Skip to main content

Table 2 Factors to estimate the exposure in the female partner after a vaginal dose: comparison with the approach from the fda draft guidance

From: Clinical trial considerations on male contraception and collection of pregnancy information from female partner: update

 

Updated proposal

FDA draft guidance

Small molecules

mAbs

Small molecules

mAbs

Pre-clinical reference model and PK parameter for safety margin calculations

 Pre-clinical reference model

NOAEL from EFD studies or MABEL if no NOAEL from EFD studies is available

NOAEL from EFD studies, no reference to MABEL

 PK parameter

AUC if NOAEL from EFD studies is available or if MABEL refers to AUC; Cmax if MABEL refers to a concentration

Cmax

Estimating exposure in female partner

 Ejaculation volume

6 mL

5 mL

 Seminal concentration

Total Cmax in plasma

1 % of total Cmax in plasma

Total Cmax in plasma

1 % of total Cmax in plasma

 Vaginal absorption

100 %

10 %

100 %

10 %

 Estimating exposure in female partner relative to vaginal dose absorbed

Extrapolates AUC and Cmax in female partner relative to the vaginal dose absorbed based on available dose-exposure

AUC of exposed male divided by 100 (ratio seminal fluid concentration: plasma concentration), by 10 (vaginal uptake), by 500 (ratio plasma volume: seminal fluid volume)

Estimates Cmax by dividing vaginal dose absorbed by blood volume (5000 mL)

Note: For mAbs the estimated C max in the female partner may be underestimated as the volume of distribution typically is the plasma

For small molecules, the estimated female C max is likely to result in an overestimation as vaginal dose divided by blood volume assumes an absorption rate similar to rapid iv injection. Indeed, pharmacokinetic data for drugs administered vaginally show that T max is not instant as per IV administration but takes several hours

 Vaginal administration: no intestinal-hepatic first pass effect

An intestinal-hepatic first pass effect would be assumed if vaginal administration is extrapolated from oral PK data, resulting in a possible underestimation of exposure to embryo/fetus.

No intestinal-hepatic first pass effect is taken into account. Thus, there is no potential for underestimation of exposure to embryo/fetus

 Placental transfer

100 %

10 % in 1st trimester; 100 % in 3rd trimester

100 %

10 % in 1st trimester; 100 % in 3rd trimester

 Uterine first pass effect

Not taken into consideration, potential underestimation of exposure to embryo/fetus

 Safety margin

300, when seminal concentration is estimated;

100, when seminal fluid concentration of molecule is known

100

10, when referring to MABEL

Not specified

  1. AUC area under the curve, C max maximum concentration, EFD embryo-fetal development, IV intravenous, mAb monoclonal antibody, MABEL minimum anticipated biological effect level, mL milliliter, NOAEL no adverse effect level, PK pharmacokinetics