Biopharmaceutics and Pharmacokinetic Processes (LADME)

Biopharmaceutics | Chapter 1 | 4th Year Pharm-D

Topic: Biopharmaceutics and Pharmacokinetic Processes (LADME)
Author: Baasir Umair, MPhil (Pharmacology)

📘 Overview

This comprehensive presentation introduces the foundational principles of Biopharmaceutics and Pharmacokinetics, focusing on the LADME system—Liberation, Absorption, Distribution, Metabolism, and Excretion. It integrates classical and modern concepts from leading texts including Shargel & Yu, Aulton’s Pharmaceutics, Martin’s Physical Pharmacy, and Rowland & Tozer.

Through detailed explanations and mechanistic insights, it bridges the gap between formulation science and clinical pharmacokinetics, showing how physicochemical properties, dosage form design, and physiological variables collectively determine a drug’s therapeutic fate.

🧩 Key Sections

1. Introduction to Biopharmaceutics & Pharmacokinetics
Explains the interrelation between formulation design, drug absorption, and clinical pharmacokinetic behavior using the LADME framework.

2. Liberation in Oral Dosage Forms
Elaborates on the disintegration and dissolution mechanisms in immediate-release, sustained-release, effervescent, and ODT formulations. Discusses excipient roles, modern dissolution media (FaSSIF, FeSSIF), and IVIVC correlations.

3. Absorption Mechanisms
Covers physicochemical and physiological factors influencing absorption—passive diffusion, active transport, paracellular pathways, and endocytosis—with clinical relevance.

4. Distribution & Disposition
Details the dynamics of plasma–tissue exchange, protein binding, and the impact of liposomal and nanoparticulate delivery on tissue targeting and bioavailability.

5. Metabolism
Comprehensive breakdown of microsomal (CYP450) and nonmicrosomal enzymes, phase I–II biotransformations, and non-enzymatic (Hoffman) elimination, highlighting prodrug strategies and nanoparticle-mediated metabolic modulation.

6. Clinical Pharmacokinetics (CPK)
Illustrates PK parameters (Cmax, Tmax, AUC, t½) and explains study design, biological sampling, and data interpretation using compartmental and noncompartmental analysis.

7. Population Pharmacokinetics (PopPK)
Discusses variability modeling through in vivo, in vitro, and in silico methods (NONMEM, Monolix, PBPK, AI-based digital twin simulations), emphasizing personalized dosing and regulatory significance.

8. Toxicokinetics (TK)
Defines safety thresholds (NOAEL, LOAEL, BMDL) and integrates TK with omics-based toxicological profiling.

9. Disposition & Excretion
Analyzes renal, biliary, and pulmonary elimination mechanisms and how sustained or nano-formulations modulate pharmacokinetic behavior.

⚗️ Learning Outcomes

After studying this presentation, viewers will be able to:

Comprehend the integrated nature of LADME processes.

Relate dosage form design to absorption and bioavailability.

Understand how physiological, biochemical, and formulation factors govern systemic drug exposure.

Interpret PK parameters and population v

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Chapter 1
Topic: Biopharmaceutics and Pharmacokinetic Processes (LADME)
2.1 Introduction
Biopharmaceutics and pharmacokinetics (PK) together describe how the body influences a drug's
fate after administration. The LADME system (liberation, Absorption, Distribution, Metabolism,
and Excretion) forms the core of drug disposition, describing each stage through which an active
pharmaceutical ingredient (API) passes from dosage form to its site of action and eventual
elimination [1].
From a biopharmaceutical perspective, understanding the physicochemical, physiological, and
formulation-related factors that affect these processes allows rational design of dosage forms and
optimization of therapeutic outcomes. Pharmacokinetics quantifies this journey through
mathematical modeling, while biopharmaceutics provides the formulation and mechanistic
foundation explaining why the kinetic profiles occur. The union of these two disciplines allows
prediction of drug behavior under real-world clinical conditions [2,3].
2.2 LADME Map and Conceptual Framework
A schematic representation shows:
 Liberation: Drug release from the dosage form into biological fluids.
 Absorption: Entry of dissolved drug into systemic circulation across biological
membranes.
 Distribution: Transfer between plasma and tissues, mediated by perfusion and protein
binding.
 Metabolism: Enzymatic and nonenzymatic conversion to metabolites.
 Excretion: Elimination via renal, biliary, or pulmonary routes.
Each component is interlinked; for instance, poor liberation slows absorption, which delays Tmax
and lowers Cmax, ultimately reducing the area under the plasma concentration–time curve (AUC).
Similarly, extensive first-pass metabolism reduces systemic availability (bioavailability, F) despite
complete absorption [4].
2.3 Liberation
2.3.1 Liberation in Oral Dosage Forms
Liberation is the first step of the LADME sequence, describing the process by which an API is
released from its formulation and dissolved in the body fluids at the site of administration. For oral
dosage forms, dissolution in gastrointestinal (GI) fluids is the critical determinant of
bioavailability.

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Immediate-Release Tablets
Immediate-release (IR) tablets are designed to disintegrate and dissolve rapidly after ingestion.
Excipients such as crospovidone (2–5%), croscarmellose sodium (1–3%), or sodium starch
glycolate (2–8%) serve as superdisintegrants by promoting capillary action and swelling within
the tablet matrix. Hydrophilic fillers like lactose and mannitol enhance wetting and dissolution.
The liberation rate here is governed by disintegration time and the wettability of drug particles.
APIs with high aqueous solubility (e.g., metformin hydrochloride) show immediate dissolution,
whereas poorly soluble APIs (e.g., carbamazepine) require surfactants or solid dispersions to
accelerate liberation [5].
Dispersible and Effervescent Tablets
Dispersible tablets are designed for rapid dispersion in water before administration. They typically
contain polyvinylpyrrolidone (PVP), microcrystalline cellulose (MCC), and effervescent couples
such as citric acid–sodium bicarbonate to generate CO₂, breaking the tablet apart. The gas
evolution increases surface area and reduces boundary layer thickness, improving dissolution
kinetics (Noyes–Whitney equation).
Compressed and Multilayer Tablets
Multilayer tablets enable sequential or simultaneous release of incompatible or multiple drugs. For
example, one layer may be immediate release (containing crospovidone), while another uses a
sustained matrix (HPMC K15M). Compression force affects porosity and thus water penetration—
too high compaction may delay liberation due to reduced pore volume.
Sustained and Controlled-Release Tablets
Sustained release (SR) formulations are designed to prolong release over hours to maintain steady
plasma concentrations. The liberation process is controlled by diffusion through hydrophilic
matrices (e.g., HPMC), erosion of polymeric coatings (ethylcellulose, Eudragit RS), or osmotic
pressure gradients. The polymer type, viscosity, and concentration are key determinants—HPMC
K100M (10–40%) is typical for 12–24-hour release.
dispersible Tablets (ODTs)
ODTs rapidly disintegrate in saliva within seconds, ideal for pediatric and geriatric patients.
Techniques like sublimation (using camphor) or lyophilization create porous matrices that allow
instant wetting and rapid liberation without water.
Capsules
Capsules release the drug via dissolution of gelatin shells.
 Hard Gelatin Capsules are filled with powder or granules. Liberation depends on shell
moisture (12–16%) and gastric pH. Cross-linking during storage can slow dissolution.

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 Soft Gelatin Capsules contain drug in oil or PEG base. Shell plasticizers (glycerin, sorbitol)
and fill viscosity regulate liberation kinetics.
Table 2.1. Excipients influencing liberation
Dosage Form Key Excipients Concentration (%) Mechanistic Role
IR Tablet Crospovidone 2–5 Swelling and capillary wetting
SR Tablet HPMC K100M 10–40 Gel matrix for controlled diffusion
Effervescent Tablet Citric acid + NaHCO₃ 10–20 CO₂ effervescence, enhanced wetting
Hard Capsule Gelatin — Shell dissolution
Soft Capsule Glycerin/Sorbitol — Shell plasticity, release control
2.3.2 Modern Methods for Studying Liberation
Historically, USP dissolution apparatus I & II were standard, employing non-physiological buffers.
Modern studies use biorelevant media—Fasted State Simulated Intestinal Fluid (FaSSIF) and Fed
State Simulated Intestinal Fluid (FeSSIF)—to mimic physiological surfactants and bile salts [6].
Microfluidic chip-based systems now simulate GI hydrodynamics, while in vitro–in vivo
correlation (IVIVC) models quantitatively link dissolution profiles to human plasma levels.
Additionally, 3D-printed tablets allow programmable liberation kinetics through gradient polymer
composition [7].
2.4 Absorption
Drug absorption represents the movement of drug molecules from the site of administration into
systemic circulation. It involves crossing epithelial membranes through multiple transport
pathways:
1. Passive Diffusion – Driven by concentration gradients (Fick’s law). Favored for small,
lipophilic, and unionized drugs.
2. Facilitated Diffusion – Carrier-mediated, saturable but energy-independent, e.g., transport
of levodopa via large neutral amino acid transporters.
3. Active Transport – Energy-dependent uptake (P-glycoprotein, OATPs). Primary active
uses ATP directly; secondary active uses ion gradients.
4. Filtration – Passage through pores, relevant for small hydrophilic molecules.
5. Paracellular Transport – Diffusion through tight junctions; limited in most epithelia but
enhanced in inflammation.
6. Ion-Pair Transport – Lipophilic ion pairs diffuse more readily than individual charged
species.

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7. Endocytosis/Exocytosis – Vesicular uptake of macromolecules, nanoparticles, and
liposomes
Biopharmaceutically, the rate-limiting step for absorption can shift depending on formulation and
physicochemical properties. For poorly soluble drugs, dissolution controls absorption, while for
highly soluble but poorly permeable drugs, membrane transport dominates.
Physicochemical Factors: Lipophilicity (log P), molecular size, ionization (pKa), and crystalline
form determine diffusibility. Weak acids (e.g., aspirin) are efficiently absorbed in the stomach
(low pH favors unionized form), whereas weak bases (e.g., diazepam) favor intestinal absorption
[8]
Formulation Factors: Particle size reduction, use of surfactants (sodium lauryl sulfate),
complexation (cyclodextrins), and lipid formulations enhance absorption.
Patient Factors: GI pH, gastric emptying, presence of food, disease states (celiac disease,
Crohn’s), and concomitant medications (e.g., PPIs altering pH) affect absorption variability.
2.5 Distribution and Disposition
Distribution refers to the reversible transfer of drug molecules between plasma and tissue
compartments. It depends on perfusion rate, membrane permeability, tissue affinity, and protein
binding.
Protein Binding: Albumin binds weak acids (warfarin, phenytoin), α₁-acid glycoprotein binds
basic lipophilic drugs (propranolol), while β-globulins and lipoproteins interact with steroids or
lipophilic xenobiotics. Only the unbound drug fraction (fu) crosses membranes and exerts
pharmacological action [9].
In biopharmaceutics, disposition integrates both distribution and elimination processes. Changes
in protein binding or tissue affinity modify apparent volume of distribution (Vd), which influences
both half-life and clearance.
Formulation can indirectly affect distribution: liposomal or nanoparticulate carriers alter tissue
targeting (e.g., doxorubicin liposomes minimize cardiac exposure).
2.6 Metabolism
Metabolism transforms lipophilic drugs into more hydrophilic metabolites for easier excretion.
The goal is detoxification and termination of activity; however, some metabolites retain activity
(codeine → morphine) or become toxic (acetaminophen → NAPQI).
2.6.1 Enzymatic Metabolism
Microsomal Enzymes

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Located in the smooth endoplasmic reticulum, these enzymes (mainly CYP450 isoforms such as
CYP3A4, CYP2D6, CYP2C9) catalyze oxidation, reduction, and hydrolysis reactions.
 Phase I reactions: oxidation (e.g., hydroxylation of benzodiazepines), reduction (nitro
reduction), hydrolysis (ester cleavage).
 Phase II reactions: conjugation via glucuronidation (UGTs), sulfation (SULTs),
acetylation (NAT), methylation (COMT), and glutathione conjugation (GSTs).
Non-Microsomal Enzymes
These include esterases, amidases, alcohol and aldehyde dehydrogenases, and monoamine
oxidases found in cytosol and mitochondria. They catalyze hydrolysis of prodrugs (e.g., enalapril
→ enalaprilat) or oxidative deamination (e.g., dopamine → DOPAC).
2.6.2 Non-Enzymatic Metabolism (Hoffman Elimination)
Some drugs undergo spontaneous degradation under physiological pH and temperature without
enzyme participation. Atracurium besylate and cisatracurium undergo Hoffman elimination,
where base-catalyzed molecular rearrangement produces inactive metabolites, independent of
hepatic or renal function [10].
2.6.3 Biopharmaceutic Relevance
Formulation strategies such as prodrugs or nanoparticles modulate metabolism. For instance, ester
prodrugs increase lipophilicity and membrane permeability, while controlled-release formulations
reduce peak concentration, minimizing saturable metabolic pathways. Nanoencapsulation shields
drugs from hepatic first-pass metabolism, enhancing oral bioavailability [11].
2.7 Clinical Pharmacokinetics (CPK)
Clinical pharmacokinetics quantifies the relationship between dosing regimen and drug
concentration–time profile to optimize therapy.
 Cmax: Peak concentration
 Tmax: Time to reach Cmax
 AUC: Total systemic exposure
 Therapeutic Index (TI): Ratio between toxic and effective concentrations.
A narrow TI (e.g., digoxin, lithium) necessitates therapeutic drug monitoring (TDM).
2.7.1 Conducting Clinical PK Studies (Animal Model Example)
Clinical PK data are often preceded by animal PK studies for extrapolation to humans.

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Experimental Scheme:
1. Study Design: Select animal model (mice, rats, rabbits) and dosing route (oral, IV).
2. Dosing: Based on body surface area scaling or mg/kg dose.
3. Sample Collection:
o Invasive: Plasma, serum, tissue, urine, feces.
o Non-Invasive: Saliva, milk, expired air, tears.
4. Analytical Methods: LC–MS/MS, GC–MS, or HPLC-UV for drug quantification.
5. Data Processing: Use compartmental or non-compartmental analysis (NCA) to derive PK
parameters—Cmax, Tmax, t½, AUC, clearance (Cl), and Vd.
Table 2.2. Biological matrices in pharmacokinetic studies.
Matrix Nature Advantages Limitations
Plasma Invasive Accurate systemic concentration Requires sampling skill
Urine
Non-
invasive
Good for excretion studies Delay in reflection of plasma change
Saliva
Non-
invasive
Convenient, reflects unbound
drug
pH dependence, low correlation for ionized
drugs
Milk
Non-
invasive
Useful for lactation safety Variable fat content
Feces
Non-
invasive
Indicates biliary excretion Labor-intensive analysis
Lungs (exhaled
air)
Non-
invasive
For volatile drugs Specialized equipment
This design allows correlation of pharmacokinetic parameters with pharmacodynamic outcomes
and bioavailability [12].
2.8 Population Pharmacokinetics (PopPK)
Population pharmacokinetics is the quantitative study of the sources and correlates of variability
in drug concentrations among individuals within a target population receiving clinically relevant
doses of a drug (Sheiner et al., 1977). Unlike traditional PK, which estimates average kinetic
parameters, PopPK aims to model both typical values and variability patterns (interindividual and
intraindividual) through mixed-effects modeling frameworks.
Methodological Approaches
(a) In Vivo Studies
In vivo PopPK studies are typically conducted using sparse sampling strategies rather than rich
sampling from every individual. Blood, plasma, urine, or other biological matrices are collected at
predesigned intervals to capture representative concentration–time data across the population.
Animal models such as mice, rats, and nonhuman primates are often used for initial
pharmacometric modeling, followed by human clinical trial data integration. Analytical

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determination of plasma concentration is done through validated bioanalytical methods, typically
LC–MS/MS or HPLC, ensuring accuracy, precision, and sensitivity.
(b) In Vitro Studies
In vitro population models employ human-derived cells or organoid systems to assess variability
in metabolism, enzyme induction, and transporter function across donors. For example, hepatocyte
donor pools differing in CYP450 genotype can be tested for differential clearance rates, thereby
predicting population-level metabolic variability.
High-throughput microsomal incubations and recombinant enzyme systems are also employed to
generate intrinsic clearance data feeding into physiologically based pharmacokinetic (PBPK)
simulations.
(c) In Silico Approaches
Modern PopPK heavily relies on in silico modeling, employing software such as NONMEM,
Monolix, and Phoenix NLME. These computational models integrate demographic, physiological,
pathophysiological, and genetic covariates to simulate virtual populations and predict
drugexposure distributions. Integration of machine learning algorithms and Bayesian estimation
has further refined real-time dose individualization and adaptive clinical trial design.
Real-Time Applications
1. Individualized Dosing: PopPK forms the foundation for model-informed precision dosing
(MIPD) in antibiotics (e.g., vancomycin), antiepileptics, and oncology therapeutics.
2. Regulatory Evaluation: Agencies such as FDA and EMA now require PopPK analyses for
dose justification in special populations (pediatric, geriatric, renal-impaired).
3. Drug Development: PopPK bridges preclinical–clinical translation by simulating drug
performance across heterogeneous populations before full-scale clinical trials.
4. Therapeutic Drug Monitoring (TDM): Real-time model-based Bayesian forecasting
improves TDM accuracy.
Advancements and Future Trends
Modern advancements include integration with:
 Physiologically Based PopPK Models (PB-PopPK): Combining PopPK and PBPK to
incorporate organ-level mechanistic insight.
 Genomic PK Modeling: Incorporating pharmacogenomic variability into PopPK models.
 AI-Driven Population Analytics: Using machine learning to predict exposure–response
outcomes dynamically in clinical settings.
 Digital Twin Simulations: Creation of virtual patient twins for predictive, personalized
dosing optimization.
Biopharmaceutical Relevance: PopPK ensures that formulation design, dissolution rate, and
bioavailability parameters translate accurately into the intended population context. It helps bridge

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in vitro–in vivo correlation (IVIVC) and guides dosage form adjustment based on population
diversity[13].
2.9 Toxicokinetics
Toxicokinetics (TK) extends PK into safety assessment, describing systemic exposure during
toxicology studies. It establishes exposure–response relationships using parameters like Cmax,
AUC, and t½ in animals at supra-therapeutic doses.
Key metrics:
 NOAEL: No-observed-adverse-effect level.
 LOAEL: Lowest-observed-adverse-effect level.
 BMDL: Benchmark dose lower limit for risk modeling.
TK data help define safety margins and extrapolate to human risk. Integration of TK with omics
(toxicogenomics, metabolomics) provides mechanistic insight into organ-specific toxicity [14].
2.10 Disposition and Excretion
Disposition encompasses distribution and elimination. Excretion primarily occurs through renal
(glomerular filtration, tubular secretion), biliary (active transporters), pulmonary, and dermal
routes.
Biopharmaceutic design can modify apparent disposition: sustained-release systems prolong
apparent t½, while nanoparticles alter tissue targeting. Drugs like gentamicin are almost entirely
renally excreted, requiring dose adjustment in renal impairment [15].
2.11 Conclusion
Understanding the LADME processes and their interdependence is central to modern
biopharmaceutics and pharmacokinetics. Formulation scientists manipulate liberation and
absorption, while clinicians rely on PK parameters to individualize therapy. The disposition of a
drug—its journey through distribution, metabolism, and excretion—ultimately determines safety
and efficacy. Integration of clinical, population, and toxicokinetics transforms these concepts from
laboratory science into precision therapeutics.
References:
1. Shargel L, Yu AB. Applied Biopharmaceutics and Pharmacokinetics. 8th ed. New York:
McGraw-Hill; 2021.
2. Rowland M, Tozer TN. Clinical Pharmacokinetics and Pharmacodynamics: Concepts and
Applications. 5th ed. Philadelphia: Lippincott Williams & Wilkins; 2019.
3. Florence AT, Attwood D. Physicochemical Principles of Pharmacy. 6th ed. London:
Pharmaceutical Press; 2021.

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4. Aulton ME, Taylor KM. Aulton’s Pharmaceutics: The Design and Manufacture of
Medicines. 6th ed. Elsevier; 2022.
5. Al-Khattawi A, et al. Disintegration mechanisms and dissolution behavior of tablets. Eur
J Pharm Sci. 2020;155:105533.
6. Klein S. The use of biorelevant dissolution media to forecast the in vivo performance of
oral dosage forms. J Pharm Pharmacol. 2019;71(4):581–602.
7. Trasi NS, Taylor LS. Dissolution of poorly water-soluble drugs: Recent advances. Mol
Pharm. 2020;17(10):3601–3614.
8. Sinko PJ. Martin’s Physical Pharmacy and Pharmaceutical Sciences. 7th ed. Philadelphia:
Wolters Kluwer; 2023.
9. Benet LZ, Hoener BA. Changes in plasma protein binding have little clinical relevance.
Clin Pharmacol Ther. 2021;109(3):585–592.
10. Bowman WC. Neuromuscular block. Br J Anaesth. 2017;119:i143–i153.
11. Rautio J, et al. Prodrugs: design and clinical applications. Nat Rev Drug Discov.
2018;17(8):559–587.
12. Peters FT. Recent advances in drug quantification from biological matrices. Bioanalysis.
2020;12(8):547–562.
13. Ette EI, Williams PJ. Population Pharmacokinetics: Methods and Applications. Springer;
202