Clinical Pharmacokinetics in Kidney Disease

Clinical Pharmacokinetics in Kidney Disease

• Kidney disease is a common comorbidity, altering drug pharmacokinetics
• Prescribing to patients with kidney disease requires knowledge of the drug, patient physiology, and pharmacokinetic principles
• Impaired kidney function affects drug clearance and volume of distribution
• Acute kidney injury (AKI) has dynamic changes in drug clearance, unlike chronic kidney disease (CKD), which has slower progression
• Recovery is possible in AKI based on the cause and treatment
• Kidney replacement therapies in AKI further complicate drug clearance quantification
• Adjusting dosing regimens can personalize care and minimize adverse effects
• Principles of pharmacokinetics guide rational dosing strategies

Introduction

• Drugs are crucial treatments for kidney disease
• Knowledge of basic pharmacokinetic principles is essential for all prescribers, especially nephrologists
• Kidney disease impacts drug handling in various ways, including chronic (slow progression) and acute (rapid changes) conditions
• Understanding how physiological changes affect drug pharmacokinetics is vital for rational drug use and treatment optimization

Relationship between Dosing Regimen and Drug Effect

• A drug's effect depends on both its pharmacokinetics (body's effect on the drug) and pharmacodynamics (drug's effect on the body)
• Pharmacokinetics includes absorption, distribution, metabolism, and excretion (ADME), each of which can be altered in kidney disease affecting therapeutic outcomes
• Drug concentration-time profiles reflect how ADME processes affect drug action, and drug exposure (e.g., maximal concentration, and area under the curve [AUC]) is associated with drug effects

Reasons to Optimize Dosing Regimens

• Sub- and supra-therapeutic drug exposures can result in treatment failure, morbidity, prolonged hospitalizations, and potentially, death
• Risks increase in drugs with narrow therapeutic indices (for example, digoxin or lithium), where even small changes in exposure can lead to toxicity

Selected Examples of Drugs Requiring Special Consideration in Kidney Disease

• Antibiotics' efficacy depends on their concentration relative to a bacteria's minimum inhibitory concentration (MIC).
• Factors that maximize antibiotic efficacy include the ratio of peak to MIC (concentration-dependent agents), the ratio of AUC to MIC, and the duration of time the plasma concentration exceeds the MIC (time-dependent agents)
• Lithium excretion is dependent on kidney function; chronic poisoning is an adverse effect in impaired kidney function
• Digoxin has a narrow therapeutic index and accumulates with impaired kidney function, requiring dose adjustments
• Cyclophosphamide and its metabolites are cleared by the kidneys, thus dosage needs to be adjusted for patients with impaired kidney function and considerations of the presence of glomerulonephritis

Novel/Direct Acting Oral Anticoagulants (NOACs/DOACs)

• NOACs/DOACs clearance varies with kidney function
• Some NOACs have dose adjustments in patients with kidney disease, and others are contraindicated
• Dabigatran exposure increased in patients with impaired kidney function due to dependence of clearance on kidney function and P-glycoprotein transporters
• Apixaban clearance less reduced and appropriate dose adjustment determined

Pharmacokinetic Principles and Parameters

• Volume of distribution (Vd) describes the drug distribution in the body
• Clearance (CL) measures the volume of blood cleared of a drug per unit time
• Elimination half-life (t1/2) measures the time required for the drug concentration to decrease by 50%
• AUC (area under the curve) is proportional to the decrease in CL
• Changes in both CL and Vd influence drug concentration-time profiles

Kidney Clearance

• Kidney clearance is influenced by glomerular filtration, active tubular secretion, and passive tubular reabsorption.
• Several factors, including individual variability and the interplay of several processes (especially nonrenal CL) in addition to kidney-related CL, can alter expected drug clearance, and dose adjustment is often required

Other Considerations

• Factors like drug-drug interactions might affect clearance, requiring dosing adjustments
• Protein binding influences drug action and may change in kidney disease, affecting free drug concentration and impacting dosing
• Dose adjustments are usually not required for drugs of low toxicity administered for a short duration, but they are essential for drugs with long elimination half-lives

This quiz covers the crucial principles of clinical pharmacokinetics specifically related to kidney disease. It highlights the importance of understanding drug clearance, dosing regimens, and patient physiology for effective prescribing. Tailored strategies for managing drug therapies in acute and chronic kidney conditions are emphasized.