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Population Pharmacokinetics of Lopinavir/Ritonavir: Changes Across Formulations and Human Development From Infancy Through Adulthood
Author(s) -
Yang Jincheng,
Nikanjam Mina,
Best Brookie M.,
Pinto Jorge,
Chadwick Ellen G.,
Daar Eric S.,
Havens Peter L.,
Rakhmanitella,
Capparelli Edmund V.
Publication year - 2018
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.1293
Subject(s) - lopinavir , pharmacokinetics , dosing , bioavailability , medicine , ritonavir , nonmem , population , lopinavir/ritonavir , blood sampling , pharmacology , pediatrics , viral load , antiretroviral therapy , human immunodeficiency virus (hiv) , immunology , environmental health
Lopinavir/ritonavir (LPV/r) is recommended by the World Health Organization as first‐line treatment for HIV‐infected infants and young children. We performed a composite population pharmacokinetic (PK) analysis on LPV plasma concentration data from 6 pediatric and adult studies to determine maturation and formulation effects from infancy to adulthood. Intensive PK data were available for infants, children, adolescents, and adults (297 intensive profiles/1662 LPV concentrations). LPV PK data included 1 adult, 1 combined pediatric‐adult, and 4 pediatric studies (age 6 weeks to 63 years) with 3 formulations (gel‐capsule, liquid, melt‐extrusion tablets). LPV concentrations were modeled using nonlinear mixed effects modeling (NONMEM v. 7.3; GloboMax, Hanover, Maryland) with a one compartment semiphysiologic model. LPV clearance was described by hepatic plasma flow (Q HP ) times hepatic extraction (E H ), with E H estimated from the PK data. Volume was scaled by linear weight (WT/70) 1.0 . Bioavailability was assessed separately as a function of hepatic extraction and the fraction absorbed from the gastrointestinal tract. The absorption component of bioavailability increased with age and tablet formulation. Monte Carlo simulations of the final model using current World Health Organization weight‐band dosing recommendations demonstrated that participants younger than 6 months of age had a lower area under the drug concentration–time curve (94.8 vs >107.4 μg hr/mL) and minimum observed concentration of drug in blood plasma (5.0 vs > 7.1 μg/mL) values compared to older children and adults. Although World Health Organization dosing recommendations include a larger dosage (mg/m 2 ) in infants to account for higher apparent clearance, they still result in low LPV concentrations in many infants younger than 6 months of age receiving the liquid formulation.