Bioequivalence and Bioavailability Forum

Dear Muneesh!

❝ I donot know any guidelines for BE studies on antidiabetic drugs […]

But me.

❝ […] there is no need to administer dextrose solution along with antidiabetic drugs.

Oops. Please check the Guidance Collection in the future.

• Metformin (final 05/2008, new draft 03/2009):

  Subjects should receive 60 mL of a solution of 20 percent glucose in water immediately following each dose and subsequently at 15 minute intervals for 4 hours during fasting and fed bioequivalence studies.

• Glimepiride (final 05/2008):

  Because of the potential for hypoglycemia from using a dose of 4 mg of glimepiride tablets, you should conduct the bioequivalence studies using the 1 mg dose. Each dose in the studies should be administered with 240 mL of 20% glucose solution to minimize hypoglycemic effects. After dosing, 60 mL of 20% glucose solution should be given to each subject every 15 minutes for the following 4 hours.

• Glipizide (draft 07/2008):

  To avoid hypoglycemic episodes in healthy volunteers, the drug products should be administered with 240 mL of 20% or 25% glucose solution in water.

• Glipizide/Metformin (final 05/2008):

  Since the drug product causes hypoglycemia, it is recommended that subjects receive 60 mL of 20 percent glucose solution in water after each dose and every 15 minutes for 4 hours during fasting and fed bioequivalence studies.

• Glyburide/Metformin (final 05/2008):

  The drug products should be administered with 240 mL of 20% glucose solution in water, followed by 60 mL of the glucose solution administered every 15 minutes for up to 4 hours after dosing.

• Glimepiride/Pioglitazone (draft 05/2009):

  To avoid hypoglycemic episodes in healthy volunteers, the drug products should be administered with 240 mL of 20% glucose solution in water. After dosing, 60 mL of 20% glucose solution should be given to each subject every 15 minutes for the following 4 hours.

• Glimepiride/Rosiglitazone (draft 11/2007):

  Because of the potential for hypoglycemia from BE studies using the 4 mg dose of glimepiride tablets, in vivo BE study of the 1 mg glimepiride/4 mg rosiglitazone maleate tablets is recommended. In addition, each dose in the study should be administered with 240 mL of 20% glucose solution to minimize hypoglycemic effects. After dosing, 60 mL of 20% glucose solution should be given to each subject every 15 min for the following 4 hours.

• Nateglinide (final 05/2008):

  A single oral dose (120 mg) should be administered with 240 mL of 20% glucose solution.

• Repaglinide (draft 08/2008):

  To avoid hypoglycemic episodes in healthy volunteers, the drug products should be administered with 240 mL of 20% aqueous glucose solution, followed by 60 ml of the glucose solution administered every 15 minutes for up to 4 hours after dosing.

• Sitagliptin/Metformin (draft 09/2008):

  The drug products should be administered with 240 mL of a 20% glucose solution in water, followed by 60 mL of the glucose solution administered every 15 minutes for up to 4 hours after dosing.

If the drug is not listed above, check the literature for the time-course of the PD-effect – not the PK profile! – and adjust the administration of glucose accordingly.

❝ You have to monitor blood sugar levels frequently and in case of hypoglycaemia, physician needs to give appropriate treatment.

Sorry, but your suggestions are ethically unacceptable.

1. Additional burden on the subjects (glucose measurements) though it’s evident that there will be a reduction in levels. Furthermore, result of measurements do not correlate well with clinical response in healthy subjects. Some may be quite sensitive to lowered glucose levels and/or a rapid drop (unlike diabetics they are not accustomed to such a situation).
   
2. How would you efficiently deal with hypoglycaemic crises in one third of the subjects occurring at the same time?

BTW, if I would experience such an AE in the first period of a study I would withdraw my consent for sure and would never return for the second period.