Pharmacokinetics and pharmacodynamics in toxicology

Smith, Dennis A.

doi:10.1080/004982597240479

Cited by 23 publications

(16 citation statements)

References 29 publications

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“…The situation is further complicated by the fact that metabolites can also be biologically active and must be accounted for when extrapolating the dose. The literature abounds with examples of these differences (Smith, 1997; Lin, 1998). Overall, inter‐species differences in drug metabolism systems are not related to size, so one would not expect extensively metabolized drugs to be amenable to allometric scaling of their clearance or dose.…”

Section: Inter‐species Differences In the Pharmacokinetic Phasementioning

confidence: 99%

To scale or not to scale: the principles of dose extrapolation

Sharma

McNeill

2009

British J Pharmacology

437

349

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The principles of inter-species dose extrapolation are poorly understood and applied. We provide an overview of the principles underlying dose scaling for size and dose adjustment for size-independent differences. Scaling of a dose is required in three main situations: the anticipation of first-in-human doses for clinical trials, dose extrapolation in veterinary practice and dose extrapolation for experimental purposes. Each of these situations is discussed. Allometric scaling of drug doses is commonly used for practical reasons, but can be more accurate when one takes into account species differences in pharmacokinetic parameters (clearance, volume of distribution). Simple scaling of drug doses can be misleading for some drugs; correction for protein binding, physicochemical properties of the drug or species differences in physiological time can improve scaling. However, differences in drug transport and metabolism, and in the dose-response relationship, can override the effect of size alone. For this reason, a range of modelling approaches have been developed, which combine in silico simulations with data obtained in vitro and/or in vivo. Drugs that are unlikely to be amenable to simple allometric scaling of their clearance or dose include drugs that are highly protein-bound, drugs that undergo extensive metabolism and active transport, drugs that undergo significant biliary excretion (MW > 500, ampiphilic, conjugated), drugs whose targets are subject to inter-species differences in expression, affinity and distribution and drugs that undergo extensive renal secretion. In addition to inter-species dose extrapolation, we provide an overview of dose extrapolation within species, discussing drug dosing in paediatrics and in the elderly. Keywords: allometric scaling; body surface area; pharmacokinetics; pharmacodynamics; dose extrapolation; species difference; paediatric dosing; physiological time Abbreviations: CAR, constitutive androstane receptor; CYP, cytochrome P450; FDA, Food and Drug Administration of the United States; fu, unbound fraction; HED, human-equivalent dose; LSD, lysergic acid diethylamide; MABEL, minimum anticipated biological effect level; MEC, minimum energy cost; MLP, maximum lifespan potential; NOAEL, no-observed adverse effect level; PXR, pregnane X receptor; SMEC, specific minimum energy cost (minimum energy cost per unit weight) British Journal of Pharmacology

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Section: Inter‐species Differences In the Pharmacokinetic Phasementioning

confidence: 99%

To scale or not to scale: the principles of dose extrapolation

Sharma

McNeill

2009

British J Pharmacology

437

349

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“…E4031 as a class III anti-arrhythmic agent was used as a positive control. It is a potent Ikr channel blocker, causing QT prolongation as part of its pharmacology (Vaughan Williams 1970, Katoh et al 1990. Dog is widely used in drug discovery and development to evaluate pharmacokinetics, metabolism and toxicology (Wright et al 1987) and has also been used in the study of TDP (Gras and Llenas 1999).…”

Section: Introductionmentioning

confidence: 99%

“…Therefore, the protein binding of a molecule in plasma can cloud the relationship between plasma concentrations and e cacy. This is especially the case when di erent compounds are being compared or when a compound is compared across species where protein binding di erences may exist (Smith 1997). Therefore, free plasma concentration data were used in the design of the current studies and to compare the data generated for the di erent compounds in the dog experiments.…”

Section: Introductionmentioning

confidence: 99%

Pharmacokinetic/pharmacodynamic assessment of the effects of E4031, cisapride, terfenadine and terodiline on monophasic action potential duration in dog

et al. 2001

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1. Torsades de pointes (TDP) is a potentially fatal ventricular tachycardia associated with increases in QT interval and monophasic action potential duration (MAPD). TDP is a side-effect that has led to withdrawal of several drugs from the market (e.g. terfenadine and terodiline). 2. The potential of compounds to cause TDP was evaluated by monitoring their effects on MAPD in dog. Four compounds known to increase QT interval and cause TDP were investigated: terfenadine, terodiline, cisapride and E4031. On the basis that only free drug in the systemic circulation will elicit a pharmacological response target, free concentrations in plasma were selected to mimic the free drug exposures in man. Infusion regimens were designed that rapidly achieved and maintained target-free concentrations of these drugs in plasma and data on the relationship between free concentration and changes in MAPD were obtained for these compounds. 3. These data indicate that the free ED50 in plasma for terfenadine (1.9 nM), terodiline (76 nM), cisapride (11 nM) and E4031 (1.9 nM) closely correlate with the free concentration in man causing QT effects. For compounds that have shown TDP in the clinic (terfenadine, terodiline, cisapride) there is little differentiation between the dog ED50 and the efficacious free plasma concentrations in man (< 10-fold) reflecting their limited safety margins. These data underline the need to maximize the therapeutic ratio with respect to TDP in potential development candidates and the importance of using free drug concentrations in pharmacokinetic/pharmacodynamic studies.

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“…Prediction of in vivo kinetic behavior remains difficult for new lead compounds (Shou, 2005). The calculated parameters are therefore prone to inaccuracies (Smith, 1997), and typically with 3 animals per concentration, variation coefficients in the range of 20-30% and more are obtained.…”

Section: Definitions Parameters and Limitationsmentioning

confidence: 99%