Pharmacokinetic-pharmacodynamic modeling of drug-induced effect on the QT interval in conscious telemetered dogs

Ollerstam, Anna; Visser, Sandra A.G.; Persson, Anna; Eklund, Göran; Nilsson, Leif; Forsberg, Tomas; Wiklund, Stig Johan; Gabrielsson, Johan; Duker, Göran; Al‐Saffar, Ahmad

doi:10.1016/j.vascn.2005.07.002

Cited by 45 publications

(27 citation statements)

References 27 publications

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“…A negative hysteresis precluded the use of a simple I max PD model. The effect delay can be caused by a slow distribution of the drug to the site of action, by an indirect mechanism in generating the effect, by slow binding and release from a receptor or by the presence of an active metabolite (Ollerstam et al. , 2006).…”

Section: Robenacoxib Pharmacokinetic Calculationsmentioning

confidence: 99%

Pharmacokinetic/pharmacodynamic modelling of robenacoxib in a feline tissue cage model of inflammation

Pelligand

King

Toutain

et al. 2011

Vet Pharm & Therapeutics

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Robenacoxib is a novel nonsteroidal anti-inflammatory drug developed for use in cats. It is a highly selective COX-2 inhibitor. Results from previous feline studies showed that, despite a short half-life in blood, the effect of robenacoxib persisted for 24 h in clinical studies. A tissue cage model of acute inflammation was used to determine robenacoxib's pharmacokinetics and its ex vivo and in vivo selectivity for COX-1 and COX-2 using serum TxB(2) and exudate PGE(2) as surrogate markers for enzyme activity, respectively. After intravenous, subcutaneous and oral administration (2 mg/kg), the clearance of robenacoxib from blood was rapid (0.54-0.71 L·h/kg). The mean residence time (MRT) in blood was short (0.4, 1.9 and 3.3 h after intravenous, subcutaneous and oral administration, respectively), but in exudate MRT was approximately 24 h regardless of the route of administration. Robenacoxib inhibition of COX-1 in blood was transient, occurring only at high concentrations, but inhibition of COX-2 in exudate persisted to 24 h. The potency ratio (IC(50) COX-1: IC(50) COX-2) was 171:1, and slopes of the concentration-effect relationship were 1.36 and 1.12 for COX-1 and COX-2, respectively. These data highlight the enzymatic selectivity and inflamed tissue selectivity of robenacoxib and support the current recommendation of once-daily administration.

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Section: Robenacoxib Pharmacokinetic Calculationsmentioning

confidence: 99%

Pharmacokinetic/pharmacodynamic modelling of robenacoxib in a feline tissue cage model of inflammation

Pelligand

King

Toutain

et al. 2011

Vet Pharm & Therapeutics

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“…where b is calculated as the slope of QT versus HR, both of which are derived from the data extracted (Ollerstam et al, 2006). Data are presented as percent changes (mean 6 S.E.M.)…”

Section: Cardiovascular Measurements In Dogsmentioning

confidence: 99%

“…These results are used for early estimations of safety margin, although a more precise quantitative prediction of the level of QT prolongation to be expected in a clinical setting will be determined in human studies. A more precise estimate of the safety margin may be obtained by applying population pharmacokinetic/pharmacodynamic (PK/ PD) modeling techniques, thus taking all data into account (Ollerstam et al, 2006;Lalonde et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

Prediction and Modeling of Effects on the QTc Interval for Clinical Safety Margin Assessment, Based on Single-Ascending-Dose Study Data with AZD3839

Sparve

Quartino

Lüttgen

et al. 2014

J Pharmacol Exp Ther

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“…Several analytical methods for quantifying dofetilide (LCMS [24], HPLC [21,25] and RIA [26] or amlodipine (HPLC [9,[27][28][29][30][31], HPLC with radioactivity detection [32], HPLC with electrochemical detection [33], LCMS [34][35][36], GCMS [37] and GC with electron capture detection [38] in biological fluids have been reported. Unfortunately, all of these described methods do not allow the quantification of both drugs in the same run.…”

Section: Amlodipine Besylate (Norvascmentioning

confidence: 99%

Simultaneous Determination of Dofetilide and Amlodipine in Plasma by HPLC

Kaddar¹,

Pilote²,

Wong³

et al. 2013

J Chromat Separation Techniq

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Dofetilide is a Class III antiarrhythmic drug useful in the management of atrial fibrillation but also known to prolong the QT interval on the ECG and to induce malignant ventricular tachyarrhythmias such as torsades de pointes (TDP). Drugs with calcium channel-blocking properties contribute to decrease the incidence of TDP. Amlodipine is a dihydropyridine calcium channel antagonist. Considering the potentially safe and useful combined use of dofetilide and amlodipine, we undertook drug biotransformation studies. To perform studies aiming to evaluate the possible pharmacokinetic interaction between these drugs, a unique sensitive HPLC assay able to quantify both drugs simultaneously was required. A sensitive and specific HPLC method using a tandem of UV/fluorescence detection was described for the analysis of amlodipine and dofetilide in plasma. The within-day and between-day precision studies showed good reproducibility with coefficients of variation less than 10% for all the analytes. The limits of detection were 0.5 ng/mL and 0.25 ng/mL and the limit of quantification were 1.7 ng/mL and 0.8 ng/mL for dofetilide and amlodipine respectively. This new method could be of great value in many applications such as in vitro and in vivo pharmacokinetic and drug-drug interactions studies, as well as therapeutic drug monitoring.

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Pharmacokinetic-pharmacodynamic modeling of drug-induced effect on the QT interval in conscious telemetered dogs

Cited by 45 publications

References 27 publications

Pharmacokinetic/pharmacodynamic modelling of robenacoxib in a feline tissue cage model of inflammation

Pharmacokinetic/pharmacodynamic modelling of robenacoxib in a feline tissue cage model of inflammation

Prediction and Modeling of Effects on the QTc Interval for Clinical Safety Margin Assessment, Based on Single-Ascending-Dose Study Data with AZD3839

Simultaneous Determination of Dofetilide and Amlodipine in Plasma by HPLC

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