Biopharmaceutics Integration of Physical Chemical and Biological Pharmacokinetic Principles and Impact on Clinical Efficacy

In the previous overview discussion, we highlighted some principles governing physical pharmacy, formulation, and PK; the assessment of any one of these is dependent on the context of the others. This interplay is often complex. The integration of these various principles is necessary to define fully the biopharmaceu-tical profile for a new drug candidate and to evaluate the utility of a particular compound to treat the intended disease. The suitability of any given parameter is always dependent on one or more other, related parameters. For example, the target solubility for a new compound depends on the dose (Curatolo, 1998; Hilgers et al., 2003), which depends on the receptor affinity and BA, which are related to the lipophilicity, which is in turn is related to the solubility. Another common goal is to define compounds with good receptor binding, which is often increased by higher lipophilicity, which can negatively impact absorption and effective dose. Failure to consider all of these factors and their interrelationships can likely lead to the selection of chemical compounds that may not be useful as drugs, or to misleading conclusions regarding interpretation of a clinical issue. Hence, the answer to a question regarding acceptable biopharmaceutical properties is often "it depends." This point is illustrated in the following general examples of integration of biopharmaceutical principles. Introduction to the Biopharmaceutics Classification System

The biopharmaceutics classification system (BCS) was originally proposed based on the understanding that absorption of drugs in the GI tract via passive diffusion is governed primarily by the amount of drug in solution at the luminal-epithelial border and the ability of that drug to diffuse across the intestinal endothelium (Amidon et al., 1995). Flux of a compound is dependent on the diffusivity (permeability) and concentration gradient (solubility). The BCS categorizes solubility and permeability of drugs as either high or low and considers the dose and ion-ization of the drug in the GI tract. A strict definition of permeability is difficult considering the factors in the GI tract that influence apparent permeability (efflux pumps, metabolism, region), and therefore permeability can be estimated from either in vitro transport in cell culture models of intestinal transport or from in vivo data on drug absorption. The BCS also recognizes the importance of the dose of a drug, as a high dose drug with low solubility is more likely to exhibit absorption difficulties than a drug with the same solubility and low dose. Conversely, high permeability of a compound may be able to overcome perceived issues with low solubility. Hence, some drugs with extremely low solubility can nevertheless show high systemic BA due to high permeability. The relative balance of these properties influences whether the absorption rate of the drug is controlled primarily by solubility, dissolution rate, or membrane transport.

The BCS can be constructively used to assess the potential for impact of various factors, including formulation variables and physiological changes, on pharmaco-logic performance. For example, BA of a drug that is highly soluble in the full pH range of the GI tract (BCS Class I or III) would not be expected to be sensitive to formulation factors in an immediate-release dosage form that shows rapid dissolution. Conversely, drugs with low solubility (BCS Class II or IV) have greater potential for effects of particle size, dissolution rate, or excipients on PK behavior. Drugs with low permeability are more likely to show variable absorption, whereas absorption of high permeability drugs could show a dependence on solubility since the rate-limiting step in this scenario is dissolution. The BCS classification of a drug has regulatory implications as well, as current guidances define whether the compound requires additional bioequivalence studies or whether biowaivers may be possible for new strengths or modified formulations (FDA, 2005; Ahr etal., 2000).

The BCS system can also be used by a formulator to provide guidance on the formulation strategy for a new compound. Class I drugs are less likely to require novel drug delivery approaches and have greater potential for equivalence among formulations, whereas Class IV drugs often pose significant challenges to overcome limitations in both solubility and permeability. For the latter, exploration of formulations that include solubilizing agents to enhance microenvironmental solubility or utilization of high energy solid-state forms to affect kinetic solubility could be warranted. Key to all of this is the dose. Impact of Physical/Chemical Properties on Absorption and Transport

The oral absorption process is complex, but for many molecules it can be simplified into a general process that, for a passive diffusion mechanism, requires dissolution followed by partitioning into and transport across the intestinal epithelium. This particular aspect of ADME is most amenable to manipulation by the pharmaceutical scientist to influence PK profile and alter in vivo performance for an orally administered drug. Once absorbed, the drug's distribution, metabolism, and elimination are dependent on the chemical structure and physiology.

GI Transit and Ionization

Throughout the GI tract, an ionizable drug can undergo multiple transitions depending on its functional groups and pKa values. The state of ionization of an ionizable compound strongly influences passage across membranes as well as solubility. For a compound to be transported efficiently across a biological membrane by a passive transcellular route, the drug must be in solution and non-ionized. These two factors normally work in opposition to each other since non-ionized molecules tend to have greater lipophilicity, which favors membrane partitioning, yet lower solubility relative to ionized species. A weak monopro-tic acid with a pKa in the range of 4-5 would be non-ionized in the stomach and as such would be at the lower range of its solubility. Once it transits to the small intestine, the drug would be predominantly ionized and have greater solubility. For a weakly basic amine, the ionization state would be reversed, with the drug predominantly ionized and most soluble in the stomach milieu, and non-ionized and less soluble in the small intestine. This might seem to suggest inherent differences in exposure for weak acids vs. bases, but this is not necessarily the case since, as noted previously, solubility is only part of the absorption equation.

Permeability is the other key determinant of exposure following oral dosing. For an ionizable compound, the ionized and non-ionized species both exist in solution, with the relative ratio determined by the pH and pKa. As the non-ionized species is absorbed, it is continually "regenerated" as the molecule drives toward a state of equilibrium that is never reached in the dynamic environment of the GI tract.

The dynamic pH environment of the GI tract impacts the utility of salts of ion-izable drugs to improve oral absorption. Although a salt form typically has greater aqueous solubility than the corresponding free form, it may not always be the best choice for clinical development. Depending on the pKa, pH-solubility factors can lead to variability in vivo due to conversion to insoluble salts (e.g., with coadmin-istration of calcium-containing foods), precipitation of insoluble free acids or free bases, or potential drug interactions with concomitantly administered drugs that affect gastric pH (Zhou et al., 2005).

Dissolution and Relationship to BA

Systemic exposure to a drug after oral administration is the culmination of a multistep process that starts with disintegration and dissolution of the dosage form in the stomach contents. Dissolution of a drug in vivo is required for intestinal absorption and is impacted by multiple factors, including the solubility of the drug, release rate from the dosage form, and subsequent phase conversions, precipitation, in situ salt formation, micellar solubilization in the small intestine by bile salts, and pH gradients.

An integral part of the formulation development cycle is development of analytical test methods to assure quality and integrity of the product intended for human use. Dissolution or drug release in vitro in aqueous media under controlled pH conditions, often with added surfactants to solubilize poorly soluble drugs, is a commonly used technique to evaluate oral drug product performance. This in vitro dissolution test is relevant as a tool to evaluate the relative performance of different prototype formulations during the formulation development and selection process, and once a product is in clinical testing to assure consistency of the manufacturing process. The development of an appropriate dissolution method should be an iterative process that is done in parallel with the formulation development since choice of dissolution apparatus, media, and other parameters will be dependent on the solubility of the API, the nature of the excipients and dosage form, and the BCS class of the drug. For a method to be useful during formulation development, it should be discriminating, i.e., be able to distinguish differences among formulation and/or process parameters that could impact the choice or in vivo performance of the formulation. On the other hand, care should be taken to avoid developing an overly discriminating method that detects differences that are artifactual and/or have no relevance to the use of the product by the patient.

An in vitro dissolution test may also be used to assess in vivo biopharmaceu-tical performance if it is physiologically relevant, i.e., is shown to be predictive of in vivo behavior. Determining the physiological relevance, however, is difficult with many drugs because of the interplay of multiple factors in a human body that affect drug absorption. The relationship of solubility to absorption in the gut is complex because of the varying composition of the GI fluid and the dynamic environment governing dissolution and absorption. The solubility determined experimentally in a compositionally defined system such as a simple buffer or solvent is a thermodynamic value that reflects the amount of drug in solution at equilibrium (which may take minutes, hours, or days to achieve). In contrast, the GI tract often contains water, fats, pH-modifiers, salts, surfactants, emulsifiers, enzymes, and food components that together determine the effective GI solubility, which may be significantly different from the solubility in an aqueous buffer. This composition also changes with time as the material moves through regions of varying pH (e.g., stomach to small intestine), in a fed or fasted state, and with secretion of pancreatic enzymes and bile salts. Consideration of these additional variables has led to the development of alternative methods to assess solubility and dissolution in biorelevant media such as simulated GI fluids (Nicolaides et al., 1999; Dressman et al., 1998) and to compartmentalized dissolution simulation systems (Parrott and Lave, 2002; Gu et al., 2005).

The only definitive way to establish physiological relevance of in vitro dissolution data is to perform a human PK study to correlate dissolution rate using a given method with the resultant PK profile. Ideally, a clear in vitro-in vivo correlation (IVIVC) can be made, but in many cases this may be elusive. The BCS class of the drug can be used to predict which compounds could potentially achieve a meaningful IVIVC. Class I and III drugs, because of their high solubility and expected rapid dissolution, would not be expected to show meaningful IVIVCs;

Class IV compounds typically exhibit variable predictability in IVIVCs due to the fact that dissolution and/or permeability could be rate-limiting factors for absorption depending on the particular compound. Class II drugs, however, are most likely to exhibit these relationships since absorption tends to be rapid, leaving dissolution as the rate-controlling step in the process (Amidon etal., 1995; Lennernas and Abrahamsson, 2005; Blume and Schug, 1999). These concepts are elaborated in later chapters.

Maximum Absorbable Dose Concept

A question often raised by scientists designing new drug candidates is "how much is enough?" with respect to solubility and permeability of a compound. In the current climate of drug discovery, key criteria for identification of clinical candidates include potent and selective binding to the target of interest, adequate safety, lack of CYP interactions, and appropriate pharmacokinetic profile to achieve the desired clinical effect. The concept of maximum absorbable dose (MAD), utilizes absorption rate constant, small intestine residence time, intestinal volume, and solubility (Johnson and Swindell, 1996). This concept mathematically illustrates once again the basic tenet of the BCS that passive GI absorption results from the interplay of permeability and solubility. The maximum amount of drug that could be expected to be absorbed based on these two parameters provides guidance as to whether the solubility and permeability are adequate. For example, for a drug with a solubility of 10 |g/mL, the estimated MAD, assuming no limitations due to site-specific absorption, could range from 0.9 mg (low permeability drug) to 90 mg (high permeability drug). Therefore, potent low dose drugs or highly permeable drugs can tolerate what may appear at first glance to be unacceptable solubility.

Impact of Active Transport Mechanisms

Active transport mechanisms are less predictable than passive transport due to the requirement for binding to a cellular membrane ligand. The involvement of active transport systems can lead to erroneous conclusions concerning the permeability of a drug if a passive diffusion mechanism has been assumed. Drug interactions are also possible among drugs that are actively transported, possibly leading to significant changes in pharmacokinetic behavior upon coadministration. Great advancements in the area of active transport mechanisms have been made over the past several years. In vitro assays are now frequently used during the early stages of drug development to screen for desirable and undesirable interactions with active transporters, yet more work is required to understand the nature of transporters fundamentally and their ultimate utility in predicting and manipulating PK behavior (Kunta and Sinko, 2004). Strategies to Achieve Target Pharmacokinetic Profile

Although many biopharmaceutical properties are determined by the chemical structure of the compound, there are multiple strategies available for exploiting the properties of any given molecule to try to achieve the desired clinical behavior. The choice of paths to explore is dependent on the nature and extent of the delivery issue to be solved. For example, if poor BA is caused by high first-pass metabolism, delivery via a non-oral route may yield sufficient blood levels for activity. Likewise, non-linear PK caused by interactions with active transport systems would not be resolved by improving the dissolution rate of the dosage form.

Route of Delivery

The target PK profile and resultant therapeutic effect (including onset and duration of activity) of any drug are influenced by the route of administration. Oral dosing is normally preferred for a chronically administered medication due to ease of dosing and general patient acceptability. However, compounds limited by solubility, permeability, or first-pass metabolism may not be amenable to the oral route. Delivery alternatives include other transmucosal routes or parenteral administration. Each has its own advantages and limitations. Intravenous administration leads to immediate blood levels and is often used to treat serious acute symptoms such as seizures or strokes. Rapid absorption can also be achieved by non-oral trans-mucosal routes, including nasal, sublingual, buccal, or inhalation (Chen et al., 2005; Shyu et al., 1993; Song et al., 2004; Berridge et al., 2000). Local treatment via ocular, inhalation, nasal, or vaginal routes may be advantageous compared to systemic delivery due to increased potency at the target and decreased systemic toxicity (Rohatagi et al., 1999). In addition, other properties of the molecule may dictate the routes that are possible. For example, protein/peptide drugs are highly susceptible to degradation upon oral administration and are not likely to diffuse across the intestinal barrier unless by a specific active transporter. As a result, these compounds are often dosed parenterally, and more extensive research is being conducted with oral and alternate non-oral routes, including inhalation (Adessi and Soto, 2002). Metabolism can also influence the choice of route of administration. Drugs that undergo high first-pass metabolism may be much more bioavailable by non-oral routes such as rectal, buccal, or nasal (Hao and Heng, 2003; Song, 2004), leading to pharmacologically relevant blood levels that cannot be achieved with oral dosing.

Chemical Modification

An alternative to formulation approaches to modify PK is chemical modification. A prodrug, for example, is a compound that has been designed with a metabol-ically labile functional group that imparts desired biopharmaceutical characteristics. Prodrugs by themselves are not pharmacologically active but revert in vivo to the active moiety through either targeted chemical or enzymatic mechanisms in the general circulation or specific tissue. This type of strategy has been used in many different ways, including modification of physical-chemical properties to improve delivery (Varia and Stella, 1984; Pochopin et al., 1994; Prokai-Tatrai and Prokai, 2003), targeting to a specific enzyme or transporter (Yang et al., 2001; Han and Amidon, 2000; Majumdar et al., 2004), antibody-directed targeting (Jung, 2001), or gene-directed targeting (Chen and Waxman, 2002; Lee et al., 2002). Although the approaches and applications are varied, they all are rationally chosen to modify a particular biopharmaceutical property while relying on in vivo generation of the parent molecule to elicit the intended pharmacologic response.

Although prodrugs have been successful in achieving intended drug delivery objectives, they have certain limitations. They may inadvertently lead to unintended consequences if not designed with a full understanding of the fundamental mechanisms of the drug's biopharmaceutical and pharmacologic behavior. For example, a strategy for increasing the oral BA of a poorly soluble drug might be to add an enzymatically labile hydrophilic functional group such as an amino acid or phosphate to modify solubility and/or dissolution rate in the intestinal lumen. This is logical for a compound with good absorption but for which BA is limited by a solubility/dissolution mechanism. However, an unintended consequence may arise if the slow absorption process is rate-limiting for systemic clearance (i.e., flip-flop kinetics) (Rowland and Tozer, 1989). In this case, the terminal elimination rate constant is actually controlled by the absorption rate, and alteration in absorption rate through prodrug modification could unmask a previously unrecognized rapid systemic clearance. This case also highlights the risks in the interpretation of data from extravascular administration and the importance of intravenous data to determine fundamental PK properties such as clearance and volume of distribution. Other unintended consequences of prodrugs could include pharmacologic activity of the prodrug itself, alterations in metabolic or elimination pathways, or drug-drug interactions. This being said, prodrugs have their place in the toolkit of the pharmaceutical scientist and can be used under the right circumstances to enable the clinical utility of a drug candidate.

Strategies to Improve Oral Absorption

Considering the frequency of use of the oral administration route and the multiple factors, both chemical and physiological, affecting oral absorption, a tremendous amount of research on strategies to improve oral absorption has been and continues to be conducted. One area of active research is modification of effective solubility and dissolution. Many of the assumptions with respect to dissolution and impact on oral absorption are based on a thermodynamic parameter such as equilibrium solubility. In reality, the GI tract is a dynamic system that is also highly influenced by kinetic as well as thermodynamic factors. Passive drug transport requires a compound to be in solution, and in some cases absorption rates and extents can be higher or lower than predicted by equilibrium solubility values. In the dynamic environment of the GI tract, the kinetic solubility, i.e., concentration of drug in solution as a function of time, may be a more relevant indicator of absorption behavior than the equilibrium solubility, considering the time frame of in vivo dissolution and absorption. Importantly, kinetic solubility can be manipulated by the formulator to improve drug product performance.

Commonly used approaches to increase effective solubility include high-energy amorphous solid systems, lipid dispersions, precipitation-resistant solutions, or micellar systems (Verreck et al., 2004; Singhal and Curatolo, 2004; Dannenfelser et al., 2004; Leuner and Dressman, 2000). Amorphous drugs are high energy solid systems that are capable of reaching higher kinetic solubility values (supersaturation) than would be expected from the equilibrium solubility of a crystalline material. This higher initial solubility may be sufficient to assure increased and more rapid absorption for a drug with good permeability. A caution with this approach is the risk that a more thermodynamically stable form may crystallize at any time during processing or storage, and this would have a major impact on the product performance in vivo.

Solutions or dispersions in lipid-based matrices have also been extensively evaluated as means to improve oral BA. Presenting the drug to the GI tract in solution removes the dissolution step, and lipid-based or amphiphilic excipients can be used to enhance solubility and dissolution rate for a hydrophobic drug. As with amorphous high energy systems, a risk with solutions and dispersions is the potential for conversion to a less soluble polymorphic form in the dosage form over time leading to potential quality issues. Addition of nucleation inhibitors such as polymers can minimize the potential for form conversion, but the preferred approach is to formulate in a system that is thermodynamically stable. This requires an exhaustive screening for polymorphs and solvates, but even with an extensive body of knowledge on known crystalline forms, the potential may exist for new forms to appear. The potential for precipitation upon dilution in the GI tract must also be considered for these types of systems, and there are ways to formulate thermo-dynamically stable systems such as microemulsions that are infinitely dilutable in an aqueous environment (Yang et al., 2004; Ritschel, 1996). The physiological factors affecting in vivo stability of dispersions and other lipid-based formulations must also be considered, since enzymes such as lipase may compromise the utility of lipid systems (Porter et al., 2004).

Immediate vs. Modified Release

Immediate release solid oral dosage forms are typically designed to disintegrate rapidly and have the API dissolve rapidly leading to rapid absorption. This type of strategy is most useful in those cases when rapid drug levels are desirable (e.g., pain relief), when therapeutic action is dependent on achievement of high Cmax values, or when safety is not adversely affected by high peak blood levels (i.e., the drug has a high therapeutic index). Drug formulations can be modified in many ways to modulate (up or down) the release rate of drug to achieve the desired PK profile. Within the realm of immediate release products, strategies that could be employed include decreasing disintegration and dissolution rates in order to blunt a high Cmax or use of micronized or nanomilled drug substance to increase surface area and dissolution rate. Prolonged release dosage forms (oral, subcutaneous, or intramuscular) (Anderson and Sorenson, 1994) can be utilized to modify the rate of release and duration of action for compounds with shorter-than-desired half-lives, or to decrease the frequency of dosing to improve patient compliance. Technologies for controlled or modified-release are numerous and must be tailored to the drug and desired PK profile. These include but are not limited to slowly eroding matrices that gradually release the drug during the entire course of GI transit; diffusion-controlled or osmotically driven systems to approximate zero-order release; and enteric-coated dosage forms, which have an outer coating barrier that is stable under acidic conditions but dissolves in the higher pH of the small intestine, effectively protecting an acid-labile drug from the low pH environment of the stomach. The choice of a particular delivery technology is tied to the properties of the material and the rationale for exploring modified-release. As with everything else that has been discussed with respect to biopharmaceutics properties, there is not a single drug delivery platform that will serve as a standard template for modified release dosage forms.

While the options for formulation are numerous, the practical options for any specific drug candidate are dictated by the physical-chemical properties of the drug and the dose. As a rule of thumb, the formulator's toolkit of delivery technologies is inversely related to the dose of the compound. Transdermal, inhalation, and nasal transport are limited to doses in the microgram to low milligram range because of transport capacity, while subcutaneous and intramuscular delivery are limited by injection volume and therefore dose and solubility. While the formulator can work to manipulate the behavior of the API in the drug product to control the delivery, the PK parameters, particularly, clearance, distribution, and metabolism, are intrinsic properties of the compound and cannot be readily manipulated directly, i.e., without some type of chemical modification of the drug candidate or coadministration of compounds that interfere with biological mechanisms (e.g., enzyme inhibitors).

Several chapters will discuss many of these concepts in further detail including dissolution (Chap. 3), BA (Chaps. 8 and 10), and excipients (Chap. 6). Chapter 9 will cover these concepts in the application of BCS to dissolution.

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