PT-014 - PHYSIOLOGICALLY BASED PHARMACOKINETIC MODEL OF DRUG DELIVERY IN THE FEMALE REPRODUCTIVE TRACT

X. Li¹, T. Straubinger², G. Valicheria³, Z. Zhang⁴, S. Achilles⁵, M. Donnelly⁶, L. Zhao⁷, E. Tsakalozou⁸, B. Chen⁹, L. Rohan¹⁰, R. Bies¹¹; ¹Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, Buffalo, NY, USA, ²University at Buffalo, ³Mage Womens Reseearch Institute, ⁴Department of Pharmaceutical Sciences, University of Pittburgh, Magee Womens Research Institute, ⁵Bill and Melinda Gates Foundation, ⁶Division of Quantitative Methods and Modeling, Office of research and Standards, Office of Generic Drugs, Center for Drug Evaluation and Research, Food and Drug Administration, ⁷Division of Quantitative Methods and Modeling, Office of Research and Standards, Office of Generic Drugs, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD, USA, ⁸Division of Quantitative Methods and Modeling, Office of Research and Standards, Office of Generic Drugs, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, ⁹Department of Obstetrics, Gynecology, and Reproductive Sciences, University of Pittsburgh, School of Medicine, ¹⁰Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Magee Womens Research Institute, ¹¹Department of Pharmaceutical Sciences, University at Buffalo.

Background: We have developed an open-source PBPK model to predict delivery of complex drug products into the vaginal/cervical/uterine luminal fluid and subsequent drug distribution into local tissues and ultimately the bloodstream.[1] Levonorgestrel (LNG) was used as a test compound for model development and validation, as it is available in several formulations including oral tablets and intrauterine devices (IUDs).

Methods: Physiological and anatomical information were obtained from an exhaustive literature search. Tissue-specific permeability rates were measured from freshly excised human cervicovaginal and uterine tissue samples. In vitro release data of three commercially available LNG IUDs, loaded with 13.5mg, 19.5mg, or 52mg LNG designed to release over 3 years, 5 years and 5-7 years, respectively, were measured. LNG PK data after oral, vaginal, and uterine administration were obtained from literature [2–8].

Results: A whole-body PBPK model predicted published luminal fluid, vaginal/uterine tissue, and plasma LNG concentrations after LNG administration via IUD and oral capsules. Data from the study by Nilsson et al [2] are shown with the simulation of concentrations in the endometrium (Figure 1a) and plasma (Figure 1b) after IUD administration.

Conclusion: A preliminary mechanistic PBPK model platform predicted vaginal and uterine concentrations of LNG following oral and IUD administration. This model platform may facilitate the exploration of new strategies for bioequivalence for complex formulations in this area.

1. Donnelly et al. J Clin Pharmacol. 2020 Dec;60 Suppl 2:S26-S33. doi: 10.1002/jcph.1760. PMID: 33274513.
2. Devoto et al. Fertility and Sterility. 2005;84:46–51.
3. Nilsson CG et al. Clinical Endocrinology. 1982;17:529–36.
4. Tremblay D et al. Contraception. 2001;64:327–31.
5. He C et al. Contraception. 1990;41:557–67.
6. Kook K et al. Contraception. 2002;66:73–6.
7. Landgren B-M et al. Contraception. 1986;33:473–85.
8. Johansson E et al. Human Reproduction. 2002;17:1472–6.