Coadministration of ticagrelor and ritonavir: Toward prospective dose adjustment to maintain an optimal platelet inhibition using the PBPK approach.
Ticagrelor is a potent antiplatelet drug metabolized by cytochrome (CYP)3A. It is contraindicated in patients with human immunodeficiency virus (HIV) because of the expected CYP3A inhibition by most protease inhibitors, such as ritonavir and an increased bleeding risk. In this study, a physiologically based pharmacokinetic (PBPK) model was created for ticagrelor and its active metabolite (AM). Based on the simulated interaction between ticagrelor 180 mg and ritonavir 100 mg, a lower dose of ticagrelor was calculated to obtain, when coadministered with ritonavir, the same pharmacokinetic (PK) and platelet inhibition as ticagrelor administered alone. A clinical study was thereafter conducted in healthy volunteers. Observed PK profiles of ticagrelor and its AM were successfully predicted with the model. Platelet inhibition was nearly complete in both sessions despite administration of a fourfold lower dose of ticagrelor in the second session. This PBPK model could be prospectively used to broaden the usage of ticagrelor in patients with ritonavir-treated HIV regardless of the CYP3A inhibition.
Clinical Pharmacology and Toxicology Service, Geneva University Hospitals, Switzerland.|School of Pharmaceutical Sciences, Geneva University, Switzerland.
N
N
Marsousi
Clinical Pharmacology and Toxicology Service, Geneva University Hospitals, Switzerland.|Swiss Center for Applied Human Toxicology (SCAHT), University of Geneva, Switzerland.
C F
CF
Samer
Division of Angiology and Haemostasis, Geneva University Hospitals, Switzerland.|Geneva Platelet Group, Faculty of Medicine, University of Geneva, Switzerland.
P
P
Fontana
Geneva Platelet Group, Faculty of Medicine, University of Geneva, Switzerland.|Department of General Internal Medicine, Rehabilitation and Geriatrics, Geneva University Hospitals, Switzerland.
J L
JL
Reny
School of Pharmaceutical Sciences, Geneva University, Switzerland.|Swiss Center for Applied Human Toxicology (SCAHT), University of Geneva, Switzerland.
S
S
Rudaz
Clinical Pharmacology and Toxicology Service, Geneva University Hospitals, Switzerland.|School of Pharmaceutical Sciences, Geneva University, Switzerland.|Swiss Center for Applied Human Toxicology (SCAHT), University of Geneva, Switzerland.
J A
JA
Desmeules
Clinical Pharmacology and Toxicology Service, Geneva University Hospitals, Switzerland.|School of Pharmaceutical Sciences, Geneva University, Switzerland.|Swiss Center for Applied Human Toxicology (SCAHT), University of Geneva, Switzerland.
Y
Y
Daali
D000241:Adenosine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D000328:Adult; D019540:Area Under Curve; D001792:Blood Platelets / Q000187:drug effects; D065692:Cytochrome P-450 CYP3A Inhibitors / Q000494:pharmacology*; D017320:HIV Protease Inhibitors / Q000494:pharmacology*; D006207:Half-Life; D006801:Humans; D007654:Ketoconazole / Q000494:pharmacology; D008297:Male; D008657:Metabolic Clearance Rate; D010975:Platelet Aggregation Inhibitors / Q000493:pharmacokinetics*; D011446:Prospective Studies; D019438:Ritonavir / Q000494:pharmacology*; D000077486:Ticagrelor; D055815:Young Adult
D065692:Cytochrome P-450 CYP3A Inhibitors; D017320:HIV Protease Inhibitors; D010975:Platelet Aggregation Inhibitors; D000077486:Ticagrelor; D000241:Adenosine; D019438:Ritonavir; D007654:Ketoconazole