DEVELOPMENT AND VALIDATION OF A SEMI-PHYSIOLOGICAL PHARMACOKINETIC (PBPK) MODEL TO PREDICT SYSTEMIC AND PULMONARY EXPOSURES AFTER INTRAVENOUS, ORAL ADMINISTRATION AND PULMONARY INHALATION OF SELECTED DRUGS, BUDESONIDE, TOBRAMYCIN AND CIPROFLOXACIN, IN HUMANS
Doctor of Philosophy
Using a semi-PBPK modeling/quantitative meta-analysis approach, this project investigated what factors affect pulmonary and systemic exposures of Budesonide (BUD), Tobramycin (TOB), and Ciprofloxacin (CIP) after inhalation:
Three structurally different pulmonary disposition models were developed for each drug, including pulmonary absorption (all three), excretion (TOB and CIP) and sequestration (TOB) in a peripheral and central lung compartment. Systemic disposition parameters were estimated using available human mean plasma (cp(t)) and sputum (cs(t)) concentration profiles after IV administration, and GI absorption parameters were estimated from these profiles after oral administration. Pulmonary disposition parameters were estimated from cp(t) and cs(t) profiles after inhalation using various devices along with their published pulmonary deposition characteristics. Appropriate covariate models accounted for effects of Cystic Fibrosis on the systemic disposition/GI absorption for TOB and CIP. Monte Carlo Simulations (MCS) were used to optimize parameters and validate the final models and parameter spaces against published data.
Despite limited available data, especially cs(t) for BUD and CIP (after IV administration), the point estimates for the final model parameters were mechanistically plausible for all three drugs and consistent with their known differences in physicochemical and ADME properties. Model predictions adequately described the observed cp(t) and cs(t) profiles as well as exposure metrics across studies.
As the most lipophilic drug, BUD showed the fastest pulmonary absorption rates and highest Fpul (83%). TOB, a very hydrophilic drug, exhibited (intracellular) pulmonary sequestration, resulting in slow pulmonary absorption and excretion and low Fpul (10%). CIP - as zwitterion - showed relatively slow pulmonary absorption and excretion, leading to low Fpul (8%); pulmonary excretion accounted for 27% of CIP overall elimination.
Results of a formal parameter sensitivity analysis demonstrated that, for all three drugs, after inhalation, (1) their systemic exposures (cp(t)) depend primarily on CLtot along with Fpul/sequestration combined with Foral; (2) increasing pulmonary exposures (cs(t)) can be accomplished by slowing down pulmonary absorption rates (kca) and/or slowing down mucociliary clearance from the lungs into the GI tract (kcm) – affirming the overall hypothesis guiding the project.
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