We studied the time course for the reversal of rifampin's effect on the pharmacokinetics of oral midazolam (a cytochrome P450 (CYP) 3A4 substrate) and digoxin (a P-glycoprotein (P-gp) substrate). Rifampin increased midazolam metabolism, greatly reducing the area under the concentration-time curve (AUC(0-∞)). The midazolam AUC(0-∞) returned to baseline with a half-life of ~8 days. Rifampin's effect on the AUC(0-3 h) of digoxin was biphasic: the AUC(0-3 h) increased with concomitant dosing of the two drugs but decreased when digoxin was administered after rifampin. Digoxin was found to be a weak substrate of organic anion-transporting polypeptide (OATP) 1B3 in transfected cells. Although the drug was transported into isolated hepatocytes, it is not likely that this transport was through OATP1B3 because the transport was not inhibited by rifampin. However, rifampin did inhibit the P-gp-mediated transport of digoxin with a half-maximal inhibitory concentration (IC(50)) below anticipated gut lumen concentrations, suggesting that rifampin inhibits digoxin efflux from the enterocyte to the intestinal lumen. Pharmacokinetic modeling suggested that the effects on digoxin are consistent with a combination of inhibitory and inductive effects on gut P-gp. These results suggest modifications to drug-drug interaction (DDI) trial designs.

Targeting tumors with antibody-based therapeutics is a complex task presenting multiple kinetic barriers. Antibody internalization and clearance inhibit uptake both in solid tumors, limited by tumor vascular permeability, and in micrometastases, limited by diffusion. Methods: A modeling exercise is used to introduce 2 simple criteria that must be less than unity for saturation of both tumors and micrometastases. The clearance modulus and the Thiele modulus are ratios of the plasma clearance rate and antibody catabolism, respectively, to the tumor tissue penetration rate. Results: Even low rates of antigen internalization from constitutive membrane turnover can significantly retard antibody penetration. Rapid clearance of single-chain variable fragments also hinders uptake, often more than counterbalancing their more rapid extravasation and diffusion. Conclusion: The model illustrates that with the large resistance from the tumor capillary, antibodies may be more suitable for targeting micrometastases than vascularized tumors.Key Words: molecular imaging; monoclonal antibodies; radionuclide therapy; biodistribution; penetration; pharmacokinetics Ant ibodies and antibody fragments are promising agents for cancer detection and treatment. One of the major restrictions of these drugs for cancer therapy is poor transport, which results in low concentrations and a lack of targeting of all cells in a tumor (1). Delivery of antibodies to tumor cells is a complex task with many rates involved, as illustrated in Figure 1. Effective therapy requires treatment of both solid, vascularized tumors and micrometastases with different pharmacokinetic parameters.Several different models have been developed to illustrate some fundamental trends in targeting. van Osdol et al. have shown that antibodies tend to exhibit a ''binding site barrier'' because of their clearance and penetration (2), and extensive work on fluid flow and macromolecular distribution has been performed by Jain (1). Using a simplified model, Graff and Wittrup highlighted the importance of antibody dose for saturating tissue and the necessity of high affinity for retention in the tumor (3).Although providing useful insights, these prior models have not fully delineated the microscopic distribution effects of antibody catabolism. The turnover rate was not examined quantitatively, and one would expect differences between an antibody binding a receptor internalized by a clathrin-coated pit mechanism, constitutive membrane turnover, and extracellular matrix protein turnover. Internalization of ErbB receptor family members, targets for 2 antibody drugs approved by the Food and Drug Administration, is well characterized (4,5). A multitude of other antibodies against various targets have also been shown to internalize at broadly varying rates (6,7), demonstrating the need for an in-depth consideration of the effects of internalization on tumor targeting. This analysis reveals that internalization has the potential to severely limit the penetration of antibodies. MATERIAL...

Inhibition of cathepsin K (CatK) is a potential new treatment for osteoporosis. In two double-blind, randomized, placebo-controlled phase I studies, postmenopausal female subjects received odanacatib (ODN), an orally active, potent, and selective CatK inhibitor, once weekly for 3 weeks or once daily for 21 days. Bone turnover biomarkers, safety monitoring, and plasma ODN concentrations were assessed. These studies showed ODN to be well tolerated. Pharmacokinetic (PK) analysis revealed a long half-life (t(1/2); 66-93 h) consistent with once-weekly dosing. Pronounced reductions in C-terminal telopeptide of type I collagen (approximately 62%) and N-terminal telopeptide of type I collagen normalized to creatinine (NTx/Cr) (approximately 62%) at trough (C(168 h)) were seen following weekly administration. Robust reductions in CTx (up to 81%) and NTx/Cr (up to 81%) were seen following daily administration. ODN exhibits robust and sustained suppression of bone resorption biomarkers (CTx and NTx/Cr) at weekly doses > or = 25 mg and daily doses > or = 2.5 mg.

AIMSTo evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of odanacatib (ODN), a cathepsin K inhibitor, in humans. METHODSTwo double-blind, randomized, placebo-controlled, single oral dose studies were performed with ODN (2-600 mg) in 44 healthy volunteers (36 men and eight postmenopausal women). RESULTSAdverse experiences (AEs) with single doses of ODN were transient and mild to moderate, with the exception of one severe AE of gastroenteritis. Headache was the most frequent AE. After absorption of ODN (initial peak concentrations 4-6 h postdose), plasma concentrations exhibited a monophasic decline, with an apparent terminal half-life of 40-80 h. The area under the curve0-24 hours (AUC0-24 h), concentration at 24 hours (C24 h) and maximum concentration (Cmax,overal) increased in a less than dose-proportional manner from 2 to 600 mg. Administration of ODN with a high-fat meal led to~100% increases in AUC0-24 h, Cmax,day1, Cmax,overall and C24 h relative to the fasted state, while administration with a low-fat meal led to a~30% increase in those parameters. Reduction of biomarkers of bone resorption, the C-and N-telopeptides of cross-links of type I collagen, (CTx and NTx, respectively), was noted at 24 h for doses Ն5 mg and at 168 h postdose for Ն10 mg. In postmenopausal women administered 50 mg ODN, reductions in serum CTx of -66% and urine NTx/creatinine (uNTx/Cr) of -51% relative to placebo were observed at 24 h. At 168 h, reductions in serum CTx (-70%) and uNTx/Cr (-78%) were observed relative to baseline. Pharmacokinetic/pharmacodynamic modeling characterized the ODN concentration/ uNTx/Cr relation, with a modeled EC50 value of 43.8 nM and~80% maximal reduction. CONCLUSIONSOdanacatib was well tolerated and has a pharmacokinetic and pharmacodynamic profile suitable for once weekly dosing.

Li-LSX zeolite (Si/Al ) 1.0) is currently the best sorbent in use in the separation of air by adsorption processes. In this present work we have synthesized fully exchanged Li-LSX zeolite and measured the room-temperature equilibrium adsorption isotherms for N 2 , O 2 , and Ar after various degrees of dehydration. The effect of the residual water on the adsorption of these atmospheric gases was then simulated using Monte Carlo techniques. Very small amounts of water in the Li-LSX zeolite have a significant effect on the adsorptive capacity of these atmospheric gases with the capacity for N 2 dropping from ≈17.4 molecules of N 2 adsorbed/unit cell for the fully dehydrated material to <2 molecules of N 2 adsorbed/unit cell when the sample contained 32 residual water molecules/unit cell, an indication that the N 2 molecules only interact with the supercage SIII Li + cations.

Odanacatib is a selective inhibitor of the cathepsin K enzyme that is expressed in osteoclasts involved in the degradation of bone organic matrix, and is being developed as a novel treatment of osteoporosis. Odanacatib has demonstrated increases in bone mineral density in postmenopausal women and is undergoing a pivotal phase III trial. The absorption, metabolism, and excretion of [ 14 C]odanacatib were studied in healthy male volunteers (n = 6) after a single oral dose of 25 mg (100 mCi). Plasma, urine, and fecal samples were collected at intervals up to 34 days postdose. The pharmacokinetics of odanacatib were characterized by slow absorption (mean time to achieve maximum plasma concentration of 14.2 hours) and long apparent elimination half-life (mean t 1/2 96.7 hours); 74.5% of the dose was recovered in feces and 16.9% in urine, resulting in a total recovery of 91.4%. Seven metabolites were identified in urine; the major pathway (methyl hydroxylation producing M8 and its derivatives) was largely dependent on CYP3A. Metabolites and odanacatib accounted for 77% and 23% of urinary radioactivity, respectively. In fecal extracts, the only radioactive components identified were odanacatib (60.9%) and M8 (9.5%). The fraction of odanacatib in feces derived from absorbed drug was estimated using a bioavailability value obtained from the results of a separate intravenous study. Collectively, the data indicate that odanacatib has a long t 1/2 on account of its low metabolic intrinsic clearance, and that metabolism (principally mediated by CYP3A) and excretion of intact parent compound account for ∼70% and ∼30% of the clearance of odanacatib in humans.

Although the primary hypothesis was not met, there were no clinically meaningful differences in PD, PK, or PK/PD parameters between older men and postmenopausal women, supporting further research on odanacatib (50 mg once weekly) as a treatment for male osteoporosis. Odanacatib was generally well tolerated.

Cathepsin K (CatK) is a cysteine protease abundantly expressed by osteoclasts and localized in the lysosomes and resorption lacunae of these cells. CatK is the principal enzyme responsible for the degradation of bone collagen. Odanacatib is a selective, reversible inhibitor of CatK at subnanomolar potency. The pharmacokinetics of odanacatib have been extensively studied and are similar in young healthy men, postmenopausal women and elderly men, and were qualitatively similar throughout Phase 1 development and in-patient studies. Following 3 weeks of 50 mg once weekly dosing the geometric mean area under the curve from 0 to 168 hours was 41.1 μM h, the concentration at 168 hours was 126 nM and the harmonic mean apparent terminal half-life was 84.8 hr. Odanacatib exposure increased in a less than dose proportional manner due to solubility limited absorption. It is estimated that approximately 70% of the absorbed dose of odanacatib is eliminated via metabolism, 20% is excreted as unchanged drug in the bile or faeces, and 10% is excreted as unchanged drug in the urine. The systemic clearance was low (approximately 13 mL/min). Odanacatib decreases the degradation of bone matrix proteins and reduces the efficiency of bone resorption with target engagement confirmed by a robust decrease in serum C-telopeptides of type 1 collagen (approximately 60%), urinary aminoterminal crosslinked telopeptides of type 1 collagen to creatinine ratio (approximately 50%) and total urine deoxypyridinoline/Cr (approximately 30%), with an increase in serum cross-linked carboxy-terminal telopeptide of type 1 collagen (approximately 55%). The 50-mg weekly dosing regimen evaluated in Phase 3 achieved near maximal reduction in bone resorption throughout the treatment period. The extensive clinical programme for odanacatib, together with more limited clinical experience with other CatK inhibitors (balicatib and ONO-5334), provides important insights into the clinical pharmacology of CatK inhibition and the potential role of CatK in bone turnover and mineral homeostasis. Key findings include the ability of this mechanism to: (i) provide sustained reductions in resorption markers, increases in bone mineral density, and demonstrated fracture risk reduction; (ii) be associated with relative formationsparing effects such that sustained resorption reduction is achieved without accompanying meaningful reductions in bone formation; and (iii) lead to increases in osteoclast number as well as other osteoclast activity (including build-up of CatK enzyme), which may yield transient increases in resorption following treatment discontinuation and the potential for nonmonotonic responses at subtherapeutic doses.