Bioequivalence and Bioavailability Forum

Hi Ghannam,

❝ I would like to know if there is any regulations in FDA regarding including smoking subjects in bioequivalence studies.

Were you too lazy to read FDA’s guidances and do you want us to explore them for you in­stead?

Nothing about the smoking status is stated in the general guidances:

• March 2003
    This guidance recommends that in vivo BE studies be conducted in individuals representative of the general population, taking into account age, sex, and race.
  
• December 2013 Draft
    In vivo BE study subjects should be representative of the general population, taking into account age, sex, and race.

The CDC estimated in 2012 18.1% of all adults (aged 18 years or older) in the USA to smoke ciga­rettes. Cigarette smoking is more common among men (20.5%) than women (15.8%).
Are 18.1% a relevant part of the general population? I would say so.¹ Or the other way ’round: Are the 81.9% non-smokers representative of the general population? Given that, I don’t see a rationale to ex­clude smokers from BE-studies in a crossover design performed for the FDA (whereas the EMA pre­fers non-smokers – without giving a justification). AFAIK, in none of FDA’s product-specific guid­ances anything is mentioned about smoking (I checked the usual suspects; see below).

An excerpt from Imre Klebovich’s last month’s presentation² in Budapest:

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Polycyclic aromatic hydrocarbons (PAHs) are potent inducers of the hepatic cytochrome P450 (CYP) iso­forms 1A1, 1A2, and possibly 2E1. Of these, 1A2 is the most important. Some drugs affected by in­duc­tion of CYP1A2 (i.e., increased metabolism): Clo­zapine, flu­vox­amine, olan­za­pine, tacrine, theoph­yl­line, coumarins (including warfarin). Examples:
───────────────────────────────────────────────────
   Drug       Metabol. pathways   ↑ CL %   ↓ AUC % 
───────────────────────────────────────────────────
Theophylline  1A2, 3A4            60–100   10fold  
Tacrine       1A2                   NA     10fold  
Clo­zapine     1A2, 2C19, 3A4        NA       50    
Moxiletine    1A2, 2D6              25       NA    
Olanzapine    1A2, 2C19, 2D6        98       NA    
───────────────────────────────────────────────────
Nicotine is an inhibitor of the OCT2-transporter in the kidneys. Therefore, in smokers higher con­cen­tra­tions were reported for the OCT2-substrate cimetidine.

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❝ I would like to know if there are any points to consider in the protocol.

If the drug is neither metabolized by one of the CYPs mentioned above nor a substrate of OCT2, smok­ing status is simply irrelevant in BE. Even for affected drugs in crossover studies any PK-inter­action would mean out (within-subject comparison). However, the between-subject variability would be substantially larger than in a BE-study per­formed in non-smokers. Hence, the bioanalytical method must be capable dealing with a wider range of con­cen­tra­tions.
For obvious reasons parallel studies of affected drugs should be per­formed in non-smokers only.

If you opt for a study in non-smokers, perform a cotinine-test. It is insufficient to rely on subjects’ statements.³ Nicotine withdrawal induces stress, which may play havoc on liver blood-flow. Not a good idea.

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1. Compare this to the 12.6% “Black or African Americans” (USA Census 2010). “Race” is spe­cif­ically mentioned in the guidances…
   
2. I Klebovich
   Drug Interactions – Alcohol, Smoking and Caffeine
   In: Klebovich I and VP Shah (ed’s), Progress Towards Tommorrow’s Future – Advances in Regu­la­tory Science Beyond Bio­equi­va­lence. Presentations of 4^th International Regulatory Workshop on A to Z on Bioequivalence, Bioanalysis, Dissolution and Bio­simi­larity.
   Arrabona Print, Győr 2014, pp 159–70. ISBN 978-615-5270-09-03
   
3. Доверяй, но проверяй (Russian proverb: Trust, but verify)