Background: Atovaquone is an alternative agent for prophylaxis and treatment of Pneumocystis pneumonia (PCP) and toxoplasmosis. However, atovaquone suffers clinical limitations of poor patient tolerability, saturable oral absorption, and nonlinear pharmacokinetics. Cochleates are a novel lipid-crystal nano-particle formulation delivery platform. This study was conducted to determine the pharmacokinetics (PK) and efficacy of CATQ in immunocompromised mice infected with P. murina.
Methods: Mice were immunocompromised with dexamethasone and infected with P. murina. In the PK study, infected mice received CATQ 100mg/kg via oral gavage, followed by sacrifice and blood and lung tissue collection at 0, 2, 4, 8, 10, 12, 24, 48, 72, and 96 hrs post-dose (n=3 mice per time point). In the efficacy study, infected mice were treated daily for 7, 14, or 21 days with one of the following: CATQ 50 mg/kg, CATQ 100mg/kg, atovaquone suspension (Mepron®) 100mg/kg, sulfamethoxazole/trimethoprim 250/50 mg/kg, or vehicle control (n= 8-10 mice per group). Mice were sacrificed and lungs were processed for microscopic enumeration of Pneumocystis asci and nuclei.
Results: In the PK study, geometric means of maximal concentrations and area under the curve were 58 µg/g and 1419 µg*h/g in the lung and 52 µg/mL and 1033 µg*h/mL in the plasma, respectively. (Fig 1). Half life was 13 hrs in plasma and 22 hrs in lungs, and Tmax was 12 hrs in both. In the treatment study, there was a significant reduction in both nuclei and asci counts in both the 50mg/kg and 100 mg/kg CATQ dose groups at Day 21 versus the negative control (C/S) (Fig 2). All treated groups showed a significant improvement in survival C/S at Day 21 (Fig 3). No overt toxicity was observed.
Conclusion: CATQ performed significantly better than commercially available atovaquone in the therapeutic study, and thus represents a novel formulation of atovaquone that is promising for both treatment and prevention of PCP. Further studies of higher doses of CATQ (200mg/kg) as well as pairing CATQ with an echinocandin are underway.
Funding: Study supported in part by the Division of Microbiology and Infectious Diseases, NIAID, NIH under contract grant HHSN272201000029I/HHSN2720003/A63. Matinas BioPharma, Inc. is commercially developing CATQ.
M. Linke, None
R. Lu, Matinas BioPharma, Inc.: Employee and Shareholder , Salary
P. Desai, None
G. Moorthy, None
R. Mannino, Matinas BioPharma, Inc.: Scientific Advisor and Shareholder , Consulting fee , Licensing agreement or royalty and Research support
C. Lambros, None
E. Tramont, None
L. Sallans, None
J. C. Craft, Matinas BioPharma, Inc.: Scientific Advisor , Consulting fee
T. Sesterhenn, None
A. Ashbaugh, None
M. Collins, None
K. Lynch, None
S. Bonitz, Matinas BioPharma, Inc.: Consultant and Shareholder , Consulting fee
J. Kovacs, None