title: Pharmacokinetics of dolutegravir when administered with mineral supplements in healthy adult subjects.
abstract: All commercially available integrase inhibitors are 2-metal binders and may be affected by co-administration with metal cations. The purpose of this study was to evaluate the effect of calcium and iron supplements on dolutegravir pharmacokinetics and strategies (dose separation and food) to attenuate the effects if significant reductions in dolutegravir exposure were observed. This was an open-label, crossover study that randomized 24 healthy subjects into 1 of 2 cohorts to receive 4 treatments: (1) dolutegravir alone, fasting; (2) dolutegravir with calcium carbonate or ferrous fumarate, fasting; (3) dolutegravir with calcium carbonate or ferrous fumarate with a moderate-fat meal; (4) dolutegravir administered 2 hours before calcium carbonate or ferrous fumarate, fasting. Plasma dolutegravir AUC(0-∞), Cmax , and C24 were reduced by 39%, 37%, and 39%, respectively, when co-administered with calcium carbonate while fasting and were reduced by 54%, 57%, and 56%, respectively, when co-administered with ferrous fumarate while fasting. Dolutegravir administration 2 hours before calcium or iron supplement administration (fasted), as well as administration with a meal, counteracted the effect. Dolutegravir and calcium or iron supplements can be co-administered if taken with a meal. Under fasted conditions, dolutegravir should be administered 2 hours before or 6 hours after calcium or iron supplements.
authors.affiliation: GlaxoSmithKline, Research Triangle Park, NC, USA.
authors.forename: Ivy
authors.initials: I
authors.lastname: Song
authors.forename: Julie
authors.initials: J
authors.lastname: Borland
authors.forename: Niki
authors.initials: N
authors.lastname: Arya
authors.forename: Brian
authors.initials: B
authors.lastname: Wynne
authors.forename: Stephen
authors.initials: S
authors.lastname: Piscitelli
mesh_terms: D000284:Administration, Oral; D000328:Adult; D019540:Area Under Curve; D002119:Calcium Carbonate / Q000494:pharmacology*; D018592:Cross-Over Studies; D019587:Dietary Supplements; D004336:Drug Antagonism; D005215:Fasting; D005260:Female; D005296:Ferrous Compounds / Q000494:pharmacology*; D018565:Food-Drug Interactions; D019428:HIV Integrase Inhibitors / Q000493:pharmacokinetics*; D006207:Half-Life; D006575:Heterocyclic Compounds, 3-Ring / Q000493:pharmacokinetics*; D006801:Humans; D008297:Male; D008657:Metabolic Clearance Rate; D010078:Oxazines; D010879:Piperazines; D011728:Pyridones; D000099226:Dolutegravir
chemical_list: D002119:Calcium Carbonate; D005296:Ferrous Compounds; D019428:HIV Integrase Inhibitors; D006575:Heterocyclic Compounds, 3-Ring; D010078:Oxazines; D010879:Piperazines; D011728:Pyridones; D000099226:Dolutegravir; C031621:ferrous fumarate
keywords: calcium carbonate; dolutegravir; drug interaction; ferrous fumarate; pharmacokinetics