title: How to handle missed or delayed doses of tacrolimus in renal transplant recipients? A pharmacokinetic investigation.
abstract: Every transplant patient will, at least occasionally, miss immunosuppressive drug doses or take them outside the prescribed times. This study aims at quantifying the impact of poor execution on tacrolimus exposure in renal transplant patients. Validated pharmacokinetic tools applied in clinical setting were used to simulate the steady-state pharmacokinetic profiles of the drug when given as the immediate-release formulation to renal transplant patients, being CYP3A5 expressors or not, and who have reached either a standard or a minimized exposure. Situations of interruption due to a missed or delayed dose were simulated and the impact on drug exposure was explored. In case of a missed dose, it was observed that: (i) a single forgotten dose can greatly impact exposure: up to 49% decrease for tacrolimus trough concentration and 70% for AUC0-12 h in patients with the highest clearance values; (ii) patients with a minimized exposure are the most affected by a missed dose; and (iii) a dose of 1.5 times the usual dose may be recommended after a total dose oversight. Considering that intra-patient exposure variability is a predictive factor of poor graft outcome, these modeling results may serve as recommendations for patients, both preventively and in response to their questions.
authors: CHU Limoges, Department of Pharmacology and Toxicology, Limoges, France; INSERM UMR 850, Limoges, France; Univ Limoges, France.
authors: Franck
authors: F
authors: Saint-Marcoux
authors: CHU Limoges, Department of Pharmacology and Toxicology, Limoges, France; INSERM UMR 850, Limoges, France; Univ Limoges, France.
authors: Jean-Baptiste
authors: JB
authors: Woillard
authors: CHU Limoges, Department of Pharmacology and Toxicology, Limoges, France; INSERM UMR 850, Limoges, France; Univ Limoges, France.
authors: Caroline
authors: C
authors: Monchaud
authors: CHU Limoges, Department of Pharmacology and Toxicology, Limoges, France.
authors: Jennifer
authors: J
authors: Friedl
authors: CHU Limoges, Department of Nephrology, Limoges, France.
authors: Frédérique
authors: F
authors: Bocquentin
authors: INSERM UMR 850, Limoges, France; Univ Limoges, France; CHU Limoges, Department of Nephrology, Limoges, France.
authors: Marie
authors: M
authors: Essig
authors: CHU Limoges, Department of Pharmacology and Toxicology, Limoges, France; INSERM UMR 850, Limoges, France; Univ Limoges, France. Electronic address: pierre.marquet@unilim.fr.
authors: Pierre
authors: P
authors: Marquet
mesh_terms: D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D016903:Drug Monitoring / Q000379:methods; D005838:Genotype; D006084:Graft Rejection / Q000378:metabolism / Q000517:prevention & control*; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism; D016030:Kidney Transplantation / Q000379:methods; D016559:Tacrolimus / Q000008:administration & dosage* / Q000493:pharmacokinetics*
chemical_list: D007166:Immunosuppressive Agents; D051544:Cytochrome P-450 CYP3A; D016559:Tacrolimus
keywords: CYP3A5; Delayed dose; Missed dose; Pharmacokinetics; Poor execution; Renal transplantation; Tacrolimus