Bronchoscopy for Local PK Studies in Healthy Volunteers
For drug products that are not intended to be absorbed into the bloodstream, bioavailability may be assessed by measurements intended to reflect the rate and extent to which the active ingredient or active moiety becomes available at the site of action. This can also be important for systematically administered drugs in order to see if the drug is available at the site of interest, e.g. the brain. So it is an attractive option to do local pharmacokinetic (PK) studies in many accessible body fluids such as synovial fluid, cerebrospinal fluid, urine, vaginal smear, and also even in tissues. However, not that many animal models have been translated to human for local PK studies. Particularly in the development of orally inhaled drugs, pulmonary deposition studies can investigate the extent and pattern of pulmonary deposition of an inhaled active substance.
What is local bronchial PK
The determination of the concentration of drugs in respiratory fluids and pulmonary tissues could be important for prediction of the therapeutic efficacy of a treatment. The disposition of drugs in the bronchial tree and pulmonary tissue is the result of a very complex and dynamic pharmacokinetic process. The penetration into bronchial secretions and sputum has been investigated for many drugs in animals and has been correlated with the activity of inhaled respiratory pharmaca. However, for many drugs, data concerning penetration and pharmacokinetic behaviour in the respiratory tract in humans are lacking. The time-concentration profile of drugs in the human bronchial tree and in the alveolar lining fluid has not been studied very well until now. Bronchoalveolar lavage may be a promising technique for evaluating drug concentrations in alveolar lining fluid and may allow us to answer some of the many remaining questions about the pharmacokinetics and pharmacodynamics in the airways and the lung parenchyma.
Indications for the technique
The main reason for doing local bronchial PK sampling is to assess the local and systemic pharmacokinetics of single and repeated doses of oral inhalation drugs for bronchodilatation, antimicrobial, or antiviral treatment. The local pulmonary drug deposition studies are also foreseen in the European guideline for the development of orally inhaled products1. Parameters of interest can be comparing local and systemic half-life, local disposition, bioavailability and potential local and systemic accumulation by measuring drug concentrations in epithelial lining fluid in bronchial alveolar lavage fluid (BALF) samples.
Additional determination of urea and red blood cells (RBCs) in blood and in BALF allows for determination of the dilution factor of the epithelial lining fluid by the saline during the BAL procedure and to correct for possible contamination of blood in the BALF.
Material and methods
The BAL procedure is performed when subjects are fasted for at least six hours to reduce the risk of vomiting during sampling. Prior to the procedure, subjects are informed on the procedure details and in accord with the subject, the physician performing the procedure decides whether the use of a mild sedative (midazolam) is indicated. A local anesthetic (e.g., xylocaine) is administered to minimize the reflex to swallow and to cough during the procedure. O2 saturation is monitored during and at least 5 min after the BAL sampling procedure. If medically required, follow-up is prolonged on a case-by-case basis.
In SGS’s experience BAL was performed two times during one study in each subject in the 1st subsegment (medial) of the right lobe of the lung (right mid lobe) or the 1st subsegment (medial) of the left lobe of the lung (left lingula) during the initial BAL procedure and in the alternate lung lobe for the second BAL procedure. The bronchoscope was advanced until placed in the desired location. An aliquot of 50 mL of sterile saline (NaCl 0.9%) was instilled and immediately aspirated and recollected (lavage 1). This was repeated three times (lavage 2 to 4) yielding four samples of recovered BALF (of minimum 10 mL per instillation). Start and stop time of the four samplings was recorded as well as the volume of the instilled and recollected fluid for each of the separate lavages. After recovery of the BALF, the wedge was lifted and the remaining fluid suctioned with gentle pressure (up to 100 mmHg). The collected BALF was used for PK analysis and for determination of urea and RBCs. Three PK samples were derived from the BALF representing following 3 BALF fractions:
- Bronchial fraction (lavage 1; contains mostly bronchial mucus and lidocaine): this fraction is mostly discarded
- Bronchiolar fraction (lavage 2 + 3)
- Alveolar fraction (lavage 4;)
All samples were centrifuged and specially prepared for further analysis. After temporary storage in the freezers, the samples were transported to one of our bioanalytical labs.
- A Phase 1, single center, open label study was performed in male healthy volunteers to evaluate local and systemic pharmacokinetics. The drug studied was an antiviral biological.
- The drug was administered to 35 healthy male volunteers by oral inhalation.
- Local pharmacokinetics (BALF) and systemic PK after single and repeated administration, urinary PK, safety, immunogenicity was determined.
- The clinical part was terminated in 5 months. Mean challenges were related to the screen failures due to in/exclusion criteria, so that 138 subjects needed to be screened in order to include all the study subjects.
- Adverse events due to the BALF sampling procedure were limited to 3 subjects with fever, and 1 with dyspnea, all 4 of moderate intensity and very well known with this procedure. The study was completed successfully providing robust data for PK/PD modeling.
Local pharmacokinetic studies and more precisely, bronchial pharmacokinetic studies are an interesting addendum for the study of respiratory inhalation drugs, and also for systematically administered drugs in order to see what is the local lung concentration and to have an idea of the lung penetration from systemic to bronchi/alveoli. It is of major importance for the development of pharmacokinetic/pharmacodynamic models to predict disease activity for the development of new drugs. We expect that these types of studies will become considered more and more by clinical researchers and will help to increase the performance of drug development in this therapeutic area.
1. Guideline on the requirements for clinical documentation for orally inhaled products (OIP). CPMP/EWP/4151/00 REV. 1, 2009
Robert Lins, MD, PhD
SGS Life Science Services
Senior Clinical Adviser - Clinical Research