The road map to oral bioavailability: an industrial perspective.

Optimisation of oral bioavailability is a continuing challenge for the pharmaceutical and biotechnology industries. The number of potential drug candidates requiring in vivo evaluation has significantly increased with the advent of combinatorial chemistry. In addition, drug discovery programmes are increasingly forced into more lipophilic and lower solubility chemical space. To aid in the use of in vitro and in silico tools as well as reduce the number of in vivo studies required, a team-based discussion tool is proposed that provides a 'road map' to guide the selection of profiling assays that should be considered when optimising oral bioavailability. This road map divides the factors that contribute to poor oral bioavailability into two interrelated categories: absorption and metabolism. This road map provides an interface for cross discipline discussions and a systematic approach to the experimentation that drives the drug discovery process towards a common goal - acceptable oral bioavailability using minimal resources in an acceptable time frame.

A novel intravenous vehicle for preclinical cardiovascular screening of small molecule drug candidates in rat.

Screening novel, poorly soluble small-molecule candidates for cardiovascular liabilities represents a key challenge in early drug discovery. This report describes a novel vehicle composed of 20% N,N-Dimethylacetamide (DMA)/40% Propylene glycol (PG)/40% Polyethylene Glycol (PEG-400) (DPP) for administration of new chemical entities (NCEs) by slow intravenous (i.v.) infusion in a preclinical anesthetized rat model. The vehicle was designed considering both available excipient safety information and solubilization potential for poorly soluble NCEs. DPP solubilized 11 drugs, 8 of which were insoluble in 5% dextrose in water (D5W), and 5 insoluble in PEG-400 to a target concentration of 30mg/mL. DPP elicits no adverse cardiovascular responses in the anesthetized rat model despite containing 40% PEG-400, a commonly used organic solvent which elicits hypertension and bradycardia that often confounds interpretation of drug effects. Three compounds demonstrating adequate solubility in both DPP and D5W were screened in the anesthetized rat model. When normalized to plasma exposure, atenolol, sotalol and enalaprilat exhibited comparable mean arterial pressure, heart rate, and cardiac contractility responses regardless of formulation. While the antihypertensive effect of nifedipine was evident with both DPP and PEG-400 formulations, pressor effects from PEG-400 confounded interpretation of the magnitude of nifedipine's response. Plasma concentrations of atenolol and enalaprilat were greater in D5W formulation whereas sotalol exposures were greater when using DPP as a vehicle. These results demonstrate the utility of DPP as an intravenous vehicle for formulating poorly soluble compounds in early preclinical screening for cardiovascular safety studies.

Head-To-Head Comparison of Different Solubility-Enabling Formulations of Etoposide and Their Consequent Solubility-Permeability Interplay.

The purpose of this study was to conduct a head-to-head comparison of different solubility-enabling formulations, and their consequent solubility-permeability interplay. The low-solubility anticancer drug etoposide was formulated in several strengths of four solubility-enabling formulations: hydroxypropyl-ß-cyclodextrin, the cosolvent polyethylene glycol 400 (PEG-400), the surfactant sodium lauryl sulfate, and an amorphous solid dispersion formulation. The ability of these formulations to increase the solubility of etoposide was investigated, followed by permeability studies using the parallel artificial membrane permeability assay (PAMPA) and examination of the consequent solubility-permeability interplay. All formulations significantly increased etoposide's apparent solubility. The cyclodextrin-, surfactant-, and cosolvent-based formulations resulted in a concomitant decreased permeability that could be modeled directly from the proportional increase in the apparent solubility. On the contrary, etoposide permeability remained constant when using the ASD formulation, irrespective of the increased apparent solubility provided by the formulation. In conclusion, supersaturation resulting from the amorphous form overcomes the solubility-permeability tradeoff associated with other formulation techniques. Accounting for the solubility-permeability interplay may allow to develop better solubility-enabling formulations, thereby maximizing the overall absorption of lipophilic orally administered drugs.

Evaluation of hepatotoxic potential of drugs by inhibition of bile-acid transport in cultured primary human hepatocytes and intact rats.

Inhibition of canalicular bile acid efflux by medications is associated with clinical liver toxicity, sometimes in the absence of major liver effects in experimental species. To predict the hepatotoxic potential of compounds in vitro and in vivo, we investigated the effect of clinical cholestatic agents on [3H]taurocholic acid transport in regular and collagen-sandwich cultured human hepatocytes. Hepatocytes established a well-developed canalicular network with bile acid accumulating in the canalicular lumen within 15 min of addition to cells. Removing Ca2+ and Mg2+ from the incubation buffer destroyed canalicular junctions, resulting in bile acid efflux into the incubation buffer. Canalicular transport was calculated based on the difference between the amount of bile acid effluxed into the Ca/Mg2+-free and regular buffers with linear efflux up to 10 min. Hepatocytes cultured in the nonsandwich configuration also transported taurocholic acid, but at 50% the rate in sandwiched cultures. Cyclosporin A, bosentan, CI-1034, glyburide, erythromycin estolate, and troleandomycin inhibited efflux in a concentration-dependent manner. In contrast, new generation macrolide antibiotics with lower incidence of clinical hepatotoxicity were much less potent inhibitors of efflux. An in vivo study was conducted whereby glyburide or CI-1034, administered iv to male rats, produced a 2.4-fold increase in rat total serum bile acids. A synergistic 6.8-fold increase in serum total bile acids was found when both drugs were delivered together. These results provide methods to evaluate inhibitory effects of potentially cholestatic compounds on bile-acid transport, and to rank compounds according to their hepatotoxic potential.

An intravenous formulation decision tree for discovery compound formulation development.

Discovery and pre-clinical animal efficacy assessment formulation development efforts are challenged by limited compound availability and stringent timelines. The implementation and use of a systematic discovery formulation scheme can facilitate this important process. We observed that nearly 85% of Pfizer, Ann Arbor discovery compounds (n>300) submitted for discovery and pre-clinical injectable formulation development in the year 2000 could be formulated by pH adjustment, cosolvent addition, or a combination of the two approaches. Based on the vehicle data generated by this laboratory, a discovery formulation decision tree, that utilizes the solubilization approaches described above, is proposed. The proposed decision tree can be adapted and modified by pharmaceutical scientists to conform to best practices put forth by their institutions for discovery animal studies requiring injectable dosage forms.