A Phase II/III Trial of Lopinavir/Ritonavir Dosed According to the WHO Pediatric Weight Band Dosing Guidelines

Pinto, Jorge; Capparelli, Edmund V.; Warshaw, Meredith G.; Zimmer, Bonnie; Cressey, Tim R.; Spector, Stephen A.; Qin, Min; Smith, Betsy; Siberry, George K.; Mirochnick, Mark

doi:10.1097/inf.0000000000001817

Cited by 8 publications

(6 citation statements)

References 13 publications

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“…The pediatric studies were pediatric AIDS Clinical Trials Group P1030, P1038, P1080, P1083, and a pediatric pharmacology research unit (PPRU) study . The adult data sets were derived from P1080 and a protocol of a national study from California Collaborative Treatment Group (CCTG) study 585 .…”

Section: Methodsmentioning

confidence: 99%

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

Yang

Nikanjam

Best

et al. 2018

The Journal of Clinical Pharma

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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.

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Section: Methodsmentioning

confidence: 99%

“…Participants received 2 NRTIs in addition to LPV/r. Intensive LPV/r PK profiles were assessed 4 weeks after the initial treatment, with up to 6 plasma samples collected during the 12‐hour dosing interval, which included a baseline and trough after observed dose …”

Section: Methodsmentioning

confidence: 99%

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

Yang

Nikanjam

Best

et al. 2018

The Journal of Clinical Pharma

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“…In order to encourage public health approach and increase access of children to ART, the WHO introduced weight-band dosing in the effort to simplify the use of mg/m2 and mg/kg methods which require the involvement calculations by the prescriber/pharmacist 15,16 . However, the main disadvantage of weight-band dosing is that the children on the higher and lower ends of one weight band are likely to receive either a higher or lower dose which may lead to toxicity or ineffective treatment.…”

Section: Discussionmentioning

confidence: 99%

Performance of the allometric power model in scaling from adult to paediatric antiretroviral dose in children at a Referral Hospital in Windhoek, Namibia

Singu¹,

Akpabio²,

Verbeeck³

2022

Afr H. Sci.

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Background: World Health Organization (WHO) advocates use of weight bands in antiretroviral therapy (ART) guidelines. Allometric scaling could be a more reliable method because it uses a non-linear approach in relating dose to body weight. This study evaluates performance of the allometric ¾ power model in comparison to WHO weight band method in children receiving ART. Methods: Records of children receiving (ABC/3TC) + DTG were reviewed. Paediatric ABC/3TC dose was calculated from the adult dose using the allometric ¾ power model and compared to WHO weight band dose. Results: WHO weight band strategy grouped 50.6% of the children in the 25 kg category and therefore received the adult dose of ABC/3TC (600 mg/300 mg); only 1.1% received this dose with allometric scaling. Mean dose (3.8 tablets) for the WHO weight band dosing method was found to be significantly higher (p<0.0001) than for allometric scaling (1.5 tablets). Conclusions: WHO weight bands may result in the 25 kg weight category receiving a much higher dose leading to ADRs. Using allometric scaling, we recommend a weight band strategy that could improve paediatric ABC/3TC dosing. Keywords: Dose; weight; children; antiretrovirals; BSA; allometric scaling.

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“…The target LPV exposure was defined as an AUC 0-12 between 40 and 160 mg•h/mL, as reported in older children, and an LPV concentration at 12 hours after dosing (C 12 ) above 1.0 mg/L. 13…”

Section: Simulationsmentioning

confidence: 99%

Population Pharmacokinetics of Pediatric Lopinavir/Ritonavir Oral Pellets in Children Living with HIV in Africa

Chupradit,

Wamalwa,

Maleche‐Obimbo

et al. 2024

Clin Pharma and Therapeutics

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Antiretroviral therapy for children living with HIV (CLHIV) under 3 years of age commonly includes lopinavir/ritonavir (LPV/r). However, the original liquid LPV/r formulation has taste and cold storage difficulties. To address these challenges, LPV/r oral pellets have been developed. These pellets can be mixed with milk or food for administration and do not require refrigeration. We developed the population pharmacokinetic (PK) model and assessed drug exposure of LPV/r oral pellets administered twice daily to CLHIV per World Health Organization (WHO) weight bands. The PK analysis included Kenyan and Ugandan children participating in the LIVING studies (NCT02346487) receiving LPV/r pellets (40/10 mg) and ABC/3TC (60/30 mg) dispersible tablets. Population PK models were developed for lopinavir (LPV) and ritonavir (RTV) to evaluate the impact of RTV on the oral clearance (CL/F) of LPV. The data obtained from the study were analyzed using nonlinear mixed‐effects modeling approach. Data from 514 children, comprising a total of 2,998 plasma concentrations of LPV/r were included in the analysis. The LPV and RTV concentrations were accurately represented by a one‐compartment model with first‐order absorption (incorporating a lag‐time) and elimination. Body weight influenced LPV and RTV PK parameters. The impact of RTV concentrations on the CL/F of LPV was characterized using a maximum effect model. Simulation‐predicted target LPV exposures were achieved in children with this pellet formulation across the WHO weight bands. The LPV/r pellets dosed in accordance with WHO weight bands provide adequate LPV exposures in Kenyan and Ugandan children weighing 3.0 to 24.9 kg.

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A Phase II/III Trial of Lopinavir/Ritonavir Dosed According to the WHO Pediatric Weight Band Dosing Guidelines

Abstract: WHO weight band dosing guidelines in children achieved adequate LPV plasma exposure but was higher than that expected with Food and Drug Administration dosing guidelines. Despite the higher LPV exposure, the treatment was well tolerated and the 24-week efficacy data were favorable.

Cited by 8 publications

References 13 publications

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

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

Performance of the allometric power model in scaling from adult to paediatric antiretroviral dose in children at a Referral Hospital in Windhoek, Namibia

Population Pharmacokinetics of Pediatric Lopinavir/Ritonavir Oral Pellets in Children Living with HIV in Africa

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