Pharmacokinetics Study Guide

📖 Core Concepts Pharmacokinetics (PK) – How the body affects a drug (absorption, distribution, metabolism, excretion – ADME). Pharmacodynamics (PD) – How the drug affects the body; PK + PD guide dosing and safety. ADME – Sequential processes: Liberation – Release of the active ingredient from its dosage form. Absorption – Movement into systemic circulation. Distribution – Dispersion throughout fluids/tissues. Metabolism – Enzymatic conversion (e.g., CYP450, UGT). Excretion – Removal via urine/bile. PK Metrics – AUC (area under the concentration‑time curve): total exposure. Cmax: peak plasma concentration. Tmax: time of Cmax. Clearance (CL): volume of plasma cleared per time. Volume of distribution (Vd): theoretical volume that would give the observed plasma concentration. Steady State – Rate of input = rate of elimination; reached after ≈3–5 × elimination half‑lives for linear PK. Modeling – Non‑Compartmental Analysis (NCA) – Direct calculation from data (trapezoidal rule). Compartmental Analysis – Fit data to differential equations (1‑, 2‑, multi‑compartment). Bioavailability (F) – Fraction of dose reaching systemic circulation unchanged; IV = 100 % (absolute), oral vs other routes (relative). --- 📌 Must Remember CL = Dose / AUC (units: L h⁻¹). Vd = Dose / C₀ for IV bolus (C₀ = initial concentration). Half‑life (t½) = 0.693 · Vd / CL (first‑order elimination). Steady‑state achieved after ≈ 3–5 × t½ of regular dosing. AUC₍τ₎ = AUC∞ at steady state for linear PK. Absolute bioavailability: \(F = \dfrac{AUC{po}\cdot Dose{iv}}{AUC{iv}\cdot Dose{po}}\). Relative bioavailability: compare AUCs of two non‑IV formulations (same dose). NCA requirement – sampling must cover absorption, distribution, and elimination phases. Two‑compartment model concentration: \(C(t)=A e^{-\alpha t}+B e^{-\beta t}\) (alpha = distribution phase, beta = elimination phase). --- 🔄 Key Processes ADME Sequence Liberation → Absorption → Distribution → Metabolism → Excretion. NCA (Trapezoidal Rule) Divide concentration‑time curve into small intervals. For each interval \([ti,t{i+1}]\): \(AUCi = \frac{(Ci + C{i+1})}{2}\,(t{i+1}-ti)\). Sum all \(AUCi\) to obtain total AUC. Compartmental Modeling (1‑Compartment, IV bolus) Differential: \(\frac{dC}{dt} = -k\,C\). Solution: \(C(t)=C0 e^{-k t}\). Two‑Compartment IV Bolus Central ↔ Peripheral exchange rates (k₁₂, k₂₁). Elimination from central: \(k{10}\). Solve coupled ODEs → biexponential equation above. --- 🔍 Key Comparisons ADME vs ADMET – ADMET adds Toxicology (T) to the classic ADME framework. NCA vs Compartmental – NCA: model‑free, requires dense sampling; Compartmental: model‑based, allows extrapolation & scenario testing. Single‑Compartment vs Two‑Compartment – Single: mono‑exponential decline, assumes uniform distribution; Two: biphasic (α → β), captures rapid distribution then slower elimination. Absolute vs Relative Bioavailability – Absolute compares to IV (100 % reference); Relative compares two non‑IV formulations. --- ⚠️ Common Misunderstandings Clearance ≠ Volume of Distribution – CL is a flow (L h⁻¹); Vd is a space (L). Half‑life ≠ Tmax – t½ describes elimination speed; Tmax is when Cmax occurs (absorption‑dependent). Steady state after one half‑life? – False; needs 3–5 half‑lives. Bioavailability = Efficacy – Bioavailability is dose reaching circulation; efficacy also depends on PD. --- 🧠 Mental Models / Intuition “Tank and Faucet” – Body = tank; drug enters via faucet (absorption); CL = drain size; Vd = tank size. Compartment as “Buckets” – Central bucket fills quickly (distribution), then slowly empties (elimination). Linear PK = Proportionality – Double the dose → double AUC, Cmax, etc. Non‑linear PK = “Traffic Jam” – Enzyme saturation = bottleneck; concentration climbs disproportionately. --- 🚩 Exceptions & Edge Cases Michaelis–Menten (non‑linear) kinetics – \(v = \dfrac{V{\max} C}{Km + C}\); occurs with saturated metabolism or active transport. Auto‑induction / inhibition – Drugs like phenytoin increase (induce) or decrease (inhibit) their own clearance over time. Active renal secretion – Can be concentration‑independent, breaking the first‑order assumption. Physiologically Based PK (PBPK) – Uses organ‑level parameters; useful for extrapolating across species or special populations. --- 📍 When to Use Which NCA – Rich, dense concentration‑time data; quick exposure metrics (AUC, Cmax, Tmax). Compartmental (1‑ or 2‑compartment) – Need to predict concentrations beyond sampling window, simulate dosing regimens, or assess distribution phases. Two‑Compartment – Most IV bolus or short‑infusion drugs showing biphasic decline. Multi‑Compartment / PBPK – Complex drugs with tissue‑specific kinetics, drug–drug interaction modeling, or pediatric/geriatric scaling. Population PK – Sparse or opportunistic samples; identify covariates (weight, renal function) for dose individualization. --- 👀 Patterns to Recognize Biphasic log‑linear plot → Two‑compartment behavior (steep α, shallow β). Linear increase of AUC with dose → First‑order (linear) kinetics. Disproportionate AUC rise at higher doses → Saturable (non‑linear) metabolism. Flat terminal phase after distribution → Elimination governed by a single rate constant (k). --- 🗂️ Exam Traps Choosing the wrong clearance formula – Remember CL = Dose / AUC, not CL = Vd / t½ (that's the relationship, not the definition). Assuming steady state after 1 half‑life – Must wait 3–5 half‑lives for ≈ 90–97 % steady‑state. Mixing absolute and relative bioavailability – Absolute uses IV reference; relative compares two non‑IV forms—values are not interchangeable. Interpreting a single exponential decline as “single‑compartment” – Verify that distribution phase is truly absent; early data points may be missing. Treating all renal excretion as first‑order – Active secretion can be concentration‑independent, leading to non‑linear clearance. ---