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Emerging Evidence in NSAID Pharmacology: Important Considerations for Product Selection
Tracy S. Hunter, PhD, MS, BS Pharm; Chip Robison, PharmD, RPh; and Philip P. Gerbino, PharmD, BSc

Emerging Evidence in NSAID Pharmacology: Important Considerations for Product Selection

Tracy S. Hunter, PhD, MS, BS Pharm; Chip Robison, PharmD, RPh; and Philip P. Gerbino, PharmD, BSc
Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used in the treatment of pain and inflammation. Emerging pharmacokinetic and pharmacodynamic evidence in NSAID pharmacology provides important criteria for selecting an appropriate NSAID. The inhibition of COX enzymes by NSAIDs affects physiologic functions in the gastrointestinal, cardiovascular, and renal systems. Of the 2 principal types of COX enzymes, COX-1 and COX- 2, the pain-relieving (anti-hyperalgesia) effects of NSAIDs are driven mainly by the inhibition of COX-2. Commonly, NSAIDs are categorized by in vitro selectivity (ie, the ratio of the NSAID concentrations required for inhibition of COX-1 and COX- 2) as selective or nonselective. Theoretically, the concept of selectivity is convenient; however, the actual relative inhibition of COX-1 and COX-2 isoenzymes measured in vitro is dose-dependent. As a result, the predicted in vivo reduction of prostanoidinduced hyperalgesia and the expected adverse effects of an NSAID are dose dependent. Individual NSAIDs also differ on pharmacokinetic and pharmacodynamic parameters such as the absorption, time to availability of drug at the site of inflammation, and persistence at the site of inflammation. NSAIDs with longer half-life durations may offer longer durations of analgesia due to continued COX enzyme inhibition, but may provide less opportunity for recovery of COX activity between doses than NSAIDs with shorter half-lives. Understanding these pharmacokinetic and pharmacodynamic factors informs selection of an appropriate NSAID among this heterogeneous class of drugs.

Am J Manag Care. 2015;21:S139-S147
Nonsteroidal anti-inflammatory drugs (NSAIDs) are a heterogeneous group of drugs widely used in managing a spectrum of conditions, including musculoskeletal conditions caused by inflammatory and degenerative joint diseases, low back pain, discomfort associated with minor injuries, and headache.1,2 As the overall US population increases in size and age, the number of individuals receiving prescription NSAIDs is likely to increase. Because a large number of NSAIDs are commercially available, it is important to consider several factors that contribute to the diversity of this drug class when choosing the most appropriate NSAID for a patient.3

As a group, NSAIDs are broadly classified as nonselective (ie, “traditional”) or selective, based on their relative preference for the cyclooxygenase (COX)-2 enzyme inhibition.1,4 Beyond this broad categorization of NSAIDs according to COX selectivity, marked variability in clinical differences exists among NSAIDs with similar degrees of COX selectivity.4 To achieve a thorough understanding of the differences among NSAIDs, it is necessary to consider the effects of dosing as well as the impact of pharmacokinetics, including absorption and half-life, on efficacy and tolerability.

The purpose of this article is to summarize considerations for informed NSAID selection based on emerging pharmacokinetic and pharmacodynamic data, as well as information from observational studies that highlight the potential impact of immediate versus extended/delayed release formulations of some NSAIDs. These considerations provide a basis for understanding how the risk for gastrointestinal (GI), cardiovascular (CV), and renal events might be mitigated.5-9

Normal COX Physiology

To distinguish among commercially available NSAIDs, it is first necessary to consider their overall mechanism of action and the physiologic systems affected by modulation of COX enzymes.10 COX enzymes are key mediators in the biosynthesis of prostanoids central to numerous biological processes, including inflammatory reactions (eg, modulation of prostaglandin D2 production by mast cells and thromboxane A2 by macrophages), protection of the gastrointestinal mucosa, hemostasis (platelet function), and maintenance of endothelial function.10,11 Two main isoforms of COX enzymes have been identified, and are referred to as COX-1 and COX-2.10,12 Although both COX enzymes are targets of NSAID therapy, notable differences include the location at which they are expressed in the body, and outcomes associated with their inhibition. COX-1 is expressed constitutively in most tissues, such as gastric mucosa and platelets, and performs protective functions in various organ systems.13 In contrast, COX-2 is induced in various cell types, such as those in the vascular endothelium and joints, during tissue damage and inflammation. The pain-relieving effects of NSAIDs due to their effects on hyperalgesia are primarily a function of COX-2 inhibition.5 However, it should be noted that agents with a higher degree of COX-2 selectivity have been associated with an increased rate of dose-related CV adverse events (AEs). In contrast, agents with a higher degree of COX-1 inhibition are principally responsible for serious gastrointestinal AEs.14

COX Inhibition of NSAIDs

Structurally, NSAIDs differ in their intrinsic ability to inhibit COX-1 and COX-2, with individual NSAIDs tending to be more selective for one COX enzyme than the other.11 Therefore, NSAIDs are normally characterized based on their in vitro COX selectivity, which has been described as the ratio of concentrations required to inhibit the activity of COX-1 or COX-2 by 50% (inhibitory concentration [IC]50 for COX-1 divided by the IC50 for COX-2) (Figure 1).5 When the ratio is close to 1.0, the NSAID is deemed a nonselective COX inhibitor; in contrast, NSAIDs with selectivity ratios <1 are considered more selective for COX-1. NSAIDs with COX selectivity ratios >1 are considered more potent in inhibiting COX- 2.5 A comparison of the ratios of IC50 for COX-1 and COX-2 among several popular NSAIDs demonstrates that diclofenac and celecoxib have a similar degree of selectivity for COX-2 (Table 1).5,11,15-20

The Relationship Between COX Selectivity and NSAID Dose

NSAID COX selectivity is not limited to the structural properties of the compound; COX-1/COX-2 selectivity is also markedly affected by the dose of NSAIDs.5,14 Therefore, although in vitro selectivity described by the IC50 may be useful as a starting point to characterize NSAID selectivity, the selective inhibition of either COX-1 or COX-2 may be better characterized based on in vivo measures of COX inhibition with dose as a continuous variable, a phenomenon referred to as achieved selectivity. In other words, in contrast to the in vitro measures of selectivity, the achieved selectivity varies according to the administered dose.5,11

Both in vitro and achieved COX isoenzyme selectivity may be determined using a human whole blood assay.5,17,21 The in vitro human whole blood assay quantitatively determines an NSAID’s ability to inhibit COX-2 activity (as indicated by prostaglandin E2 [PGE2] levels). The procedure involves (1) obtaining whole blood samples from healthy individuals, (2) eliminating any contribution of COX-1 enzyme activity to PGE2 production by incubating the blood sample in the presence of aspirin for 24 hours, and (3) adding lipopolysaccharide (LPS) to the blood sample, which stimulates COX-2 enzymes to produce PGE2 in the presence of various concentrations of NSAIDs in vitro.17,22 The degree of COX-2 inhibition is then analyzed to estimate the concentration of an NSAID at which production of the COX-2 activity marker PGE2 is reduced by half—the in vitro 50% inhibitory concentration, or IC50.17 A similar procedure can be used to determine the inhibitory effect of a given NSAID on COX-1 at several different concentrations by monitoring levels of the COX-1 enzyme activity marker thromboxane B2. In this instance, neither aspirin nor LPS are added to the whole blood samples.17,22 With these data, the in vitro IC50 value for COX-1 inhibition in human whole blood for a given NSAID can be estimated.17 Comparing the COX-2 and COX-1 IC50 values as a ratio provides an estimate of an NSAID’s selectivity but does not indicate the actual ratio of inhibition of COX-2 to COX-1 achieved in vivo at commonly prescribed NSAID doses. However, the whole blood assay can be used to determine the degree of COX-1/COX-2 inhibition (the achieved selectivity) in vivo at NSAID concentrations equivalent to in vivo blood levels in humans administered commonly prescribed NSAID doses (Figure 1B).5 Thus, in vivo measures of COX-1/COX-2 inhibition may provide a more clinically relevant view of the relationship between NSAID dose and selectivity.5,23

Achieved selectivity for various NSAIDs can be found in a number of pharmacologic studies where the COX-inhibitory effects of NSAIDs are assessed by administering commonly prescribed NSAIDs to healthy human volunteers. In these studies, diclofenac was associated with a greater percentage of inhibition of COX-2 compared with therapeutic doses of other traditional NSAIDs and celecoxib.6,7 The mean percent inhibition of COX-2 was 93.9% for diclofenac (50 mg 3 times daily), 77.5% for meloxicam (15 mg daily), 71.5% for naproxen (500 mg twice daily), and 71.4% for ibuprofen (800 mg 3 times daily) (Figure 2).6 At these same doses, naproxen and ibuprofen demonstrated higher percentages of COX-1 inhibition compared with diclofenac and meloxicam. Mean COX-1 inhibition was 95% for naproxen, 89% for ibuprofen, 53% for meloxicam, and 50% for diclofenac.6 A more recent study used similar methodology for determining COX-1 and COX-2 inhibition— ie, whole blood samples for LPS-induced PGE2 formation as a measure of COX-2 inhibition and serum thromboxane B2 generation in clotting whole blood for determining COX-1 activity. This study compared the COX inhibition of diclofenac (75 mg twice daily) with celecoxib (200 mg twice daily) and etoricoxib (90 mg daily) and found that, at anti-arthritic doses, diclofenac demonstrated significantly (P <.001) greater maximal COX-2 inhibition than etoricoxib and celecoxib.24 Diclofenac and celecoxib demonstrate virtually superimposable dose-response relationships for COX-2 and COX-1, suggesting that they have similar COX selectivity profiles, yet different potencies (Figure 3).16,25-27 These data suggest the importance of understanding achieved selectivity when deciding on the appropriate dose.

NSAID Dose, COX-2 Selectivity, and Anti-Hyperalgesic Effects

Determining the drug concentration necessary for achieving pain relief is another important consideration when selecting the appropriate NSAID, due to their anti-hyperalgesic effects. IC80 concentrations of NSAIDs for COX-2 have been found to correlate with analgesia.19,28 The ratio of IC50 values for COX-1 to COX-2 inhibition for each NSAID provides some indication of the relative inhibitory activity of each NSAID on the COX-1 and COX-2 isoenzymes.11,15 The selectivity of diclofenac for COX-2 over COX-1 inhibition in vitro is lower than that of celecoxib, but diclofenac provides greater COX-2 selectivity than meloxicam, etodolac, ibuprofen, and naproxen.11 Specifically, the concentration of diclofenac necessary to reduce the activity of COX-1 by 50% is 29 times the concentration of diclofenac needed to reduce the activity of COX-2 by 50%; the same ratio for celecoxib is slightly higher at 30.11,15 In contrast with the selectivity of celecoxib and diclofenac, the IC50 selectivity ratio for meloxicam is 18 (Table 1).15-20

The Effect of NSAID Dosing on Adverse Events

The risks of GI and CV AEs are related to the same mechanisms associated with NSAID benefits—namely, inhibition of COX-dependent prostanoids synthesis.11 For example, COX-1 inhibition has been associated with decreased platelet aggregation and GI toxicity.6,14,20 Prostaglandin I2 (PGI2), a prostanoid with cardioprotective properties, is generated by COX-2 and promotes vasodilation and inhibition of platelet aggregation. The inhibition of PGI2 is thought to be a plausible mechanism for CV risks associated with the use of NSAIDs, such as myocardial infarction.5,11 Available data from observational studies strongly suggest that GI and CV events and renal failure are related to total daily dose in patients treated with NSAIDs.8,9,29,30

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