Population Pharmacokinetics of Lopinavir/Ritonavir: Changes Across Formulations and Human Development From Infancy Through Adulthood
Year: 2018
Type: article
Abstract: 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 (QHP) times hepatic extraction (EH), with EH 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/m2) 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.
DOI: 10.1002/jcph.1293
Institutions: University of California San Diego, Universidade Federal de Minas Gerais, Northwestern University, University of California, Los Angeles, The Lundquist Institute, Harbor–UCLA Medical Center, Children's Hospital of Wisconsin, Medical College of Wisconsin, Elizabeth Glaser Pediatric AIDS Foundation, Children's National, George Washington University
Language: English
Field: Medicine
Domain: Health Sciences
Open Access status: green
Awards: LOC-IMPAACT Leadership Group, G1754130222, Statistical and Data Management Center-Pediatric,Adolescent, and Maternal CTG, G2635632090, G2655925270, G3045663399, Pediatric and Developmental Pharmacology for Inflammatory and Infectious Diseases, G778533135, G803170016, G9000030691, G9000140988, G9000153711, SDMC - IMPAACT Leadership Group
OpenAlex ID: W2892487298