Plasma clearance

Plasma (total, systemic...) clearance is determined by all the individual metabolizing/eliminating organ clearances and involves mainly liver and kidney clearances. Plasma clearance (a volume per time, i.e. a flow) expresses the overall ability of the body to eliminate a drug by scaling the drug elimination rate (amount per time) by the corresponding plasma concentration level. The interpretation of plasma clearance and inter-species comparisons are made easier by computing the overall body extraction ratio (from 0 to 1), which is the ratio of the body clearance divided by cardiac output. Plasma clearance is the most important pharmacokinetic parameter because it is the only one which controls the overall drug exposure (for a given bioavailability) and it is the parameter which allows computation of the dosage required to maintain an average steady-state plasma concentration.     

Impact of early versus later fluoroquinolone treatment on the clinical; microbiological and resistance outcomes in a mouse-lung model of Pasteurella multocida infection

The early curative uses of antimicrobial drugs such as fluoroquinolones before the onset of symptoms in veterinary medicine may be regarded as irrational antibiotic consumption. However, it should be stressed that in early curative antimicrobial treatment as in metaphylaxis, the bacterial burden at the infection site is often very low, and so the rapid eradication of the bacterial population could result. We investigated the impact of early versus later curative administrations of 1 or 40 mg/kg of marbofloxacin on the survival of mice, the eradication of the targeted pathogen and the selection of resistant bacteria in a mouse lung infection with Pasteurella multocida. In this model, for a given marbofloxacin dose, the clinical and bacteriological outcomes were better, and the selection of resistance less frequent, for the early rather than for the late treatment. Moreover, the early administration of 1mg/kg led to better clinical and similar bacteriological (eradication and selection of resistance) outcomes than the late administration of 40 mg/kg marbofloxacin. Our results suggest that the optimal doses for the animals' cure could be lower when administered early during the time course of the infection than when administered after the disease outbreak. As the main argument against early treatments such as metaphylaxis is the possible enhancement of resistance at the gut level, further studies should assess if lower doses of antibiotic administered to all the animals of a herd could have less impact on the commensal digestive flora than higher doses only administered to animals showing clinical symptoms.     

The pharmacokinetic-pharmacodynamic approach to a rational dosage regimen for antibiotics

Pharmacokinetic-pharmacodynamic (PK/PD) surrogate indices (AUIC, AUC/MIC, C(max)/MIC, T>MIC) for measuring antibiotic efficacy are presented and reviewed. As clinical trials are not sufficiently sensitive to establish a dosage regimen which guarantees total bacteriological cure (Pollyanna phenomenon), PK/PD indexes have been proposed from in vitro, ex vivo, and in vivo infection models and subsequently validated in retrospective or prospective human clinical trials. The target value for time-dependent antibiotics (beta-lactams, macrolides) is a time above the MIC (T>MIC) of 50-80% of the dosage interval, while for concentration-dependent antibiotics (quinolones and aminoglycosides), the area under the inhibitory curve (AUIC, or more simply AUC/MIC of about 125h) is the best surrogate indicator of activity. Using the latter drugs, high concentrations achieved early during therapy are desirable to prevent the development of resistance. A C(max)/MIC ratio greater than 10-12 seems to be an appropriate target for aminoglycosides.     

Bioavailability and its assessment

Bioavailability is a key pharmacokinetic parameter which expresses the proportion of a drug administered by any nonvascular route that gains access to the systemic circulation. Presented in this review are the different approaches to measurement of bioavailability (absolute and relative), including the case in which intravenous administration is impossible. The rate of drug absorption is also discussed with special emphasis on the possible difficulties encountered using C(max) and T(max) or curve fitting to evaluate the rate of drug absorption.     

Volumes of distribution

Volumes of distribution are proportionality constants between total amount of drug in the body and plasma concentrations. As snapshot plasma drug concentrations may be measured in different conditions (at equilibrium, under pseudo-equilibrium condition,...), several volumes of distribution have been defined. The two most relevant are the volume of distribution at equilibrium (V(ss)), and the volume of distribution during pseudo-equilibrium (V(area)). Volumes of distribution are used to compute a loading dose (V(ss)) or the residual amount of drug in the body knowing plasma concentrations (V(area)). Volume of distribution may be interpreted in terms of drug distribution having recourse to physiological models involving drug binding to plasma and tissues. Volumes of distribution should be determined early in drug development programmes and those having a large volume of distribution may be selected to obtain a long terminal half-life even for drugs having a relatively high clearance.     

How nutrient availability influences acclimation to shade of two (pioneer and late-successional) Mediterranean tree species?

Examining ecological limits to shade acclimation at whole-plant level is determinant for evaluating the success of sapling establishment in low-light environments. We studied nutritional effects on whole-plant development in response to shade in two Mediterranean forest tree species with different successional status: the early-successional Pinus halepensis Mill. and the late-successional Quercus pubescens Wild. Through a nursery-based factorial experimental design approach, we measured height increment along 2 years and final leaf, stem and root biomass in both species saplings subjected to two lights and two soil nutrient availability treatments. The shade avoidance response was exclusive to P. halepensis, appeared as timely dependent, and persisted longer in saplings exposed to higher nutrient availability. Q. pubescens benefited from the higher nutrient availability by lowering the light-driven plastic response in aerial support investment and belowground carbon allocation, whereas P. halepensis heightened its light-driven plastic response. These contrasted responses are thus clearly related to the shade acclimation strategy of each species: the shade-intolerant P. halepensis enhances shade avoidance when non-nutrient-limited, whereas the shade-tolerant Q. pubescens assumes a conservative strategy by limiting phenotypic plasticity-induced costs. Maintaining greater shade avoidance in non-nutrient-limited soil conditions might be an adaptive advantage for P. halepensis seedlings growing in the understory, in response to gap formation in the overstory. In contrast, the more conservative and less costly shade responsiveness of Q. pubescens may confer it a better adaptive advantage in long-term light-limited environments.     

A pharmacokinetic model to document the actual disposition of topical ivermectin in cattle

Ivermectin is a worldwide-used antiparasitic drug largely administered to cattle as a topical formulation (pour-on). The actual plasma and faecal disposition of pour-on ivermectin in cattle was documented using an original pharmacokinetic model, and taking into account the oral ingestion of the topical drug following physiological licking as a secondary route of exposure. Six pairs of monozygotic twin cattle received successively one i.v. and two pour-on administrations of ivermectin at a 3-5-month interval. For one pour-on administration, the twins were separated into an unrestrained group and a group where self- and allo-licking were prevented. Ivermectin concentrations in the plasma and faeces were determined by HPLC. Licking resulted in a high intra-and inter-individual variability of systemic exposure after topical application. By the means of pharmacokinetic modelling, we showed that 58-87% of the pour-on dose was ingested, while only 10% was absorbed percutaneously. Approximately 72% of the ingested ivermectin transited directly into the faeces, resulting in a 7-fold higher faecal excretion of the parent drug than in the non-lickers. We conclude that topical administration does not guarantee a controlled drug delivery in cattle. More importantly, the simulations revealed that non-treated cattle could get easily contaminated by allo-licking, raising the public health problem of unexpected drug residues in edible tissues.     

Should licking behavior be considered in the bioavailability evaluation of transdermal products?

Antiparasitic drugs, and especially macrocyclic lactones (MLs), are often formulated as pour-on products because of their ease of administration, convenience, and reduction of stress in treated animals. However, because of self- and allo-grooming, much of a drug administered transdermally may be systemically absorbed via the oral route, creating highly variable pharmacokinetic and pharmacodynamic response in treated (and untreated) animals. Testing bioequivalence (BE) of pour-on drugs in cattle under laboratory conditions (with restricted licking) ignores a major factor of drug disposition of these drugs and thus fails to predict therapeutic equivalence in the target population under clinical conditions of use. Therefore, the interanimal and intra-animal variability associated with licking behavior should be considered as a biological fact, rather than a noise that needs to be reduced or eliminated. As a result, it is recommended that the BE testing for pour-on products in cattle be conducted by evaluating both the mean and distribution of bioavailability parameters between the reference and test products when animals are not prevented from allo- and self-licking.     

Population pharmacokinetics of marbofloxacin in horses: preliminary analysis

Population pharmacokinetic of marbofloxacin was investigated on 21 healthy and 16 diseased horses to assess interindividual variability of drug exposure. Demographic, physiologic and disease covariables were tested using mixed effects models. As a preliminary analysis, this study has demonstrated that none of the tested covariables were significant in regression models for compartmental volumes or clearance of distribution, but the clinical status of the horse (healthy/diseased) was a significant covariable (P < 0.01) for systemic clearance. Clearance had a lower mean and a higher variance for diseased horses than healthy horses, with respectively a mean of 0.209 and 0.284 L/h/kg and a coefficient of variation of 52 and 15%. Consequently, variability of AUC was greater in diseased horses. Considering an AUC/MIC ratio below 60 h as a prediction of poor efficacy, a dosage regimen of 2 mg/kg intravenous was deemed to be inadequate for 19% of diseased horses if the MIC of the bacteria was 0.1 microg/mL. However 93% of diseased horses could achieve a ratio above 125 h, predicting a very good efficacy, for the MIC(90) of Enterobacteriacae (0.027 microg/mL).