Biology subjects

Marzinke, M. A.

Publications and source records attributed to Marzinke, M. A..

3 recordsLinked to original sources

bioRxiv2025

Cethromycin Pharmacokinetics and Pharmacodynamics for Single Dose Cure of Plasmodium berghei Liver Stages

Cethromycin combines a quinoline nucleus and a macrolide for broad spectrum antibacterial and antiprotozoan activity. Here we characterized the murine pharmacokinetics and Plasmodium berghei lifecycle stage pharmacodynamics for the cethromycin base. Liver pharmacokinetic studies in mice show peak mM drug levels in the liver with 20 hour sustained levels above 10 M. Peak concentrations in the liver were double the lung and about 440 times that of plasma. Immunofluorescence imaging of in vitro cethromycin-treated infected hepatocytes shows complete ablation of the apicoplast. We observed complete cure of P. berghei liver stage infection by single oral dose of 60 mg/kg in mice which is equivalent to the 5 mg/kg human dose of 300 mg a day used in bacterial pneumonia studies. Cethromycin at 60 mg/kg daily for 7 days was curative in the high parasitemic P. berghei mouse model. Both mosquito membrane feeding of P. falciparum gametocytes incubated with 20 M cethromycin and oral dosing in mice demonstrated no decrease in oocyst numbers. Cethromycin has been evaluated for efficacy against bacterial pneumonia in more than 5,000 patients with good safety profiles. Cethromycin has potential for rapid clinical development for casual malaria prophylaxis and possibly radical cure of dormant liver P. vivax.

microbiology↗

bioRxiv2020

Preventive efficacy of a tenofovir alafenamide fumarate nanofluidic implant in SHIV-challenged nonhuman primates

Pre-exposure prophylaxis (PrEP) using antiretroviral oral drugs is effective at preventing HIV transmission when individuals adhere to the dosing regimen. Tenofovir alafenamide (TAF) is a potent antiretroviral drug, with numerous long-acting (LA) delivery systems under development to improve PrEP adherence. However, none has undergone preventive efficacy assessment. Here we show that LA TAF using a novel subcutaneous nanofluidic implant (nTAF) confers partial protection from HIV transmission. We demonstrate that sustained subcutaneous delivery through nTAF in rhesus macaques maintained tenofovir diphosphate concentration at a median of 390.00 fmol/106 peripheral blood mononuclear cells, 9 times above clinically protective levels. In a non-blinded, placebo-controlled rhesus macaque study with repeated low-dose rectal SHIVSF162P3 challenge, the nTAF cohort had a 62.50% reduction (95% CI: 1.72% to 85.69%; p=0.068) in risk of infection per exposure compared to the control. Our finding mirrors that of tenofovir disoproxil fumarate (TDF) monotherapy, where 60.00% protective efficacy was observed in macaques, and clinically, 67.00% reduction in risk with 86.00% preventive efficacy in individuals with detectable drug in the plasma. Overall, our nanofluidic technology shows potential as a subcutaneous delivery platform for long-term PrEP and provides insights for clinical implementation of LA TAF for HIV prevention.

bioengineering↗

bioRxiv2019

A Subcutaneous Implant of Tenofovir Alafenamide Fumarate Causes Local Inflammation and Tissue Necrosis in Rabbits and Macaques

We describe the in vitro and in vivo evaluation of a subcutaneous reservoir implant delivering tenofovir alafenamide hemifumarate (TAF) for the prevention of HIV infection. These long-acting reservoir implants were able to deliver antiretroviral drug for over 90 days in vitro and in vivo. We evaluated the implants for implantation site histopathology and pharmacokinetics in plasma and tissues for up to 12 weeks in New Zealand White rabbits and rhesus macaque models. A dose-ranging study in rabbits demonstrated dose-dependent pharmacokinetics and local inflammation up to severe necrosis around the active implants. The matched placebos showed normal wound healing and fibrous tissue encapsulation of the implant. We designed a second implant with a lower release rate and flux of TAF and achieved a median cellular level of tenofovir diphosphate of 42 fmol per 106 rhesus macaque peripheral blood mononuclear cells at a dose of 10 {micro}g/kg/day. This dose and flux of TAF also resulted in adverse local inflammation and necrosis near the implant in rhesus macaques. Inflammation in the primates was markedly lower in the placebo group than the active implant. The histological inflammatory response to the TAF implant at 4 and 12 weeks in primates was graded as a severe reaction. Thus, while we were able to achieve sustained target dose we observed unacceptable inflammatory response locally at the implant tissue interface.

pharmacology and toxicology↗