Time of effect duration and administration interval for sitagliptin in patients with kidney failure

Abstract

A measure correlating the time course of the effect with the time course of concentrations could be helpful in drug dosing. We propose a new equation with explicit solutions for calculating the effect duration. A specific effect fraction is selected (fr) and the time of fractional effect duration (TED.fr) can be derived as a function of the elimination half-life by combining linear elimination kinetics with sigmoid effect dynamics. This new measure is applied to the example of sitagliptin, whose elimination half-life increases from 10.1 to 28.4 h in patients with kidney failure. Under normal multiple-dose conditions, the 24-h sitagliptin administration interval corresponds to a 0.90 time of fractional effect duration (TED.90). A dose reduction to one-fourth or 25 mg every 24 h is proposed for patients with kidney failure; this results in a TED.90 of 45 h, i.e. 21 h longer than the proposed 24-h administration interval (+88 %). The proportional dosing alternative of 100 mg every 96 h would result in a TED.90 of 64 h, which is 32 h less than the 96-h administration interval (-33 %). With a half dose of 50 mg and a doubled administration interval of 48 h, the TED.90 is 51 h in kidney failure, only 3 h longer than the latter administration interval (+6 %). We conclude that our general equation can be applied to rapidly calculate the specific time of effect duration for the different dose schedules.

Proteínas lácteas como fuente dietaria de biopéptidos antidiabéticos: Estudio de la nutracéutica de los lácteos en la diabetes mellitus desde la biología computacional

“…Los hallazgos reportados en estudios previos ponen en evidencia el perfil bioactivo de las proteínas lácteas (20), no obstante, carecen de una descripción de la potencia de inhibición de DPP-IV y de las características de absorción y excreción que facilitan la comparación con medicamentos empleados en la farmacoterapia actual. Keller et al (21) determinaron para la sitagliptina un efecto terapéutico con un pEC50 cercano a 7,52, a partir del cual se infiere que los biopéptidos, al exhibir valores de pEC50 considerablemente menores, carecen de la potencia inhibitoria de los fármacos iDPP-IV.…”

Pharmacokinetics and Clinical Use of Incretin-Based Therapies in Patients with Chronic Kidney Disease and Type 2 Diabetes

“…Sitagliptin was generally well tolerated, with a lower risk of hypoglycaemia (6.2 versus 17.0 %) and weight loss (-0.6 kg) versus weight gain (?1.2 kg), relative to glipizide [45]. A general equation has been proposed to rapidly calculate the specific time of effect duration for the different dose schedules in the case of CKD [46].…”

The Use of Gene Ontology Term and KEGG Pathway Enrichment for Analysis of Drug Half-Life

“…Therefore, the metabolic abilities of the hepatic microsomal enzymes may greatly affect the speed of drug metabolism and may further influence their half-lives [23]. For the elimination processes, the kidney is the junction of the urinary system and the circulating system and also affects the half-life of drugs [24, 25]. For example, the accumulation of aminoglycosides has been confirmed during diseases of the kidney [26].…”