Safety studies. The enhancer excipients used in GIPET were developed due to their known safety as approved food additives. Several regulatory
bodies have reviewed the data on safety and concluded that the materials in GIPET formulations have low toxicity potential
(6). Phase I and II studies showed that exposures could be given safely on a repeated basis.
A legitimate concern with intestinal absorption-promoting technologies is the impact on general intestinal permeability. Although
the clinical experience thus far has not suggested that this concern is an issue in vivo, intestinal-permeability studies were carried out in human subjects after intrajejunal administration of GIPET I, followed
by tracer molecules with low oral absorption largely restricted to the paracellular route. The aim was to establish intestinal
permeability recovery time in the presence of typical components of a GIPET formulation. The polar sugar, mannitol (molecular
weight of 182.17 g/mol), is absorbed paracellularly across the gut and is excreted unchanged in the urine. Oral bioavailability
of mannitol is approximately 25%, and this amount appears in the urine because it is freely filtered and not reabsorbed by
renal tubules. Another polar disaccharide sugar, lactulose (molecular weight of 342.30 g/mol), also is absorbed paracellularly,
but only to a level of 1% due to its larger molecular radius. The ratio of the urinary excretion is a well-established noninvasive
indicator of human intestinal paracellular permeability in vivo (7). When the intestinal barrier function is compromised, the urinary lactulose-to-mannitol excretion ratio (LMER) increases
because lactulose absorption is preferentially increased. In an open-label, partially randomized study using up to 24 human
subjects, the marker molecules were given orally at 20, 40, or 60 min following intrajejunal instillation of GIPET I. The
combined data showed that only when the sugars were administered 20 min after the fatty acid, the urinary LMER ratio increased
(see Table I). Therefore, in subjects receiving three separate doses of GIPET I, the effect of the agent on intestinal permeability
was very small (Aspirin has been reported to increase permeability as much as 40 times more than GIPET)(8). The observed increases
were reversed quickly (i.e., no effect at 40 min). The three doses of GIPET I were considered safe and well tolerated in the
Table I: Timing of effect of GIPET I on human intestinal permeability using urinary execretion of polar sugars as a surrogate
Phase I clinical studies. Although rodent and canine oral delivery data with absorption-promoting technologies can be impressive, significant differences
in the intestinal physiology of species suggest that the only true species model for humans is human (9). Studies to date
of GIPET in man have focused on different types of Biopharmaceutics Classification Scheme (BCS) Class III compounds, including
small-molecule bisphosphonates (e.g., alendronate and zolendronate), a polysaccharide (e.g., low molecular-weight heparin,
and peptides (e.g., desmopressin and acyline). All Phase I clinical studies showed a significant increase in oral bioavailability
where absorption in control patients was negligible and showed that the GIPET platform can deliver therapeutic levels of these
BCS Class III molecules (see Table II). The preclinical and clinical development results for one model molecule, acyline,
Table II: Phase I oral bioavailability data with GIPET.
Acyline, a decapeptide, is a gonadotropin-releasing hormone (GnRH) antagonist that suppresses luteinizing hormone and testosterone
in man. It has the potential to treat hormone-dependent conditions, such as prostate and breast cancer, or to treat benign
conditions, such as endometriosis. However, for therapeutic use, it currently has to be injected, which limits its clinical
utility. Also, acyline is difficult to formulate as an injectable because it tends to form a gel. This gel results in a sustained-release
injection, which is not always desirable to maximize therapeutic benefit. As a result, there is a clinical need for orally
active GnRH antagonists, such as acyline. Proceeding from positive data in the preclinical dog model, the authors investigated
GIPET-enhanced oral acyline in eight healthy men (18–55 years of age) in a PK and PD study (see Figure 3). Oral acyline was
administered on three occasions, each separated by one week. The subjects received progressively increasing doses of 10, 20,
and 40 mg of GIPET-acyline after an overnight fast and continued to fast for four hours post dose. Blood for the measurement
of serum-leutinizing hormone, follicle-stimulating hormone (FSH), testosterone, and acyline was obtained before each dose
of GIPET-acyline and at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, and 48 h and 7 days after each dose. Complete blood counts and
comprehensive metabolic panels were obtained 24 h after each dose for assessment of safety.
Figure 3: Acyline serum levels achieved: Figure 3(a) shows results from a preclinical dog model; Figure 3(b) shows results
from Phase I clinical studies for GIPET-enhanced acyline.
Results showed that mean serum acyline concentrations rose immediately after oral administration with all three doses and
were undetectable in all subjects 48 h after dosing, except for one subject in the 40-mg group. Due to the large degree of
variability between subjects, there were no significant differences in the PK parameters between doses. Acyline was not detected
in the serum of any subject seven days after dosing (see Table III). Serum LH, FSH, and testosterone were significantly suppressed
by all doses of GIPET-acyline after 6 h, with maximum suppression 12 h post dose. The average suppression of serum FSH 12
h post-dose was 28 ± 5% compared to 70 ± 10% suppression of serum LH. The difference is most likely due to the fourfold greater
serum half-life of FSH compared to LH (320 versus80 min). The suppression of testosterone closely matched that of LH, with
levels below the lower limit of the normal range(< 8.4 nmol/L) 12 h after the 40-mg dose (see Figure 4).
Figure 4: Testosterone levels following administration of 10-, 20-, and 40-mg GIPET-enhanced acyline tablets. GIPET is a registered
trademark of Merrion Pharmaceuticals.
A repeat dose study of GIPET-acyline showed a similar PK profile with no accumulation of drug. The acyline Phase I clinical
studies clearly showed the clinical potential for this advanced drug-delivery platform.
Table III: Oral acyline pharmacokinetic parameters.