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Pharmacokinetic Profile of OPC‐8212 in Humans: A New, Nonglycosidic, Inotropic Agent
Author(s) -
Ohnishi Akihiro,
Ishizaki Takashi
Publication year - 1988
Publication title -
the journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.92
H-Index - 116
eISSN - 1552-4604
pISSN - 0091-2700
DOI - 10.1002/j.1552-4604.1988.tb03206.x
Subject(s) - pharmacokinetics , volunteer , urine , steady state (chemistry) , pharmacology , dosing , chemistry , medicine , oral administration , endocrinology , biology , agronomy
OPC‐8212, a new inotropic agent, was administered orally as a single 7.5‐, 15‐, 30‐, 60‐, 120‐, or 240‐mg dose in a sequentially ascending order to 21 male healthy volunteers to determine the pharmacokinetic profile. Each volunteer received one of the six doses after an overnight fast. After the single‐dose study was completed and the safety and tolera‐bility were ascertained, 3 of the 21 volunteers participated in a 15‐day repeated‐dose (30 mg once daily) study to determine the steady‐state kinetic profile. The AUC 0‐∞ and C max values were proportional to doses (mg or mg/kg, P <.001). The mean elimination t 1/2 , apparent oral clearance (CL/FJ and percentage fraction of dose excreted unchanged in urine up to 336 hours postdose (fe 0–336 ) appeared to be comparable among the six single doses examined. The overall mean (±SEM) kinetic parameters obtained from the 21 subjects were: 44.7 ± 1.2 hours for t 1/2 , 0.284 ± 0.018 L/hv or 4.49 ± 0.28 mL/hr/kg for CL/F, and 17.7 ± 0.9% for fe 0–336. A steady state of the drug appeared to be attained by about day 9 after the initiation of the repeated dosing: the mean postdose 2‐ and 24‐hour plasma drug concentrations observed during days 9 to 15 ranged from 6.3 ± 0.5 μg/ig/mL to 6.9 ± 0.6 fig/ml and from 3.6 ± 0.7 μg/mL to 4.0 ± 0.6 μg/mL, respectively. The mean fraction of the daily dose excreted unchanged in urine over the dosing interval (fe 0‐r ) during days 9 to 15 ranged from 19.2 ± 1.4% to 25.6 ± 0.6%. The mean elimination t 1/2 and CL/F observed after the final dose were comparable not only to the overall mean but also to that from the same 30 mg in the single‐dose study. The results suggest that the elimination of OPC‐8212 is dose independent and the plasma concentrations attained are proportional to doses. The drug appears neither to inhibit nor to induce its own metabolism during the repeated doses. This new, nonglycosidic, inotropic agent may be given on a once‐daily basis (like digoxin) to treat patients with congestive heart failure.