title: Optimized administration regimen of lopinavir for a myocardial ischaemia reperfusion study in Sprague-Dawley rats.
abstract: Pharmacokinetics of drugs may differ between small and large mammals (including humans); therefore, drug testing in animal models must be carefully designed. Sprague-Dawley rats were used in cardiac experiments, during which the lopinavir concentration in serum had to match human therapeutic levels (4-10 μg/mL). Lopinavir was administered as a co-formulated drug of lopinavir and ritonavir. It was found that after a single administration of a standard human peroral dose (lopinavir 13.3 mg/kg of body weight), the serum concentration of lopinavir was only one-tenth of the target level. It remained below the minimum target level even after 10-fold the standard dose was administered. After initial pilot tests, a dose escalation study was conducted with oral doses 10- and 15-fold the standard clinical dose of lopinavir (i.e. 133 and 200 mg/kg, respectively). A second administration 2 h later effectively increased and maintained higher concentrations during the experimental ischaemia and reperfusion periods. A dose-dependent increase in serum concentration of the drug was observed. Thus, the target therapeutic serum level of lopinavir in the rats was achieved by administrating 10- to 15-fold the standard human dose twice, separated by a 2 h interval.
authors.affiliation: Division of Cardiovascular Diseases, Mayo Clinic, 13400 E Shea Blvd, Scottsdale, AZ 85259, USA.
authors.forename: M
authors.initials: M
authors.lastname: Katayama
authors.forename: P
authors.initials: P
authors.lastname: Jiamsripong
authors.forename: A E
authors.initials: AE
authors.lastname: Bukatina
authors.forename: T R
authors.initials: TR
authors.lastname: Lombari
authors.forename: E M
authors.initials: EM
authors.lastname: McMahon
authors.forename: N M
authors.initials: NM
authors.lastname: Gades
authors.forename: M
authors.initials: M
authors.lastname: Belohlavek
mesh_terms: D000818:Animals; D002851:Chromatography, High Pressure Liquid; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D017320:HIV Protease Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics*; D006993:Hypnotics and Sedatives / Q000008:administration & dosage; D007274:Injections, Intraperitoneal; D061466:Lopinavir / Q000008:administration & dosage / Q000493:pharmacokinetics*; D008297:Male; D017202:Myocardial Ischemia / Q000188:drug therapy*; D015425:Myocardial Reperfusion / Q000379:methods*; D010424:Pentobarbital / Q000008:administration & dosage; D051381:Rats; D017207:Rats, Sprague-Dawley; D019438:Ritonavir / Q000008:administration & dosage / Q000493:pharmacokinetics*; D013045:Species Specificity
chemical_list: D004338:Drug Combinations; D017320:HIV Protease Inhibitors; D006993:Hypnotics and Sedatives; D061466:Lopinavir; D010424:Pentobarbital; D019438:Ritonavir