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Factors to estimate the exposure in the female partner after a vaginal dose: comparison with the approach from the fda draft guidance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  Updated proposal FDA draft guidance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