Ng. Mcelvaney et al., PHARMACOKINETICS OF RECOMBINANT SECRETORY LEUKOPROTEASE INHIBITOR AEROSOLIZED TO NORMALS AND INDIVIDUALS WITH CYSTIC-FIBROSIS, The American review of respiratory disease, 148(4), 1993, pp. 1056-1060
Recombinant secretory leukoprotease inhibitor (rSLPI), a recombinant f
orm of a natural airway inhibitor of neutrophil elastase (NE), is a po
tential therapeutic agent for cystic fibrosis (CF), a condition charac
terized by airway derangement mediated in part by the large burden of
NE on the CF respiratory epithelial surface. After in vitro studies th
at demonstrated that aerosolized rSLPI retains its form and function,
rSLPI was administered via aerosol to normal individuals and individua
ls with CF to determine the pharmacokinetics of in vivo rSLPI augmenta
tion of the anti-NE defenses of the respiratory epithelial surface. Af
ter rSLPI aerosolization to normal individuals (100 mg single dose or
100 mg twice daily for 1 wk) there was a marked increase in SLPI level
s and anti-NE capacity in airway epithelial lining fluid (ELF) at 1 h,
diminishing gradually over 4 to 12 h. Interestingly, the ELF SLPI lev
els and anti-NE capacity achieved 12 h after 1 wk of rSLPI aerosols we
re no different than those 12 h after a single dose of rSLPI, suggesti
ng that rSLPI does not accumulate on the respiratory epithelial surfac
e after aerosolization. The ability of rSLPI to suppress NE in vivo wa
s evaluated by aerosolization of rSLPI to individuals with CF, first a
s an escalating dose to assess safety, and then at doses of 100 mg twi
ce daily for 1 wk or 50 mg twice daily for 2 wk. Before aerosol, SLPI
levels in ELF of individuals with CF were the same as in normal indivi
duals, but unlike normal individuals, individuals with CF had active N
E in ELF (12.4 +/- 3.0 muM) indicating that the SLPI in CF ELF was ina
ctive. After aerosolization of 100 mg rSLPI twice daily for 1 wk there
was a reduction in ELF active NE. In contrast, ELF active NE levels w
ere not reduced with 50 mg twice daily, likely due to the failure of t
his dose regime to sufficiently elevate ELF SLPI levels. These data sh
ow that rSLPI is functional after both in vitro and in vivo aerosoliza
tion and can significantly suppress the NE burden in the CF lung but m
ust be given regularly and in sufficient quantity to be effective.