Computational modeling of drug disposition MCQs With Answer

Introduction:

Computational modeling of drug disposition is an essential component of modern pharmacokinetics and drug development. This blog presents focused MCQs to help M.Pharm students deepen their understanding of physiologically based pharmacokinetic (PBPK) models, compartmental and non-compartmental approaches, parameter estimation, scaling, and model validation. Questions emphasize practical interpretation, mathematical foundations, software applications, and advanced concepts such as sensitivity analysis, population PK, and non-linear kinetics. Each question is designed to reinforce theoretical knowledge and foster the ability to apply computational strategies to predict absorption, distribution, metabolism, and excretion (ADME) in drug development and regulatory contexts.

Q1. What is the primary distinction between physiologically based pharmacokinetic (PBPK) models and traditional compartmental models?

• PBPK models represent the body with compartments based on physiological organs and blood flow; compartmental models use empirical compartments not necessarily tied to anatomy
• PBPK models always use fewer parameters than compartmental models
• Compartmental models require detailed tissue-specific permeability data, PBPK models do not
• Compartmental models cannot describe non-linear kinetics, PBPK models can

Correct Answer: PBPK models represent the body with compartments based on physiological organs and blood flow; compartmental models use empirical compartments not necessarily tied to anatomy

Q2. In a simple one-compartment IV bolus model with first-order elimination, which equation describes the concentration-time profile?

• C(t) = C0 * e^(–kel * t)
• C(t) = (Dose/Cl) * (1 – e^(–ka * t))
• C(t) = C0 / (1 + kel * t)
• C(t) = (F * Dose / Vd) * e^(–Cl * t)

Correct Answer: C(t) = C0 * e^(–kel * t)

Q3. Which parameter primarily determines the initial distribution phase in a multicompartment PK model?

• Inter-compartmental clearance (Q) and tissue volumes
• Systemic clearance (Cl) only
• Bioavailability (F)
• Elimination half-life at steady state

Correct Answer: Inter-compartmental clearance (Q) and tissue volumes

Q4. In PBPK modeling, what role does tissue-to-plasma partition coefficient (Kp) play?

• Determines the extent of drug distribution into tissues relative to plasma
• Directly sets the drug’s metabolic clearance in the liver
• Represents bioavailability after oral dosing
• Defines the absorption rate from the gut lumen

Correct Answer: Determines the extent of drug distribution into tissues relative to plasma

Q5. Which numerical method is most commonly used to solve ordinary differential equations in PK models implemented in software like MATLAB or R?

• Runge–Kutta methods
• Fourier transform
• Simpson’s rule
• Monte Carlo integration

Correct Answer: Runge–Kutta methods

Q6. In population pharmacokinetic modeling, what is the main purpose of including covariates (e.g., weight, renal function)?

• To explain inter-individual variability in pharmacokinetic parameters and improve predictive performance
• To force the model to fit a single subject better
• To reduce the number of observations required in a study
• To transform non-linear kinetics into linear kinetics

Correct Answer: To explain inter-individual variability in pharmacokinetic parameters and improve predictive performance

Q7. Which statement best describes identifiability of PK model parameters?

• Parameters are identifiable if unique values can be estimated from the available data and model structure
• Identifiability means parameters have low variability across subjects
• Identifiability implies that each parameter is biologically meaningful
• Parameters are identifiable when their standard errors are zero

Correct Answer: Parameters are identifiable if unique values can be estimated from the available data and model structure

Q8. What is the primary reason to perform sensitivity analysis in computational drug disposition modeling?

• To determine which parameters most influence model outputs and prioritize experimental measurements
• To increase the number of parameters to fit
• To convert a PBPK model into a compartmental model
• To ensure the software runs faster

Correct Answer: To determine which parameters most influence model outputs and prioritize experimental measurements

Q9. Which situation most likely indicates non-linear (saturable) pharmacokinetics?

• Clearance decreases as dose increases due to saturation of metabolic enzymes
• Half-life remains constant irrespective of dose
• Plasma concentration is proportional to dose across all dose ranges
• Absorption rate is much faster than elimination rate

Correct Answer: Clearance decreases as dose increases due to saturation of metabolic enzymes

Q10. In physiologically based models, how is hepatic clearance most commonly represented mechanistically?

• As hepatic blood flow-limited or enzyme-limited (well-stirred, parallel-tube, or dispersion) models
• Only by a single first-order elimination rate constant without physiology
• As a diffusion-limited process across the kidney
• By modeling enterohepatic recirculation only

Correct Answer: As hepatic blood flow-limited or enzyme-limited (well-stirred, parallel-tube, or dispersion) models

Q11. Which metric derived from non-compartmental analysis (NCA) is essential to estimate systemic exposure?

• Area under the plasma concentration–time curve (AUC)
• Cmax divided by Tmax
• Apparent volume of distribution at steady state (Vss) only
• Ka (absorption rate constant) exclusively

Correct Answer: Area under the plasma concentration–time curve (AUC)

Q12. When performing interspecies scaling of clearance, which approach incorporates physiological differences between species?

• Physiologically based scaling (PBPK allometric scaling with organ blood flows and enzyme ontogeny)
• Simple dose normalization by body weight without physiological parameters
• Assuming identical clearance per kg across species
• Using only human clinical data without preclinical input

Correct Answer: Physiologically based scaling (PBPK allometric scaling with organ blood flows and enzyme ontogeny)

Q13. In Monte Carlo simulations for PK/PD, what is the main objective?

• To quantify uncertainty and variability in predicted outcomes by sampling parameter distributions
• To find a single best-fit parameter set
• To analytically solve differential equations
• To reduce computation time by deterministic approximation

Correct Answer: To quantify uncertainty and variability in predicted outcomes by sampling parameter distributions

Q14. Which of the following best characterizes enterohepatic recirculation in drug disposition models?

• Drug excreted into bile is reabsorbed from the intestine, causing secondary peaks in plasma concentration
• Metabolic conversion in the kidney followed by immediate excretion
• Irreversible binding to plasma proteins preventing elimination
• Zero-order absorption from the gut lumen

Correct Answer: Drug excreted into bile is reabsorbed from the intestine, causing secondary peaks in plasma concentration

Q15. What is the purpose of model qualification/validation in computational drug disposition?

• To assess predictive performance using independent data and to ensure model reliability for intended use
• To increase the number of parameters until the fit is perfect
• To ensure the model runs on multiple operating systems
• To guarantee that the model will never need updating

Correct Answer: To assess predictive performance using independent data and to ensure model reliability for intended use

Q16. In absorption modeling, what does the parameter Fa represent?

• The fraction of administered dose that is absorbed across the gut wall
• The absolute bioavailability including first-pass effect
• The rate constant of gastric emptying
• The fraction of drug metabolized by CYP enzymes

Correct Answer: The fraction of administered dose that is absorbed across the gut wall

Q17. Which technique is commonly used to estimate PK model parameters from concentration–time data when residual error is heteroscedastic?

• Weighted least squares or maximum likelihood methods with heteroscedastic error models
• Ordinary least squares with no weighting
• Non-weighted median regression exclusively
• Principal component analysis

Correct Answer: Weighted least squares or maximum likelihood methods with heteroscedastic error models

Q18. Which software is specifically designed for PBPK modeling and includes built-in physiological databases for humans and preclinical species?

• PK-Sim / MoBi (Open Systems Pharmacology)
• Excel without add-ins
• Word processing software
• PowerPoint

Correct Answer: PK-Sim / MoBi (Open Systems Pharmacology)

Q19. In a two-compartment model, what is the significance of the micro-rate constants k12 and k21?

• They represent rates of drug transfer between central and peripheral compartments
• They are equivalent to systemic clearance values
• They denote absorption and elimination rate constants respectively
• They measure fraction unbound in plasma

Correct Answer: They represent rates of drug transfer between central and peripheral compartments

Q20. Which approach is most appropriate to incorporate enzyme maturation (ontogeny) when predicting pediatric PK using computational models?

• Include age-dependent expression or activity functions for metabolizing enzymes in the PBPK model
• Apply adult clearance values scaled linearly by body weight only
• Assume pediatric patients have the same physiology as neonates always
• Exclude renal function as it is irrelevant in pediatrics

Correct Answer: Include age-dependent expression or activity functions for metabolizing enzymes in the PBPK model

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