Considerations in the Design of Toxicokinetic Programs

Cayen, Mitchell N.

doi:10.1177/019262339502300208

Cited by 21 publications

(15 citation statements)

References 38 publications

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“…In the preclinical area, bioanalytical methods are used to support toxicokinetic studies to evaluate systemic exposure of the drug and metabolites and to help correlate exposure to any target organ toxicity . It is required that these toxicology studies are carried out according to the principals of good laboratory practices (GLPs).…”

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confidence: 99%

Evaluation of a Four-Channel Multiplexed Electrospray Triple Quadrupole Mass Spectrometer for the Simultaneous Validation of LC/MS/MS Methods in Four Different Preclinical Matrixes

Yang¹,

Mann²,

Little³

et al. 2001

Anal. Chem.

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A four-channel multiplexed electrospray interface on a triple quadrupole mass spectrometer was evaluated for the simultaneous validation of LC/MS/MS methods for the quantitation of loratadine and its metabolite, descarboethoxyloratadine, in four different biological matrixes. The assays were performed in rat, rabbit, mouse, and dog plasma from 1 to 1000 ng/mL using 96-well solid-phase extraction for sample preparation. The limit of quantitation of 1 ng/mL corresponded to 5.56 pg of each analyte injected on-column. For the drug, quality control samples (n = 6 at four concentrations) had precision ranging from 0.967 to 16.0% and accuracy ranging from -8.44 to 10.5% across all four species. For the metabolite, the precision ranged from 0.684 to 11.0% and the accuracy was between 6.36 and -9.06%. Intersprayer cross talk for the multiplexed electrospray ion source was evaluated as a function of analyte concentration and was less than 0.08% at concentrations as high as 1000 ng/mL. These results demonstrate the feasibility of using parallel analysis to reduce the time required for method validation and to increase sample throughput in drug development studies.

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mentioning

confidence: 99%

Evaluation of a Four-Channel Multiplexed Electrospray Triple Quadrupole Mass Spectrometer for the Simultaneous Validation of LC/MS/MS Methods in Four Different Preclinical Matrixes

Yang¹,

Mann²,

Little³

et al. 2001

Anal. Chem.

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show abstract

“…Appropriate monitoring of the plasma or serum levels of the parent compound and metabolites is critical within any pivotal repeat-dose toxicology study to assess exposure (Cayen, 1995). As noted previously, determining the PK parameters, for example, C max or AUC, is integral to the study design and will need to be incorporated into all repeateddose study protocols.…”

Section: Toxicokinetic Evaluationmentioning

confidence: 99%

Repeated‐Dose Toxicity Studies in Nonclinical Drug Development

Azri-Meehan¹,

Latriano²

2013

Nonclinical Safety Assessment

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“…Some direct adverse clinical signs correlate better with C max than with AUC. Moreover, in practice, toxicologic studies with small animals are—in order to minimize the stress to the animals—performed typically with a maximum of 3 to 5 plasma samples (Cayen, 1995; Dahlem et al, 1995). Careful selection of the sample times is essential, since these sample times will directly influence the accuracy of AUC and C max to reflect the actual mean plasma exposure.…”

Section: Definitions Parameters and Limitationsmentioning

confidence: 99%