Bioequivalence and Bioavailability Forum

Hi Helmut&all!
Following up upon our previous discussion about Capectabine.

Old guidance:
Widening of the usual acceptance criteria for Cmax is not accepted because capecitabine is considered a “critical dose” drug.

New guidance:
Since high intra-individual variability (CVintra > 30 %) is expected, the applicants might follow respective guideline recommendations.

Is something changed in the minds of PKWP members?

Dear all,


Anyone gone through the EMA response to comments on Tadalafil?

As per EMA “GUIDELINE ON THE INVESTIGATION OF BIOEQUIVALENCE” it is mentioned as “In general, a bioequivalence study should be conducted under fasting conditions as this is considered to be the most sensitive condition to detect a potential difference between formulations...... However, for products with specific formulation characteristics (e.g. microemulsions, solid dispersions), bioequivalence studies performed under both fasted and fed conditions are required unless the product must be taken only in the fasted state or only in the fed state."

In draft product specific BE guidance for Tadalafil Tablets it was mentioned that “The reference product is considered to have specific formulation characteristics to enhance the rate of absorption of the drug and therefore, it cannot be assumed that the impact of food will be the same regardless of formulation. The product can be taken without regard to food. Thus, both fasted and fed state comparisons of test to reference formulations are required."


There were several comments submitted to EMA on the above mentioned point quoting that the “Cialis contains conventional excipients. There are no special ingredients, matrix formation or solubility enhancers, except for the commonly used wetting agent – sodium lauryl sulfate (SLS) and the formulation was prepared using conventional wet granulation process. Apart from this Cialis SmPC recommends intake of the reference medicinal product on an empty stomach or irrespective of food intake. So looking into all this only fasting study should be required.”


To this the response from EMA is “If the generic is manufactured using the same technology and similar formulas as the originator it may be justifiable to deviate from the guidance by avoiding the fed study.”


Same technology and similar formulas as originator!! Seriously?


Are there chances that the same requirement can be extended to other products (where a surfactant has been added/micronized API used and/or some specific technology used for originators) whenever the new set of BE guidance will be available?


Life is tough!!!!

Dear all,

EMA published today a batch of 9 new guidances: asenapine, entecavir, lenalidomide, prasugrel, rivaroxaban, sitagliptin, tacrolimus, ticagrelor, zonisamide. Date for coming into effect: 01 November 2016.

Dear all,

on 01 August the EMA published a new batch of product specific guidances for comment:

• Abiraterone tablets 250 mg.
  
• Exenatide powder and solvent for prolonged-release suspension for injection, 2 mg, and powder and solvent for prolonged-release suspension for injection in pre-filled pen, 2 mg.
  
• Paliperidone palmitate depot suspension for injection 25, 50, 75, 100 and 150 mg.
  
• Vandetanib film-coated tablets 100 and 300 mg.
  
• Vemurafenib fim-coated tablets 240 mg.

End of consultation is 31 October 2016.

❝ Dear all, today the EMA published a new batch of product specific guidances (capecitabine, ..."

To capecitabine, ANVISA recommends strength 150 mg and healthy volunteers. Can I imagine a replicate study (partial or full) assuming a total dose of 450 mg (3x150 mg) to 600 mg (4x150 mg), respectively, to each subject in a short time between the periods (WO ~ 1 hour)?