Chapter 2  ·  Module 5  ·  Visual Summary

Pharmacokinetic Principles and Clinical Applications

Half-life, clearance, steady state, nonlinear kinetics, therapeutic drug monitoring, special populations, and pharmacokinetic-pharmacodynamic relationships

Core Pharmacokinetic Relationships

Half-Life

t½ = (0.693 × Vd) / CL

  • Derived parameter — not independent
  • Increases if Vd increases (more tissue reservoir)
  • Decreases if CL increases
  • 5 half-lives: 97% elimination or 97% of steady state

Clearance

CSS = Dose rate / CL

  • Sole determinant of steady-state concentration
  • Vd does NOT affect steady-state level (only time to reach it)
  • Halve CL (renal failure, enzyme inhibition) → double CSS at same dose
  • Total CL = hepatic + renal + other pathways

Steady State

5 half-lives to reach 97%

  • Time determined by t½ only — not dose or interval
  • Loading dose: fills Vd immediately → bypasses accumulation time
  • Larger dose interval → greater peak-trough fluctuation
  • Frequent dosing (vs. half-life) → less fluctuation

Nonlinear (Saturable) Pharmacokinetics

Phenytoin — Paradigm Drug

Michaelis-Menten kinetics

  • Metabolized by CYP2C9/2C19; enzymes saturate at therapeutic concentrations
  • Near saturation: small dose increase → disproportionately large concentration rise
  • Half-life not constant: lengthens as concentration rises
  • Adjust in small increments (25–50 mg/day); wait longer for steady state at higher doses
  • CYP2C9 inhibitors (fluconazole, amiodarone) → sudden toxicity risk

Other Zero-Order Examples

Ethanol and high-dose aspirin

  • Ethanol: alcohol dehydrogenase saturated at all drinking concentrations → constant elimination rate (~7–10 g/h); blood alcohol falls linearly, not exponentially
  • Aspirin at anti-inflammatory doses (>2–3 g/day): sulfotransferase saturation → prolonged, variable half-life
  • At zero-order kinetics: no true half-life; time to elimination depends on concentration

Therapeutic Drug Monitoring

Drug Sample Timing Target Key Caveat Monitoring Metric
Vancomycin Trough (or AUC-guided) AUC/MIC 400–600 mg·h/L AUC/MIC preferred over trough alone; trough alone over-estimates nephrotoxicity risk AUC/MIC ratio
Aminoglycosides Peak (30 min post-infusion) and trough (pre-dose) Peak/MIC ≥ 8–10; trough < 1 μg/mL Once-daily dosing has high peak; trough should be undetectable to limit nephrotoxicity Cmax/MIC
Phenytoin Trough (pre-dose) 10–20 μg/mL (total); 1–2 μg/mL (free) Correct for albumin: adjusted level = measured / (0.2 × albumin + 0.1) in hypoalbuminemia Total or free level
Digoxin ≥ 6–8 h post-dose 0.5–0.9 ng/mL (heart failure); <2.0 ng/mL Never draw during distribution phase; hypokalemia potentiates toxicity even at normal levels Trough-equivalent level
Lithium 12 h post-dose (trough) 0.6–1.2 mEq/L (acute); 0.4–0.8 (maintenance) Renal clearance parallels sodium; sodium depletion (diuretics, low-sodium diet) → lithium toxicity Trough serum level
Timing rule: All levels must be drawn at steady state (after 5 half-lives). A level drawn before steady state is reached will underestimate the eventual steady-state concentration. Never draw aminoglycoside or digoxin levels during distribution phase.

Pharmacokinetics in Special Populations

Population Clearance Volume of Distribution Protein Binding Key Implication
Neonates Reduced (immature CYP, GFR 20–30% of adult) Increased for hydrophilic (high body water ~80%) Low albumin → higher free fraction of acidic drugs Lower doses, longer intervals; adjust for developmental stage, not just weight
Elderly Reduced renal (GFR falls ~0.75–1 mL/min/yr after age 40); reduced hepatic blood flow (high-extraction drugs) Increased for lipophilic (fat ↑, lean mass ↓) Modestly reduced albumin in ill/malnourished Creatinine may appear normal despite reduced GFR; lower doses; watch for accumulation of lipophilic drugs (benzodiazepines)
Pregnancy Increased renal (GFR +50–60%); CYP3A4/2D6 induced; CYP1A2/2C19 reduced Increased (blood volume +40–50%, total body water expanded) Modestly reduced (hemodilution) Drug levels often fall during pregnancy — monitor and increase doses; reduce back to pre-pregnancy doses post-partum
Obesity Increased renal (hyperfiltration); variable hepatic Increased for lipophilic drugs; near-normal for hydrophilic Generally normal Lipophilic drugs: use total body weight. Hydrophilic drugs: use lean body weight. Vancomycin: total body weight for loading dose

Antimicrobial Pharmacokinetic–Pharmacodynamic Patterns

Pattern 1 — Time-Dependent

T>MIC

  • Index: Time free drug > MIC
  • Target: 40–70% of dosing interval
  • Drugs: beta-lactams (penicillins, cephalosporins, carbapenems)
  • Strategy: frequent dosing or continuous infusion
  • Higher peak does NOT improve killing

Pattern 2 — Concentration-Dependent

Cmax / MIC

  • Index: peak concentration / MIC
  • Target: Cmax/MIC ≥ 8–10
  • Drugs: aminoglycosides, fluoroquinolones
  • Strategy: large infrequent doses to maximize peak
  • Once-daily aminoglycoside: high peak + drug-free interval reduces nephrotoxicity

Pattern 3 — AUC-Dependent

AUC / MIC

  • Index: AUC over 24 h / MIC ratio
  • Target: AUC/MIC 400–600 mg·h/L (vancomycin)
  • Drugs: vancomycin, linezolid
  • Strategy: optimize total daily exposure
  • Vancomycin AUC/MIC monitoring preferred over trough alone