Absorption

Currently, the model accommodates four routes of administration - oral, intramuscular (IM), intravenous (IV) and subcutaneous (SC) only. Additional options follow the selected route of administration.

There are currently two absorption models available - 'Simple absorption model' and an 'Advanced absorption model'.

Stomach is the first compartment of the gastrointestinal tract (GIT) in the PBPK model. The model simulates a fasted environment and the average resident time in the stomach was 0.5 h.

The small intestine has been divided into seven different compartments.¹ Drug transition through the small intestine occurs depending on the various transit rates of stomach, duodenum, jejunum and ileum. Absorption occurs simultaneously across the seven compartments of the small intestine. The administered oral drug is assumed to be in solution instantly for absorption. There is no reabsorption occurring from the colon.

Intestinal metabolism and first pass metabolism have been included in the model before the drug reaches the systemic circulation. For this minimal absorption model, the fraction escaping the gut metabolism (Fg) and first pass (Fh) have been computed for a well-stirred model using the following equations:^2,3

where,

Q_g is the blood flow rate through the intestine

f_ub is the fraction unbound in blood

CL_int,gut and CL_hep are the intrinsic gut clearance and hepatic clearance respectively

Q_hv is the total blood flow through the liver

Read more about clearance parameters used in the PBPK models here

There are two absorption states available - fasted and fed state. The fasted state simulates the gastrointestinal tract in a fasted condition whereas the fed state simulates the GIT in a fed condition.

The fed state accounts for the presence of food in the stomach and small intestine which can affect the drug dissolution and absorption. The presence of food can alter the pH of the stomach and small intestine, delay gastric emptying time, stimulate bile flow and change the blood flow to the GIT. These changes can impact the solubility, dissolution rate and permeability of the drug leading to altered absorption characteristics.

Different absorption rate methods are available to compute the absorption rate constant (Ka) of the drug. They are - P_eff based methods, polar surface area based methods, rat and human effective permeability methods and user defined K_a method.

Based on the selected computational method, the user is provided with the necessary input fields to compute the absorption rate constant (K_a) of the drug.

The most common in vitro experiments to assess the drug's apparent permeability (P _app) through the small intestine across the apical-basolateral layer is using cell monolayers such as Caco-2 or MDCK cells. The values are generally reported as cm.s^-1. If this data is not readily available, polar surface area (PSA) and hydrogen bond donors (HBD) can be used.

Polar surface area (PSA) is the sum of the surface area of all the polar atoms consisting mainly oxygen and nitrogen including any attached hydrogen atoms in a drug. The value entered should be in sq. angstroms (Ų).

The effective permeability (P_eff, in cm.s^-1) of the drug is the in vivo permeability in humans. This P_eff is computed using IVIVE obtained from various literature sources as follows:

The rate of absorption (K_a, in h^-1) in humans is computed using P_eff as follows:⁶

The user is required to select the type of absorption input that is being provided. The corresponding absorption value should be entered for the selected absorption type (in the appropriate units i.e. either in ×10⁻⁶ cm.s⁻¹ or Ų or h⁻¹). If there is no apparent permeability available for the drug, an option to enter the Kₐ value is also provided. This scalar would multiply the absorption rate (Kₐ) by the provided input.

There is also an option to adjust the absorption value using the optional box under the 'Other inputs' tab to input any scalar ('Absorption scalar').

Please note: This absorption value would remain constant for the entire simulation. Currently, the model does not have any transporter data or induction/inhibition included.

Note: If the apparent permeability value is 15 × 10^-6 cm.s^-1, please enter 15 for Caco-2 and 150 for MDCK cells. The model would then multiply this value by ×10^-6 and ×10^-7 respectively.

The dose for intravenous administration and infusion are given in the veinal compartment.

Intramuscular and subcutaneous administration have a depot compartment for the administered dose and drug release occurs into the surrounding area around the depot. This area is considered as a percent of the muscle or adipose tissue and is represented as intramuscular or subcutaneous compartment in the PBPK model as a physiological representation of the drug released from the depot into the surrounding blood capillaries.⁸

Infusion requires one more input - infusion time. If the time of infusion is zero, then this administration is treated as IV bolus.

Selection of an intravenous (IV) route does not require further absorption inputs as the model considers the provided dose as IV bolus.

Upon selection of intramuscular (IM) administration, a few input boxes are provided - Release mechanism, injection volume, release rate and units

Various release mechanisms are available to simulate the drug release from the depot compartment into the surrounding muscle compartment. They are - first-order and zero-order release, currently limited to 2 fractions.

Please note: You can request for additional fractions to be included by reaching out to us at here. We shall try to accommodate your request in future updates.

Various release mechanisms are available to simulate the drug release from the depot compartment into the surrounding muscle compartment. They are - first-order and zero-order release, currently limited to 2 fractions.

The model follows a similar pattern as the intramuscular administration with from the subcutaneous depot compartment releasing the drug into the surrounding adipose tissue.

1. Yu LX, Crison JR, Amidon GL. Compartmental transit and dispersion model analysis of small intestinal transit flow in humans. International Journal of Pharmaceutics. 1996;140(1):111-8. https://doi.org/10.1016/0378-5173(96)04592-9
2. Mistry M, Houston JB. Glucuronidation in vitro and in vivo. Comparison of intestinal and hepatic conjugation of morphine, naloxone, and buprenorphine. Drug Metabolism and Disposition. 1987;15(5):710-7. https://dmd.aspetjournals.org/content/dmd/15/5/710.full.pdf
3. Ito K, Houston JB. Comparison of the Use of Liver Models for Predicting Drug Clearance Using in Vitro Kinetic Data from Hepatic Microsomes and Isolated Hepatocytes. Pharmaceutical Research. 2004;21(5):785-92. https://doi.org/10.1023/B:PHAM.0000026429.12114.7d
4. Sun D, Lennernas H, Welage L, Barnett J, Landowski C, Foster D, et al. Comparison of Human Duodenum and Caco-2 Gene Expression Profiles for 12,000 Gene Sequences Tags and Correlation with Permeability of 26 Drugs. Pharmaceutical Research. 2002;19(10):1400-16. https://doi.org/10.1023/A:1020483911355
5. Gertz M, Harrison A, Houston JB, Galetin A. Prediction of Human Intestinal First-Pass Metabolism of 25 CYP3A Substrates from In Vitro Clearance and Permeability Data. Drug Metab Dispos 2010 July 1, 2010;38(7):1147-58. https://doi.org/10.1124/dmd.110.032649
6. Yu LX, Amidon GL. A compartmental absorption and transit model for estimating oral drug absorption. Int J Pharm. 1999;186(2):119-25. https://doi.org/10.1016/S0378-5173(99)00147-7
7. Rajoli RK, Back DJ, Rannard S, Freel Meyers CL, Flexner C, Owen A, et al. Physiologically Based Pharmacokinetic Modelling to Inform Development of Intramuscular Long-Acting Nanoformulations for HIV. Clin Pharmacokinet. 2015 Jun;54(6):639-50. https://doi.org/10.1007/s40262-014-0227-1
8. Winiwarter S, Bonham NM, Ax F, Hallberg A, Lennernäs H, Karlén A. Correlation of Human Jejunal Permeability (in Vivo) of Drugs with Experimentally and Theoretically Derived Parameters. A Multivariate Data Analysis Approach. Journal of Medicinal Chemistry. 1998;41(25):4939-49. https://doi.org/10.1021/jm9810102