Describe the nursing implications of pharmacokinetics and pharmacodynamics

Clinical Pharmacodynamics and Pharmacokinetics

A considerable number of studies have found that the bactericidal activity of vancomycin is concentration independent once a concentration of four to five times the MIC for the organism is reached. Finding the pharmacodynamic parameter able to predict vancomycin treatment success has not been straightforward,53 but it seems that the 24-hour AUC/MIC ratio is the best predictor of efficacy in clinical studies.54,55 For example, in patients with MRSA pneumonia, higher rates of clinical success and more rapid bacterial eradication were associated with achievement of an AUC24/MIC ratio ≥400.55 Of note, no relationship between percentage of time higher than the MIC and response was found in this study.55

For the correct interpretation of the data related to studies addressing the pharmacodynamics of vancomycin, the following considerations should be taken into account: (1) Because vancomycin susceptibility is determined by methods that significantly differ from the standard broth microdilution method (e.g., vancomycin MICs by Etest are onefold or 0.5–1.5 log2 dilution higher than broth microdilution MICs, whereas automated methods such as Sensititre [Thermo Scientific/TREK Diagnostic Systems; Oakwood, OH] and Vitek-2 [BioMérieux, Durham, NC], tend to underestimate the MICs value), small variations in the MIC will represent significant changes in the AUC/MIC ratio; (2) trough level is used as a surrogate marker for AUC because the latter is not calculated in clinical practice; (3) in patients with serious infections, especially those caused by MRSA, vancomycin levels may be used to modify the dose to attain the target serum level; (4) maximal optimization of the vancomycin dosing does not seem to be required for less serious MRSA infections, such as most acute bacterial skin and skin structure infections (ABSSSI), for which dosing based on renal function and actual patient weight is likely to be adequate; (5) measurement of the peak value is not recommended; and (6) low trough vancomycin levels (<10 µg/mL) have been associated with development of hVISA isolates.

For serious infections caused by MRSA, such as endocarditis, bacteremia, arthritis, osteomyelitis, meningitis, pneumonia, and severe ABSSSI, the consensus from the IDSA, the American Society of Health-System Pharmacists, and the Society of Infectious Diseases Pharmacists published in 2009 recommends trough vancomycin concentration between 15 and 20 µg/mL.56 In those receiving vancomycin as a continuous infusion, the recommended target plateau concentration has been 20 to 25 µg/mL. The range of recommended trough serum levels between 15 and 20 µg/mL has been correlated with a 24-hour AUC (±standard deviation) of 418 ±152,46 which will achieve a vancomycin AUC/MIC ratio ≥400 if the MIC of the infecting strain is ≤1 µg/mL. To attain these levels, the vancomycin dose is usually 15 to 20 mg/kg every 8 to 12 hours based on actual body weight in patients with normal renal function. Indeed, a recent prospective study found that dosing vancomycin based on AUC estimation rather than on trough concentration was associated with lower rates of nephrotoxicity, shorter duration of therapy, and lower overall vancomycin exposure.57

Pharmacokinetic and Pharmacodynamic Properties of Anticholinesterases

A large number of clinical studies have examined the pharmacokinetic and pharmacodynamic characteristics of neostigmine, pyridostigmine, and edrophonium.

The pharmacokinetic profiles of neostigmine, pyridostigmine, and edrophonium are presented inTable 28.3. Most studies have used a two-compartment model to establish pharmacokinetic characteristics of each agent. Following a bolus administration, plasma concentrations peak rapidly and decline significantly within the first 5 to 10 minutes. This is followed by a slower decline in plasma concentrations due to the elimination phase.79 In general, the pharmacokinetic profiles of all three anticholinesterases are similar. Early studies suggested that the duration of edrophonium was too short for clinical use. However, studies using larger doses (0.5 or 1.0 mg/kg) demonstrated that the elimination half-life of edrophonium was not significantly different from that of neostigmine or pyridostigmine and that edrophonium could produce prompt and sustained reversal of neuromuscular blockade.80,81 The longer elimination half-life of pyridostigmine likely accounts for the longer duration of action compared with the other anticholinesterase drugs.82

The pharmacokinetics of anticholinesterases can be influenced by renal function, age, and body temperature. The elimination half-life of all three agents is altered by the presence of renal insufficiency or failure (seeTable 28.3). Renal excretion accounts for approximately 50% of plasma clearance of neostigmine; elimination half-life is significantly prolonged and serum clearance decreased in anephric patients.83 Similarly, renal function accounts for 70% to 75% of serum clearance of pyridostigmine and edrophonium.82,84 The reduced plasma clearance of the anticholinesterases in renal failure patients provides a “margin of safety” against the risk of postoperative “recurarization” (the effects of the NMBD persist longer than that of the reversal agent, resulting in a worsening of residual paresis). The pharmacokinetics of edrophonium have been examined in older adult (age > 70 years) patients. When compared with a younger cohort, older adult patients exhibited a significant decrease in plasma clearance (5.9 ± 2 vs. 12.1 ± 4 mL/kg/min) and a prolonged elimination half-life (84.2 ± 17 vs. 56.6 ± 16 minutes).85 Mild hypothermia (reduction in core temperature of 2°C) more than doubles the duration of action of intermediate-acting NMBDs.86 In a study of human volunteers cooled to 34.5°C, the central volume of distribution of neostigmine decreased 38% and the onset time of maximal blockade increased from 4.6 to 5.6 minutes.87 However, the clearance, maximal effect, and duration of action of neostigmine were not altered by a reduction in body temperature. Therefore if hypothermia influences the degree of neuromuscular recovery, it is likely secondary to an effect on the pharmacology of NMBDs (not the anticholinesterase).

2.20.2.2.1 Pharmacodynamic biomarkers

PD biomarkers are markers of a certain pharmacological response that is directly linked to engagement of the primary molecular target by the drug. As such, PD markers intervene upstream in the cascade of events that ultimately lead to the disease and are thus also referred to as proximal biomarkers as opposed to distal biomarkers (or efficacy biomarkers). Importantly, PD markers are modulated by drug treatment in a drug concentration-dependent manner and hence, correlate drug concentration to target occupancy when not at saturation. These biomarkers are crucial in gaining insight into disease mechanisms for first-in-class drugs with a novel nonvalidated mechanism of action. For example, if the PD biomarker indicates a strong target engagement but this relates to a lack of clinical effect, it is very likely that the biological process that is modulated does not play a prominent role in the pathophysiology leading to the disease, or that the patient population was inadequately selected. Ideally, a suitable PD biomarker should therefore be identified early on in the drug development process before or during proof-of-efficacy animal studies. The translatability of the PD biomarker from animal models to humans is critical such that any findings from preclinical studies can be appropriately bridged to the clinical setting. For example, the robustness and suitability of soluble IL-6 receptor levels as a PD biomarker for anti-IL-6 receptor biologics (ALX-0061 and tocilizumab) has been shown both nonclinically9 and clinically.10

3.3 PD Biomarkers and Linkage to Clinical End Points

PD biomarkers play a clear role in ensuring that the pharmacology of novel therapeutics is adequately tested in early clinical studies. For most therapeutics currently in development, direct target, MOA, and general asthma inflammatory biomarkers are now routinely being measured. The remaining question concerns the linkage between the PD biomarkers and clinical end points. The underlying molecular pathways driving end points such as asthma exacerbations, FEV1, and symptoms are extremely complex, likely multifactorial, and different for each end point. PD biomarkers such as FeNO, cytokines, eosinophils, and IgE are each likely to play some part in the pathophysiology underlying the clinical end points of asthma, but they do not tell the whole story. Continued evaluation of the mechanisms of novel therapeutics in different patient subsets will help further the understanding of the molecular pathways underlying the symptoms characteristic of asthma. Because a direct link between the PD biomarkers and clinical end points generally applied to asthma clinical trials has not been established to date, caution should be exercised when using PD biomarkers to predict clinical outcome and to compare different therapeutics directly. Using PD biomarkers to compare different therapeutics and predicting clinical outcome can only be effectively done when comparing therapeutics blocking the same target, as may be the case with follow-on biologics.

Population Pharmacoepigenomics in Relation to Pharmacodynamics

Pharmacodynamics is the branch of pharmacology dealing with the mechanisms of action of drugs. Pharmacodynamics involves the study of the biochemical and physiological changes produced by drugs in the body during the prevention and treatment of disease. It is well known that the major way by which drugs act is via drug receptors [50]. Like pharmacokinetics, pharmacodynamics is known to vary between individuals and populations. Population pharmacodynamics refers to the study of the variability in pharmacological effects of drugs between individuals when standard dosage regimens of drugs are administered [51]. Like in the case of pharmacokinetics, many variables in patients can influence pharmacodynamics (Table 33.2). These include age [33,52], sex [53], racial and ethnic factors [54,55], and disease statuses [53]. It is likely that epigenetics plays a major role in the ways by which all these patient variables modify the mechanisms of action of drugs in the body (Table 33.3) [2,42,56–58]. However, at present, like in the case of pharmacokinetics, very little is known about how the epigenetic regulation of genes underlying drug receptors varies between individuals and within and between populations, and how interindividual differences in the epigenetic regulation of genes encoding drug receptors contribute to interindividual differences in pharmacodynamics [2,42].

Table 33.2. Patient Variables Affecting Pharmacodynamics

VariablesReferencesAge[52]Sex[34]Race and ethnicity[54,55]Disease status[50,53]

Table 33.3. Evidence for an Epigenetic Basis for Patient Variables Affecting Pharmacokinetics and Pharmacodynamics

VariablesReferencesAge[40]Sex[45]Body weight[46]Race and ethnicity[43]Diet and nutrition[47]Disease status[48]

3.3 Pharmacodynamic/response biomarker

Pharmacodynamic/response (PD) biomarkers present a vast spectrum of applications from the early phases of the discovery research to the clinical trials, and later, during the clinical practice. This type of biomarker may be defined as “a biomarker used to show that a biological response occurred in an individual exposed to a medical product or an environmental agent” (FDA-NIH Biomarker Working Group, 2016). Broadly, these biomarkers provide information about proof of mechanism, proof of concept, selection of optimal biological dosing, and understanding response/resistance mechanisms.

As a proof of mechanism, PD biomarkers indicate that the drug acts on its key target, such as the evaluation of receptor occupancy or monitoring ligand disposition. The results collected in this respect facilitate the construction of pharmacokinetic-pharmacodynamic models in later stages.

As a proof of concept, PD biomarkers are used to prove that the action of the drug on its key target modifies the course of the disease. For example, in initial studies of drug development, measurements of PD biomarkers in animal models of the disease are used to highlight its potential therapeutic efficacy in humans providing information about the active doses for human pharmacological effects. PD biomarkers are also used in clinical trials, being crucial to establish optimal biological doses and dosing frequency. In most cases, primary outcomes of clinical trials are PD biomarkers determinations, such as laboratory measurements or radiographic images that allow to predict clinical benefits. But also, these biomarkers are secondary or surrogate endpoints, providing complementary information to support efficacy (see below). Thus, PD biomarkers represent an essential role in clinical trials providing relevant information about the clinical benefit of the drug needed for its final approval to be marketed.

Why is it important as nurses to understand pharmacology pharmacokinetics and pharmacodynamics?

What are nursing implications in pharmacology?

What is the importance of pharmacodynamics in nursing practice?

What is the importance of knowing the pharmacokinetics and pharmacodynamics of drugs?