Preview

Translational Medicine

Advanced search

On the assessment of contamination and analysis of control samples in toxicokinetics studies

https://doi.org/10.18705/2311-4495-2024-11-4-351-363

Abstract

Relevance. The evaluation of control samples contamination is a necessary element for confirming the correctness of toxicokinetic studies (TK), concomitant with the study of toxicity of drugs and products. At the same time, insufficient elaboration of existing regulatory documents necessitates discussion of practical aspects and improvement of the regulatory framework. Purpose. The work is devoted to the consideration of experimental experience of control samples contamination in TK studies. Materials and methods. As experimental examples, two studies of TK drugs performed using rabbits with oral administration of study drugs for 28 (Study 1) or 90 (Study 2) days were considered. Results. Study 1 revealed a contamination level of 17–25 % (on the first and last days of study drug administration, respectively). Contamination of bioassays can occur in vivo (contamination of animals) and ex vivo (at the stage of bioassay sampling, at the pre-analytical stage and analytical stage). The nature of the analyte detection in the samples made it possible to exclude contamination in vivo, and the results of an internal investigation suggested that it occurred at the stage of biosample selection. In Study 2, a number of preventive measures were implemented and a slight level of contamination was obtained (0.83 %), which did not affect the completeness and correctness of results interpretation. Conclusion. Based on experimental experience, recommendations for minimizing and preventing contamination of control samples during the biological part, pre-analytical and analytical stages of studies were formulated. Presumably, in the presence of a random nature of contamination indicating its ex vivo origin, the level of contamination not exceeding 25 % can be considered insignificant, i.e. not leading to further deviation and cancellation of the results of the entire study

About the Authors

V. M. Kosman
RMC “Home оf Pharmacy”
Russian Federation

Vera M. Kosman, PhD, head of analytical laboratory

Zavodskaya str., 3, building 245, Kuzmolovsky settlement, Leningrad Region, 188663


Competing Interests:

The authors declare no conflict of interest



M. V. Karlina
RMC “Home оf Pharmacy”
Russian Federation

Marina V. Karlina, PhD, head of department of technology, kinetics and analysis of drugs

Zavodskaya str., 3, building 245, Kuzmolovsky settlement, Leningrad Region, 188663


Competing Interests:

The authors declare no conflict of interest



E. M. Petrova
RMC “Home оf Pharmacy”
Russian Federation

Elizaveta M. Petrova, junior researcher of analytical laboratory

Zavodskaya str., 3, building 245, Kuzmolovsky settlement, Leningrad Region, 188663


Competing Interests:

The authors declare no conflict of interest



M. N. Makarova
RMC “Home оf Pharmacy”
Russian Federation

Marina N. Makarоva, PhD, DSci (Medicine), director

Zavodskaya str., 3, building 245, Kuzmolovsky settlement, Leningrad Region, 188663


Competing Interests:

The authors declare no conflict of interest



V. G. Makarov
RMC “Home оf Pharmacy”
Russian Federation

Valery G. Makarov, PhD, DSci (Medicine), Professor, scientific supervisor

Zavodskaya str., 3, building 245, Kuzmolovsky settlement, Leningrad Region, 188663


Competing Interests:

The authors declare no conflict of interest



References

1. Welling PG. Differences between pharmacokinetics and toxicokinetics. Toxicol Pathol. 1995;23(2):143–7. DOI: 10.1177/019262339502300207.

2. Pozharitskaya O, Shikov A, Makarov V. Toxicokinetics — Methodological Approaches. Laboratory Animals for Science. 2019;1. https://doi.org/10.29296/2618723X-2019-01-06 In Russian

3. Zimmer D. Drugs in control samples in nonclinical safety studies: a reconsideration. Bioanalysis. 2016; (10):1003–7. DOI: 10.4155/bio-2016-0066.

4. Nicholls I, Kolopp M, Pommier F, et al. The presence of drug in control samples during toxicokinetic investigations--a Novartis perspective. Regul Toxicol Pharmacol. 2005;42(2):172–8. DOI: 10.1016/j.yrtph.2005.03.004.

5. Hill HM, Smith GT. Evaluation and Elimination of Carryover and/or Contamination in LC-MS Bioanalysis., In: Handbook of LC-MS Bioanalysis (Best Practices, Experimental Protocols, and Regulations). Ed. by Li W, Zhang J, Tse F. 2013, 259–273. DOI: 10.1002/9781118671276.ch21.

6. Maronpot RR, Ramot Y, Koyanagi M, et al. Tenday and four-week toxicity and toxicokinetics studies of alpha-glycosyl isoquercitrin in juvenile Göttingen minipigs. Toxicology Research and Application. 2019;3. DOI: 10.1177/2397847319855087.

7. Li Y, Liu TT, Jin HT, et al. A comparison of toxicity and toxicokinetics in rats and dogs following twentyeight-day, repeat-dose oral administration of nifurtimox. Toxicol Res (Camb). 2017;6(4):544–553. DOI: 10.1039/c7tx00061h.

8. Lacour B, Lucas A, Auchère D, et al. Chronic renal failure is associated with increased tissue deposition of lanthanum after 28-day oral administration. Kidney Int. 2005;67(3):1062–9. DOI: 10.1111/j.1523-1755.2005.00171.x.

9. McLeod C, Cox A, Bramall N. The need for contamination control in studies on lanthanum biodisposition. Kidney Int. 2005;68(6):2906. DOI: 10.1111/j.1523-1755.2005.00583_1.x.

10. D’Haese PC, Behets GJ, De Broe ME, Damment SJ. Lanthanum pharmacokinetics: are rat data misleading? Kidney Int. 2005;68(6):2907–8. DOI: 10.1111/j.1523-1755.2005.00583_3.x.

11. Hughes NC, Wong EY, Fan J, Bajaj N. Determination of carryover and contamination for mass spectrometry-based chromatographic assays. AAPS J. 2007;9(3):E353–60. DOI: 10.1208/aapsj0903042.

12. Clouser-Roche A, Johnson K, Fast D, Tang D. Beyond pass/fail: a procedure for evaluating the effect of carryover in bioanalytical LC/MS/MS methods. J Pharm Biomed Anal. 2008.;47(1):146–55. DOI: 10.1016/j.jpba.2007.12.019.

13. Kim K, Lee H, Lee JJ, et al. Identification of a frit-related sample carryover in newborn screening by tandem mass spectrometry. J Mass Spectrom Adv Clin Lab. 2023;27:56–60. DOI: 10.1016/j.jmsacl.2023.01.001.


Review

For citations:


Kosman V.M., Karlina M.V., Petrova E.M., Makarova M.N., Makarov V.G. On the assessment of contamination and analysis of control samples in toxicokinetics studies. Translational Medicine. 2024;11(4):351-363. (In Russ.) https://doi.org/10.18705/2311-4495-2024-11-4-351-363

Views: 198


Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 License.


ISSN 2311-4495 (Print)
ISSN 2410-5155 (Online)