PI-052 - A MODELING APPROACH TO EXPEDITE THE DEVELOPMENT OF A NEW LONG-ACTING CONTROLLED-RELEASE MULTIPURPOSE FORMULATION CONTAINING MEDROXYPROGESTRONE ACETATE

D. Oliveira¹, M. Cottrell¹, J. Dumond¹, J. King¹, T. Le¹, A. Schauer¹, S. Benhabbour¹; ¹University of North Carolina Chapel Hill, Chapel Hill, NC, USA.

Background: Novel technologies like in situ forming implants (ISFI) could extend dosing intervals and support multipurpose prevention of pregnancy and HIV. One such ISFI in development contains medroxyprogesterone acetate for contraception. Here we used PK modeling to characterize the ISFI drug absorption in mice compared to the reference long-acting injectable (LAI) DEPO-SUBQ®104 (Pfizer, Inc., New York, NY) over 90 days.

Methods: Mice received single medroxyprogesterone injections as follows: 65μg IV bolus (n=24), 7.5mg SC bolus (n=30), and 3mg ISFI (n=12) or 7.5mg (LAI) (n=12). The LAI dose was scaled for a human dose equivalent. Blood was collected using sparse sampling (3 samples/time) at 5min, 1, 3, 24, and 72 hrs following IV/SC bolus, and at 3h, 3, 14, 30, 60, and 90days following ISFI/LAI dosing. Plasma concentrations were measured by LC MS/MS. Absolute SC bioavailability (F) was determined from IV and SC bolus data via sparse NCA. To compare absorption rates of the ISFI and LAI, first a 2-compartment population macroconstant model was fit to IV plasma data and optimized for eta shrinkage, relative standard error, and goodness of fit. The mean unit impulse response (UIR) from this model was then used to deconvolve absorption rates (μg/day) of ISFI and LAI. All analyses used PHOENIX WinNonlin/NLME® 8.3 (Certara Inc., Princeton, NJ).

Results: Medroxyprogesterone’s SC F was 43%. Mean (%CV) IV PK parameter estimates were A= 2,506ng/mL (75%), α= 10.5hr-1 (85%), B= 439ng/mL (10%), and β= 0.65hr-1 (6%). At 30 days, median (IQR) estimated absorption rates were 124 (87 - 148) μg/day for LAI vs 7.9 (6.0 – 10.4) μg/day for ISFI. At 90 days, median (IQR) estimated absorption rates were 2.7 (0.49 – 3.6) μg/day for LAI vs 5.2 (3.8 - 9.3) μg/day for ISFI. The two formulations exhibited different absorption rate dispositions over the course of 90 days (Figure 1), with ISFI demonstrating a more controlled absorption after initial burst compared to LAI.

Conclusion: This is the first report of medroxyprogesterone’s SC F in mice. Our modeling approach reveals that compared to the LAI absorption rate at 90 days, ISFI absorption rates were consistently higher over the anticipated dosing interval. Thus, continued ISFI medroxyprogesterone development in humans is appropriate based on PK.