From the Guidelines
The most critical pharmacokinetic parameters for determining drug safety are clearance, volume of distribution, half-life, and bioavailability, as they directly influence drug accumulation, toxicity risk, and dosing requirements. When considering these parameters, it's essential to understand how age-related changes affect them, as outlined in a 2022 review by the European Society of Cardiology Working Group on Cardiovascular Pharmacotherapy 1.
Key Pharmacokinetic Parameters
- Clearance: Measures how quickly the body removes a drug, directly affecting drug accumulation and toxicity risk.
- Volume of distribution: Indicates how widely a drug spreads throughout the body, influencing dosing requirements and potential for tissue-specific toxicity.
- Half-life: Determines dosing frequency and predicts how long drug effects will persist, with longer half-lives increasing the risk of drug accumulation.
- Bioavailability: Affects how much active drug reaches systemic circulation, crucial for avoiding underdosing or overdosing.
Age-Related Changes
As people age, several physiological changes occur that can significantly impact these pharmacokinetic parameters, including:
- Decreased gastric acid production and emptying, which can delay drug absorption but not necessarily alter the amount absorbed 1.
- Reduced splanchnic blood flow, motility, and absorption surface, which can be affected by antacids and laxatives, further altering drug absorption.
- Changes in gut wall transporters and first-pass metabolism, leading to decreased first-pass effect and increased oral bioavailability of certain drugs like diltiazem, opioids, propranolol, simvastatin, and verapamil 1.
Clinical Implications
Understanding these age-related changes is crucial for safe and effective drug prescribing, especially in older adults with cardiovascular disease. Accurate determination of renal function, such as estimated glomerular filtration rate (eGFR), is critical for adjusting dose requirements of renally cleared drugs, as reduced renal function can lead to increased exposure and risk of adverse drug reactions (ADRs) 1. The use of equations like the CKD-EPI equation is recommended for estimating eGFR in adults of any age, but it's also important to consider the limitations of these equations in older populations, where serum creatinine levels may not accurately reflect renal function due to reduced muscle mass and other factors 1.
From the FDA Drug Label
12.3 Pharmacokinetics Absorption Following a single 200 mg oral dose of hydroxychloroquine sulfate to healthy male volunteers, whole blood hydroxychloroquine Cmax was 129.6 ng/mL (plasma Cmax was 50. 3 ng/mL) with Tmax of 3.3 hours (plasma Tmax 3.7 hours). Distribution Hydroxychloroquine sulfate is extensively distributed to tissues. Elimination A half-life of 123. 5 days in plasma were observed following a single 200 mg oral hydroxychloroquine sulfate dose to healthy male volunteers. Metabolism Significant levels of three metabolites, desethylhydroxychloroquine (DHCQ), desethylchloroquine (DCQ), and bidesethylhydroxychloroquine (BDCQ) were found in plasma and blood, with DHCQ being the major metabolite Excretion Renal clearance in patients with rheumatoid arthritis treated with hydroxychloroquine sulfate for at least 6 months was similar to that in single dose studies in healthy volunteers, suggesting that no change in clearance occurred with chronic dosing.
The most important pharmacokinetic parameters in determining drug safety for hydroxychloroquine are:
- Absorption: The fraction of the dose absorbed, which can vary greatly among patients.
- Distribution: The extensive distribution to tissues, which can lead to accumulation and potential toxicity.
- Elimination: The long half-life of 123.5 days in plasma, which can lead to prolonged exposure and potential toxicity.
- Metabolism: The formation of significant metabolites, including desethylhydroxychloroquine, desethylchloroquine, and bidesethylhydroxychloroquine.
- Excretion: The renal clearance, which can be affected by renal function and may lead to accumulation and potential toxicity in patients with renal impairment 2.
From the Research
Pharmacokinetic Parameters
The most important pharmacokinetic parameters in determining drug safety include:
- Elimination half-life
- Volume of distribution
- Total clearance
- Fraction of administered dose eliminated by the kidneys
- Free fraction in plasma
- Bioavailability 3
Factors Affecting Pharmacokinetic Parameters
These parameters can be affected by various factors, such as:
- Drug interactions: co-administration of certain drugs can alter the pharmacokinetics of other drugs, leading to increased toxicity or reduced efficacy 4
- Renal function: impaired renal function can affect the clearance of drugs, leading to increased plasma concentrations and potential toxicity 5
- Hepatic function: impaired hepatic function can affect the metabolism of drugs, leading to increased plasma concentrations and potential toxicity 4
Clinical Implications
Understanding these pharmacokinetic parameters is crucial in clinical practice, as it can help clinicians: