Understanding the suitability of established antibiotics for oral inhalation from a pharmacokinetic perspective: an integrated model-based investigation based on rifampicin, ciprofloxacin and tigecycline in vivo data.

BACKGROUND: Treating pulmonary infections by administering drugs via oral inhalation represents an attractive alternative to usual routes of administration. However, the local concentrations after inhalation are typically not known and the presumed benefits are derived from experiences with drugs specifically optimized for inhaled administration. OBJECTIVES: A physiologically based pharmacokinetic/pharmacodynamic (PBPK/PD) model was developed to elucidate the pulmonary PK for ciprofloxacin, rifampicin and tigecycline and link it to bacterial PK/PD models. An exemplary sensitivity analysis was performed to potentially guide drug optimization regarding local efficacy for inhaled antibiotics. METHODS: Detailed pulmonary tissue, endothelial lining fluid and systemic in vivo drug concentration-time profiles were simultaneously measured for all drugs in rats after intravenous infusion. Using this data, a PBPK/PD model was developed, translated to humans and adapted for inhalation. Simulations were performed comparing potential benefits of oral inhalation for treating bronchial infections, covering intracellular pathogens and bacteria residing in the bronchial epithelial lining fluid. RESULTS: The PBPK/PD model was able to describe pulmonary PK in rats. Often applied optimization parameters for orally inhaled drugs (e.g. high systemic clearance and low oral bioavailability) showed little influence on efficacy and instead mainly increased pulmonary selectivity. Instead, low permeability, a high epithelial efflux ratio and a pronounced post-antibiotic effect represented the most impactful parameters to suggest a benefit of inhalation over systemic administration for locally acting antibiotics. CONCLUSIONS: The present work might help to develop antibiotics for oral inhalation providing high pulmonary concentrations and fast onset of exposure coupled with lower systemic drug concentrations.

Inferring pulmonary exposure based on clinical PK data: accuracy and precision of model-based deconvolution methods.

Determining and understanding the target-site exposure in clinical studies remains challenging. This is especially true for oral drug inhalation for local treatment, where the target-site is identical to the site of drug absorption, i.e., the lungs. Modeling and simulation based on clinical pharmacokinetic (PK) data may be a valid approach to infer the pulmonary fate of orally inhaled drugs, even without local measurements. In this work, a simulation-estimation study was systematically applied to investigate five published model structures for pulmonary drug absorption. First, these models were compared for structural identifiability and how choosing an inadequate model impacts the inference on pulmonary exposure. Second, in the context of the population approach both sequential and simultaneous parameter estimation methods after intravenous administration and oral inhalation were evaluated with typically applied models. With an adequate model structure and a well-characterized systemic PK after intravenous dosing, the error in inferring pulmonary exposure and retention times was less than twofold in the majority of evaluations. Whether a sequential or simultaneous parameter estimation was applied did not affect the inferred pulmonary PK to a relevant degree. One scenario in the population PK analysis demonstrated biased pulmonary exposure metrics caused by inadequate estimation of systemic PK parameters. Overall, it was demonstrated that empirical modeling of intravenous and inhalation PK datasets provided robust estimates regarding accuracy and bias for the pulmonary exposure and pulmonary retention, even in presence of the high variability after drug inhalation.

Integration of physiological changes during the postpartum period into a PBPK framework and prediction of amoxicillin disposition before and shortly after delivery.

The objective of this study was to develop a physiologically based pharmacokinetic (PBPK) model for amoxicillin for non-pregnant, pregnant and postpartum populations by compiling a database incorporating reported changes in the anatomy and physiology throughout the postpartum period. A systematic literature search was conducted to collect data on anatomical and physiological changes in postpartum women. Empirical functions were generated describing the observed changes providing the basis for a generic PBPK framework. The fraction unbound ([Formula: see text]) of predominantly albumin-bound drugs was predicted in postpartum women and compared with experimentally observed values. Finally, a specific amoxicillin PBPK model was newly developed, verified for non-pregnant populations and translated into the third trimester of pregnancy (29.4-36.9 gestational weeks) and early postpartum period (drug administration 1.5-3.8 h after delivery). Pharmacokinetic predictions were evaluated using published clinical data. The literature search yielded 105 studies with 1092 anatomical and physiological data values on 3742 postpartum women which were used to generate various functions describing the observed trends. The [Formula: see text] could be adequately scaled to postpartum women. The pregnancy PBPK model predicted amoxicillin disposition adequately as did the postpartum PBPK model, although clearance was somewhat underestimated. While more research is needed to establish fully verified postpartum PBPK models, this study provides a repository of anatomical and physiological changes in postpartum women that can be applied to future modeling efforts. Ultimately, structural refinement of the developed postpartum PBPK model could be used to investigate drug transfer to the neonate via breast-feeding in silico.

Towards a Quantitative Mechanistic Understanding of Localized Pulmonary Tissue Retention-A Combined In Vivo/In Silico Approach Based on Four Model Drugs.

Increasing affinity to lung tissue is an important strategy to achieve pulmonary retention and to prolong the duration of effect in the lung. As the lung is a very heterogeneous organ, differences in structure and blood flow may influence local pulmonary disposition. Here, a novel lung preparation technique was employed to investigate regional lung distribution of four drugs (salmeterol, fluticasone propionate, linezolid, and indomethacin) after intravenous administration in rats. A semi-mechanistic model was used to describe the observed drug concentrations in the trachea, bronchi, and the alveolar parenchyma based on tissue specific affinities (Kp) and blood flows. The model-based analysis was able to explain the pulmonary pharmacokinetics (PK) of the two neutral and one basic model drugs, suggesting up to six-fold differences in Kp between trachea and alveolar parenchyma for salmeterol. Applying the same principles, it was not possible to predict the pulmonary PK of indomethacin, indicating that acidic drugs might show different pulmonary PK characteristics. The separate estimates for local Kp, tracheal and bronchial blood flow were reported for the first time. This work highlights the importance of lung physiology- and drug-specific parameters for regional pulmonary tissue retention. Its understanding is key to optimize inhaled drugs for lung diseases.

Muscle to Brain Partitioning as Measure of Transporter-Mediated Efflux at the Rat Blood-Brain Barrier and Its Implementation into Compound Optimization in Drug Discovery.

Movement of xenobiotic substances across the blood-brain barrier (BBB) is tightly regulated by various transporter proteins, especially the efflux transporters P-glycoprotein (P-gp/MDR1) and breast cancer resistance protein (BCRP). Avoiding drug efflux at the BBB is a unique challenge for the development of new central nervous system (CNS) drugs. Drug efflux at the BBB is described by the partition coefficient of unbound drug between brain and plasma (Kp,uu,brain) which is typically obtained from in vivo and often additionally in vitro measurements. Here, we describe a new method for the rapid estimation of the in vivo drug efflux at the BBB of rats: the measurement of the partition coefficient of a drug between brain and skeletal muscle (Kp,brain/muscle). Assuming a closely similar distribution of drugs into the brain and muscle and that the efflux transporters are only expressed in the brain, Kp,brain/muscle, similar to Kp,uu,brain, reflects the efflux at the BBB. The new method requires a single in vivo experiment. For 64 compounds from different research programs, we show the comparability to other approaches used to obtain Kp,uu,brain. P-gp- and BCRP-overexpressing cell systems are valuable in vitro tools for prescreening. Drug efflux at the BBB can be most accurately predicted based on a simple algorithm incorporating data from both in vitro assays. In conclusion, the combined use of our new in vivo method and the in vitro tools allows an efficient screening method in drug discovery with respect to efflux at the BBB.