Chapter 2  ·  Module 5 of 5  ·  Pharmacokinetics

Pharmacokinetic Principles and Clinical Applications

Half-life, clearance, steady state, nonlinear kinetics, therapeutic drug monitoring, special populations, and antimicrobial PK/PD targets

Abbreviations: CL = clearance  ·  Vd = volume of distribution  ·  t½ = elimination half-life  ·  Css = steady-state plasma concentration  ·  LD = loading dose  ·  Km = Michaelis constant  ·  Vmax = maximum elimination rate  ·  TDM = therapeutic drug monitoring  ·  MIC = minimum inhibitory concentration  ·  PK/PD = pharmacokinetic/pharmacodynamic
Sections 1 & 2 — Half-Life, Clearance, and Steady State

Sections 1 & 2

Core Pharmacokinetic Relationships

Half-Life Formula

t½ = 0.693 × Vd ÷ CL

  • Derived parameter — not independent
  • Increases if Vd increases (more tissue reservoir to drain)
  • Decreases if CL increases (faster removal from plasma)
  • Determines time to steady state and washout time

Steady-State Concentration

Css = Dose Rate ÷ CL

  • CL is the sole determinant of Css
  • Vd does NOT affect Css — only time to reach it
  • Double the dose → double the Css
  • Reduce CL by half (renal failure) → double the Css at same dose

5 Half-Lives Rule

97% Steady State

  • Steady state reached after 4–5 t½ regardless of dose or interval
  • Loading dose: fills Vd immediately → bypasses accumulation time without changing Css
  • LD = target Css × Vd
  • Washout: drug falls to <3% of Css after 5 t½ from last dose
Section 3 — Nonlinear Pharmacokinetics

Section 3

Saturable (Michaelis-Menten) Elimination — Phenytoin Paradigm

Michaelis-Menten Kinetics

Rate = Vmax × C ÷ (Km + C)

  • Below Km: elimination is first-order (proportional to concentration)
  • Above Km: elimination rate approaches Vmax — becomes zero-order
  • Phenytoin: Km ≈ 5–10 mg/L — within its therapeutic range
  • Near saturation: small dose increase → disproportionately large, unpredictable concentration rise
  • Consequence: dose increases must be in small steps (25–50 mg); level monitoring mandatory

Other Nonlinear Drugs

Zero-Order Situations

  • Ethanol: alcohol dehydrogenase saturated at all social 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
  • Fluoxetine at high doses: CYP2D6 saturation contributes to nonlinear accumulation
Section 4 — Therapeutic Drug Monitoring

Section 4

When to Monitor, When to Sample, How to Interpret

TDM Indications

Three Required Conditions

  • 1. Narrow therapeutic index
  • 2. Large interpatient pharmacokinetic variability
  • 3. Well-established concentration-effect relationship
  • Classic TDM drugs: vancomycin, aminoglycosides, digoxin, lithium, phenytoin, cyclosporine, tacrolimus, theophylline

Sampling Timing Rules

When to Draw the Level

  • Must be at steady state (≥5 t½ of regular dosing)
  • A level before steady state underestimates eventual Css
  • Aminoglycosides: draw peak 1 h post-dose; trough before next dose
  • Digoxin: wait ≥6–8 h after IV dose (distribution complete)
  • Vancomycin: AUC-guided monitoring preferred; draw two levels per dosing interval

Timing rule: All levels must be drawn at steady state. A level drawn before steady state is reached will underestimate the eventual Css. Never draw aminoglycoside or digoxin levels during the distribution phase — the falsely elevated result will lead to inappropriate dose reduction.

Section 5 — Pharmacokinetics in Special Populations

Section 5

Neonates, Elderly, Pregnancy, and Obesity

PK Parameter Neonates Elderly Pregnancy Obesity
Renal clearance Markedly reduced (immature GFR) Reduced (~1 mL/min/year after age 40) Increased 40–50% (GFR rises) Variable; may increase with BMI
Hepatic metabolism Markedly reduced (immature CYPs, UGT) Reduced first-pass; CYP modestly reduced CYP3A4, 2D6 increased; others unchanged Generally increased; higher first-pass for high-extraction drugs
Vd (hydrophilic) Increased (high body water fraction) Decreased (reduced lean mass, body water) Increased (plasma volume expansion) Little change or slight increase
Vd (lipophilic) Reduced (less adipose tissue) Increased (more adipose tissue) Increased (expanded adipose + total body water) Markedly increased (adipose accumulation)
Protein binding Reduced (low albumin, AAG) Mildly reduced albumin; increased AAG in illness Reduced albumin → increased free fraction of acidic drugs Often normal or mildly altered
Section 6 — Antimicrobial PK/PD Patterns

Section 6

Time-Dependent, Concentration-Dependent, and AUC-Dependent Killing

Time-Dependent

T>MIC

  • Index: time free drug exceeds MIC
  • Target: 40–70% of dosing interval
  • Strategy: frequent dosing or continuous infusion to maximize time above MIC
  • Drugs: beta-lactams (penicillins, cephalosporins, carbapenems)

Concentration-Dependent

Cmax / MIC

  • Index: peak concentration ÷ MIC
  • Target: Cmax/MIC ≥ 8–10
  • Strategy: high single doses with extended intervals to maximize peak
  • Drugs: aminoglycosides (once-daily dosing), metronidazole

AUC-Dependent

AUC / MIC

  • Index: AUC over 24 h ÷ MIC
  • Target: AUC/MIC 400–600 mg·h/L (vancomycin); >125 (fluoroquinolones)
  • Strategy: optimize total daily drug exposure regardless of timing
  • Drugs: vancomycin, fluoroquinolones

Chapter 2 Complete  ·  Pharmacokinetics

This chapter built the quantitative framework for understanding what the body does to drugs. Absorption and bioavailability determine how much drug reaches the circulation and how quickly; the first-pass effect, formulation type, and physicochemical properties all shape this entry step. Distribution — governed by Vd, protein binding, and tissue barriers — determines where drug goes once it enters the blood. Metabolism and elimination set the rate of drug removal, with CYP450 isoforms, enzyme induction and inhibition, renal filtration and secretion, and enterohepatic recirculation as the primary mechanisms.

The integration of these four processes into half-life, clearance, and steady-state relationships provides the mathematical backbone for all dosing decisions. Nonlinear kinetics, TDM, and special population adjustments translate that backbone into individualized clinical practice. The antimicrobial PK/PD framework shows how these principles directly determine whether a drug cures or fails.

The chapters that follow apply this pharmacokinetic reasoning to specific drug classes — cardiovascular, CNS, autonomic, anti-infective, and all others. Every dosing decision in those chapters is ultimately a pharmacokinetics problem answered with the tools developed here.

References

Author / Source Title Publication
Katzung BG, ed. Basic and Clinical Pharmacology, 15th edition McGraw-Hill, 2021
Brunton LL, Knollmann BC, eds. Goodman & Gilman's The Pharmacological Basis of Therapeutics, 14th edition McGraw-Hill, 2023
Rowland M, Tozer TN Clinical Pharmacokinetics and Pharmacodynamics: Concepts and Applications, 4th edition Lippincott Williams & Wilkins, 2011
Brunton LL, Hilal-Dandan R, Knollmann BC, eds. Goodman & Gilman's The Pharmacological Basis of Therapeutics, 13th edition McGraw-Hill, 2018
Patsalos PN, et al. Antiepileptic drugs: best practice guidelines for therapeutic drug monitoring Epilepsia, 2008; 49(7):1239–1276
Rybak MJ, et al. Therapeutic monitoring of vancomycin for serious methicillin-resistant Staphylococcus aureus infections American Journal of Health-System Pharmacy, 2020; 77(11):835–864
Craig WA Pharmacokinetic/pharmacodynamic parameters: rationale for antibacterial dosing of mice and men Clinical Infectious Diseases, 1998; 26(1):1–12
Allegaert K, van den Anker JN Clinical pharmacology in neonates: small individuals, large differences European Journal of Clinical Pharmacology, 2015; 71(9):1029–1035
Koren G, et al. Pharmacokinetics of the pregnant woman and fetus Clinical Pharmacokinetics, 2018; 57(6):653–672
Hanley MJ, Abernethy DR, Greenblatt DJ Effect of obesity on the pharmacokinetics of drugs in humans Clinical Pharmacokinetics, 2010; 49(2):71–87