The lower limit of quantification in pharmacokinetic analyses

Woodward, Andrew; Whittem, Ted

doi:10.1111/jvp.12778

Cited by 12 publications

(13 citation statements)

References 14 publications

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“…The signal-to-noise ratio at 0.0156 ng/ml was >10, therefore, the limit of detection was deemed to be below this level. A lower limit of quantification is not reported, as recently recommended (32).…”

Section: Lcms Methodsmentioning

confidence: 99%

The Surface Area to Volume Ratio Changes the Pharmacokinetic and Pharmacodynamic Parameters in the Subcutaneous Tissue Cage Model: As Illustrated by Carprofen in Sheep

2022

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IntroductionPharmacokinetic and pharmacodynamic models can be powerful tools for predicting outcomes. Many models are based on repetitive sampling of the vascular space, due to the simplicity of obtaining samples. As many drugs do not exert their effect in the vasculature, models have been developed to sample tissues outside the bloodstream. Tissue cages are hollow devices implanted subcutaneously, or elsewhere, that are filled with fluid allowing repetitive sampling to occur. The physical dimensions of the cage, namely, the diffusible surface area to volume ratio, would be expected to change the rate of drug movement into and out of tissue cages.MethodsSeven sheep were implanted with five pairs of tissue cages, subcutaneously. Each pair of cages had a different length but a fixed diffusible surface area, so the surface area to volume ratio differed. Carrageenan was injected into half of the cages in each animal during one sampling period in a cross-over design. Samples from each cage and the bloodstream were obtained at 14-time points during two sampling periods. The concentration of carprofen was measured using LC–MS/MS and the results were modeled using nonlinear mixed-effects techniques. Prostaglandin metabolites were also measured and the change over time was analyzed using linear mixed effect modeling.ResultsThe presence of carrageenan within an animal changed the systemic pharmacokinetics of carprofen. The rate of drug movement into and out of the tissue cages varied with the surface area to volume ratio. The concentration time curve for prostaglandin metabolites changed with cage size.ConclusionThe surface area volume ratio of tissue cages will influence the calculated pharmacokinetic parameters and may affect calculated pharmacodynamics, thus, it is an important factor to consider when using tissue cage data for dosing regimes.

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Section: Lcms Methodsmentioning

confidence: 99%

The Surface Area to Volume Ratio Changes the Pharmacokinetic and Pharmacodynamic Parameters in the Subcutaneous Tissue Cage Model: As Illustrated by Carprofen in Sheep

2022

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“…For data below the analytical limit of quantification (BLQ; Woodward and Whittem, 2019a), the data points were defined as left-censored at the limit of quantification, 0.03 mg/L. All BLQ points were replaced in the data set with 0.03 mg/L and flagged as censored.…”

Section: Methodsmentioning

confidence: 99%

Population physiologically based modeling of pirlimycin milk concentrations in dairy cows

Woodward

Morin

Whittem

2020

Journal of Dairy Science

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Predictions of drug residues in milk are critical in food protection and are a major consideration in the economics of treatment of mastitis in dairy cows. Nonlinear mixed-effects modeling (NLME) has been advocated as a suitable pharmaco-statistical method for the study of drug residues in milk. Recent developments in physiologically based pharmacokinetic (PBPK) modeling of intramammary drugs allow the combination of a mechanistic description of milk pharmacokinetics with NLME methods. The PBPK model was applied to NLME analysis of a data set consisting of milk drug concentrations from 78 healthy cows and 117 with clinical mastitis. Pirlimycin milk pharmacokinetics were adequately described by the model across the range of observed concentrations. Mastitis was characterized by increased variance in milk production volume. Udder residual volume was larger in cows with 1, or 2 or greater diseased mammary glands than in the healthy cows. Low-producing cows had a greater risk of prolonged milk residues. With the exclusion of the low-production cows, the model predicted that healthy cows required a milk discard time 12 h longer than that indicated by the label, and the diseased cows 36 h longer than indicated by the label. More pirlimycin was systemically absorbed in the gram-positive infected compared with the gram-negative infected or healthy cows, suggesting a greater risk of violative meat residues in gram-positive infected cows. Using NLME and PBPK models, we identified factors associated with changes in pirlimycin milk residues that may affect food safety. This model extends the verification of a simple physiologically based framework for the study of intramammary drugs.

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“…For the cephapirin data set, the residual milk concentrations were treated as measures of alveolar concentration in the model, but the foremilk data from this study were not modelled (Stockler et al, ). For each data set, data points below the analytical method limit of quantification were excluded from the analysis (Woodward & Whittem, ) as censored regression methods were considered outside the scope of this study.…”

Section: Methodsmentioning

confidence: 99%

Physiologically based modelling of the pharmacokinetics of three beta‐lactam antibiotics after intra‐mammary administration in dairy cows

Woodward

Whittem

2019

Vet Pharm & Therapeutics

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Understanding the pharmacokinetics of intra‐mammary antibiotics is important for the prediction of drug residues in milk and for the design of optimal dosage regimens. Unfortunately, compartmental pharmacokinetic models are not valid for this unique system. A minimal physiologically based pharmacokinetic model is presented incorporating the physiology of milk secretion, drug administration at the quarter level, drug absorption and dispersion, drug retention during the inter‐milking interval and episodic drug elimination at milking. The primary objective of the study was the development and exploration of a model for major factors controlling drug concentration in milk, rather than generation of rigorously predictive pharmaco‐statistical models for any particular drug. This model was implemented in a two‐stage approach, using published concentration data for penicillin, cefuroxime, cephapirin and desacetyl‐cephapirin in milk of healthy cows. Model simulations evaluated sensitivity and developed predictions of drug residues. The model successfully predicted both drug concentrations and drug residues in milk. The postmilking residual milk volume did not adequately explain antibiotic pharmacokinetics, requiring additional considerations for drug retention. Local sensitivity analysis indicated that increasing the number of quarters treated, the dosage, or the duration of the inter‐milking interval prolonged both the persistence of drug residues and the duration that antibiotic concentration exceeded typical minimum inhibitory concentrations. The model was flexible across different beta‐lactam drugs as a general description of intra‐mammary pharmacokinetics. This model is suitable for the design and analysis of dosage regimens, and could be applied for the prediction of withholding periods when these antibiotic preparations are used off‐label. The final model indicates that explicit consideration of the milking regimen is fundamental to the design and interpretation of pharmacokinetic studies of antibiotics in bovine milk.

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The lower limit of quantification in pharmacokinetic analyses

Cited by 12 publications

References 14 publications

The Surface Area to Volume Ratio Changes the Pharmacokinetic and Pharmacodynamic Parameters in the Subcutaneous Tissue Cage Model: As Illustrated by Carprofen in Sheep

The Surface Area to Volume Ratio Changes the Pharmacokinetic and Pharmacodynamic Parameters in the Subcutaneous Tissue Cage Model: As Illustrated by Carprofen in Sheep

Population physiologically based modeling of pirlimycin milk concentrations in dairy cows

Physiologically based modelling of the pharmacokinetics of three beta‐lactam antibiotics after intra‐mammary administration in dairy cows

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