Making Better Drugs: Decision Gates in Non-Clinical Drug Development

Pritchard, J. Frederick; Jurima-Romet, Malle; Reimer, Mark L. J.; Mortimer, Elisabeth; Rolfe, Brenda; Cayen, Mitchell N.

doi:10.1038/nrd1131

Cited by 228 publications

(130 citation statements)

References 42 publications

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“…For this reason, major efforts are focused on evaluating drug clearance and other pharmacokinetic parameters of new chemical entities (2,3). Currently, drug discovery and preclinical development programs are plagued by unreliable models and escalating costs.…”

Section: Discussionmentioning

confidence: 99%

“…With cost of drug development escalating to $400 million/drug there is an urgent need for the development of rigorous models of liver metabolism in the context of ADME/Tox (absorption, distribution, metabolism, excretion, and toxicity) screening. This need is exacerbated by the failure of animal studies to predict drug clearance and toxicity, as well as the disastrous clinical and financial consequences of postmarket drug withdrawal (2,3).…”

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confidence: 99%

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Oxygen-mediated enhancement of primary hepatocyte metabolism, functional polarization, gene expression, and drug clearance

Kidambi

Yarmush

Novik³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

190

147

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The liver is a major site for the metabolism of xenobiotic compounds due to its abundant level of phase I/II metabolic enzymes. With the cost of drug development escalating to over $400 million/ drug there is an urgent need for the development of rigorous models of hepatic metabolism for preclinical screening of drug clearance and hepatotoxicity. Here, we present a microenvironment in which primary human and rat hepatocytes maintain a high level of metabolic competence without a long adaptation period. We demonstrate that co-cultures of hepatocytes and endothelial cells in serum-free media seeded under 95% oxygen maintain functional apical and basal polarity, high levels of cytochrome P450 activity, and gene expression profiles on par with freshly isolated hepatocytes. These oxygenated co-cultures demonstrate a remarkable ability to predict in vivo drug clearance rates of both rapid and slow clearing drugs with an R 2 of 0.92. Moreover, as the metabolic function of oxygenated co-cultures stabilizes overnight, preclinical testing can be carried out days or even weeks before other culture methods, significantly reducing associated labor and cost. These results are readily extendable to other culture configurations including three-dimensional culture, bioreactor studies, as well as microfabricated co-cultures. drug discovery ͉ liver metabolism ͉ tissue engineering

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Oxygen-mediated enhancement of primary hepatocyte metabolism, functional polarization, gene expression, and drug clearance

Kidambi

Yarmush

Novik³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

190

147

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“…5 The data from these assays have allowed medicinal chemists to focus their efforts on compounds with improved metabolic stability. 6 Detailed metabolite identification studies are also done more routinely, which provide information on how to strategically replace or block metabolically labile sites. 7 Additionally, in vivo PK studies are regularly conducted in drug discovery, which helps to build in vitro−in vivo PK relationships.…”

Section: ■ Introductionmentioning

confidence: 99%

Mitigating Heterocycle Metabolism in Drug Discovery

2012

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In the past few decades, drug metabolism research has played an ever increasing role in the design of drugs. 1−3 In vitro metabolism assays 4 have become an integral part of the routine profiling of compounds made in drug discovery. 5 The data from these assays have allowed medicinal chemists to focus their efforts on compounds with improved metabolic stability. 6 Detailed metabolite identification studies are also done more routinely, which provide information on how to strategically replace or block metabolically labile sites. 7 Additionally, in vivo PK studies are regularly conducted in drug discovery, which helps to build in vitro−in vivo PK relationships. 4 The positive influence that these advances in PKDM sciences have had on drug discovery is reflected in the fact that fewer drug candidates fail in the clinic for PKDM related issues. 8 This suggests that medicinal chemists are successfully integrating the data generated by their PKDM colleagues into the design of compounds with fewer metabolic liabilities.Extensive data from metabolism studies have allowed medicinal chemists to develop general principles for reducing compound metabolism. These methods include, but are not limited to, reducing lipophilicity, altering sterics and electronics, introducing a conformational constraint, and altering the stereochemistry of their compounds. While no single method is able to solve every metabolic problem, these principles do give medicinal chemists guidance on how to improve the metabolic liabilities of their compounds. If the specific site of metabolism is known, medicinal chemists block the site, typically with a fluorine, or replace the metabolically labile group with a bioisostere. 9 While several authors have reviewed these techniques for reducing metabolism, 5,10,11 there is no review that summarizes different approaches to improving the metabolic stability of heterocycles. In this review, we summarize examples where changes were made at or near the heterocycle to improve metabolic stability. By summarizing these examples, we hope to provide a useful guide to medicinal chemists as they attempt to improve the metabolic profile of their own heterocyclic compounds.The majority of the examples that are included in this review came from searching the online open access database CHEMBL. 12 In addition to having pharmacology data on compounds from the medicinal chemistry literature, CHEMBL has over 120 000 points of data on the ADMET properties of compounds. With the help of the visualization software Spotfire, we were able to cull examples from the CHEMBL ADMET data that focused on heterocycles. We also identified examples from papers that cite leading reviews in the drug metabolism field 13−18 and were present in other recent reviews on drug metabolism. 19−22 The main criteria that we placed on the examples selected for this review was that the change made to improve metabolism had to occur at or near the heterocycle and nowhere else on the molecule. This allowed us to eliminate examples where a change made t...

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“…An increase of the very low bioavailability of the weak base was feasible with permeability enhancers, surfactants, acidic excipients, amorphization, and with fumaric acid co-crystal formation. The fumaric acid co-crystal was selected for development [84] however the strongly pH dependent solubility profile and high water solubility of the co-crystal former caused further issues.…”

Section: Partially Amorphous Api Containing Formulation: F7mentioning

confidence: 99%

“…Formation of co-crystals can solve several pharmaceutical issues raised during preformulation [2] and formulation development e.g. by solubility, dissolution, bioavailability, chemical stability, decreasing hygroscopicity modulation [3,84]. Formation of co-crystals could be a new path to improve physico-chemical and biopharmaceutical…”

Section: Introductionmentioning

confidence: 99%

Pharmaceutical development of co-crystals

Venczel

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EARLY DRUG FORMULATION -FORMULATION POSSIBILITIES OF List of tables AIMSThe aims of this thesis are former has ten times higher solubility than the drug itself. However high aqueous solubility of co-crystal forms can lead to rapid convervation and hinter performance [20] that is why one of the main role of formulation experts is to work in a strong collaboration with chemical and analytical experts to protect physical integrity of co-crystals during the formulation work. Designing of co-crystalsCo-crystals are supramolecular homo-(I and III) or heterosynthons (II and IV) presented on is not suitable to reach the sink condition for active pharmaceutical ingredients, which are practically insoluble in aqueous solutions. In contrast to the past, when the majority of research compounds had a relatively small molecular weight and acceptable solubility, the Three active pharmaceutical ingredients were evaluated and compared. These are: SAR1 as a weak base, its di-HCl salt and its co-crystal with fumaric acid. All API study batches were manufactured in laboratory scale from 10 g to 30 g. Resynthesis batch of the fumaric acid cocrystal was manufactured in 0.7 kg scale. Active pharmaceutical ingredient in the area of flow-through dissolutionAn origin molecule of Sanofi coded as a "C" model material was used for FaSSIF (fasted state simulated intestinal fluid) and FeSSIF (fed state simulated intestinal fluid) dissolution study.The same "C" model API and its sevaral salt forms were applied to show the benefits of flow through dissolution during salt selection studies. BuffersBuffer solutions were prepared according to the USP and Ph. Eur. recommendations 39, 40. Pharmaceutical excipientsCremophor ELP was ordered from BASF. Cremophor ELP, a purifed grade of Cremophor EL was specially developed for sensitive active ingredients, as the higher purity was found to improve their stability 41. Tween 80, lactic acid, citric acid, Span 85, PEG 200, sodium hydroxide were purchased from Merck while Eudragit L100-55 was ordered from Evonic.Some pharmaceutical excipients such as mannitol, sulfobuthyl  cyclodextrin, vitamin E TPGS, PVP K25, sodium docusate, Miglyol 812 N, sodium dodecyl sulfate, methyl cellulose, HPMC, crospovidone, microcrystalline cellulose, magnesium stearate and colloidal silica anhydrous were ordered from the internal warehouse of Sanofi. METHODS Chemical manufacturing SAR1 as a fumaric acid co-crystalThe reactor was charged with acetone (12 L), SAR1 base Form III (592 g, 1.29 mol) and fumaric acid (600 g, 5.16 mol). The slurry was stirred at room temperature for 24 hours, the crystals were filtered off, washed with water (1 L) and ethanol (1 L), and dried in a vacuum at 80°C for five hours. Yield: 723 g (94.0%) pale yellow powder [42]. The purity of the product was: 98.9% (HPLC). SAR1 as a dihydrochloride saltSAR1 (29 g) was added to methanol (1370 ml) under nitrogen. The suspension of API was stirred in Ultra-Turrax system for 30 minutes at room temperature. The concentrated hydrochloric acid (8.03 ml, 2....

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Making Better Drugs: Decision Gates in Non-Clinical Drug Development

Cited by 228 publications

References 42 publications

Oxygen-mediated enhancement of primary hepatocyte metabolism, functional polarization, gene expression, and drug clearance

Oxygen-mediated enhancement of primary hepatocyte metabolism, functional polarization, gene expression, and drug clearance

Mitigating Heterocycle Metabolism in Drug Discovery

Pharmaceutical development of co-crystals

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