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Pharmacokinetic and pharmacodynamic variability of fluindione in octogenarians.

ABSTRACT: In the PREPA observational study, we investigated the factors influencing pharmacokinetic and pharmacodynamic variability in the responses to fluindione, an oral anticoagulant drug, in a general population of octogenarian inpatients.Measurements of fluindione concentrations and international normalized ratio (INR ) were obtained for 131 inpatients in whom fluindione treatment was initiated. Treatment was adjusted according to routine clinical practice. The data were analyzed using nonlinear mixed-effects modeling, and the parameters were estimated using MONOLI X 3.2. The pharmacokinetics (PK) of fluindione was monocompartmental, whereas the evolution of INR was modeled in accordance with a turnover model (inhibition of vitamin K recycling). Interindividual variability (II V) was very large. Clearance decreased with age and with prior administration of cordarone. Patients who had undergone surgery before the study had lower IC50 values, leading to an increased sensitivity to fluindione. Pharmacokinetic exposure is substantially increased in elderly patients, warranting a lower dose of fluindione.

SUBMITTER: Comets E

PROVIDER: S-EPMC3789273 | biostudies-literature | 2012 May

REPOSITORIES: biostudies-literature

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Pharmacokinetic and pharmacodynamic variability of fluindione in octogenarians.

Comets E E Diquet B B Legrain S S Huisse M-G MG Godon A A Bruhat C C Chauveheid M-P MP Delpierre S S Duval X X Berrut G G Verstuyft C C Aumont M-C MC Mentré F F

Clinical pharmacology and therapeutics 20120501 5

In the PREPA observational study, we investigated the factors influencing pharmacokinetic and pharmacodynamic variability in the responses to fluindione, an oral anticoagulant drug, in a general population of octogenarian inpatients.Measurements of fluindione concentrations and international normalized ratio (INR ) were obtained for 131 inpatients in whom fluindione treatment was initiated. Treatment was adjusted according to routine clinical practice. The data were analyzed using nonlinear mixe ...[more]

PMID: 22472992

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Project description:BackgroundDexmedetomidine is only approved for use in humans as an intravenous medication. An oral formulation may broaden the use and benefits of dexmedetomidine to numerous care settings. The authors hypothesized that oral dexmedetomidine (300 mcg to 700 mcg) would result in plasma concentrations consistent with sedation while maintaining hemodynamic stability.MethodsThe authors performed a single-site, open-label, phase I dose-escalation study of a solid oral dosage formulation of dexmedetomidine in healthy volunteers (n = 5, 300 mcg; followed by n = 5, 500 mcg; followed by n = 5, 700 mcg). The primary study outcome was hemodynamic stability defined as lack of hypertension, hypotension, or bradycardia. The authors assessed this outcome by analyzing raw hemodynamic data. Plasma dexmedetomidine concentrations were determined by liquid chromatograph-tandem mass spectrometry. Nonlinear mixed effect models were used for pharmacokinetic and pharmacodynamic analyses.ResultsOral dexmedetomidine was associated with plasma concentration-dependent decreases in heart rate and mean arterial pressure. All but one subject in the 500-mcg group met our criteria for hemodynamic stability. The plasma concentration profile was adequately described by a 2-compartment, weight allometric, first-order absorption, first-order elimination pharmacokinetic model. The standardized estimated parameters for an individual of 70 kg was V1 = 35.6 [95% CI, 23.8 to 52.8] l; V2 = 54.7 [34.2 to 81.7] l; CL = 0.56 [0.49 to 0.64] l/min; and F = 7.2 [4.7 to 14.4]%. Linear models with effect sites adequately described the decreases in mean arterial pressure and heart rate associated with oral dexmedetomidine administration. However, only the 700-mcg group reached plasma concentrations that have previously been associated with sedation (>0.2 ng/ml).ConclusionsOral administration of dexmedetomidine in doses between 300 and 700 mcg was associated with decreases in heart rate and mean arterial pressure. Despite low oral absorption, the 700-mcg dose scheme reached clinically relevant concentrations for possible use as a sleep-enhancing medication.Editor’s perspective

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Pharmacokinetic and pharmacodynamic variability of fluindione in octogenarians.

Publications

Pharmacokinetic and pharmacodynamic variability of fluindione in octogenarians.

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