Key Takeaways
- Half-life determines how long a drug stays in your system - after 5 half-lives, ~97% is eliminated
- First-order kinetics means a constant fraction (not amount) of drug is eliminated per unit time
- Steady-state is achieved after 4-5 half-lives, where drug input equals elimination
- Individual factors like genetics, age, and organ function can vary drug clearance by 5-20 fold
- GLP-1 agonists have high bioavailability (89%) and predictable linear pharmacokinetics
The Foundation: What is Pharmacokinetics?
Pharmacokinetics (PK) is the quantitative study of drug movement through the body over time. Often summarized as "what the body does to the drug," it encompasses four fundamental processes known as ADME:
- Absorption: How the drug enters systemic circulation
- Distribution: How the drug spreads throughout body tissues
- Metabolism: How the drug is chemically transformed
- Elimination: How the drug and its metabolites leave the body
Understanding these processes allows us to predict drug concentrations at any time point, optimize dosing regimens, and explain why the same dose can produce different effects in different people.
Compartmental Models: Simplifying Complexity
One-Compartment Model
The simplest pharmacokinetic model treats the entire body as a single, well-mixed compartment. This model assumes:
- Instantaneous and homogeneous drug distribution
- Rapid equilibration between blood and tissues (15-30 minutes)
- Linear elimination kinetics
Mathematical representation:
C(t) = C₀ × e^(-ke × t)
Where:
C(t) = concentration at time t
C₀ = initial concentration
ke = elimination rate constant (0.693/t½)
t = time elapsed
Best suited for: Hydrophilic drugs confined to extracellular fluid, drugs with small volumes of distribution, and situations where simplified modeling is acceptable.
Two-Compartment Model
More realistic for most drugs, this model recognizes that drug distribution isn't instantaneous:
- Central compartment: Blood and highly perfused organs (heart, lungs, kidneys, liver)
- Peripheral compartment: Slowly perfused tissues (muscle, fat, bone)
- Biphasic elimination: Rapid distribution phase followed by slower elimination phase
Mathematical representation:
C(t) = A × e^(-α × t) + B × e^(-β × t)
Where:
A, B = hybrid constants
α = distribution rate constant
β = elimination rate constant
α > β (distribution faster than elimination)
Clinical significance: Most GLP-1 agonists follow two-compartment kinetics. The initial distribution phase affects early drug effects, while the elimination phase determines dosing frequency.
Key Pharmacokinetic Parameters
Half-Life (t½): The Universal Clock
Half-life is the time required for drug concentration to decrease by 50%. It's constant for each drug following first-order kinetics and doesn't change with dose.
| Half-Lives Elapsed | % Remaining | % Eliminated | Clinical Significance |
|---|---|---|---|
| 1 | 50% | 50% | Noticeable decrease in effect |
| 2 | 25% | 75% | Sub-therapeutic for most drugs |
| 3 | 12.5% | 87.5% | Minimal clinical effect |
| 4 | 6.25% | 93.75% | Near complete elimination |
| 5 | 3.125% | 96.875% | Considered "eliminated" |
Volume of Distribution (Vd): Where Does the Drug Go?
Volume of distribution is a theoretical volume that relates drug amount in the body to plasma concentration. It doesn't represent a real physiological space but indicates drug distribution extent.
Calculation and interpretation:
Vd = Total drug in body / Plasma concentration
Vd = Dose / C₀ (after IV bolus)
Low Vd (~0.05-0.2 L/kg): Drug confined to blood
Medium Vd (~0.2-0.7 L/kg): Drug in extracellular fluid
High Vd (>0.7 L/kg): Extensive tissue distribution
GLP-1 agonists typically have low Vd due to high plasma protein binding (>99%), meaning they primarily remain in the bloodstream rather than distributing extensively into tissues.
Clearance (CL): The Body's Elimination Capacity
Clearance represents the volume of plasma completely cleared of drug per unit time. It's the most important parameter for determining maintenance dose requirements.
Key relationships:
CL = ke × Vd
CL = Dose / AUC
t½ = 0.693 × Vd / CL
Maintenance Dose Rate = CL × Css,target
Where Css,target = desired steady-state concentration
Bioavailability (F): How Much Actually Gets In?
Bioavailability is the fraction of administered dose that reaches systemic circulation unchanged. For subcutaneous injections, it accounts for incomplete absorption and local degradation.
GLP-1 agonist bioavailability:
- Semaglutide SubQ: 89%
- Tirzepatide SubQ: ~80%
- Oral semaglutide: 0.4-1% (requires absorption enhancer)
First-Order Kinetics: The Foundation of Predictable Dosing
Most drugs, including all GLP-1 agonists, follow first-order elimination kinetics. This means the rate of elimination is proportional to the amount of drug present - a constant fraction is eliminated per unit time, not a constant amount.
Mathematical Principles
Differential equation:
dC/dt = -ke × C
Solving this gives:
C(t) = C₀ × e^(-ke × t)
ln(C) = ln(C₀) - ke × t
This creates a straight line on semi-log plot
Slope = -ke/2.303 (for log₁₀ scale)
Clinical Implications
- Predictable elimination: Half-life remains constant regardless of dose
- Linear dose-response: Doubling the dose doubles the concentration
- Accumulation predictability: Can calculate steady-state levels mathematically
- Simple dose adjustments: Proportional changes in dose produce proportional changes in exposure
Steady-State: When Input Equals Output
Steady-state occurs when the rate of drug administration equals the rate of elimination. At this point, plasma concentrations fluctuate predictably between doses but average concentration remains constant.
Time to Steady-State
The 5 Half-Life Rule:
Steady-state is reached after approximately 5 half-lives, regardless of dose or dosing frequency:
- After 3.3 half-lives: 90% of steady-state
- After 4.3 half-lives: 95% of steady-state
- After 5 half-lives: 96.9% of steady-state
- After 6.6 half-lives: 99% of steady-state
GLP-1 Agonist Steady-State Timeline
| Medication | Half-Life | 90% Steady-State | 95% Steady-State | 99% Steady-State |
|---|---|---|---|---|
| Semaglutide | 7 days | 23 days | 30 days | 46 days |
| Tirzepatide | 5 days | 16.5 days | 21.5 days | 33 days |
| Exenatide ER | 2 weeks | 6.6 weeks | 8.6 weeks | 13.2 weeks |
Calculating Steady-State Concentrations
For repeated dosing:
Css,avg = (F × Dose) / (CL × τ)
Css,max = Css,avg × [1 / (1 - e^(-ke × τ))]
Css,min = Css,max × e^(-ke × τ)
Where:
F = bioavailability
τ = dosing interval
Css = steady-state concentration
Individual Variation: Why One Size Doesn't Fit All
Genetic Factors
Genetic polymorphisms can account for 20-95% of variability in drug response. Key factors include:
- CYP450 enzymes: Polymorphisms create poor, intermediate, extensive, and ultra-rapid metabolizers
- Transporter proteins: Affect drug absorption and distribution
- Receptor variations: Influence drug efficacy and side effects
- Clinical impact: Can alter drug clearance by 5-20 fold between individuals
Physiological Factors
Age-Related Changes:
- Decreased renal clearance (~1% per year after age 40)
- Reduced hepatic blood flow
- Altered body composition
- Increased inter-individual variability
Organ Function:
- Kidney disease: Reduced renal clearance
- Liver disease: Impaired metabolism
- Heart failure: Altered distribution
- GI disorders: Variable absorption
Body Composition Effects
Body weight and composition significantly affect pharmacokinetics:
- Volume of distribution: Increases with body weight (Vd ∝ Weight^0.7)
- Clearance scaling: CL ∝ Weight^0.75 (allometric scaling)
- Lipophilic drugs: Greater distribution in obese patients
- Hydrophilic drugs: Distribution limited to lean body mass
Clinical relevance for GLP-1 agonists: Despite weight-based PK differences, fixed dosing is used because efficacy and safety are consistent across weight ranges in clinical trials.
How GLP3 Planner Models Drug Levels
The Simulation Algorithm
GLP3 Planner uses a discrete-time simulation approach with hourly time steps to model drug concentrations:
Core algorithm:
1. Initialize: amount_in_body = 0
2. For each hour from start to end:
a. Check if dose scheduled
b. If yes: amount_in_body += dose × bioavailability
c. Calculate elimination:
amount_eliminated = amount_in_body × (1 - e^(-ke))
d. Update: amount_in_body -= amount_eliminated
e. Record concentration = amount_in_body / Vd
3. Plot concentration vs time
Model Parameters for Each Drug
| Parameter | Semaglutide | Tirzepatide | Retatrutide |
|---|---|---|---|
| Half-life | 168 hours (7 days) | 120 hours (5 days) | 144 hours (6 days)* |
| ke (hr⁻¹) | 0.00413 | 0.00578 | 0.00481 |
| Bioavailability | 89% | 80% | 85%* |
| Vd (L/kg) | 0.12 | 0.15 | 0.14* |
*Estimated values for retatrutide based on preliminary data
Understanding Your Plot
The Sawtooth Pattern
Each dose creates a spike followed by exponential decay. The regular peaks and troughs form a characteristic sawtooth pattern that becomes consistent at steady-state.
Accumulation Phase
Early doses accumulate because the drug isn't fully eliminated between doses. The accumulation factor depends on the dosing interval relative to half-life.
Steady-State Plateau
When the amount eliminated between doses equals the dose amount, concentrations plateau. The average concentration remains constant despite fluctuations.
Advanced Concepts in Pharmacokinetic Modeling
Nonlinear Pharmacokinetics
While GLP-1 agonists follow linear kinetics, understanding nonlinear kinetics helps appreciate why these drugs are easier to dose:
- Saturable elimination: When enzymes become saturated (e.g., phenytoin, alcohol)
- Dose-dependent half-life: Higher doses take disproportionately longer to eliminate
- Unpredictable accumulation: Small dose increases can cause large concentration changes
- Clinical advantage of linear kinetics: Predictable, proportional dose adjustments
Population Pharmacokinetics
Modern drug development uses population PK modeling to understand variability:
Components of variability:
Cᵢⱼ = f(Dose, Time, θᵢ) × εᵢⱼ
Where:
θᵢ = individual parameters = θₚₒₚ × e^(ηᵢ)
θₚₒₚ = population typical value
ηᵢ = inter-individual variability
εᵢⱼ = residual variability
Allometric Scaling
Body size affects PK parameters in predictable ways based on metabolic theory:
- Clearance: CL = CLstd × (Weight/70)^0.75
- Volume: Vd = Vd,std × (Weight/70)^1.0
- Half-life: Relatively unchanged (effects cancel out)
- Clinical application: Explains why many drugs use weight-based dosing
Practical Applications for GLP-1 Agonist Therapy
Optimizing Your Dosing Schedule
Key principles:
- Consistency is key: Same day and time each week maintains stable levels
- Missed dose management: Understanding half-life helps decide whether to take or skip
- Travel adjustments: Can shift by ±2 days without significant impact
- Dose escalation timing: Wait 4-5 weeks at each dose for full effect assessment
Understanding Side Effect Timing
Pharmacokinetics explains why side effects follow predictable patterns:
- Peak effects: Occur 1-3 days post-injection when concentrations highest
- Adaptation: Receptor desensitization reduces side effects despite stable drug levels
- Dose escalation: Each increase temporarily worsens side effects until adaptation
- Strategic timing: Some patients inject Friday evening to manage weekend side effects
Drug Interactions: A PK Perspective
GLP-1 agonists have minimal drug interactions due to their pharmacokinetic properties:
- No CYP450 involvement: Metabolized by proteolysis, not liver enzymes
- High protein binding: But displacement interactions not clinically significant
- Main interaction: Delayed gastric emptying affects oral drug absorption timing
- Clinical management: Take other medications 30-60 minutes before GLP-1 injection
Frequently Asked Questions
Why does it take so long to reach steady-state?
Steady-state timing depends entirely on half-life, not dose or frequency. With semaglutide's 7-day half-life, it takes 35 days (5 × 7) to reach 97% of steady-state. This is a mathematical certainty based on first-order kinetics. Loading doses can achieve target levels faster but don't change the time to true steady-state.
Does body weight affect how much medication I need?
While pharmacokinetic parameters scale with body weight (clearance ∝ weight^0.75, volume ∝ weight^1.0), GLP-1 agonists use fixed dosing because clinical trials showed similar efficacy and safety across all weight ranges. The drugs' wide therapeutic window accommodates PK variability without dose adjustment.
Why do side effects improve over time despite constant drug levels?
This phenomenon, called tolerance or tachyphylaxis, occurs through receptor desensitization and physiological adaptation. GLP-1 receptors downregulate with chronic stimulation, and the GI system adapts to delayed emptying. This explains why gradual dose escalation is more tolerable than starting at high doses.
Can I split my weekly dose into multiple injections?
Theoretically, splitting doses would reduce peak-to-trough fluctuation (lower Cmax, higher Cmin) while maintaining the same average concentration. However, this isn't recommended because: 1) Clinical trials used weekly dosing, 2) The long half-life already minimizes fluctuation, 3) Multiple injections increase burden without proven benefit. The microdosing article explores this concept further.
Limitations of Pharmacokinetic Modeling
While PK modeling provides valuable insights, it's important to understand its limitations:
Model Assumptions
- Instantaneous absorption: Reality involves 24-72 hour absorption phase for SubQ injections
- Perfect adherence: Assumes doses taken exactly as scheduled
- No variability: Uses population average parameters, not individual values
- Linear kinetics: Assumes no saturation at any dose level
- Single compartment: Simplification of multi-compartment reality
Clinical Correlation
Important: Plasma concentration doesn't directly correlate with clinical effect. Factors like receptor sensitivity, tolerance development, and individual response variability mean two people with identical drug levels may experience different effects. PK modeling helps understand drug behavior but doesn't predict individual clinical outcomes.
When Models Matter Most
PK modeling is most useful for:
- Understanding accumulation during dose escalation
- Predicting impact of missed doses
- Planning medication switches or discontinuation
- Educational understanding of drug behavior
- Research and drug development
Clinical Application Summary
Understanding pharmacokinetics empowers you to make informed decisions about your medication regimen. The key takeaways for GLP-1 agonist therapy are:
- Be patient - it takes 4-5 weeks to reach steady-state
- Consistency in dosing time maintains stable levels
- Side effects often improve despite constant drug levels
- Individual variation is normal and expected
- The long half-life provides flexibility for missed doses
Always work with your healthcare provider to optimize your individual treatment plan based on your response, not just pharmacokinetic predictions.