Chapter 16 – In Vivo Evaluation of Oral Dosage Form Performance

365Developing Solid Oral Dosage Forms: Pharmaceutical Theory and Practice © 2009, Elsevier Inc. 16.1 INTRODUCTION The oral route of administration is essentially the most common drug administration route, and per- haps one of the most convenient. This convenience often only comes, however, after many years of dili- gent research effort and progressive development programs. New solid oral dosage formulations, for example, must be strategically designed to success- fully withstand the physiological milieu of the gas- trointestinal (GI) tract, and then subsequently allow for adequate absorption of the drug into the systemic circulation. In addition, this complex sequence of events must be precisely orchestrated to occur within a clinically relevant time period so that the intended therapeutic response can be produced. The ultimate goal is to develop an efficacious, cost-effective, and convenient drug product that can be administered safely and reliably to patients. Solid oral dosage formulations must, therefore, be designed to produce predictable and consistent sys- temic drug exposure in the human body. As such, the in vivo performance of any new oral formulation must be thoroughly evaluated during drug development. A systematic set of prospectively planned, and appropri- ately designed, in vivo pharmacokinetic studies should provide the data needed to achieve this task. Information presented in this chapter is intended as a synoptic overview of the in vivo evaluation of solid oral dosage form performance. Readers should expect to gain a general understanding of some commonly used development approaches, as well as a focused perspective on the basic underlying pharmacokinetic principles. 16.2 GENERAL PURPOSE OF IN VIVO PERFORMANCE EVALUATIONS Over the development cycle of a solid oral dosage form, a series of multiple in vivo performance evalu- ations—including clinical and nonclinical pharma- cokinetic assessments—are usually conducted once a prototype formulation with acceptable in vitro characteristics has been identified. Data from in vivo animal studies can provide useful preliminary infor- mation about drug absorption rates and GI absorption sites, for example. Animal data can also offer early insights into potential mechanisms of drug distribu- tion, metabolism, and elimination. Data from in vivo human studies, on the other hand, can provide clini- cally useful information about oral bioavailability, bioequivalence, and the effects of food or other factors (e.g., gastric pH) on the pharmacokinetic behavior of the final oral dosage form in human subjects. Human pharmacokinetic data can also provide relevant knowledge about the relationship between drug expo- sure and clinical response (e.g., safety and efficacy). Successful development of a new solid oral dos- age form ultimately depends on the absorption char- acteristics, and overall capacity of the drug product to modulate the magnitude and duration of an C H A P T E R 16 16 In Vivo Evaluation of Oral Dosage Form Performance Honghui Zhou and Kathleen Seitz II. BIOPHARMACEUTICAL AND PHARMACOKINETIC EVALUATIONS OF DRUG MOLECULES AND DOSAGE FORMS 16. IN VIVO EVALUATION OF ORAL DOSAGE FORM PERFORMANCE366 anticipated pharmacological response. For most drugs with extravascular (e.g., oral, subcutaneous) routes of administration, absorption is usually a complex, multi-step process comprising many interrelated phys- ico-chemical and physiological factors. After a solid dosage formulation is orally administered, for exam- ple, two basic processes must occur before the active drug substance can be absorbed into the systemic cir- culation: disintegration and dissolution. Disintegration generally involves the breakdown of the drug product into smaller particles. Dissolution denotes the process by which these smaller particles subsequently dissolve in a solvent. Factors that could potentially affect disin- tegration and dissolution of a solid oral dosage form include the physico-chemical properties (e.g., stability, solubility, and particle size) of the drug substance, the inherent characteristics of any added excipients (e.g., stabilizing or binding agents), and other condition- related factors (e.g., pH of the dissolution medium). Key initial research objectives of in vivo perform- ance evaluations of a new solid oral dosage form therefore typically include the following: 1. determine the product’s ability to release the active drug substance from the dosage form; 2. identify residence times of both the dosage form and the released drug at the absorption site; 3. locate the GI regional site of drug absorption; 4. describe the capacity of the GI mucosal tract to absorb the drug; and 5. evaluate other physiological factors (e.g., gastric emptying rates and intestinal motility patterns) that may potentially affect the overall drug absorption process. 16.3 ANIMAL PHARMACOKINETIC EVALUATIONS As the development phase of an investigational drug product progresses, in vivo animal studies are typically conducted before any human studies are initially performed. Animal models can effectively be used to screen prototypes of a solid oral dosage formulation, for example, and to obtain early phar- macokinetic knowledge of a pilot product’s in vivo absorption characteristics. Fundamental animal data can also be used to identify the main absorption site within the GI tract, and document preliminary absorp- tion mechanisms for the novel drug formulation. Consequently, animal data from in vivo pharmacoki- netic evaluations are often used to support selection of an optimal formulation, and guide the overall design of the final product’s dosage form. Researchers generally need to consider two main issues when planning in vivo pharmacokinetic studies in animals. First, the appropriate animal species that will yield optimal results must be selected. Secondly, a reliable method of extrapolating the animal data must be identified that can adequately predict the drug’s pharmacokinetic behavior in humans. 16.3.1 Animal Species Selection Preclinical evaluation of a new drug’s pharmacoki- netics should be conducted in an animal species with anatomical and physiological characteristics that are relevant to the research objectives. Because of the inher- ent differences in the GI tract between many animal species and humans, for example, selecting an optimal animal model for an oral drug absorption study can be challenging. Preclinical studies of a new solid oral dosage form such as a tablet or capsule, for instance, would require an animal species that can accommo- date the drug without any untoward physiological responses, such as mucosal trauma from ingesting the human-scale dosage form. Other important factors to consider when selecting one species over another include the anatomical arrangement of the animal’s blood and lymph supply to the gut, as well as any characteristic secretory levels of gastric and pancreatic juices and normative interdigestive motility patterns. Animal models that are routinely used to study the in vivo performance of human-scale oral dosage forms include primates, dogs, pigs, and rabbits. Smaller ani- mals such as rats, mice, and other small rodents, on the other hand, are seldom used for these types of studies, because of the obvious physical limitations of their diminutive GI tracts. Nonhuman primates are relatively large animals, however, and may initially appear most suitable for standard in vivo pharmacoki- netic studies of solid oral dosage forms. Primates such as macaque monkeys, for example, have adequate gut dimensions, and their GI morphology is also gen- erally similar to that of humans. Nevertheless, sev- eral practical issues relating to higher resource costs, and restricted supply availability, often preclude the widespread use of nonhuman primates in oral drug absorption studies. Rabbits are more readily available, and less costly than other animal models such as monkeys, pigs or dogs. Nevertheless, several important physiologi- cal and anatomical differences between rabbits and humans limit their use as an appropriate model in an oral drug absorption study. Several researchers have had some success in modifying the gastric-emptying characteristics of rabbits to be more aligned with that of humans. 1 In general, though, bioavailability of even II. BIOPHARMACEUTICAL AND PHARMACOKINETIC EVALUATIONS OF DRUG MOLECULES AND DOSAGE FORMS 367 immediate-release (IR) oral formulations cannot be sufficiently correlated between rabbits and humans. Pigs have also occasionally been used for oral bioa- vailability studies, but with limited overall success. 2,3,4 Dogs, however, have been used more extensively than any of these other animal models for in vivo eval- uations of oral drug absorption. Dogs essentially have suitable anatomy and physiology of the stomach. Typical gastric dimensions for mongrel dogs weighing 15–25 kg are particularly similar to those of humans, for example. In addition, dogs have GI motility cycles, gastric emptying patterns, physiological responses to feeding, and bile secretion profiles, that are also gener- ally similar to those of humans. 5 Nonetheless, several important anatomical and physiological GI differences between dogs and humans must also be considered whenever pharmacokinetic studies of oral dosage forms are either being designed or reported. The typical canine gastric emptying rate in a fed state is slower than that of humans, for example, and canine gastric pH is essentially higher than that of humans. Intestinal dimensions and GI tran- sit times also vary from dogs to humans. For exam- ple, the length of a dog’s small intestine is only about half the length of a human’s, and a dog’s colon is also generally shorter than a human colon. These anatomical differences may explain the over- all faster transit time noted in dogs versus humans. In a fasted state, for example, transit time for dogs is approximately half the time for humans, and this generally holds true for different oral dosage forms including granules, pellets, and tablets. To account for this relatively accelerated transit time, in vivo dog models have occasionally been pretreated with drugs that can delay GI motility, and subsequently prolong intestinal residence time of the investi- gational oral dosage form. 6,7 In general, however, incomplete systemic availability is usually observed in dogs, particularly in studies of controlled-release (CR ) dosage forms (e.g., where drug release times may exceed the GI transit time in dogs), and other dosage forms that are not otherwise well-absorbed in the colon. Even though the dog has some characteristics that are similar to those of the human and may allow for reasonable extrapolation, other physiologic features unique to the dog can affect pharmacokinetics, mak- ing extrapolations between canines and humans unreliable. Some key differences are shown as following:8 ● basal acid secretion in dogs (0.1 – 0.4 mEq/hour) is lower than that of humans (2 – 5 Eq/hour); 8 ● larger inter-individual variability in gastric pH in dogs than in humans; ● fasted dogs have a slightly higher (1 – 2 pH units) small intestinal pH than humans; 9 ● transit time in fasted dogs is approximately 2-fold shorter than in humans (111 versus 238 minutes); 9 ● dogs secrete bile salts at a higher rate (49 – 90 mmol/L) in comparison with humans (3 – 45 mmol/L);10 ● some cytochromes P450 (CYP450) isozymes are unique to the dogs have been identified (e.g., 2B11, 2C21, 2D15, 3A12, 3A26). Thus, the pharmacokinetic/absorption results obtained from the dogs should be interpreted with caution. Chiou et al. found that the absorption data in dogs, based on 43 compounds including bases, acids, zwit- terions, and neutral compounds, did not predict the human absorption very well (r2 � 0.51). 11 Moreover, it is also worth noting that the small number of animals along with the substantially large inherent inter-animal variability in physiologic characteristics may further complicate the human absorption projection. Regardless of which species is used, animal data obtained from these types of early stage in vivo stud- ies can clearly offer considerable insight, and early knowledge of a new oral dosage form’s general phar- macokinetics. In addition, when these animal data are carefully used with an appropriate interspecies scal- ing method, the pharmacokinetic behavior in humans may also be better predicted. 16.3.2 Animal Data Extrapolation Interspecies data extrapolation (i.e., scaling) is a routine practice in the biopharmaceutical industry, and often represents a necessary activity in the ethi- cal development of novel therapeutic drugs and bio- logics. While in vivo animal studies of a new dosage form are typically required by international regulatory authorities, institutional review boards, and ethics committees before research studies may be performed with human subjects, the obvious challenge involves the appropriate interpretation of the animal data, and an accurate prediction of the human pharmacokinetic response. Interspecies scaling is essentially based on the assumption that several anatomical, physiological, and biochemical similarities exist among animals of differ- ent species. 12,13 Pharmacokineticists and other research- ers in the industry may use one of two basic scaling approaches: mechanistic (i.e., physiology-based) or mathematical (i.e., allometry-based) methods. The phys- iology-based methods that involve determinations of organ weights, tissue perfusion, and metabolic reaction rates, for example, are inherently more complicated, 16.3 ANIMAL PHARMACOKINETIC EVALUATIONS II. BIOPHARMACEUTICAL AND PHARMACOKINETIC EVALUATIONS OF DRUG MOLECULES AND DOSAGE FORMS 16. IN VIVO EVALUATION OF ORAL DOSAGE FORM PERFORMANCE368 costly, and thus generally not as popular. In contrast, the simpler allometric methods that basically incor- porate applied mathematical equations are seen more routinely in drug development programs, and may be particularly helpful in the selection of first-in-human dosage forms. 14,15 The simple allometric method is based on a power function: Y W� a b where: Y is the pharmacokinetic parameter of interest (e.g., clearance) W is body weight a and b represent the equation coefficient and expo- nent, respectively. Using the log transformation: log log log Y a b W� � the parameter values are simply plotted against the body weight data on a log-log scale with a y-intercept equal to log a and a slope equal to b . Practical limitations of using this simple method to predict human pharmacokinetic parameters have been documented, however, and revised methods have been proposed. 16 For example, one revised method includes brain weight in the equation, whereas another revision uses the animal’s maximum life-span potential. 15 The simple allometric method is based on a fundamental assumption that a pharmacokinetic parameter of interest is related to the body weight, no matter what the species of the animal is. Apparently this method ignores the interspecies differences in enzymatic metabolism, renal elimination capacity, absorption characteristics, gastric pH and emptying rate, and intestinal residence time, etc. Regardless of which allometric method is ulti- mately selected, researchers must exercise a standard caution whenever animal pharmacokinetic data is extrapolated and used to predict estimates of human pharmacokinetic parameters. That is, predictive val- ues for allometric interspecies scaling methods vary considerably, and are significantly influenced by a number of experimental factors including the selected study design, animal model, and drug product. 15 Nonetheless, several helpful journal publications and relevant literature reviews are available that presently offer practical advice to industry researchers who wish to apply interspecies scaling methods in pharmacoki- netic studies of therapeutic drugs and biologics. 14–18 16.4 HUMAN PHARMACOKINETIC EVALUATIONS Successful clinical development of a safe and effec- tive solid oral drug product is often preceded by mul- tiple in vivo evaluations and iterative refinements in the investigational dosage formulation. An optimal dosage regimen must ultimately be identified that can maintain therapeutic drug concentrations and avoid toxicities. Human pharmacokinetic studies are, therefore, routinely performed to determine the bio- availability of a solid oral dosage form. Clinical phar- macokinetic studies are also conducted in humans to determine the potential effects of food, and other fac- tors, on the pharmacokinetics of the drug. A sound understanding of the drug’s absorption, distribution, metabolism, and elimination is essential to the devel- opment and approval of any solid oral drug product. 16.4.1 Bioavailability and Bioequivalence Bioavailability and bioequivalence studies are often critical components of any new drug applica- tion. Bioavailability essentially describes the overall rate and extent of drug absorption for a given dos- age formulation. Data from bioavailability studies are routinely used during drug development to iden- tify the product’s pharmacokinetics, optimize thera- peutic dose regimens, and support product labeling requirements. Bioequivalence, on the other hand, generally describes the extent to which the bioavailability of a particular drug product (i.e., the test product) com- pares with that of another known drug product (i.e., the reference product). Data from bioequivalence stud- ies are often used to establish a link between different test formulations (e.g., an early phase 1 formulation versus a later phase 3 or to-be-marketed formulation). Post-approval bioequivalence studies may also be required, for example, when a major change occurs in a manufacturing method. Bioequivalence studies are also generally used to compare a generic version of a drug product with the corresponding reference-listed drug. In general, oral bioavailability can simply be con- sidered as the proportion of an orally administered dose that ultimately becomes available to the sys- temic circulation. When a drug is administered orally (or by any other extravascular route), for example, a sufficient amount of the administered dose must be absorbed during a certain time period before the intended pharmacologic effect can manifest. Thus, the bioavailability of an orally administered drug clearly depends on a combination of factors, including the II. BIOPHARMACEUTICAL AND PHARMACOKINETIC EVALUATIONS OF DRUG MOLECULES AND DOSAGE FORMS 369 physico-chemical characteristics of the drug formu- lation, and the physiological state of the GI system. Pharmacokineticists must therefore consider each of these factors when designing and conducting oral bio- availability and bioequivalence studies. Two different types of oral bioavailability will be discussed in this chapter: absolute and relative bio- availability. Absolute oral bioavailability is a special case in which the systemic exposure of an oral dosage form is determined relative to that of its intravenous (IV) dose form. In contrast, relative oral bioavailability compares the rate and extent of absorption of one dos- age formulation (e.g., oral solution) to another dosage formulatio