Bioequivalence and Bioavailability Forum

❝ Dear Sir

      ↑↑↑↑ Not interested in opinions of female members of the Forum?

❝ […] thank you very much for keeping such a wonderful webiste for others, it has been extremely helpful.

Welcome!

❝ I have a question about the subject inclusion in a bioequivalence study: […]

❝ I wonder if it is ok to maximize the homogeneity of subjects, especially for those highly variable drugs. Because recently a few studies found that genetics play an important role in determining the intra-individual variability.

❝ So we think if we recruit subjects with same genotype, we can have a smaller intra-indivdual variability therefore a smaller sample size.

You are raising very interesting questions! Quoting from one of Les Benet’s presentations¹:

What is the justification for studying
bioequivalence in healthy volunteers?

“Variability is the enemy of therapeutics” and is
also the enemy of bioequivalence. We are trying
to determine if two dosage forms of the same drug
behave similarly. Therefore we want to keep any
other variability not due to the dosage forms at a
minimum. We choose the least variable “test
tube”, that is, a healthy volunteer.

EMA followed the same rationale in their GL – minimize variability. This idea is even more clear for parallel designs, where geno-/phenotyping is mandatory (only a BE-study in one panel is required). For most drugs extensive/fast (E/FM) metabolizers are more common than poor/slow metabolizers (P/SM). Geno-/phenotyping is also important in cross-over studies, especially if steady state in PMs might lead to safety problems (example: paroxetine).

Not sure were FDA’s requirement comes from. At times when Individual Bioequivalence (IBE) was dis­cussed, one major topic was the subject-by-formulation interaction – which can be assessed only in a full replicate design. One idea was to explore subgroups (sex, age, ethicity, genotypes, …). It became immediately evident that a stratification for all possible combinations (keeping the power of com­pa­ri­sons at a reasonable level) is simply impossible unless one would opt for extremely high sample sizes. Therefore, the guidance states:

We recommend that the total number of subjects in the study provide adequate power for BE demonstration, but it is not expected that there will be sufficient power to draw conclusions for each subgroup. Statistical analysis of subgroups is not recommended. We recommend that restrictions on admission into the study generally be based solely on safety con­si­der­ations.

(my emphasis)

Generally we would expect that genotypes should be of no particular importance in BE, since the com­parison between treatments is done within subjects. However, you are correct that there are some examples in the literature showing the opposite – if the intra-subject variability differs between geno­types.

• Yong Chung et al. (2010)²
  Tacrolimus in healthy subjects (2×2 cross-over), subgroup analysis CYP3A5*1/*1+CYP3A5*1/*3 (n=16) and CYP3A5*3/*3 (n=13); %CV_W.
  PK metric  G1   G2
──────────────────
AUC0-t     30   42
Cmax       29   44
  
  
• Gonzales-Vacarezza et al. (2013)³
  Mirtazapine is eliminated by CYP2D6 and CYP3A and undergoes significant presystemic elimination following oral administration. PMs (subjects with no active CYP2D genes) have a higher AUC (+79%) compared to EMs (one or more active genes). EMs show a higher first-pass effect following oral administration. %CV_W from two 2×2 cross-over studies:
  Group 0: no active CYP2D6 genes (n=7)
  Group 1: 1 active CYP2D6 gene (n=26)
  Group 2: ≥2 active CYP2D6 genes (n=35)
  PK metric   G1    G2    G3   total
──────────────────────────────────
AUC0-t      7.7   8.5  15.0   12.3
Cmax       21.4  22.2  24.9   23.4

❝ But we wonder if we are rational (or allowed) to do so.

I don’t think so. At least the last sentence of FDA’s quotation speaks against selection of specific genotypes…

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1. Benet LZ. Why Do Bioequivalence Studies in Healthy Volunteers? 1^st MENA Regulatory Conference on Bioequivalence, Biowaivers, Bioanalysis and Dissolution. Amman, Jordan, 23 September 2013. free download
   
2. Yong Chung J, Jung Lee Y, Bok Jang S, Ahyoung Lim L, Soo Park M, Hwan Kim K. CYP3A5*3 Genotype Associated With Intrasubject Pharmacokinetic Variation Toward Tacrolimus in Bioequivalence Study. Ther Drug Monit. 2010;32(1);67–72. doi:10.1097/FTD.0b013e3181c49a4c
   
3. González-Vacarezza N, Abad-Santos F, Carcas-Sansuan A, Dorado P, Peñas-Lledó E, Estévez-Carrizo F, Llerena A. Use of pharmacogenetics in bioequivalence studies to reduce sample size: an example with mirtazapine and CYP2D6. Pharmacogenomics J. 2013;13(5):452–5. doi:10.1038/tpj.2012.29