082: Mechanistic Physiologically-based Pharmacokinetic Modeling to Predict Bictegravir Drug Disposition in Pregnancy

Statement of Purpose, Innovation or Hypothesis: Bictegravir (BIC) is a potent HIV-1 integrase strand transfer inhibitor and is used in a fixed dose combination with emtricitabine (FTC) and tenofovir alafenamide (TAF) (oral once daily BIC/FTC/TAF 50/200/25 mg) for HIV-1 treatment[1]. BIC Is metabolized by CYP3A4 and UGT1A1 and is highly protein bound (~99.7%)[1]. Pregnancy can affect drug disposition due to temporal physiological and metabolic changes, including an increase in CYP3A4 and UGT1A1 activity, as well as increased fraction unbound (f_u)[2], leading to increased metabolism of substrates and potentially lowered total plasma concentrations. Indeed, in a clinical study conducted to investigate steady state pharmacokinetics (PK) of BIC/FTC/TAF during pregnancy and postpartum [3], BIC maternal plasma exposures (AUC_tau, C_max and C_tau) was lower during pregnancy compared to postpartum. The objectives of the current work are to develop a BIC pregnancy physiologically-based pharmacokinetic model (PBPK) to predict maternal BIC plasma concentrations at various gestational ages and validate the developed model by comparison with the observed BIC concentrations.

Description of Methods & Materials: First, the non-pregnant PBPK model (Simcyp Simulator V.22) was populated with physicochemical and PK parameters of BIC and verified with postpartum/non-pregnant clinical PK data [3]. Postpartum PK was assumed to have returned to non-pregnant state [4]. Following this, all drug-specific parameters, except the f_u were fixed (f_u increases during pregnancy) and the Simcyp pregnancy model parameters (ie. pregnancy specific changes in metabolic enzyme levels/distribution) were used to make predictions in pregnant population in the 2^nd and 3^rd trimesters. These simulations were verified with observed data during pregnancy[3] and the predicted parameters were considered suitable if within ±50% deviation from the observed values.

Data & Results: The developed pregnancy PBPK model successfully predicted plasma-concentration time profiles of BIC in the 2^nd and 3^rd trimester. The median maternal total plasma exposures: C_max and AUC_0-24 were within 5% and 10% deviation, respectively, from the observed values during the 2^nd trimester. Median unbound plasma exposures were overpredicted by up to 30% from the observed values. Similarly, in the third trimester, median total plasma exposures: C_max and AUC_0-24 were within 5% and 12% of the observed values, respectively.

Interpretation, Conclusion or Significance: The developed pregnancy PBPK model for BIC reliably predicted PK of BIC during pregnancy. Overall, the findings suggest that PBPK models can be utilized in pregnant participants to assess the disposition of ARVs during pregnancy. In future work, we plan to apply the developed pregnancy model to predict exposures across varying gestational ages for BIC and potentially other molecules with similar metabolic disposition, as well as project drug-drug interactions (with rifamycins and other commonly co-administered agents) during pregnancy.

Disclosures:

Citations/References: 1. Di Perri G. Infez Med. 2019 Dec 1 2. Soma-Pillay, Priya et al. Cardiovasc J Afr. 2016 Mar-Apr; 27(2): 89–94 3. Zhang et al. AIDS 2024 Jan 1;38(1):F1-F9 4. İnce, S. et al. ENT Diseases: Diagnosis and Treatment during Pregnancy and Lactation. Springer, Cham. 2022

Additional Information/Authors: none