10th International Aerosol Conference September 2 - September 7, 2018 America's Center Convention Complex St. Louis, Missouri, USA
Abstract View
Formulation Development and In Vivo Pharmacokinetics of Topotecan for Targeted Treatment of Lung Cancer
PHILIP KUEHL, Michael Burke, Ramesh Chand, Devon Dubose, June Liu, Mathewos Tessema, Lovelace Biomedical, 2425 Ridgecrest Dr. SE, Albuquerque, NM
Abstract Number: 1542 Working Group: Aerosols in Medicine
Abstract Purpose: Lung cancer remains one of the leading causes of cancer death worldwide with approximately 10% to 15% of lung cancers are of small cell histology. Small cell lung cancer (SCLC) has a very aggressive course, with a median overall survival of about 1 to 2 years with only up to 12% of patients surviving for 5 years after diagnosis even in early stages of the disease. Topotecan (TPT) is a FDA approved chemotherapeutic agent that is active in the treatment of SCLC and is one of the only second-line treatment options. TPT is currently delivered by oral or IV delivery and some patients encounter adverse side effects. Therefore, a novel spray dried powder formulation of TPT has been engineered for inhalation delivery to allow for the direct delivery of this potent compound in a non-obtrusive way and limit systemic exposure. This developed formulation was evaluated in non-clinical rodent pharmacokinetic studies to quantify local drug concentrations at the site of action. The local drug concentrations at the site of action will be used to select dose(s) for non-clinical efficacy models.
Methods: A powder fit for pulmonary delivery through inhalation containing TPT free base was developed and spray-dried on a small-scale custom spray dryer (BLD-35) with 35kg/hr. drying gas capacity from a 100% aqueous solution at 4wt% solids. The solution was adjusted to a pH of 3.5 using HCl to ensure complete dissolution of TPT. Functional excipients, Trehalose and L-leucine, were added for additional stability and particle formation. The developed formulation was characterized for solid state, chemical and aerosol characteristics to confirm its formulation applicability. The formulation was evaluated in a rat nose-only inhalation exposure pharmacokinetic study. The IV dose was 0.7 mg/Kg based on the scaled clinical dose and two inhalation doses of 0.14 and 0.79 mg/kg were delivered. Aerosols were monitored for total aerosol concentration, topotecan aerosol concentration and particle size distribution. Following dosing animals were serially sacrificed for systemic blood and plasma analysis by LCMS. Average concentration versus time profile modeled with non-compartmental analysis.
Results: The final dry powder was 70/20/10 Trehalose/Leucine/TPT (w/w%) and was characterized to be highly respirable free from fusion. The final formulation contained amorphous Trehalose and TPT while also having crystallized leucine character. Testing in a clinical device indicated emitted fractions from a capsule and device was 94.0 ± 3.3 % and the corresponding MMAD, GSD, and FPF (<5 microns) were; 2.9 ± 0.3, 1.9 ± 0.2, and 62.0 ± 1.1 respectively. Topotecan pulmonary deposited doses were 0.13 and 0.79 mg/kg and the IV dose was 0.7 mg/kg. The particle size distribution was measured to be 3.0 µm MMAD. The LCMS analysis showed measurable levels of topotecan throughout almost all time points. The non-compartmental analysis showed a bi-phasic elimination profile from the plasma for IV and inhalation dosing. The inhalation delivery showed increased exposure to the lung tissue for similar doses when compared to IV. The lung tissue exposure approached dose proportionality over the dose range studies. The clearance from the lung was slower following inhalation than IV dose (~ 5 hr. half-life vs 1.2 hr. half-life).
Conclusion: The work presented here demonstrates the feasibility of manufacturing a therapy containing TPT by spray drying. The collected dry powder retained purity, aerosolized in the pulmonary range and was comprised of desirable characteristics by In Vitro assessments. The in vivo PK analysis indicated that when delivered via inhalation and IV topotecan exhibits a bi-phasic elimination profile with increased exposure to the lung tissue following similar dosing IV and inhalation. These results suggest that that with a similar dose the exposure to the lung tissue is increase by a factor of 30. Therefore, inhalation delivery of up to 30-fold lower dose of topotecan than IV could provide similar efficacy for lung cancer and thereby significantly improve toxicity that is greatly limiting the clinical use of this potent anticancer agent.
This study was supported by grant from the NIH/NCI to Drs. Kuehl and Tessema (R01CA193532).