title: A Population Pharmacokinetic/Pharmacodynamic Model Predicts Favorable HDL Cholesterol Changes Over the First 5 Years in Children Treated With Current Efavirenz-Based Regimens.
abstract: Efavirenz use is associated with changes in cholesterol concentrations, but it is unclear whether this effect is related to drug concentrations. Using efavirenz and cholesterol plasma concentrations measured in 87 antiretroviral-naive children in Thailand, we assessed indirect response models to describe the evolution of high- and low-density lipoprotein (HDL, LDL) cholesterol concentrations in relation to efavirenz plasma concentrations over time where efavirenz was assumed to either stimulate cholesterol production or inhibit its elimination. Simulations of cholesterol evolution for children with different average efavirenz concentrations (Cav ) according to their assumed status of "fast" or "slow" metabolizers of efavirenz were performed. At treatment initiation, children's median (interquartile range, IQR) age was 8 years (5 to 10), body mass index z-score 0.01 (-1.05 to 1.44), HDL 31 mg/dL (24 to 44), and LDL 83 mg/dL (69 to 100). Median (IQR) efavirenz Cav was 1.7 mg/L (1.3 to 2.1) during the period of observation. The best model describing the evolution of HDL and LDL cholesterol concentrations over time assumed that efavirenz inhibited their elimination. HDL concentrations increase over 5 years, whereas LDL concentrations increased only during the first 4 months and then returned to baseline levels afterward. Simulations predicted that, after 3 years, HDL would increase to 63 mg/dL in "fast" metabolizers and 97 mg/dL in "slow" metabolizers of efavirenz. The population pharmacokinetic-pharmacodynamic (PK-PD) model shows that favorable HDL cholesterol changes can be expected in children with current efavirenz dosing guidelines over 5 years of treatment.
authors.affiliation: Institut de Recherche pour le Développement (IRD UMI 174), France, and Faculty of Associated Medical Sciences, Chiang Mai University, Chiang Mai, Thailand.|Department of Statistics, Faculty of Science, Kasetsart University, Bangkok, Thailand.|Ecole Doctorale de Santé Publique, Université Paris Saclay, France.
authors.forename: Nontiya
authors.initials: N
authors.lastname: Homkham
authors.affiliation: Institut de Recherche pour le Développement (IRD UMI 174), France, and Faculty of Associated Medical Sciences, Chiang Mai University, Chiang Mai, Thailand.|Harvard School of Public Health, Boston, MA, USA.
authors.forename: Tim R
authors.initials: TR
authors.lastname: Cressey
authors.affiliation: Department of Statistics, Faculty of Science, Kasetsart University, Bangkok, Thailand.
authors.forename: Lily
authors.initials: L
authors.lastname: Ingsrisawang
authors.affiliation: Unité de Recherche Clinique Paris Centre, Assistance Publique Hôpitaux de Paris, France.|CIC1419, INSERM & APHP, EAU08 Université Paris Descartes Sorbonne Paris Cité, France.
authors.forename: Naïm
authors.initials: N
authors.lastname: Bouazza
authors.affiliation: Prapokklao Hospital, Chanthaburi, Thailand.
authors.forename: Chaiwat
authors.initials: C
authors.lastname: Ngampiyaskul
authors.affiliation: Chonburi Hospital, Chonburi, Thailand.
authors.forename: Suchat
authors.initials: S
authors.lastname: Hongsiriwon
authors.affiliation: Kalasin Hospital, Kalasin, Thailand.
authors.forename: Sakulrat
authors.initials: S
authors.lastname: Srirojana
authors.affiliation: Nakornping Hospital, Chiang Mai, Thailand.
authors.forename: Suparat
authors.initials: S
authors.lastname: Kanjanavanit
authors.affiliation: National Health Security Office Chiang Mai Branch (Region 1), Chiang Mai, Thailand.
authors.forename: Sorakij
authors.initials: S
authors.lastname: Bhakeecheep
authors.affiliation: Institut de Recherche pour le Développement (IRD UMI 174), France, and Faculty of Associated Medical Sciences, Chiang Mai University, Chiang Mai, Thailand.|Institut d'Etudes Démographiques, Paris, France.
authors.forename: Sophie Le
authors.initials: SL
authors.lastname: Coeur
authors.affiliation: Institut de Recherche pour le Développement (IRD UMI 174), France, and Faculty of Associated Medical Sciences, Chiang Mai University, Chiang Mai, Thailand.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Salvadori
authors.affiliation: Unité de Recherche Clinique Paris Centre, Assistance Publique Hôpitaux de Paris, France.|CIC1419, INSERM & APHP, EAU08 Université Paris Descartes Sorbonne Paris Cité, France.
authors.forename: Jean Marc
authors.initials: JM
authors.lastname: Treluyer
authors.affiliation: Institut de Recherche pour le Développement (IRD UMI 174), France, and Faculty of Associated Medical Sciences, Chiang Mai University, Chiang Mai, Thailand.|Harvard School of Public Health, Boston, MA, USA.
authors.forename: Gonzague
authors.initials: G
authors.lastname: Jourdain
authors.affiliation: Unité de Recherche Clinique Paris Centre, Assistance Publique Hôpitaux de Paris, France.|CIC1419, INSERM & APHP, EAU08 Université Paris Descartes Sorbonne Paris Cité, France.
authors.forename: Saik
authors.initials: S
authors.lastname: Urien
mesh_terms: D000480:Alkynes; D048588:Benzoxazines / Q000097:blood* / Q000493:pharmacokinetics / Q000627:therapeutic use; D002648:Child; D002675:Child, Preschool; D008076:Cholesterol, HDL / Q000097:blood*; D015331:Cohort Studies; D003521:Cyclopropanes; D005260:Female; D015658:HIV Infections / Q000097:blood* / Q000188:drug therapy* / Q000453:epidemiology; D006801:Humans; D008297:Male; D008954:Models, Biological; D011159:Population Surveillance; D011237:Predictive Value of Tests; D013785:Thailand / Q000453:epidemiology; D016896:Treatment Outcome
chemical_list: D000480:Alkynes; D048588:Benzoxazines; D008076:Cholesterol, HDL; D003521:Cyclopropanes; C098320:efavirenz
keywords: children; efavirenz; lipids; pharmacodynamics; pharmacokinetics