Pharmacokinetics of Oral Absorption PDF

178    Chapter 8 8 »» Pharmacokinetics of Describe t...

178    Chapter 8 8 »» Pharmacokinetics of Describe the model parameters that form the foundation of drug the observed clinical data (“top-down” approach) or based on the broader understanding of the human body and its mechanisms Oral Absorption absorption and bioavailability of oral dosage forms. (“bottom-up” approach) (Jamei et al, 2009). A top-down model is often specified with the assistance of “black boxes” (such as the compartment model). In a bottom-up approach the elements of the »» Discuss how ka and k may John Z. Duan system are first specified in great detail. These elements are then influence Cmax, tmax, and AUC linked together to form larger subsystems, which in turn are and how changes in these linked, sometimes in many levels, until a complete top-level sys- parameters may affect drug tem is formed. The goals of the two approaches are the same: to safety in a clinical situation. make physiologically plausible predictions. Chapter Objectives INTRODUCTION This chapter will introduce the basic concept of the physiolog- »» Define oral drug absorption ically based absorption kinetics (the bottom-up approach) with Extravascular delivery routes, particularly oral dosing, are impor- and describe the absorption tant and popular means of drug administration. Unlike intravenous some examples followed by the detailed explanation of the tradi- process. administration, in which the drug is injected directly into the gen- tional top-down approach, and finally, the combination of the two »» Introduce two general eral circulation (see Chapters 4–7), pharmacokinetic models after approaches is proposed. approaches used for studying extravascular drug administration must consider drug absorption absorption kinetics and their from the site of administration, for example, the gut, the lung, etc. similarities and differences. The aim of this chapter is to study the kinetics of absorption. BASIC PRINCIPLES OF PHYSIOLOGICALLY Before delving into the details, it is important to clarify the defini- BASED ABSORPTION KINETICS »» Understand the basic principles tion of absorption. (BOTTOM-UP APPROACH) for physiologically based There are three different definitions of absorption in exis- absorption kinetics. The physiologically based absorption models provide a quantita- tence. Traditionally, absorption occurs when drug reaches the »» Describe the oral one- systemic circulation, or sometimes when it reaches the portal vein tive mechanistic framework by which scaled drug-specific param- compartment model and blood stream. In recent years, a new definition is presented, in which eters can be used to predict the plasma and, importantly, tissue explain how this model drug is assumed to be absorbed when it leaves the lumen and concentration–time profiles of drugs following oral administra- simulates drug absorption from crosses the apical membrane of the enterocytes lining the intestine tion. The main advantage of physiology-based pharmacokinetic the gastrointestinal tract. (GastroPlus manual). It is important to distinguish among these (PBPK) models is that they can be used to extrapolate outside the definitions when the kinetics study is performed, especially during studied population and experimental conditions. For example, »» Calculate the pharmacokinetic comparisons of the study results. PBPK can be used to extrapolate the absorption process in healthy parameters of a drug volunteers to that in a disease population if the relevant physiologi- that follows the oral one- Drug absorption from the gastrointestinal (GI) tract or any other extravascular site is dependent on (1) the physicochemical cal properties of the target population are available. The trade-off for compartment model. this advantage is a complex system of differential equations with a properties of the drug and the environment in the small intestine, »» Calculate the fraction of drug (2) the dosage form used, and (3) the anatomy and physiology of considerable number of model parameters. When these parameters absorbed in a one-compartment the absorption site, such as surface area of the GI tract, stomach- cannot be informed from in vitro or in silico1 experiments, PBPK model using the Wagner–Nelson emptying rate, GI mobility, and blood flow to the absorption site. models are usually optimized with respect to observed clinical data. method. Extravascular drug delivery is further complicated by variables at Parameter estimation in complex models is a challenging task asso- ciated with many methodological issues. »» Calculate the fraction of drug the absorption site, including possible drug degradation and sig- nificant inter- and intrapatient differences in the rate and extent Historically, PBPK approach stemmed from a natural thinking absorbed in a two-compartment of absorption. The variability in drug absorption can be mini- for elucidating the kinetics of absorption. The first pharmacoki- model using the Loo–Riegelman mized to some extent by proper biopharmaceutical design of the netic model described in the scientific literature was in fact a method. dosage form to provide predictable and reliable drug therapy PBPK model (Teorell, 1937). However, this model led to great »» Describe the conditions that difficulty in computations due to lack of computers. Additionally, (Chapters 15–18). Although this chapter will focus primarily on may lead to flip-flop of ka and k oral dosing, the concepts discussed here may be easily extrapo- the in vitro science was not advanced enough to obtain the neces- during pharmacokinetics (PK) lated to other extravascular routes. sary key information. Therefore, the lack of in vitro and in silico data analysis. There are generally two methodologies to study the kinetics of techniques hindered the development of PBPK approach for many absorption. Pharmacokinetic models can be built based mainly on 1In silico refers to computer-based models. 177  Pharmacokinetics of Oral Absorption    179 years. Recently, PBPK development has been accel- two directions, indicating the drug transit among erated mainly due to the explosion of computer sci- these compartments. Each transit process, repre- ence and the increasing availability of in vitro sented by an arrow in Fig. 8-1, can be expressed by systems that act as surrogates for in vivo reactions a differential equation. The model equations follow relevant to absorption. the principles of mass transport, fluid dynamics, and Parameter estimation in PBPK models is chal- biochemistry in order to simulate the fate of a sub- lenging because of the large number of parameters stance in the body. Most of the equations involve involved and the relative small amount of observed linear kinetics. For example, for non-eliminating data usually available. An absorption model consists tissues, the following principles are followed: the 180   of a set of values for the absorption scale factors, “rate of change of drug in the tissue” is equal to the transit times, pH assignments, compartment geome- “rate in” (QT · CA) minus the “rate out” (QT · CvT) as tries (individual compartment radii and lengths, and shown in Equation 8.1. volume), and pharmacokinetic parameters that pro- vide the best predictions for a compound in human. dCT VT = QTCA − QTCvT (8.1) For example, an advanced absorption transit model dt developed in GastroPlus™2 contains nine compart- ments, which represent the five segments of the GI where Q = blood flow (L/h), C = concentration tract—stomach, duodenum, jejunum, ileum, and (mg/L), V = volume (L), T = tissues, A = arterial, v = ch um 1 2 lon en um um 1 2 3 Co colon. The fluid content, carrying dissolved and venous, CvT = CT/(Kp/B:P), B:P = blood-to-plasma Sto ma Du od Jej un Jej un Ileu m Ileu m Ileu m Ce cum As c undissolved compound, passes from one compart- ratio. On the other hand, Michaelis–Menten nonlin- Unreleased Hepatic Hepatic ment to the next, simulating the action of peristaltic ear kinetics is used to describe saturable metabolism Vein Artery Liver motion. Within each compartment, the dynamic and carrier-mediated transport. Undissolved interconversion between dissolved and undissolved The PBPK approach can specifically define the Dissolved compound is modeled. Dissolved compound can be absorption for a specific drug product. Figure 8-2 Portal Vein absorbed across the GI tract epithelium. The volume shows the simulation results using PBPK software GI Tract Enterocyte of each compartment, which represents the fluid GastroPlus for several drugs with different physico- Venous Arterial Portal Vein Flow Flow content, is modeled dynamically, simulating the fol- chemical properties. The first column lists the drug lowing processes: names and the second column is the pKa of the com- FIGURE 8-1 A graphic representation of drug absorption from the GI tract. pound. The solubility factor (Sol Factor) is the ratio Transit of the fluid with characteristic rate con- of the solubility of the completely ionized form of an stants through each compartment ionizable group to the completely unionized form. Gastric secretion into the stomach, and biliary and The figure also lists the solubility and logD pH pro- pancreatic secretions into the duodenum files for each drug (two green vertical lines indicate Absorption of fluid from duodenum, jejunum, ileum, pH 1.2 and 7.5, respectively). Notice that the color of and large intestine the cells for dose number (Dose No), absorption Figure 8-1 shows the graphic representation of number (Abs No), and dissolution number (Dis No) this model. As seen, each of the nine compartments changes depending on the physicochemical and bio- is divided into four subcompartments: unreleased, pharmaceutical properties of the drug selected. The undissolved, dissolved, and enterocyte. colors approximate the four Biopharmaceutical In the figure, the compartments and subcom- Classification System (BCS) categories. All green partments in GI tract are connected to each other by indicates high permeability, high solubility, and arrows. These arrows are of either one direction or rapid dissolution (BCS Class I). Red absorption number and green dose number may indicate low 2GastroPlus permeability and high solubility (BCS Class III). All is a mechanistically based simulation software package that simulates absorption, pharmacokinetics, and pharmacodynamics red may indicate low permeability and low solubility in human and animals (http://www.simulations-plus.com/Products (BCS Class VI). These color systems are not perfect.aspx?GastroPlus&grpID=3&cID=16&pID=11). cutoffs for the BCS, but they represent most drugs.  182     Chapter 8 Based on the in vitro properties and assuming a ABSOROPTION KINETICS set of general physiological conditions, the absorp- tion profiles, the absorption amount in each of the (THE TOP-DOWN APPROACH) nine compartments, and the plasma concentration The top-down approach is a traditional methodology profiles are predicted in the last three columns, to study the kinetics of drug absorption. With the respectively. In the “Absorption & Dissolution” col- advances of statistical methods and computer sci- umn, the profiles for the total dissolved (red), the ence, many software packages are available to calcu- absorbed (cyan, the absorption is defined as the drug late the pharmacokinetic parameters. The following leaves the lumen and crosses the apical membrane of sections provide the basic concepts and rationales. the enterocytes lining the intestine), the cumulative amount entering portal vein (blue), and the cumula- tive amount entering systemic circulation (green) are PHARMACOKINETICS characterized. These profiles along with the informa- OF DRUG ABSORPTION Sol Factor Dose No Abs No Compartmental Dis No Solubility pH Drug LogD pH Profile Absorption & Dissolution Plasma Concentration tion about the amount absorbed in each compartment pka profile absorption give the plasma concentration profiles as shown in In pharmacokinetics, the overall rate of drug absorp- Metoprolol tartrate Metoprolol 1.0 Metoprolol the last column. As seen, due to the physicochemical AmtDiss AmtPV Metoprolol tion may be described as either a first-order or a zero- 150 AmtAbs Total SC 93.0% Concentration (µg/mL) 3 93% 0.5 150 0.25 6.257 × 10 150 Amount (mg) 0.20 Solubility (mg/mL) 0.0064 0.0 100 2.663 property differences, the rate and the extent of 100 9.39 35.9 order input process. Most pharmacokinetic models Mass (mg) logD 100 36.7% 0.15 –0.5 50 20.4% 17.6% 0.10 8.9% 50 –1.0 50 0% 4.7% 2.6% 0.4% 1.7% 0.05 absorption vary among the drugs listed. assume first-order absorption unless an assumption 0.00 Stomach Duodenum Jejunum 1 Jejunum 2 IIeum 1 IIeum 2 IIeum 3 Caecum Asc colon AmtAbs –1.5 0 0 0 5 10 15 20 25 5 10 15 20 0 2 4 6 8 10 0 2 4 6 8 10 Time (h) Time (h) Drug absorption from the gastrointestinal tract pH pH 3 Ketoprofen Ketoprofen of zero-order absorption improves the model signifi- is a highly complex process dependent upon numer- cantly or has been verified experimentally. AmtDiss AmtPV 60 AmtAbs Total SC Ketoprofen 99.9% Concentration (µg/mL) Ketoprofen 2.5 2 50 50 99.9% 0.9792 Amount (mg) Solubility (mg/mL) 2.0 9.075 17.29 40 40 4.39 35.3 ous factors. In addition to the physicochemical 40 Mass (mg) The rate of change in the amount of drug in the logD 30 55.7% 1.5 30 1 20 31.6% 1.0 20 10 6.8% 20 0% 1.6% 0.4% 0.2% 2.7% 0.8% 0.5 10 properties of the drug as shown in Fig. 8-2 (with body, dDB/dt, is dependent on the relative rates of 0.0 Stomach Duodenum Jejunum 1 Jejunum 2 IIeum 1 IIeum 2 IIeum 3 Caecum Asc colon AmtAbs 0 0 0 0 5 10 15 20 25 5 10 15 20 0 2 4 6 8 10 0 2 4 6 8 10 Time (h) Time (h) limited extents), characteristics of the formulation drug absorption and elimination (Fig. 8-3). The net pH pH Carbamazepine Carbamazepine 1.5 Carbamazepine and interplay with the underlying physiological 20 rate of drug accumulation in the body at any time is AmtDiss AmtPV Carbamazepine 99.3% 99.5% AmtAbs Total SC Concentration (µg/mL) 200 1.5 15 200 Solubility (mg/mL) Amount (mg) 1.0 150 6.8376 11.83 5.299 8.546 1.0 logD 150 properties of the GI tract play important roles. In equal to the rate of drug absorption less the rate of Mass (mg) 503 10 100 31.6% 100 21.4% 0.5 50 10.5% 12.7% 0.5 5 7.1% 4% 8.6% 3.6% 50 0% GastroPlus, the formulation types that can be 0.0 drug elimination, regardless of whether absorption Stomach Duodenum Jejunum 1 Jejunum 2 IIeum 1 IIeum 2 IIeum 3 Caecum Asc colon AmtAbs 0 0 0.0 0 5 10 15 20 25 0 2 4 6 8 10 0 2 4 6 8 10 5 10 15 20 Time (h) pH pH Time (h) –0.5 Atenolol Atenolol selected include both immediate release (IR) formu- rate is zero-order or first-order. AmtDiss AmtPV lations (solution, suspension, tablet, and capsule) 150 Atenolol 37.9% Concentration (µg/mL) 3 –1.0 AmtAbs Total SC 0.3 5.761 × 10 100 40 37.9% Atenolol dDB dDGI dDE Solubility (mg/mL) Amount (mg) 0.0025 80 0.367 100 30 0.2 and controlled release (CR) formulations (enteric- logD 9.33 16.2 –1.5 = − Mass (mg) (8.2) 60 20 11.9% 40 10 3.8% 8.5% 6% 0.1 dt dt dt 50 –2.0