Olafur S. Gudmundsson

Discovery pharmaceutics--challenges and opportunities.

Most pharmaceutical companies are now evaluating compounds for druglike properties early in the discovery process. The data generated at these early stages allow upfront identification of potential development challenges and thus selection of the best candidates for lead nomination. Most often, lead nomination candidates are selected based on pharmacological and toxicological data. However, many drugs in development suffer from poor biopharmaceutical properties due to suboptimal physiochemical parameters. The poor biopharmaceutical properties often lead to extended timelines and a higher cost of developing the compounds. To avoid these problems and choose the best compounds from a biopharmaceutical perspective, physicochemical parameters such as solubility, lipophilicity, and stability need to be evaluated as early as possible. Furthermore, the preformulation approaches used to evaluate the compounds for their pharmacokinetic and toxicological properties need to be optimized. This minireview summarizes some of the parameters and approaches that can be used to evaluate compounds in the early stages of drug discovery.

Reductions in log P improved protein binding and clearance predictions enabling the prospective design of cannabinoid receptor (CB1) antagonists with desired pharmacokinetic properties.

Several strategies have been employed to reduce the long in vivo half-life of our lead CB1 antagonist, triazolopyridazinone 3, to differentiate the pharmacokinetic profile versus the lead clinical compounds. An in vitro and in vivo clearance data set revealed a lack of correlation; however, when compounds with <5% free fraction were excluded, a more predictable correlation was observed. Compounds with log P between 3 and 4 were likely to have significant free fraction, so we designed compounds in this range to give more predictable clearance values. This strategy produced compounds with desirable in vivo half-lives, ultimately leading to the discovery of compound 46. The progression of compound 46 was halted due to the contemporaneous marketing and clinical withdrawal of other centrally acting CB1 antagonists; however, the design strategy successfully delivered a potent CB1 antagonist with the desired pharmacokinetic properties and a clean off-target profile.

Oral Delivery of Highly Lipophilic Poorly Water-Soluble Drugs: Spray-Dried Dispersions to Improve Oral Absorption and Enable High-Dose Toxicology Studies of a P2Y1 Antagonist

BMS-B is a highly lipophilic compound (clog P 7.72) with poor aqueous solubility (<10 ng/mL at pH 1 and 6.5). The compound exhibits low bioavailability in preclinical species when dosed as cosolvent solution formulations, with reduced exposure upon dose escalation. The purpose of this study was to evaluate spray-dried dispersions (SDDs) for enhancing oral exposure and enabling toxicology studies of BMS-B. SDD solids of BMS-B were prepared with 10%-25% drug in hydroxypropyl methylcellulose acetate succinate and showed an enhanced dissolution profile relative to the neat form of the compound. When dosed in rats and monkeys at 5 mg/kg, the SDD exhibited comparable exposure relative to the solution formulation. The SDD was also dosed in rats at 200 and 400 mg/kg and showed dose-proportional exposure compared to the solution formulation. Based on in vitro and in vivo data, the SDD formulation was selected for the toxicology study of BMS-B in rats. In summary, although the SDD approach could be quite challenging for highly lipophilic compounds because of the limitation on wetting and dissolution, the present study demonstrated that SDD can be applied in drug discovery to enhance oral exposure and enable preclinical toxicology studies of highly lipophilic poorly water-soluble compounds.

Utility of in situ sodium alginate/karaya gum gels to facilitate gastric retention in rodents.

Target validation or demonstration of efficacy requires adequate in vivo exposure of tool molecules to determine their activity in order to validate the model or show the potential usefulness of the pharmacophore. Early discovery work is often carried out with compounds which possess undesirable PK properties in small rodents where the discovery formulation scientist is often forced to dose 2-4 times per day. Gastric retentive formulations in small rodents (rats/mice) could enable increased duration of exposure for compounds with narrow absorption windows or increased residence time for compounds with targets located in the GI tract. The aim of this work is to establish an easily administered gastric retentive gel for rodents in situ using a mixture of sodium alginate and karaya gum. Feasibility studies were conducted in Sprague-Dawley rats using barium sulfate as a radio-opaque tracer. The results show that gastric retention of barium was achieved for rats dosed with the gel formulation relative to a barium suspension. The gastric residence time of the gel varied from 1h to >8h (n=3). The data suggest that sodium alginate/karaya gum gels may be a useful tool to achieve gastric retention in rodent studies.

Lipophilic salts of poorly soluble compounds to enable high-dose lipidic SEDDS formulations in drug discovery

Graphical abstract Figure. No caption available. ABSTRACT Self‐emulsifying drug delivery systems (SEDDS) have been used to solubilize poorly water‐soluble drugs to improve exposure in high‐dose pharmacokinetic (PK) and toxicokinetic (TK) studies. However, the absorbable dose is often limited by drug solubility in the lipidic SEDDS vehicle. This study focuses on increasing solubility and drug loading of ionizable drugs in SEDDS vehicles using lipophilic counterions to prepare lipophilic salts of drugs. SEDDS formulations of two lipophilic salts—atazanavir‐2‐naphthalene sulfonic acid (ATV‐2‐NSA) and atazanavir‐dioctyl sulfosuccinic acid (ATV‐Doc)—were characterized and their performance compared to atazanavir (ATV) free base formulated as an aqueous crystalline suspension, an organic solution, and a SEDDS suspension, using in vitro, in vivo, and in silico methods. ATV‐2‐NSA exhibited ˜6‐fold increased solubility in a SEDDS vehicle, allowing emulsion dosing at 12 mg/mL. In rat PK studies at 60 mg/kg, the ATV‐2‐NSA SEDDS emulsion had comparable exposure to the free‐base solution, but with less variability, and had better exposure at high dose than aqueous suspensions of ATV free base. Trends in dose‐dependent exposure for various formulations were consistent with GastroPlus™ modeling. Results suggest use of lipophilic salts is a valuable approach for delivering poorly soluble compounds at high doses in Discovery.

Discovery of a Parenteral Small Molecule Coagulation Factor XIa Inhibitor Clinical Candidate (BMS-962212)

Factor XIa (FXIa) is a blood coagulation enzyme that is involved in the amplification of thrombin generation. Mounting evidence suggests that direct inhibition of FXIa can block pathologic thrombus formation while preserving normal hemostasis. Preclinical studies using a variety of approaches to reduce FXIa activity, including direct inhibitors of FXIa, have demonstrated good antithrombotic efficacy without increasing bleeding. On the basis of this potential, we targeted our efforts at identifying potent inhibitors of FXIa with a focus on discovering an acute antithrombotic agent for use in a hospital setting. Herein we describe the discovery of a potent FXIa clinical candidate, 55 (FXIa Ki = 0.7 nM), with excellent preclinical efficacy in thrombosis models and aqueous solubility suitable for intravenous administration. BMS-962212 is a reversible, direct, and highly selective small molecule inhibitor of FXIa.

Utility of Gastric-Retained Alginate Gels to Modulate Pharmacokinetic Profiles in Rats

A gastric-retentive formulation amenable to dosing in rodents has the potential to enable sustained release in a preclinical setting. This may be useful to provide systemic exposure over a longer duration or to increase duration of exposure for compounds with targets localized in the gastrointestinal tract. Previous work has shown that a mixture of 1% sodium alginate and 0.625% karaya gum in the presence of a calcium chelator can form gels in situ that are gastric retained in rats. The aim of this work was to define the physicochemical boundaries of compounds within this technology and their relation to in vivo release using a series of model compounds with high permeability but varying solubility. In vitro data demonstrated a good correlation between solubility and initial release rates from the gels. In vivo studies were conducted in Sprague-Dawley rats to compare the exposure profile of compounds dosed in gel relative to a standard formulation. In vivo data were consistent with trends from the in vitro studies. These data suggest that, in conjunction with an understanding of compound solubility, sodium alginate/karaya gum gels may be a useful tool to modulate exposure profiles in rodent models in a preclinical setting.

Case Study: Ximelagatran: A Double Prodrug of Melagatran

Ximelagatran was designed to increase the bioavailability of melagatran, a potent thrombin inhibitor, by eliminating charges and thus increasing the lipophilicity of the molecule. Melagatran, like most other thrombin inhibitors, contains a strongly basic benzamidine group with a pKa of 11.5 that is protonated at the pH of the intestinal tract and hinders intestinal absorption. Furthermore, melagatran also contains an acidic carboxylic group with a pKa of 2.0, which is ionized at physiological pH. Melagatran also contains a secondary amine with a pKa of 7.0. The effect of the charges on the oral absorption of melagatran was observed when the compound was initially dosed orally and a low and variable bioavailability of 3–7% was observed (Gustafsson et al., 2001).

Case Study: Valacyclovir: A Prodrug of Acyclovir

Valacyclovir is an L-valyl ester prodrug of acyclovir that is used for the treatment of herpes, varicella zoster, and cytomegaloviruses. Valacyclovir was developed to increase the oral absorption and plasma levels of acyclovir. Increased plasma concentrations of acyclovir are important in maintaining antiviral activity, especially in immunocompromised patients and in the treatment of less sensitive viruses such as VZV and CMV (Beauchamp et al., 1992). Suboptimal exposures can lead to more resistant viral strains. To achieve high enough exposures, acyclovir must be dosed intravenously or in multiple high doses (de Miranda and Burnette, 1994). In the design of valacyclovir, the following criteria were met: it was as safe as acyclovir, efficiently converted, and gave exposures after oral administration that were comparable to plasma levels of intravenously dosed acyclovir. Several reviews describe the development, pharmacokinetics, and efficacy of valacyclovir (Crooks and Murray 1994; Beutner, 1995; Perry and Faulds, 1996).

Case Study: Famciclovir: A Prodrug of Penciclovir

Famciclovir was designed as an orally bioavailable prodrug of penciclovir, an antiviral agent with activity against herpes simplex virus types 1 (HSV-1) and 2 (HSV-2) and varicella-zoster virus (VZV) (Boyd et al., 1987; 1988). Penciclovir similarly to other guanosine analogs (De Miranda and Good, 1992; De Miranda et al., 1981), is poorly absorbed when given orally to rodents and humans (Boyd et al., 1988; Filer et al., 1994). Initially, various mono and dicarboxylic esters of penciclovir were made (Harnden et al., 1987), but none of these compounds resulted in significantly improved plasma concentration, of penciclovir when administered orally (Harnden et al., 1989). The physicochemical properties of penciclovir are, furthermore, influenced by the polar guanine ring, and it was thought that modifications on that ring might lead to improved absorption. The 6-deoxy derivative was made, since it was known from previous work with acyclovir (Krenitsky et al., 1984) that it would be oxidized to form penciclovir. When esters of the 6-deoxy derivative were tested a significant increase in bioavailability was observed (Harnden et al., 1989). After further evaluation of the stability of the 6-deoxy esters (Harnden et al., 1989), the diacetyl derivative, famciclovir, was selected for further development due to its improved stability in human duodenal contents (Jarvest, 1994). For more details on the design of famciclovir the reader is referred to several recent reviews (Jarvest, 1994; Jarvest et al., 1998).