Anne,
Green Bruce,
Nijs Steven,
Vis Peter,
Opsomer Magda,
Tomaka Frank L.,
Hoetelmans Richard M. W.
Publication year - 2016
Publication title -
the journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.92
H-Index - 116
eISSN - 1552-4604
pISSN - 0091-2700
DOI - 10.1002/jcph.746
Subject(s) - etravirine , pharmacokinetics , pharmacodynamics , medicine , quartile , amprenavir , pharmacology , population , reverse transcriptase inhibitor , area under the curve , viral load , chemistry , human immunodeficiency virus (hiv) , antiretroviral therapy , virology , confidence interval , biochemistry , hiv 1 protease , protease , enzyme , environmental health
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 0h and AUC 0‐12h 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 −1 , respectively. Overall, median (range) estimated etravirine C 0h and AUC 0‐12h 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 0‐12h 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.