Table 2.

Factors to estimate the exposure in the female partner after a vaginal dose: comparison with the approach from the fda draft guidance

	Updated proposal		FDA draft guidance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

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