Bioequivalence and Bioavailability Forum

Dear Dan & all!

❝ Maybe it would be helpful (at least interesting) to have a look at this thread:

THX for bringing this goodie back to our attention!

I like to share another story with you. Within 2000 and 2007 we performed six studies with MPH. As this was our standard we included both sexes. Furthermore, no gender-related difference in PK are reported in the literature. The last protocol was not accepted by the German BfArM:

A justification according to §7(2)12 GCP-V¹ why the chosen sex distribution in the group of trial subjects is appropriate in order to identify possible sex-specific differences in the effi­cacy or safety of the investigational medicinal product being tested is missing.
The intended participation of healthy female volunteers of childbearing age in this phase I clinical trial is generally to be justified because the applicant apparently does not plan to inves­tigate gender differences and the investigational medicinal products are contra­indi­cated during pregnancy. A comparison between male and female subjects is not included in the stat­is­tics section.

We gave in and added an explorative analysis of gender differences² to the SAP. In subsequent studies the sponsor opted for males only…

In the course of a type II variation this year the RMS Germany raised in their Preliminary Variation Assessment Report (PVAR) the following Question (in V.2.3 Clinical efficacy):

• The Applicant is asked to clarify if in PK studies in healthy adult subjects resp. adult patients gender related differences of the pharmacokinetic properties have been seen.

Oh no, not again! My response (pending) – reassessing all mixed-gender studies:

1. Extending the common statistical model to assess bioequivalence (effects: sequence, subject within sequence, period, and formulation) by two fixed effects:
   • gender
     
   • treatment-by-gender interaction
2. Subjecting the main PK metric for extent of absorption (AUC_t) to regression analyses:
   • dose adjusted by gender (logistic regression)
     
   • dose adjusted by body weight (linear regression)
     
   • dose adjusted by body weight (LR, stratified by gender)
3. Setting up a Population PK model: One-compartment open with extravascular administration; two absorption compartments (both receiving 50% of the total dose) with independent rates of absorption (k_a1, k_a2) and lag-times (t_lag1, t_lag2) and a common rate of elimination (k_el). Three models were compared:
   • Simple model
     
   • Covariate model 1 (body weight ⇒ V)
     
   • Covariate model 2 (body weight ⇒ V, gender ⇒ V, k_el)

Outcome: There was a weak (i.e., nonsignificant) correlation between body weight and AUC_t, inde­pen­dent from sex. Body weight as a covariate in the PopPK model clearly improved fits. Everything else was just a complete waste of time.

---

References:
1. German Ordinance on the implementation of Good Clinical Practice in the conduct of clinical trials on medicinal products for use in humans (GCP Ordinance – GCP-V)
   
2. Schütz H, Fischer R, Großmann M, Mazur D, Leis HJ, Ammer R. Lack of bioequivalence between two methylphenidate extended modified release formulations in healthy volunteers. Int J Clin Pharm Ther. 2009;47(12):761–9. doi 10.5414/CPP47761