Pharmacokinetics and Virological Efficacy after Switch to Once-Daily Lopinavir-Ritonavir in Treatment-Experienced HIV-1-Infected Children

Foissac, Frantz; Urien, Saı̈k; Hirt, Déborah; Frange, Pierre; Chaix, Marie Laure; Tréluyer, Jean‐Marc; Blanche, Stéphane

doi:10.1128/aac.00166-11

Cited by 18 publications

(12 citation statements)

References 15 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Lopinavir/ritonavir therapy is not currently recommended for once daily use in pediatric patients and its use has been associated with lower troughs and worse virologic control in ARV-experienced children. (29) …”

Section: Discussionmentioning

confidence: 99%

Pharmacokinetics of Lopinavir/Ritonavir Crushed Versus Whole Tablets in Children

Best

Capparelli

Diep

et al. 2011

JAIDS Journal of Acquired Immune Deficiency Syndromes

View full text Add to dashboard Cite

Objective Lopinavir/ritonavir (Kaletra®) is first line therapy for pediatric HIV infection. In clinical practice, Kaletra® tablets are occasionally crushed for pediatric administration. This study compared lopinavir/ritonavir exposure between whole and crushed tablets in HIV-infected children. Design This was a randomized, open-label, cross-over study of pediatric patients taking lopinavir/ritonavir as part of their antiretroviral regimen. Each subject had two separate (within 30 days) steady-state 12-hour pharmacokinetic (PK) studies with crushed and whole 200/50 mg lopinavir/ritonavir tablets. Methods PK blood samples were drawn at 0 (pre-dose), 1, 2, 4, 6, 8, and 12 hours post-dose. Lopinavir and ritonavir plasma concentrations measured by high performance liquid chromatography were used to calculate non-compartmental area under the concentration versus time curve (AUC) and clearance (CL/F). Wilcoxon signed-rank tests compared PK values between crushed and whole tablets. Results Twelve children, median age of 13 years (10–16 years), took 550/138 mg/m2/day lopinavir/ritonavir divided every 12 hours. The median lopinavir AUC following crushed and whole tablets were 92 mg*hr/L and 144 mg*hr/L, respectively, with an AUC ratio of 0.55 (p=0.003). Median ritonavir AUC of crushed and whole tablets were 7 mg*hr/L and 13.3 mg*hr/L, respectively, with an AUC ratio of 0.53 (p=0.006). Conclusions Administration of crushed 200/50 mg lopinavir/ritonavir tablets to children significantly reduced lopinavir and ritonavir exposure with a decrease in AUC by 45% and 47%, respectively. The administration of crushed tablets would require higher doses and therapeutic drug monitoring to ensure adequate lopinavir exposure in patients requiring this practice. The use of crushed lopinavir/ritonavir tablets should be avoided, if possible.

show abstract

Section: Discussionmentioning

confidence: 99%

Pharmacokinetics of Lopinavir/Ritonavir Crushed Versus Whole Tablets in Children

Best

Capparelli

Diep

et al. 2011

JAIDS Journal of Acquired Immune Deficiency Syndromes

View full text Add to dashboard Cite

show abstract

“…18 C 50LPV was the concentration at which the drug effect reaches 50% of its maximum. The individual trough concentrations for all patients were obtained using Bayesian estimation approach from the population pharmacokinetic model previously published in the same pediatric population.…”

Section: Hiv Dynamic Modelmentioning

confidence: 99%

“…18 The parameters of the model were the production rate constant of uninfected TC (So), elimination rate constant of TC (Td), elimination rate constant of IC (δ), production rate constant of VL (p), infection rate constant of TC (β), VL at baseline (VL 0 ), CD4 at baseline (CD4 0 ) and C 50LPV . 18 The parameters of the model were the production rate constant of uninfected TC (So), elimination rate constant of TC (Td), elimination rate constant of IC (δ), production rate constant of VL (p), infection rate constant of TC (β), VL at baseline (VL 0 ), CD4 at baseline (CD4 0 ) and C 50LPV .…”

Section: Population Modelingmentioning

confidence: 99%

Concentration-response Model of Lopinavir/Ritonavir in HIV-1–infected Pediatric Patients

Bouazza¹,

Urien²,

Blanche³

et al. 2014

Pediatric Infectious Disease Journal

Self Cite

View full text Add to dashboard Cite

show abstract

“…Indeed, the covariates were evaluated via upward-backward model building, as previously described (25). A covariate was selected if (i) it produced a minimum decrease of 6.63 units ( 2 with 1 degree of freedom, P Ͻ 0.01) in the objective function value (OFV), (ii) it produced a reduction in the variability of the pharmacokinetic parameter(s), as assessed by the associated BSV, and (iii) its effect was physiologically plausible.…”

Section: Methodsmentioning

confidence: 99%

Population Pharmacokinetics Study of Recommended Zidovudine Doses in HIV-1-Infected Children

Fauchet

Tréluyer

Frange

et al. 2013

Antimicrob Agents Chemother

Self Cite

View full text Add to dashboard Cite

The aims of this study were to describe the pharmacokinetics of zidovudine (ZDV) and its biotransformation to its metabolite, 3*-azido-3*-deoxy-5*-glucuronylthymidine (G-ZDV), in HIV-infected children, to identify factors that influence the pharmacokinetics of ZDV, and to compare and evaluate the doses recommended by the World Health Organization (WHO) and the Food and Drug Administration (FDA). ZDV concentrations in 782 samples and G-ZDV concentrations in 554 samples from 247 children ranging in age from 0.5 to 18 years were retrospectively measured. A population pharmacokinetic model was developed with NONMEM software (version 6.2), and the pharmacokinetics of ZDV were best described by a one-compartment model with first-order absorption and elimination. The effect of body weight on the apparent elimination clearance and volume of distribution was significant. The mean population parameter estimates were as follows: absorption rate, 2.86 h ؊1 ; apparent elimination clearance, 89.7 liters · h ؊1 (between-subject variability, 0.701 liters · h ؊1 ); apparent volume of distribution, 229 liters (betweensubject variability, 0.807 liters); metabolic formation rate constant, 12.6 h ؊1 (between-subject variability, 0.352 h ؊1 ); and elimination rate constant of G-ZDV, 2.27 h ؊1 . On the basis of simulations with FDA and WHO dosing recommendations, the probabilities of observing efficient exposures (doses resulting in exposures of between 3 and 5 mg/liter · h) with less adverse events (doses resulting in exposures below 8.4 mg/liter · h) were higher when the FDA recommendations than when the WHO recommendations were followed. In order to improve the FDA recommendations, ZDV doses should be reconsidered for the weight band (WB) of 20 to 40 kg. The most appropriate doses should be decreased from 9 to 8 mg/kg of body weight twice a day (BID) for the WB from 20 to 29.9 kg and from 300 to 250 mg BID for the WB from 30 to 39.9 kg. The highest dose, 300 mg BID, should be started from body weights of 40 kg. Z idovudine (ZDV) was the first antiretroviral drug allowed by the Food and Drug Administration (FDA) and approved for the treatment of children with HIV infection (1). It was the most prescribed monotherapy in children and adults, and currently, ZDV-containing regimens are still recommended as first-line combination regimens for infants and children by the World Health Organization (WHO) (2). However, limited pharmacokinetic (PK) studies have been conducted in children (small size, narrow range of ages and/or body weight, single-dose regimen, and the doses administered were different from the last doses recommended) (3-11).Recommended dosing regimens have changed in recent years. Before 2009, the ZDV dosage was based on the body surface area (BSA). The recommended oral dose was 480 mg/m 2 /day given as 240 mg/m 2 twice daily (BID) or 160 mg/m 2 three times daily (TID) (12). The equivalent weight-based dose of 480 mg/m 2 /day for an average child with a BSA of 1 m 2 and a weight of 32 kg is approximately 15 mg/kg of body wei...

show abstract

Pharmacokinetics and Virological Efficacy after Switch to Once-Daily Lopinavir-Ritonavir in Treatment-Experienced HIV-1-Infected Children

Cited by 18 publications

References 15 publications

Pharmacokinetics of Lopinavir/Ritonavir Crushed Versus Whole Tablets in Children

Pharmacokinetics of Lopinavir/Ritonavir Crushed Versus Whole Tablets in Children

Concentration-response Model of Lopinavir/Ritonavir in HIV-1–infected Pediatric Patients

Population Pharmacokinetics Study of Recommended Zidovudine Doses in HIV-1-Infected Children

Contact Info

Product

Resources

About