The use of isotopes in the determination of absolute bioavailability of drugs in humans

@article{Lappin2006TheUO,
  title={The use of isotopes in the determination of absolute bioavailability of drugs in humans},
  author={Graham Lappin and Malcolm Rowland and Ronald Colin Garner},
  journal={Expert Opinion on Drug Metabolism \& Toxicology},
  year={2006},
  volume={2},
  pages={419 - 427}
}
Absolute bioavailability studies in humans are not routinely performed as part of the drug registration process. They tend to be reasonably demanding, not least because toxicology data are required to support intravenous administration of a drug. Moreover, the classical crossover design of an absolute bioavailability study can suffer from artefacts caused by concentration-dependent pharmacokinetics. Many of the problems associated with absolute bioavailability studies can be alleviated using… 

Re-introduction of a Novel Approach to the Use of Stable Isotopes in Pharmacokinetic Studies

TLDR
Utilization of a stable isotope approach can markedly improve the efficiency and accuracy of bioavailability and bioequivalence studies particularly for highly variable drugs in formulations that are qualitatively and quantitatively the same and for studies designed for QbD investigations.

Combining Isotopic Tracer Techniques to Increase Efficiency of Clinical Pharmacokinetic Trials in Oncology

TLDR
A plea here for a hybrid trial approach, where both radiolabeled drug and stable isotopically labeled drug are administered to patients to assess both the absolute bioavailability and absorption, distribution, metabolism and excretion in a single clinical trial experiment.

Biomedical accelerator mass spectrometry: recent applications in metabolism and pharmacokinetics.

TLDR
This review addresses the metabolism and pharmacokinetics relevant to cases where therapeutic drug concentrations are achieved in humans and early knowledge about a drug's clearance, volume of distribution, absolute bioavailability and metabolism can affect the development of a new drug candidate.

AMS method validation for quantitation in pharmacokinetic studies with concomitant extravascular and intravenous administration.

TLDR
The authors describe the primary elements of AMS when used with LC separation and how this off-line technique differs from LC-MS and discuss how the principles of bioanalytical validation might be applied to determine selectivity, accuracy, precision and stability of methods involving LC followed by AMS analysis.

Approaches to intravenous clinical pharmacokinetics: Recent developments with isotopic microtracers

  • G. Lappin
  • Medicine, Biology
    Journal of clinical pharmacology
  • 2016
TLDR
The intravenous administration has been termed a microtracer and obviates intravenous toxicology requirements as well as simplifying formulations and the method has been extended to the study of prodrug–to–active drug kinetics and to obtaining clearance, volume of distribution, and absolute bioavailability at steady‐state conditions.

Biomedical accelerator mass spectrometry: recent applications in metabolism and pharmacokinetics

TLDR
This review addresses the metabolism and pharmacokinetics relevant to cases where therapeutic drug concentrations are achieved in humans and early knowledge about a drug's clearance, volume of distribution, absolute bioavailability and metabolism can affect the development of a new drug candidate.

An AMS method to determine analyte recovery from pharmacokinetic studies with concomitant extravascular and intravenous administration.

TLDR
A method of internal standardisation is described where the UV response of the nonlabeled analyte, spiked in excess into the matrix being analysed, is used for internal standardization, so that the recovery for each individual sample analyzed can be ascertained.

Quantifying exploratory low dose compounds in humans with AMS.

Early human ADME using microdoses and microtracers: bioanalytical considerations.

Quantitative assessment of metabolites of drug candidates in early-phase clinical development presents an analytical challenge when methods, standards and assays are not yet available. Radioisotopic

Use of Accelerator Mass Spectrometry in Human Health and Molecular Toxicology.

TLDR
Recent advances in the AMS technology at Lawrence Livermore National Laboratory have allowed for direct coupling of AMS with complementary capabilities such as HPLC via a liquid sample moving wire interface, offering greater sensitivity compared to that of graphite-based analysis, therefore enabling the use of lower 14C and chemical doses, which are imperative for clinical testing.
...

References

SHOWING 1-10 OF 35 REFERENCES

Estimation of the absolute bioavailability of flecainide using stable isotope technique

TLDR
The data indicate that the variable bioavailability of flecainide is due both to metabolism and absorption, and highlights the potential of stable isotope technique in the investigation of such issues.

Bioavailability of imipramine tablets relative to a stable isotope-labeled internal standard: Increasing the power of bioavailability tests

TLDR
The power of the new methodology to detect differences between drug formulations, when, in fact, such differences exist, is shown to be superior to that of conventional bioavailability tests.

Concurrent intravenous administration of a labeled tracer to determine the oral bioavailability of a drug exhibiting Michaelis-Menten metabolism

TLDR
The theoretical accuracy of concurrent administration of labeled intravenous tracer and oral doses to estimate the bioavailability of drugs exhibiting Michaelis-Menten kinetics was determined by computer simulation and error was consistent with these hypotheses.

Theoretical considerations in the calculation of bioavailability of drugs exhibiting Michaelis-Menten elimination kinetics

  • G. RubinT. Tozer
  • Biology, Medicine
    Journal of Pharmacokinetics and Biopharmaceutics
  • 2005
TLDR
These simulations showed that the most accurate determination of bioavailability requires knowledge of the direct contribution of oral absorption to the concentration of drug entering the liver, and showed that if a drug has a large volume of distribution or a large absorption rate constant, or both, use of the much simpler conventional method of bio availability determination may be appropriate even in cases where the degree of saturation is substantial.

Absolute bioavailability in man of N‐acetylprocainamide determined by a novel stable isotope method

TLDR
Absorption of a single oral dose of N‐acetylprocainamide (NAPA) was studied in 3 normal subjects and a new stable isotope method that entailed intravenous injection of NAPA− 13C at the same time that an unlabeled N APA capsule was given orally was determined.

The use of accelerator mass spectrometry to obtain early human ADME/PK data

TLDR
Accelerator mass spectrometry (AMS), a technology new to the pharmaceutical industry, is an ultrasensitive technique for measuring tracers such as 14C that enables other studies such as absolute bioavailability to be conducted earlier if required.

Bioavailability Studies of Drugs with Nonlinear Pharmacokinetics: II. Absolute Bioavailability of Intravenous Phenytoin Prodrug at Therapeutic Phenytoin Serum Concentrations Determined by Double‐Stable Isotope Technique

TLDR
The authors describe a double‐stable isotope method that obviates two problems of measurement of the absolute bioavailability of phenytoin (PHT) derived from test doses of Pheny toin prodrug (PPD) at therapeutic PHT serum concentrations.

The Application of Accelerator Mass Spectrometry to Absolute Bioavailability Studies in Humans: Simultaneous Administration of an Intravenous Microdose of 14C‐Nelfinavir Mesylate Solution and Oral Nelfinavir to Healthy Volunteers

TLDR
The moderate bioavailability of nelfinavir was due to significant first‐pass metabolism rather than low absorption, limiting the potential of formulation improvement to decrease pill burden.

Pharmacokinetics of primaquine in man. I. Studies of the absolute bioavailability and effects of dose size.

TLDR
The pharmacokinetics of primaquine have been examined in five healthy volunteers who received single oral doses of 15, 30 and 45 mg of the drug, on separate occasions, and were unaffected by either dose size, or route of administration.

Oral bioavailability and first-pass effects.

  • K. C. Kwan
  • Biology
    Drug metabolism and disposition: the biological fate of chemicals
  • 1997
TLDR
An integrated set of strategies emerges that appears capable of providing estimates of the individual contributions attributable to absorption, losses in the gut lumen, and first-pass elimination in the Gut wall and the liver.