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Characterization of the relationship between the pharmacokinetics of tolvaptan and the pharmacodynamic effects on urine volume after single and multiple doses of intravenous OPC—61815 and oral tolvaptan―A population pharmacokinetic/pharmacodynamic model―
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JPY
Abstract
Background/Objectives OPC-61815, a prodrug of the aquaretic drug tolvaptan, is being developed for administration as an intravenous infusion for patients with congestive heart failure(CHF). We developed a population pharmacokinetic/pharmacodynamic(PK/PD)model to characterize the relationship between the PK of tolvaptan and the PD effect of an increase in urine volume in patients with CHF and fluid retention. Methods Individual post hoc PK parameters were estimated and used to develop the model using a sequential approach. Goodness-of-fit and visual predictive check plots were generated to evaluate the adequacy of the final model. Interval urine volumes with varying OPC-61815 infusion durations were simulated and compared with oral tolvaptan. Results The base PK╱PD model consisted of four compartments: water intake, water in edema, water in plasma, and urine. Relationships between tolvaptan exposure and urine volume on day 1 of administration of OPC-61815 and tolvaptan for all doses were adequately described; thereafter, urine volumes at OPC-61815 ≤16 mg and tolvaptan ≤15 mg doses were adequately predicted, but were under-predicted at higher tolvaptan daily doses. The maximum increase in urine volume occurred faster with an OPC-61815 infusion of ≤1 hour versus ≥6 hours, based on the simulation. Conclusions The effect of tolvaptan on urine volume following OPC-61815 infusion and oral tolvaptan administration at clinical or lower doses was adequately described by a semi-mechanistic PK╱PD model incorporating circadian rhythm under the assumption that tolvaptan inhibits reabsorption of filtrated water. Based on the simulation with different infusion durations, an OPC-61815 1-hour infusion appears optimal. (Jpn Pharmacol Ther 2022;50:765‒79)
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