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

Abstract

Lopinavir/ritonavir (LPV/r) is recommended by the World Health Organization (WHO) 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 six 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) with a one compartment semi-physiologic model. Lopinavir 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 (FH) and the fraction absorbed from the GI tract (FABS). The absorption component of bioavailability increased with age and tablet formulation. Monte Carlo simulations of the final model using current WHO weight band dosing recommendations demonstrated that participants younger than 6 months of age had lower AUC (94.8 vs >107.4 mcg•hr/mL) and Cmin (5.0 vs > 7.1 mcg/mL) values compared to older children and adults. Although WHO dosing recommendations include a larger dosage (mg/m2) in infants to account for higher apparent clearance (CL/F), they still result in low LPV concentrations in many infants younger than 6 months of age receiving the liquid formulation.

Reduced Exposure to Piperaquine, Compared to Adults, in Young Children Receiving Dihydroartemisinin‐Piperaquine as Malaria Chemoprevention

“…Likewise, terminal concentrations were 35–60% lower at 32 and 104 weeks compared with adult values. Our results suggest that CYP450 metabolism is greater than expected in young children when compared with adults, as shown for other CYP450 substrates . CYP450 enzymes mature to adult levels over the first 12 months of life .…”

Pharmacokinetics and Safety of Zidovudine, Lamivudine, and Lopinavir/Ritonavir in HIV-infected Children With Severe Acute Malnutrition in Sub-Saharan Africa: IMPAACT Protocol P1092

“… 17 Our CL/F values were also comparable with those previously reported in children from both resource rich and poor countries. 17 , 18 …”

Optimizing Pediatric Dosing Recommendations and Treatment Management of Antiretroviral Drugs Using Therapeutic Drug Monitoring Data in Children Living With HIV

“…A dramatic decrease in relative clearance with increasing age was noted in the first 2 years of life, and an increase in bioavailability was observed when children were switched from liquid formulation to tablet formulation, providing evidence for the need to re-evaluate current dosing of LPV in young children or perhaps change to a different formulation such as LPV/r oral pellets. 107 LPV/r oral pellets have shown to increase exposure compared with the liquid LPV/r formulation in children in the CHAPAS-2 trial and were associated with high levels of viral suppression in the LIVING study. 108,109 These oral pellets are currently approved by the WHO and the FDA under the PEPFAR program.…”