Long-Term Prophylaxis and Pharmacokinetic Evaluation of Intramuscular Nano- and Microparticle Decoquinate in Mice Infected with P. berghei Sporozoites

Abstract

Decoquinate nanoparticle and microparticle suspended in an oily vehicle to retard drug release are evaluated for long-term malaria prophylaxis. Pharmacokinetic studies in normal animals and antimalarial efficacy in liver stage malaria mice were conducted at various single intramuscular-decoquinate doses for 2, 4, 6, or 8 weeks prior to infection with P. berghei sporozoites. The liver stage efficacy evaluation was monitored by using an in vivo imaging system. Full causal prophylaxis was shown in mice with a single intramuscular dose at 120 mg/kg of nanoparticle decoquinate (0.43 μm) for 2-3 weeks and with microparticle decoquinate (8.31 μm) injected 8 weeks earlier than inoculation. The time above MIC of 1,375 hr observed with the microparticle formulation provided a 2.2-fold longer drug exposure than with the nanoparticle formulation (624 hr). The prophylactic effect of the microparticle formulation observed in mice was shown to be 3-4 times longer than the nanoparticle decoquinate formulation.

Creation of a long-acting nanoformulated dolutegravir

“…Nanoparticle based systems are readily taken up by cells and disseminated into tissues to form drug depots at these sites for subsequent slow release 20 . Other controlled release injection site drug depot formulations include microparticle carrier systems 21 , 22 . However, microparticles tend to aggregate limiting their usage due to lack of particle homogeneity, leading to injection site reactions 23 .…”

ELQ-331 as a prototype for extremely durable chemoprotection against malaria

“…These results are also impressive in comparison to the scant available results from other drugs tested for LAI-C. In two studies of engineered drug particles injected IM, mice were protected against P. berghei sporozoite challenge for 56 days by a microsuspension of decoquinate (120 mg/kg) in peanut oil (8), and for 28 days by atovaquone nanoparticles (200 mg/kg) (7). In unpublished studies of IM prodrugs of atovaquone and ELQ-300, apparent MECLAI-c values for atovaquone and ELQ-300 were established based on protection against sporozoite challenge 14 days after injection, and duration of efficacy was then predicted based on how long the MECLAI-C was exceeded (Presentation by Chatterjee, A.K., TCP4: Intramuscular injections for malaria chemoprotection, in Symposium: What kind of molecules are needed to control and eradicate malaria?…”

“…The results of vaccine studies to-date indicate that a feasible, highly-effective, and durably-protective vaccine will not be available soon (2). At the same time, an increasing body of information has demonstrated the safety and efficacy of long-acting injectable (LAI) medications to treat other conditions (3)(4)(5)(6), and pilot studies have shown durable protection against malaria in mice after intramuscular (IM) drug injection (7,8). Together, these observations prompted the Medicines for Malaria Venture (MMV) to develop the first drug TPP for long-acting injectable chemoprotection (LAI-C) against malaria (9).…”

Accumulation of TB-Active Compounds in Murine Organs Relevant to Infection by Mycobacterium tuberculosis

“…Data from comparative studies for compounds related to those in this study are scarce, as only plasma concentrations of DQ, a quinolone derivative (Figure 1), have been assessed (Li et al, 2017). A study involving the quinolone antibiotics LVX, ciprofloxacin (CIP), and ampicillin, administered at a significantly higher dose (120 mg/kg) in a Streptococcus pneumoniae-infected mouse model, showed large maximal lung concentrations of 5.95, 1.10, and 1.71 µg/g, respectively (Ishida et al, 1999).…”