Less than lifetime limits for N-nitrosamine mutagenic impurities

MOST ESTABLISHED cancer risk assessments are based on lifetime exposures, ie, 70 years; but lifetime exposures are rarely the norm in either clinical development or indeed commercial products. Consequently, ICH M7¹ introduced the concept of “less than lifetime” (LTL) limits; based on the precept that the “cancer risk of a continuous low dose over a lifetime would be equivalent to the cancer risk associated with an identical cumulative exposure averaged over a shorter duration”.¹ For example, a drug administered once per day for six months (ie, <12 months) would have an acceptable intake per dose of 20μg¹ – this is 13.3 times greater than the generic value for whole lifetime dosing, ie, 1.5 μg/day – which is the default threshold of toxicological concern (TTC). However, ICH M7 indicated that, “Some structural groups were identified to be of such high potency that intakes even below the TTC would theoretically be associated with a potential for a significant carcinogenic risk”. This group of high potency mutagenic carcinogens, referred to as the “cohort of concern”, comprises aflatoxin-like-, N-nitroso-, and alkyl-azoxy compounds.¹ Nonetheless, many commentators have argued that the concepts inherent in ICH M7 are still applicable; but the allowable intakes need to be far lower to account for the increased toxicity.²

EFPIA, in a recent briefing document on N-nitrosamines,³ supported this view stating that, “Where applicable, acceptable intakes may be adjusted for LTL exposure using the same principles that are applicable for any mutagenic carcinogen (regardless of potency)”. EFPIA indicates that for class 1 N-nitrosamines, the LTL acceptable intakes should be based on the safety factors defined in ICH M7 (ie, for treatment durations of <1 month, >1‑12 months, >1-10 years and >10 years to lifetime – the lifetime acceptable intakes would be increased by factors of approximately 80, 13.3, 6.7 and one respectively). For class 2 and class 3 nitrosamines (of unknown carcinogenic potential) LTL acceptable intakes could be applied to the proposed lifetime acceptable intake for any N-nitrosamine of 44 ng/day, which should be the subject of an ICH M7 addendum. Bercu et al.⁴ assessed whether applying LTL concepts to N-nitrosamines would control exposure to an acceptable excess cancer risk in humans. Using the most potent member of the class, N-nitrosodiethylamine (NDEA), as a model compound, they leveraged empirical data comparing exposure duration (as a proportion of lifespan) and the incidence of cancer in rodent bioassays, demonstrating that the LTL acceptable intake derived using the ICH M7 guidance would not exceed a negligible additional risk of cancer. Thus they demonstrated that this approach is “protective for potential carcinogenic risk to patients over the exposure durations typical of clinical trials and many prescribed medicines”.⁴

Additionally, N-nitrosamines are an extremely heterogenous class of chemicals with mutagenic potency spanning four orders of magnitude and approximately 20 percent of this class are reported as non-mutagenic.⁵ The factors leading to reduction in mutagenic potency are also well established, including molecular size, electronic factors and steric considerations.⁶ Some nitrosamines tend to be less mutagenic, ie, bicyclic nitrosamines⁷ or even in extremis non-mutagenic, ie, N-nitrosovalsartan.⁸ However, both EMA and FDA have approached the applicability of LTL dosing for this class of compounds very cautiously. FDA⁹ has indicated that “less than lifetime (LTL) adjustments are not appropriate for nitrosamine impurities”, which can “induce tumours in multiple species at relatively low doses and after very short durations of dosing, including single doses”.⁹ As such, there may be little regulatory appetite for the application of LTL concepts to commercial product; however, the applicability of LTL to clinical development should not be ruled out.

References

1. ICH M7(R1). Assessment and control of DNA reactive (mutagenic) impurities in pharmaceuticals to limit potential carcinogenic risk.
2. Elder DP, Johnson GE, Snodin DJ. Tolerability of risk: A commentary on the nitrosamine contamination issue. J Pharm Sci. 110(6), 2021, 2311-2328.
3. EFPIA position with respect to safety related aspects of EMA and Health Canada requests for N-nitrosamine evaluations.  https://www.efpia.eu/media/580596/efpia-position-with-respect-to-safety-related-aspects-of-ema-and-health-canada-requests-for-n-nitrosamine-evaluations.pdf. Accessed on 19 September 2021.

4. Bercu JP, Masuda-Herrera MJ, Johnson G, et al. Use of less-than-lifetime (LTL) durational limits for nitrosamines: Case study of N-nitrosodiethylamine (NDEA). Reg Pharm Toxicol. 2021; 123: 104926.
5. Thresher A, Foster R, Ponting DJ, et al. Are all nitrosamines concerning? A review of mutagenicity and carcinogenicity data. Reg Tox Pharmacol. 116, 2020, 104749.
6. Thomas R, Thresher A, Ponting DJ. Utilisation of parametric methods to improve percentile-based estimates for the carcinogenic potency of nitrosamines. Reg Tox Pharmacol. 121, 2021, 104875.
7. Ohwada T, Ishikawa S, Mine Y, et al. 7-Azabicyclo[2.2.l]heptane as a structural motif to block mutagenicity of nitrosamines. Bioorg & Med Chem 19, 2011, 2726-2741.
8. HMA/EMA. Lessons learnt from presence of N-nitrosamine impurities in sartan medicines. 27 October 2020. EMA/503522/2020.
9. AAM/CHPA/PhRMA Questions for May 4th FDA-Industry Meeting to Discuss Nitrosamine Impurities in Pharmaceuticals. May 04th 2021.