Utilizing Pharmacometrics to Facilitate Generic Drug Development of Orally Inhaled Products and Optimize Pharmacotherapy of Antifibrinolytics
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AbstractThis thesis has two parts. The first part is related to the pharmacokinetic (PK) batch-to-batch variability of orally inhaled products, which may pose challenges for generic product development. I applied the techniques of pharmacometrics to propose and evaluate alternative PK bioequivalence (BE) study designs using Advair Diskus as an example product, aiming to facilitate generic development. First, population PK models for Advair Diskus were developed and qualified to simulate PK BE study. Next, the effect of batch-to-batch variability on the establishment of BE was evaluated using the developed models. Batch-to-batch variability substantially elevates the probability of reaching a false conclusion in a PK BE study for equivalent and inequivalent comparisons. Therefore, ignoring batch-to-batch variability when presenting will increase the risk of either patients being treated with an inequivalent formulation or pharmaceutical companies not obtaining approval for an equivalent formulation. This calls for alternative PK BE approaches to account for the batch-to-batch variability. I proposed and evaluated a two-phase study framework that uses a pilot study to select reference and test batches for the pivotal BE study. A parallel design with ≥ 12 patients per sequence or a crossover design with ≥ 6 patients per sequence is recommended for the pilot study design. The proposed criteria for selecting batches based on the pilot study results include (1) 0.9 ≤ T/R ≤ 1.11 and (2) higher conditional power. The two-phase study design offers the flexibility to select batches in a PK study to minimize the impact of batch-to-batch variability on the generics development. The two-phase framework might be applied to other products with similar characteristics and high batch-to-batch variability in the reference products. The second part of this thesis used pharmacometrics to optimize the pharmacotherapy of an anti-fibrinolytic, tranexamic acid (TXA), in special patient populations. The PK and pharmacodynamics (PD) of TXA in special populations are understudied; therefore, the PK/PD-driven optimal doses for them are unknown. First, I characterized the PK and PD of TXA in pregnancy and found that pregnant women have up to 30% higher clearance and volume of distribution than the general non-pregnant population. A dose of 650 mg maintains both PK and PD targets for > 1 hour in most patients, which is recommended as the postpartum prophylactic dose for future confirmatory clinical studies. In addition, I evaluated a current dosing regimen for cardiac surgery patients who use cardiopulmonary bypass (CPB) during their surgeries from a PK perspective. This dosing regimen consists of a long infusion of TXA at 100 mg/hr for 5 hours before CPB initiation, a 1 g bolus of TXA at CPB initiation, and another 1 g bolus at the end of CPB. While kidney function affects the clearance of TXA, and the CPB procedure increases the volume of distribution of TXA, the current dosing regimen was confirmed to provide sufficient TXA exposure (15 mg/L) from CPB initiation till 3 hours post-CPB, achieving the therapeutic goal. Both studies contribute to understanding how TXA dosing can be optimized in special patient populations.
DescriptionUniversity of Maryland, Baltimore, School of Pharmacy, Ph.D., 2023
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