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J Clin Pharmacol. 2018 Dec;58(12):1604-1617. doi: 10.1002/jcph.1293. Epub 2018 Sep 25.

Population Pharmacokinetics of Lopinavir/Ritonavir: Changes Across Formulations and Human Development From Infancy Through Adulthood.

Author information

1
Skaggs School of Pharmacy and Pharmaceutical Science, University of California, San Diego, CA, USA.
2
Division of Hematology-Oncology, University of California, San Diego, CA, USA.
3
Division of Host-Microbe Systems and Therapeutics, University of California San Diego School of Medicine, San Diego, CA, USA.
4
Division of Immunology, School of Medicine, Federal University of Minas Gerais, Minas Gerais, Brazil.
5
Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
6
Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Los Angeles, CA, USA.
7
Division of Pediatric Infectious Diseases, Medical College of Wisconsin and Children's Hospital of Wisconsin, Milwaukee, WI, USA.
8
Division of Pediatric Infectious Diseases, Children's National Medical Center, The George Washington University, Washington, DC, USA.
9
Elizabeth Glaser Pediatric AIDS Foundation, Washington, DC, USA.

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.

KEYWORDS:

HIV; lopinavir; pediatrics; population pharmacokinetics; ritonavir; semiphysiologic modeling

PMID:
30252146
PMCID:
PMC6604805
[Available on 2019-12-01]
DOI:
10.1002/jcph.1293

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