Alza

Bioentrepreneur who revolutionized drug delivery and screening.

BCS class III hydrophilic compounds are often associated with low oral bioavailability due to their poor epithelial permeability in the gastrointestinal tract. In this study, we reported an approach of incorporating a drug complex into an in situ gelling muco-adhesive carrier to achieve an improved bioavailability of a poorly absorbed hydrophilic compound. A new molecular entity (RWJ-445167) from Johnson and Johnson was used as a model compound. The compound was first complexed with sodium lauryl sulfate (SLS). The complex was then incorporated into an in situ gelling muco-adhesive carrier Cremophor for formulation characterization and rat pharmacokinetic (PK) studies. The study results showed that RWJ-445167 bound to SLS at a stoichiometric ratio. By complexing with SLS, the compound became lipophilic. The aqueous solubility of RWJ-445167 dropped to 0.58 mg/mL for the complex from 61 mg/mL for the free compound, while the partitioning coefficient of the complex increased to 7.59, compared with 0.05 of the free compound. In the rat PK study, with duodenal administration, the complex in the in situ-gelling formulation achieved 28.24% of bioavailability, compared to 4.26% of the free compound solution. The enhanced bioavailability was also significantly higher than those in the RWJ-445167/SLS physical mixture in Cremophor (14.91%), the complex in non-gelling carrier PEG 400 (9.95%) and the RWJ-445167/SLS physical mixture in PEG 400 carrier (8.60%). The study demonstrates that incorporation of a drug complex into an in situ gelling formulation provides a new approach to improving bioavailability of BCS class III drugs.

Introduction: The fentanyl HCl patient-controlled transdermal system (PCTS) is a self-contained, preprogrammed, noninvasive analgesic delivery system for acute pain management. We carried out three studies with the following objectives: study I to evaluate the relationship between fentanyl absorption and the magnitude of current applied to the system; study II to determine dose-proportionality for the fentanyl HCl PCTS (25 and 40μg); and study III to describe the effects of single- and multiple-day administration on the pharmacokinetics of fentanyl delivered by the PCTS.

Extensive first-pass metabolism can significantly limit a drug's oral exposure levels. In this work, we introduce an innovative approach for increasing the oral bioavailability of a drug that undergoes extensive reversible glucuronidation and enterohepatic recirculation through intraduodenal coadministration of the deconjugating enzyme β-glucuronidase. Intraduodenal administration of JNJ-10198409 (10 mg/kg) with β-glucuronidase (34,000-140,000 units/kg) to catheterized rats resulted in a significant increase (p < 0.005) in the mean area under the plasma concentration versus time curve (AUC; approx. threefold) and maximum plasma concentration (C(max); approx. twofold) of JNJ-10198409. The AUC and C(max) were 60 ± 18 ng h/mL and 76 ± 29 ng/mL, respectively, with no enzyme and 177 ± 55 ng h/mL and 129 ± 41 ng/mL, respectively, with β-glucuronidase coadministered. Moreover, the AUC of the primary glucuronide metabolite increased approximately sevenfold from 1173 ± 361 (ng h)/mL with no enzyme coadministered to 8723 ± 2133 ng h/mL with coadministered enzyme. These pharmacokinetic data support the hypothesis that when the primary glucuronide is secreted into the duodenum via the bile duct, the glucuronide is converted by β-glucuronidase back to the parent compound. The parent compound is then reabsorbed and reconjugated, resulting in elevated systemic exposures to both parent and glucuronide. Potential clinical and preclinical applications and considerations for this approach are discussed.

Pegylated liposomal formulations contain lipid conjugated to polyethylene glycol. The disposition of encapsulated drug is dictated by the composition of the liposome, thus altering the pharmacokinetic (PK) profile of the drug. Allometric scaling is based on a power-log relationship between body weight (W) and drug clearance (CL) among mammals and has been used to compare the disposition of nonliposomal drugs across species. The objectives of this study were to use allometric scaling to: (1) compare the disposition of pegylated liposomal drugs across speciesand determine the best scaling model and (2) predict PK parameters of pegylated liposomal drugs in humans. The PK of pegylated liposomal CKD-602 (S-CKD602), doxorubicin (Doxil ® ), and cisplatin (SPI-077) were compared. PK studies ofS-CKD602, Doxil ® , and SPI-077 were performed at the maximum tolerated dose (MTD) in male and female mice, rats, dogs and patients with refractory solid tumors. The allometric equation used to evaluate the relationship between W and CL in each species was CL = a(W) m (a = empirical coefficient; m = allometric exponent). Substitution of physiological variables other than body weight, such as factors representative of the mononuclear phagocyte system (MPS) were evaluated. Dedrick Plots and Maximum Life-Span Potential (MLP) were used to determine scaling feasibility. Standard allometry demonstrated a relationship between clearance of S-CKD602, Doxil ® , and SPI-077 and body, spleen, liver, and kidney weights, total monocyte count, and spleen and liver blood flow. However, using scaling to predict CL of these agents in humans often resulted in differences >30%. Despite a strong correlation between body weight and MPS-associated variables with CL among preclinical species, the use of the equations did not predict CL. Thus, new methods of allometric scaling and measures of MPS function need to be developed.