Less than daily administration

Risk Assessment Strategy / Tools & Technology
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Anyone have experience with drugs that are administered monthly, etc.? In these cases, the MDD would be less relevant given the cumulative effect.

Thanks, Jason

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MDD is max dose taken by patient in a day. so even if drugs administered once in a month, its the dose administered that particular day which should be considered as MDD for calculation of limits. Hope it helps…

thanks for raising this concern, its further discussion will be interesting….

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Hi Jason,

I agree with Sarvesh, MDD will remain unchanged. The only potential impact is the cumulative lifelong dose, which according to ICH M7 you would be able to calculate. If it is dosed once monthly, you have 12 dosing days per year, and 840 days in a lifetime, considering 70 years . This would mean that, in case that LTL is accepted, you would be able to use <10 years even if the drug is chronic

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Just wondering if @SusanFelter could help us understand or build the connection of this particular scenario with LTL. Thanks

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Hi Jason,

In Brazil, ANVISA experts have clearly stated that for long-acting products administered as a single dose (monthly, quarterly, etc.), the MDD should correspond to the maximum dose administered on the day of dosing. This value should not be normalized or divided by the expected duration of action.

The reasoning is that toxicological assessment should consider both the cumulative exposure over time and the potential toxicological impact associated with the administration of the full dose at a single time point. Therefore, as a conservative approach, the MDD remains the maximum amount administered in one day, regardless of how long the pharmacological effect lasts.

Best regards,

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Hi Jason,
I was looking into this subject recently due to the reference to a potential adjustment factor for detected nitrosamines in IV bags from the FDA/CDER. Here are two papers that I found helpful. Naiffer mentioned one of the authors in this discussion.

Evaluating the lifetime cumulative dose as a basis for carcinogenic potency of nitrosamines – a key tenet underpinning less-than-lifetime approaches for establishing acceptable intake limits - ScienceDirect

Mutagenic and carcinogenic potency determinations for NDMA support the cumulative dose assumption underpinning the less-than-lifetime Threshold of Toxicological Concern | Archives of Toxicology | Springer Nature Link

I hope you are well!

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Appreciate all the comments. This is in line with how I understand the regulations as well, but it seems that this case is not really considered.

Thanks

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Thanks, @MTwohig . I’ll dive deeper on this.

I’m doing great! Hope you are too.

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