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Current Drug Metabolism, 2004, 5, 375-388

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Biopharmaceutic Classification System: A Scientific Framework for Pharmacokinetic Optimization in Drug Research Manthena V.S. Varma, Sateesh Khandavilli, Yasvanth Ashokraj, Amit Jain, Anandbabu Dhanikula, Anurag Sood, Narisetty S. Thomas, Omathanu Pillai, Pradeep Sharma, Rajesh Gandhi, Shrutidevi Agrawal, Vinod Nair and Ramesh Panchagnula* Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), Phase X, SAS Nagar, Punjab 160062, India Abstract: The tenets of biopharmaceutics, solubility and permeability, are of pivotal importance in new drug discovery and lead optimization due to the dependence of drug absorption and pharmacokinetics on these two properties. A classification system for drugs based on these two fundamental parameters, Biopharmaceutic Classification System (BCS), provides drug designer an opportunity to manipulate structure or physicochemical properties of lead candidates so as to achieve better “deliverability”. Considering the facts for failure of NCEs, drug research, once concentrating on optimizing the efficacy and safety of the leads, dramatically transformed in the past two decades. With the enormous number of molecules being synthesized using combinatorial and parallel synthesis, high throughput methodologies for screening solubility and permeability has gained significant interest in pharmaceutical industry. Ultimate aim of the drug discovery scientist in pharmacokinetic optimization is to tailor the molecules so that they show the features of BCS class I without compromising on pharmacodynamics. Considerations to optimize drug delivery and pharmacokinetics right from the initial stages of drug design propelled need for “High Throughput Pharmaceutics” (HTP). In silico predictions and development of theoretical profiles for solubility and lipophilicity provides structure based biopharmaceutical optimization, while in vitro experimental models (microtitre plate assays and cell cultures) validate the predictions. Thus, biopharmaceutical characterization during drug design and early development helps in early withdrawal of molecules with insurmountable developmental problems associated with pharmacokinetic optimization.

1. INTRODUCTION In recent years, drug discovery program have dramatically changed from “empirical-based” to “knowledge-based” rational drug design. Advancements in biotechnology and combinatorial synthetic approaches, clubbed with high throughput screening (HTS) for pharmacological activity have converged the healthcare systems to produce increasing number of diverse new chemical entities (NCEs). However, this rational design of molecules does not necessarily mean rational drug delivery, since the drug molecules do not always deliver themselves [1]. Drug development in the past used to be initiated after identification of most active molecule. However this approach lead to a number of drawbacks with the problems being that many molecules which are put into development had poor physicochemical (solubility, stability) and biopharmaceutical (permeability and enzymatic stability) properties, as a consequence of which about 40% of NCEs fail to reach the market place [2]. Many investigational new drugs (INDs) fail during preclinical and clinical development, with an estimated 46% of compounds entering clinical development are dropped due to unacceptable efficacy and 40% due to safety reasons [3]. Pharmacokinetic optimization with

respect to ADME (absorption, distribution, metabolism and elimination) at the drug discovery phase would be most valuable in reducing NCEs failing in late preclinical and clinical development, since efficacy and safety issues are related in part to pharmacokinetic profiles. With the new prepreclinical paradigm of compound optimization in early phase of drug discovery, pharmaceutical companies are working to integrate biopharmaceutical screening in the initial stages of drug discovery, in order to cut down the number of NCEs failing in the latter stages of drug development [4]. Fig. (1) shows the drug discovery phases and the integration of biopharmaceutical screening during lead optimization in the process of selecting candidates for preclinical and clinical development. Screening of libraries for solubility and permeability and the integration of charge state and/or physiological variables with these processes as the drug moves down the gastro intestinal tract (GI) provides useful biopharmaceutical screens in early development. This article covers the aspects of optimizing solubility and permeability, the fundamental properties of BCS which determines intestinal permeability of drugs, in the process of pharmacokinetic optimization for orally active compounds in drug research. 2. BCS AND ORAL ABSORPTION

*Address correspondence to this author at the Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), Phase X, SAS Nagar, Punjab 160062, India; Tel: +91 0172 2214 682/687; E-mail: [email protected] 1389-2002/04 $45.00+.00

Peroral route of drug administration is the most preferred with respect to patient compliance and obvious commercial reasons. However, many molecules especially those resulting © 2004 Bentham Science Publishers Ltd.

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Fig. (1). Schematic representation of current drug research program illustrating integration of drug discovery and development by biopharmaceutic characterization. Gene sequences for targets that have been identified by genomics are cloned and expressed as target proteins and are validated by functional proteomics, which are suitable for screening with libraries of small drug-like molecules synthesized from combinatorial chemistry using quantitative binding assays (HTS). Initial ‘hits’ generated from HTS are chemically modified with SBDD and MM strategies to synthesize ‘lead’ molecules with improved properties. Lead molecules are further optimized for solubility and permeability properties to improve deliverability of NCEs without loosing target binding affinity. Identification of these fundamental properties, solubility and permeability, that determines deliverability of the molecules lead to BCS, which classifies drugs into four groups. Drugs with high solubility and high permeability are grouped into class I, low solubility and high permeability into class II, high solubility and low permeability into class III, and low solubility and low permeability into class IV. Key: HTS, high-throughput screening; MM, molecular modeling; SBDD, structure based drug design; NCEs, new chemical entities; BCS, biopharmaceutic classification system.

from combinatorial and parallel synthesis are not biopharmaceutically optimized to enable peroral deliverability, for the reasons that these technologies shift the leads towards (i) more lipophilic, potentially less soluble compounds and (ii) compounds with a higher number of hydrogen bonding acceptors and donors and large molecular volume, resulting in less permeability. Solubility and permeability are the fundamental properties determining the bioavailability of an orally active drug. Based on these properties Amidon et al. [5] proposed biopharmaceutic classification system (BCS), which in present times is serving as a guide for regulatory and industrial purposes [6, 7]. This concept exploring dose number, dissolution number, and absorption number of an orally administered drug clearly dictates its systemic availability. These three numbers are associated with a number of multifaceted hurdles, which include (i) physicochemical properties of the molecule (solubility/dissolution) (ii) stability of drug in GI environment (acid degradation) (iii) enzymatic stability in GI lumen, epithelium and liver (iv) permeability (molecular weight, log P, H-bonding efficiency) and (v) substrates specificity to various biological transporters and efflux systems of intestinal epithelium including Pglycoprotein (P-gp). Dose number (Do) is characterized by the volume required for solubilising the maximum dose strength of the drug

Do =

M / VO CS

Eq. 1

Where CS is the solubility, M is the dose and VO is the volume of water taken with the dose, which is generally set to 250ml. Dissolution number (Dn) is characterized by the time required for drug dissolution which is the ratio of the intestinal residence time and the dissolution time

Dn =

< Tsit > 3DCS < Tsit > = < Tdiss > r 2ρ

Eq. 2

Where D is diffusivity, ρ is density and r is the initial particle radius. Absorption number (An) is characterized by the time required for absorption of the dose administered which is a ratio of residence time and absorptive time

An =

< Tsit > Peff < Tsit > = < Tabs > R

Eq. 3

Where Peff is the permeability and R is the gut radius.

Biopharmaceutic Classification System

Drug with complete absorption show Do1. Although BCS provides a mechanistic framework for intestinal absorption of drugs and was framed to establish in vitro–in vivo correlation (IVIVC) for peroral products, it has far-reaching implications in drug discovery, development and delivery. Traditionally, permeability has been used as a single parameter to predict human intestinal absorption, and the amount of drug available in solution at the site of absorption (i.e. solubility) was very rarely considered [8-10]. It is expected that better prediction of absorption can be made by integrating both solubility and permeability [11]. With a set of 27 novel oxazolidinone class of antimicrobial agents, it was observed that molecules which showed high aqueous solubility and permeability in Caco-2 monolayers are completely absorbed as predicted and experimentally determined in rats (Fig. (2)). While molecules with high permeability but low solubility has good to moderate fraction absorbed and molecules with both poor solubility and poor permeability resulted in less fraction dose absorbed [11]. However, molecules with high solubility but low permeability demonstrated complete absorption, suggesting the importance of considering solubility along with permeability in modeling oral absorption. The central theme of integrating BCS in drug discovery is to optimize solubility and/or permeability, the essential biopharmaceutical processes, in the early phases by structural modifications or searching for alternative strategies.

Fig. (2). Biopharmaceutic classification of a set of 27 novel oxazolidinone class antimicrobial agents, which showed low (∆), good to moderate (l) and complete (o) bioavailability in rats. Data was adopted from Hilgers et al. [11]. Caco-2 permeability limit for high permeability was set based on reported discussions [91]. Solubility boundary was arbitrarily set based on Do=1 (Eq. 1), taking 250ml as VO and assuming a maximum dose strength of 500mg for all the molecules. Key: HS-HP: Class I, high solubility-high permeability; LS-HP: Class II, low solubility-high permeability; HS-LP: Class III, high solubility-low permeability; LS-LP: Class IV, low solubility-low permeability.


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3. OVERCOMING BARRIERS TO INTESTINAL DRUG ABSORPTION The barrier function of intestinal epithelial membrane is the culmination of both physicochemical and biochemical factors. Physicochemical properties play significant role in determining the intestinal absorption of many drugs. However, poor physicochemical properties may sometimes be overcome by carrier-mediated transport, while biochemical barriers like efflux pumps and intestinal metabolic enzymes may significantly limit oral bioavailability. 3.1. Solubility and Dissolution For a drug to absorbed it must be presented in the form of aqueous solution at the site of absorption, thus solubility and dissolution, which regulate the extent and kinetics of drug liberation are the important determinants in oral bioavailability. Incorporation of ionizable/polar groups into the structure, salt generation and prodrug approach are the primary methods in solubility optimization. The development of various peptidomimetics like HIV protease inhibitors and fibrinogen receptor (GP IIb:IIIa) antagonists are good examples that illustrate the concept and importance of drug solubility in drug selection and drug development. In order to improve oral bioavailability, it may be necessary to change solubility by designing modifications in non-pharmacophore regions (first approach). Vacca et al. [12] initially developed a series of hydroxyethylene dipeptide isosteres, represented by L-685, 434 (1), and were found to be highly potent and selective HIV protease inhibitors. Although they are highly potent and selective, the main drawback was that they lacked aqueous solubility and acceptable pharmacokinetic profile, resulting in poor bioavailability [13]. The efforts made to increase the solubility by incorporating a basic amine (replacement of tert-butyl carbamate and Phe moieties with decahydroisoquinoline tert-butylamide) into the backbone of this series, led to the development of a novel class of hydroxylamine pentanamide isosteres, represented by L-704, 486, with a favorable oral pharmacokinetics but its efficacy was diminished. When decahydroisoquinoline tert-butylamide group was replaced with two tertbutyl carboxamide 4substituted piperazines, the basic amine improved aqueous solubility and N4 gave a chance for further modifications that could balance hydrophilic and hydrophobic requirements. The 3-pyridyl methyl substitution at N4 (lead to the discovery of indinavir) provided both lipophilicity for binding to the target and a weakly basic nitrogen further increased aqueous solubility. Indinavir sulfate (2) is the clinical formulation, because of improved aqueous solubility (>450mg.ml-1) and consistent bioavailability [14]. Development of ritonavir is another such example where solubility approach had been applied in the drug development [15, 16]. A similar case was reported in a series of benzamidine containing non-peptide fibrinogen receptor (GP IIb:IIIa) antagonists [17]. The highly potent compounds when dosed orally to marmoset showed very low oral activity and as a result of their poor aqueous solubility. Introduction of a central piperazine ring showed improved oral activity possible due to improved solubility.

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phosphatase cleavage of phosphate group, rapid lactonization serves to regenerate paclitaxel. However, the in vivo efficacy is yet to be evaluated. HO

HO HN

O

HN

HO

tBu

HO HN

O

N

O

(1) L-685 434

3.2. Permeability: Transport

O

O

N

(2) Indinavir

N H

One of the techniques commonly used to overcome the problems of poor and erratic bioavailability is the prodrug approach, wherein the physicochemical properties of the drug are improved by bioreversible chemical alteration. The most common prodrug strategy involves the incorporation of a polar or ionizable moiety into the parent compound to improve aqueous solubility [18]. Low aqueous solubility of benzimidazole carbamates like mebendazole and albendazole makes them less suitable for the treatment of systemic infections. The synthesis of N-alkoxy carbomyl prodrugs has been shown to increase the aqueous solubility of mebendazole by 2 fold [19]. These derivatives serve to decrease the melting point of these compounds while maintaining lipophilicity. This practical example illustrates the potential for prodrugs to improve oral bioavailability by increasing the aqueous concentration gradient driving force for absorption. In “ad hoc prodrug approach” the target activity is optimized first irrespective of pharmacokinetic properties and once the target activity is demonstrated, the pharmacokinetic properties are optimized by prodrug design without altering the pharmacophore in the active chemical [20]. Such an approach may well prove most useful or even indispensable in the development of therapeutic peptides and antisense drugs. Though the application of this approach in drug research is uncommon, it was successfully applied in the development of enalapril, an angiotensin converting enzyme inhibitor. The “post hoc prodrug approach” (prodrugs of established drugs) has been successfully used to improve water solubility of the corticosteroids, vitamins and benzodiazepins. Phenytoin is another example of a drug where the prodrug approach has been considered to increase water solubility [18]. A series of prodrugs of phenytoin with improved aqueous solubilities have been evaluated. The disodium salt of the phosphate ester of 3-hydroxymethyl phenytoin was found to be 4500 times more soluble than phenytoin and the parent compound was generated rapidly in vivo. Improvement in solubility of paclitaxel drug by “collapsible prodrug” approach was demonstrated [21]. Phosphonoxyphenyl propionate esters of paclitaxel showed much improved solubility (>10mg.ml-1 against only 0.25µg.ml-1 for paclitaxel), which on subsequent to alkaline

Passive

and

Carrier-Mediated

Permeability is an important, but still unpredictable determinant of absorption and it is informative to explore mechanisms contributing to permeability given the interest in development of structure-based computational models of this property. Lipophilicity of drug molecules as an empirical rule influences its ADME. Fig. (3). shows the arbitrary relationships between log D and the parameters of ADME (intestinal permeability, volume of distribution [22], metabolic clearance and the renal clearance [23]). These relationships are much established at least for a structurally related series of compounds, making lipophilicity as the primary parameter in lead optimization. Within a homologous series, drug absorption usually increases as lipophilicity rises and is maintained at a plateau for a few units of log D after which there may be a steady decrease, giving a parabolic relation [24] (Fig. (3)). Similar parabolic relationship has been found between log D and biological activity [25]. Merino et al. [26] showed a sigmoidal relationship between absorption rate and log P in a series of 6-fluoroquinolones and β-blockers respectively. In general, a log D value between 0 and 3 constitutes an optimal window for passive drug absorption. A log P or log D value below 0 means that the compound is hydrophilic, and hence it will have a good solubility but it may have poor permeability. Whereas, a value far higher than 3 means that the compound is highly lipophilic and the partitioning of the molecule out of membrane to aqueous phase limits the permeability.

Fig. (3). Correlation between lipophilicity and various parameters of ADME (intestinal permeability, volume of distribution, metabolic clearance and renal clearance). Both X-axis and Y-axis are on arbitrary scales and the relationships are the usual trends reported.

Addition of hydrophilic and lipophilic groups and the prodrug approaches are reported for improving permeability of drugs. Increasing lipophilicity by esterification of C-ter-

Biopharmaceutic Classification System

minal carboxyl group and/or acylation of phenolic hydroxyl group on Tyr1 of a dermorphin tetrapeptide analog, N(α)1-iminoethyl-Tyr-D-MetO-Phe-Meβ-Ala-OH demonstrated improvement in bioavailability [27]. Development of orally bioavailable peptide based renin inhibitor A-72 517 by Kleinert et al. [28] is a good example for improving oral absorption by altering the physicochemical properties like partition coefficient and solubility. Initially Kleinert and his colleagues developed A-64 662 (enalkiren) a first generation renin inhibitor that is effective intravenously but shown to lack oral bioavailability [28]. Then they devised A-72 517 a close analogue of A-64 662 to improve oral bioavailability by improving oral absorption as well as metabolic stability. The P2-site histidine and NH2-terminal β-alanine residues of A-64 662 are more basic than their counterparts in A-72 517 and contain nitrogen-bound protons capable of forming hydrogen bonds. Consequently, A-72 517 is the more lipophilic compound with a log P of 4.6 (in octanol–water, pH 7.4), as compared with a log P of 2.6 for A-64 662, and the aqueous solubilities of the salts are 10 mg.ml-1 and 100 mg.ml-1, respectively. These physicochemical properties of A-72 517 along with its proteolytic stability made it orally bioavailable (53% in dog). Ho et al. [29] suggested that the relationship between the apparent n-octanol/water partition coefficient and passive permeability is complex and this single parameter correlation is not always reliable. However the correlation may exists for a homologous series of compounds but this relationship has been found to be inconsistent among a diverse group of drugs, especially for peptides [30], amide containing drugs [31] and many basic amines [32]. Many basic amines show a much higher partition into membranes than one would expect considering their log D (octanol/water) values [32]. This is because n-octanol can only support the efficient partitioning of the neutral form of the drug whereas biomembrane, as a consequence of having negatively charged phosphate head groups, can support the partitioning of both neutral and positively charged form of amines. In such cases membrane/water partition values log D (membrane/water) and ∆log D [(octanol/water)-(membrane/ water)] are good models for permeability. In the case of peptide drugs log D (octanol/water) values will not correlate well with permeability data because, peptide drugs have much polar functionality that form hydrogen bonds with hydroxyl groups in aqueous phase. As octanol can also form hydrogen bonds with peptides and amide drugs, it will give misleading higher partition values that will not correlate with permeability. However, correlations can be achieved between the permeabilities of peptides and the number of potential hydrogen bonds that peptides can make with water, suggesting that desolvation of the polar bonds in the molecule is a determinant of permeability. Hence, partition coefficients between heptane–ethylene glycol or the differences in partition coefficients between octanol buffer and isooctane/ cyclohexane buffer (∆log P), both of which are experimental estimates of hydrogen bond or desolvation potential are good descriptors for permeability of peptides through intestinal membrane as well as blood-brain barrier (BBB) [33-35]. Von Geldern and colleagues reported the improvement of oral absorption profile of azole-based ETA-selective antagonists through rational structural modifications suggested by ∆log


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P [(octanol/water)-(cyclohexane/water)], which tends to emphasize the hydrogen bonding capacity of molecule, relative to its hydrophobicity [35]. Other molecular properties that need to be controlled in drug design are the molecular size and hydrogen bonding capacity. These along with lipophilicity determine the passive permeability of drugs (transcellular and paracellular). Rule-of-five proposed by Lipinski and coworkers from an analysis of 2245 drugs from World Drug Index found a good place in libraries screening for obvious reasons [36]. As implemented in the Pfizer registration systems the rule-of five generates an alert for compounds when any of the two following conditions are not satisfied. ¡

Molecular weight Number of hydrogen bond acceptors ¡ Number of hydrogen bond donors

< <
1x10-6cm.s-1, whereas drugs with intestinal absorption of 1 and 100% had P app between 0.1 and 1x10 -6cm.s-1. Cogburn et al., [92] Rubas et al. [93] and Stewart et al. [94] showed similar relations, however with more than 10 fold difference in Caco-2 Papp values. This inter-laboratory variability demands model validation and thus, classification of drugs based on permeability requires the use of internal standards with a range of permeability and known human bioavailability. In situ intestinal perfusion in anaesthetized animals is more reliable technique over in vitro models because of the intact blood supply and innervation, reducing the risk of overestimating drug absorption due to impaired barrier function. Although the model is not very amenable for increased throughput, it is very often used for selection of orally potent candidates in preclinical development. In vivo pharmacokinetic studies in laboratory animals, although is time and labor intensive, provides more reliable data for permeability estimations. Rats serve as a good model for in vivo pharmacokinetic studies because of (i) ease in handling and (ii) efficiency in predicting dose-independent and dosedependent oral absorption in humans [95, 96]. Correlations of human oral dose absorbed to that in rats, dogs and monkeys are shown in Fig. (6). Fraction of oral dose absorbed in rats and monkeys showed good linear correlations (slope near to unity) with fraction absorbed in humans [95, 97], while dogs showed a poor relation [98]. However, 22 of 43 drugs studied were virtually completely absorbed in both dogs and humans. It is interesting to note that many relatively hydrophilic drugs have complete and faster absorption in dogs, which could be due to difference in the gastric emptying, intestinal transit and luminal degradation/ metabolism [98]. Although good correlation was observed with fraction dose absorbed in monkeys and human, comparison of oral bioavailability revealed considerably lower bioavailability in monkeys for several drugs, which was attributed to the greater first-pass metabolism of monkeys, taking place the gut wall, liver or both [97]. Thus, careful interpretation of animal data provides best possible human bioavailability forecasting. In vivo cassette dosing and plasma pooling methodologies improves the throughput for screening pharmacokinetic properties in preclinical development. Cassette dosing involves concurrent dosing of multiple compounds to animals in an effort to reduce the number of animals, the total time and cost required [99]. Plasma pooling provides opportunity to reduce the analysis time and cost required, where the samples from in vivo pharmacokinetic studies are pooled and analyzed to determine the overall bioavailability [100]. CONCLUSION Peroral being the most preferred route of delivery, determination of basic biopharmaceutic parameters during early stages of drug discovery lead to early pharmacokinetic optimization. The sophistication of drug delivery has increased with the emergence of BCS, which addresses fundamental solubility and permeability characteristics. Thus,

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Fig. (6). Correlation between human intestinal drug absorption and intestinal absorption in various in vivo animals models used in preclinical development. Graphs were reproduced from [95, 97, 98].

selection of delivery strategies based on these parameters is likely to takeover the traditional empirical approaches. The whole concept of generating biopharmaceutic data, for a large number of compounds obtained by rational drug design, using computational models, limited in vitro experiments and a few in vivo studies, termed as “High Throughput Pharmaceutics” which when integrated with combinatorial chemistry, molecular modeling and HTS (referred to as “Property-based drug design”), may significantly improve the success rate and at the same time reduce the time and cost involved in development. Readily available computational tools for intestinal absorption aid chemist’s decision-making process and also are useful in drug development and delivery for predicting the blood levels and to anticipate problems that may be encountered during delivery. With the available models, it is possible to reasonably predict the drug absorption and the resulting pharmacokinetics. Lipophilicity, polar surface area and size are critical properties of drugs influencing the rate of membrane transport. For drugs with slow transport (BCS Class II-IV) efflux transport and intestinal metabolism becomes more significant. Modeling these parameters and integrating with BCS might result in improved pharmacokinetic optimization in early development stages.

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