Abstract
Objective
Our objective was to examine the relationship between colchicine plasma concentrations and clinical and demographic factors and to determine the relationship between colchicine concentrations and colchicine efficacy and colchicine‐specific adverse events.
Methods
Post hoc analyses were undertaken using data from a 12‐month randomized controlled trial involving 200 people with gout that compared low‐dose colchicine to placebo for the first six months while starting allopurinol, with a further six‐month follow‐up. Steady‐state colchicine plasma concentrations were measured 30 to 80 minutes post dose (assumed peak) and just before the dose (trough) at month three, and creatine kinase (CK) levels were measured at months zero, three, and six. Self‐reported gout flares, adverse events, and serious adverse events were collected monthly.
Results
Peak and trough colchicine concentrations were available for 79 participants in the colchicine arm. Multivariable analysis showed that those taking a statin and non‐Māori and non‐Pacific ethnicity were independently associated with higher trough concentrations, and age older than 60 years was independently associated with higher peak concentrations. Trough and peak colchicine concentrations were significantly higher in those who had any adverse event between months four and six. However, there was no association between colchicine concentrations and colchicine‐specific adverse events (gastrointestinal and muscle) or with CK changes in the colchicine‐treated patients.
Conclusion
Trough or peak colchicine concentrations are not associated with gout flare prophylaxis efficacy. There is no consistent relationship between colchicine concentrations and colchicine‐specific adverse events. Although colchicine concentrations increase with concomitant statin use, this does not result in muscle‐related adverse events. These findings indicate that colchicine therapeutic drug monitoring is of limited value in clinical practice.
INTRODUCTION
Low‐dose oral colchicine (0.5 mg once or twice daily) is one of the first‐line recommended therapies for prevention of gout flares when commencing urate‐lowering therapy. 1 Although colchicine may be effective, it has a number of potential adverse events, of which the most common are gastrointestinal, including nausea and diarrhea. In people with gout, gastrointestinal adverse events are dose dependent, with more gastrointestinal adverse events observed in those who received a higher dose (4.8 mg over four hours) versus a low dose (1.8 mg over one hour) in a study of gout flares, albeit with no difference in circulating maximum concentration (Cmax) between the two colchicine doses in healthy volunteers. 2 Other less common adverse events include bone marrow suppression and neuromyotoxicity, which may occur with more prolonged use. 3
SIGNIFICANCE & INNOVATIONS.
Colchicine concentrations increase with concomitant statin use; this does not result in muscle‐related adverse events.
Regular monitoring of creatine kinase (CK) may not be required; rather, targeted measurement of CK in individuals with muscle symptoms may be more appropriate.
Colchicine therapeutic drug monitoring is of limited value in clinical practice.
Impaired kidney function, which is common in people with gout, is reported to be a predictor of colchicine adverse events. 4 Because of the risk, it has been suggested that a complete blood count and a creatine kinase (CK) measurement should be performed every six months in patients who are receiving long‐term prophylactic colchicine, defined as 0.5 mg daily for six or more months. 5 The prolonged period suggested for anti‐inflammatory prophylaxis and the risk of adverse events have led to a general reluctance to use prophylaxis by many clinicians and people with gout. A study of a nurse‐led educational intervention for people with gout with recurrent flares reported that only 4% of participants opted for anti‐inflammatory prophylaxis when urate‐lowering therapy was increased. 6 Thus, the ability to accurately predict who may obtain the most clinical benefit with the least adverse events based on clinical factors would be of clinical use.
Colchicine is rapidly absorbed from the gastrointestinal tract, with an oral bioavailability of around 50% on average. Colchicine is primarily eliminated through biliary excretion and feces. Colchicine is mainly transported into the gastrointestinal tract by the multidrug resistance transporter molecule P‐glycoprotein. 7 Enteric and hepatic cytochrome P450 3A4 (CYP3A4), which catalyzes demethylation of colchicine to inactive metabolites, also contributes to colchicine metabolism, along with a minor (10%–20%) contribution to elimination via the kidneys. 8 Importantly, CYP3A4 and P‐glycoprotein are very frequently colocalized, such that many drugs mutually and robustly inhibit CYP3A4 and P‐glycoprotein. 9 Colchicine is also subject to a range of drug interactions, particularly with CYP3A4 inhibitors, which can result in a doubling of colchicine plasma concentrations, and with P‐glycoprotein inhibitors, which may quadruple colchicine concentrations. 10
Therapeutic drug monitoring (TDM) is the use of drug concentrations to guide therapy to improve drug efficacy and/or reduce toxicity. It has particular benefits for drugs with a narrow therapeutic range, in which the difference between clinically effective concentrations and concentrations associated with adverse events is small. Colchicine has a narrow therapeutic range, with many patients experiencing dose‐dependent gastrointestinal toxicity. Plasma colchicine concentrations have been measured in some cases of fatal colchicine overdose, with levels ranging from 10 to 250 ng/mL (10–250 μg/L). 11 Effective steady‐state plasma concentrations have been reported to range from 0.5 to 3 μg/L, with toxic effects occurring 12 at approximately 3 μg/L. Colchicine doses of 0.5 mg twice daily and 0.6 mg daily have been reported to maintain serum levels within the steady‐state range in healthy individuals and those with mild to moderate renal impairment or concomitant use of most interacting medications. 13
To date no studies have specifically examined the relationship of colchicine concentrations with clinical efficacy and/or colchicine‐specific adverse events in people with gout. Thus, the aim of this study was to examine the relationship between colchicine concentrations and clinical and demographic factors, including age, body weight, renal function, sex, ethnicity, and concomitant medications, and to determine the relationship between colchicine concentrations and colchicine efficacy (defined as occurrence of gout flares) and colchicine‐specific adverse events, with a particular focus on gastrointestinal and muscle‐related adverse events.
MATERIALS AND METHODS
Study design
Post hoc analyses of the 12‐month “Is colchicine prophylaxis required with start‐low go‐slow allopurinol dose escalation in gout?” noninferiority randomized controlled trial were undertaken (ACTRN 12618001179224). The methods and results of the full trial have been reported. 14 Briefly, this was a one‐year double‐blind placebo‐controlled noninferiority trial with participants randomized 1:1 to colchicine at 0.5 mg daily or placebo for the first six months. All participants commenced allopurinol, increasing monthly to achieve a target urate level of <0.36 mmol/L. Starting doses of allopurinol were 50 mg daily in those with estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2 and 100 mg daily in those with eGFR ≥60 mL/min/1.73 m2. The allopurinol doses were increased monthly by 50 mg daily in those with eGFR <60 mL/min/1.73 m2 and by 100 mg daily in those with eGFR ≥60 mL/min/1.73 m2 until the serum urate level was <0.36 mmol/L (6 mg/dL) for three consecutive visits. Ethical approval was obtained from the Health and Disability Ethics Committee, New Zealand (18/STH/156), and all participants provided written informed consent.
Participants were seen in person every three months by study coordinators, with intervening monthly telephone assessments. Gout flares, defined as self‐reported gout flares requiring treatment, were recorded at each monthly assessment. Adverse events and serious adverse events were collected monthly and coded according to Common Terminology Criteria for Adverse Events (CTCAE v5.0). Participants were asked about the occurrence of any adverse events as well as colchicine‐specific adverse events (abdominal pain, nausea, vomiting, diarrhea, muscle weakness, and myalgia). Blood samples were obtained monthly for serum urate and creatinine; every three months for complete bloodcount, alanine transaminase, alkaline phophatase, and gamma glutamyl transferase; and at baseline, month three, and month six for CK. Nonfasting plasma samples were collected for trough colchicine plasma concentrations (just before the next colchicine dose) and the assumed peak (30–60 minutes post dose) colchicine concentrations at month three.
Colchicine assay
Colchicine concentrations in plasma were performed using a liquid chromatography tandem mass spectrometry (LC‐MS/MS) assay developed and validated by Clinical Pharmacology, University of Otago, Christchurch and Toxicology, Canterbury Health Laboratories. Briefly, 50 mL of the internal standard (IS) colchicine‐d6 (5.0 ng/mL colchicine‐d6 in water) was added to 50 mL of the plasma sample, followed by 200 mL of acetonitrile to precipitate the proteins for plasma sample cleanup. After centrifugation, the clear supernatant was diluted 1:1 with the mobile phase, and then a 10‐mL aliquot was injected into the AB Sciex API 4000 LC‐MS/MS system. The AB Sciex API 4000 LC‐MS/MS system consisted of a Shimadzu LC‐20AD HPLC system (Shimadzu Corporation) interfaced with an AB Sciex API 4000 triple quadrupole mass spectrometer (Applied Biosystems) equipped with a TurboIonSpray source. Chromatographic separation of colchicine and colchicine‐d6 was achieved under gradient elution of 10 mM ammonium acetate and acetonitrile using an Agilent Poroshell 120 EC‐C18 50 × 3.0 mm, 2.7‐μm column (Agilent Technologies). Colchicine and the IS colchicine‐d6 were monitored by performing multiple‐reaction monitoring scans in positive electrospray ionization mode. The optimized precursor‐to‐product ion transitions monitored for colchicine [M + H]+ and colchicine‐d6 [M + H]+ were mass/charge (m/z) 400.2 > 358 and m/z 406.2 > 362, respectively. Analyst software (Applied Biosystems) was used to control the equipment, to coordinate data acquisition, and to analyze data. Under the chromatographic conditions employed, the total analysis time was six minutes for each sample, and colchicine and colchicine‐d6 peaks were free of interference from any other peaks present in the plasma blanks. The colchicine standard curve was adequately fitted by 1/x weighted quadratic regressions over the concentration range of 0.1 to 10 ng/mL (r > 0.999), and the lower limits of the quantification was 0.1 ng/mL. The accuracy and precision were assessed at the low‐, medium‐, and high‐level quality controls (QCs). There was no constant direction to the bias (ie, plus or minus) for QCs, and the mean values were within ±4.0% of the spiked values. The intraday and interday coefficients of variation over the analyzed concentration ranges were <7.0%. The recoveries of colchicine from plasma at concentrations of QC were similar and consistent, with mean values >90%. No significant matrix effects were observed.
Statistics
Peak and trough colchicine concentrations at month three were compared between the demographic and clinical features using one‐way analysis of variance (ANOVA). Similarly, these concentrations were compared between disease states, the occurrence of gout flares, and the presence of treatment‐emergent adverse events using one‐way ANOVA. A multivariable regression analysis was also undertaken to explore the potentially independent associations of the demographic and clinical features with the peak and trough colchicine concentrations at month three. These regression models included all the demographic and clinical features and used forward and backward stepwise procedures. Gout flare states at the month six visit were defined as previously described 15 : (1) patient acceptable state (PASS), no gout flares in the preceding six months; (2) low disease activity (LDA) state, one flare in the preceding six months; and (3) non‐LDA/PASS, more than one gout flare in each of the preceding six months. CK levels and changes at months three and six were compared between the demographic and clinical features using one‐way ANOVA. The associations between colchicine and CK concentrations were tested using Pearson's correlation coefficients. The colchicine and CK concentrations were log transformed before analysis to normalize distributions and are summarized as geometric means or geometric mean ratios (GMRs) with 95% confidence intervals (CIs). All analyses were undertaken using SPSS v29.0. Analyzed data may be made available to external collaborators upon reasonable request following review by the trial steering committee with appropriate acknowledgments.
RESULTS
Baseline characteristics of participants included in this analysis
Peak and trough colchicine concentrations were available for 79 participants in the colchicine arm. Demographics of the 79 participants at month three are outlined in Supplementary Table 1. The median time between the dose of colchicine and peak samples was 30 (interquartile range 30–70) minutes.
Relationship between colchicine concentrations and participant variables
As expected, mean trough colchicine concentrations were lower than mean peak concentrations (0.30 ng/mL vs 0.61 ng/mL; P < 0.001). Trough colchicine concentrations were significantly higher in participants who were >60 years of age, were of non‐Māori or non‐Pacific ethnicity, had eGFR <60 mL/min/1.73 m2, had a body mass index of <30, and were taking a statin (Table 1). Peak colchicine concentrations were also significantly higher in those >60 years of age and those taking a statin (Table 1).
Table 1.
Relationship between mean trough and peak colchicine concentrations and clinical and demographic factors*
| Trough colchicine concentration, ng/mL | Peak colchicine concentration, ng/mL | |||
|---|---|---|---|---|
| Mean (95% CI) | P | Mean (95% CI) | P | |
| Age | 0.002 | 0.01 | ||
| <60 y (n = 44) | 0.24 (0.20–0.29) | 0.51 (0.41–0.64) | ||
| ≥60 y (n = 35) | 0.39 (0.31–0.48) | 0.77 (0.61–0.98) | ||
| Sex | 0.55 | 0.62 | ||
| Female (n = 6) | 0.26 (0.10–0.69) | 0.71 (0.34–1.47) | ||
| Male (n = 73) | 0.30 (0.26–0.35) | 0.61 (0.51–0.72) | ||
| Ethnicity | 0.005 | 0.09 | ||
| Māori (n = 12) | 0.20 (0.12–0.33) | 0.57 (0.34–0.98) | ||
| Pacific peoples (n = 11) | 0.21 (0.13–0.34) | 0.40 (0.26–0.62) | ||
| Non‐Māori/non‐Pacific peoples (n = 56) | 0.35 (0.30–0.41) | 0.68 (0.56–0.82) | ||
| eGFR | 0.002 | 0.14 | ||
| ≤60 mL/min/1.73 m2 (n = 12) | 0.49 (0.33–0.74) | 0.76 (0.50–1.18) | ||
| >60 mL/min/1.73 m2 (n = 67) | 0.27 (0.34–0.32) | 0.59 (0.49–0.71) | ||
| BMI | 0.02 | 0.22 | ||
| <30 (n = 32) | 0.37 (0.31–0.45) | 0.69 (0.56–0.87) | ||
| ≥30 (n = 47) | 0.26 (0.21–0.32) | 0.57 (0.45–0.71) | ||
| Statin | <0.001 | 0.02 | ||
| Yes (n = 19) | 0.49 (0.38–0.64) | 0.87 (0.61–1.25) | ||
| No (n = 60) | 0.26 (0.22–0.30) | 0.55 (0.46–0.66) | ||
| Calcium channel blocker | 0.72 | 0.18 | ||
| Yes (n = 8) | 0.32 (0.16–0.64) | 0.86 (0.51–1.44) | ||
| No (n = 71) | 0.30 (0.25–0.35) | 0.59 (0.50–0.71) | ||
BMI, body mass index; CI, confidence interval; eGFR, estimated glomerular filtrtation rate.
Multivariable analysis showed that those taking a statin (0.39 ng/mL vs 0.22 ng/mL, GMR 1.76, 95% CI 1.30–2.40) and those of non‐Māori or non‐Pacific ethnicity (0.39 ng/mL vs 0.26 ng/mL, GMR 1.54, 95% CI 1.15–2.05) were independently associated with higher trough colchicine concentrations. Only age >60 years (0.77 ng/mL vs 0.51 ng/mL, GMR 1.51, 95% CI 1.10–2.07) was independently associated with higher peak colchicine concentrations.
Relationship between colchicine concentrations, gout flares, and gout disease activity states
There was no significant difference in mean trough or peak colchicine concentrations at month three between the three gout flare states in months one to six (Table 2). Likewise, there was no association between colchicine concentrations at month three and experience of at least one gout flare between months zero and three or months four and six (Table 2). There was no association between colchicine concentration at month three and experience of at least one gout flare between months seven and nine, the period immediately after colchicine had been stopped (Table 2).
Table 2.
Peak and trough colchicine concentrations and gout flare outcomes*
| Trough colchicine concentration, ng/mL | Peak colchicine concentration, ng/mL | |||
|---|---|---|---|---|
| Mean (95% CI) | P | Mean (95% CI) | P | |
| Months 1–6 | 0.52 | 0.52 | ||
| PASS (n = 28) | 0.33 (0.25–0.42) | 0.70 (0.53–0.92) | ||
| LDA (n = 16) | 0.32 (0.23–0.44) | 0.59 (0.41–0.85) | ||
| Non‐LDA/PASS (n = 35) | 0.27 (0.22–0.34) | 0.57 (0.44–0.72) | ||
| Months 0–3 | 0.42 | 0.37 | ||
| No flare (n = 39) | 0.32 (0.26–0.4) | 0.67 (0.53–0.84) | ||
| Flare (n = 39) | 0.29 (0.23–0.35) | 0.57 (0.45–0.72) | ||
| Months 3–6 | 0.21 | 0.13 | ||
| No flare (n = 3) | 0.36 (0.25–0.53) | 0.79 (0.54–1.15) | ||
| Flare (n = 52) | 0.28 (0.23–0.34) | 0.56 (0.46–0.69) | ||
| Months 7–9 | 0.28 | 0.11 | ||
| No flare (n = 19) | 0.35 (0.26–0.48) | 0.83 (0.59–1.15) | ||
| Flare (n = 43) | 0.29 (0.23–0.35) | 0.60 (0.48–0.75) | ||
PASS: no gout flares in the preceding six months; LDA: one flare in the preceding six months; non‐LDA/PASS: more than one gout flare in each of the preceding six months. CI, confidence interval; LDA, low disease activity state; PASS, patient acceptable state.
Relationship between colchicine concentrations and colchicine‐specific adverse events
Trough and peak colchicine concentrations were significantly higher in those who had any adverse event between months four and six (Table 3). However, there was no significant association between colchicine concentrations and colchicine‐specific gastrointestinal or muscle‐related adverse events. The small number of participants with myalgia or muscle cramps (n = 1–2) precluded further analysis of differences in colchicine concentrations.
Table 3.
Relationship between trough and peak colchicine concentrations and AEs*
| Trough colchicine concentration, ng/mL | Peak colchicine concentration, ng/mL | |||
|---|---|---|---|---|
| Mean (95% CI) | P | Mean (95% CI) | P | |
| Any AE months 0–6 | 0.27 | 0.26 | ||
| Yes (n = 70) | 0.31 (0.26–0.36) | 0.64 (0.53–0.76) | ||
| No (n = 9) | 0.24 (0.14–0.40) | 0.47 (0.27–0.82) | ||
| Any AE months 0–3 | 0.46 | 0.45 | ||
| Yes (n = 60) | 0.31 (0.26–0.37) | 0.64 (0.52–0.78) | ||
| No (n = 19) | 0.27 (0.19–0.38) | 0.55 (0.40–0.75) | ||
| Any AE months 4–6 | 0.01 | 0.04 | ||
| Yes (n = 55) | 0.34 (0.29–0.40) | 0.69 (0.57–0.83) | ||
| No (n = 24) | 0.22 (0.17–0.29) | 0.47 (0.35–0.65) | ||
| Any gastrointestinal AE months 0–6 | 0.87 | 0.38 | ||
| Yes (n = 26) | 0.29 (0.22–0.40) | 0.56 (0.41–0.75) | ||
| No (n = 53) | 0.30 (0.25–0.36) | 0.65 (0.53–0.79) | ||
| Any gastrointestinal AE months 0–3 | 0.46 | 0.29 | ||
| Yes (n = 23) | 0.27 (0.20–0.38) | 0.54 (0.38–0.75) | ||
| No (n = 56) | 0.31 (0.26–0.37) | 0.65 (0.54–0.79) | ||
| Any gastrointestinal AE months 4–6 | 0.50 | 0.28 | ||
| Yes (n = 7) | 0.35 (0.14–0.92) | 0.82 (0.47–1.43) | ||
| No (n = 72) | 0.30 (0.25–0.34) | 0.60 (0.50–0.71) | ||
| Any muscle AE months 0–6 | 0.36 | 0.18 | ||
| Yes (n = 13) | 0.35 (0.23–0.54) | 0.52 (0.31–0.88) | ||
| No (n = 66) | 0.29 (0.25–0.34) | 0.64 (0.53–0.76) | ||
| Any muscle AE months 1–3 | 0.96 | 0.44 | ||
| Yes (n = 7) | 0.30 (0.14–0.62) | 0.50 (0.20–1.27) | ||
| No (n = 72) | 0.30 (0.26–0.35) | 0.63 (0.53–0.74) | ||
| Any muscle AE months 4–6 | 0.20 | 0.83 | ||
| Yes (n = 8) | 0.40 (0.26–0.62) | 0.58 (0.28–1.21) | ||
| No (n = 71) | 0.29 (0.25–0.34) | 0.62 (0.41–0.75) | ||
| Any muscle weakness months 0–6 | 0.62 | 0.25 | ||
| Yes (n = 11) | 0.33 (0.20–0.53) | 0.49 (0.26–0.91) | ||
| No (n = 68) | 0.30 (0.25–0.35) | 0.64 (0.54–0.76) | ||
| Any muscle weakness months 0–3 | 0.46 | 0.24 | ||
| Yes (n = 5) | 0.24 (0.09–0.65) | 0.42 (0.10–1.82) | ||
| No (n = 74) | 0.30 (0.26–0.35) | 0.63 (0.54–0.74) | ||
| Any muscle weakness months 4–6 | 0.20 | 0.83 | ||
| Yes (n = 8) | 0.40 (0.26–0.62) | 0.58 (0.28–1.21) | ||
| No (n = 71) | 0.29 (0.25–0.34) | 0.62 (0.52–0.73) | ||
AE, adverse event; CI, confidence interval.
Relationship between participant demographics and CK and colchicine concentrations
In all trial participants (N = 200), baseline CK levels were significantly higher in men, those >60 years of age, Pacific peoples, those with eGFR >60 mL/min/1.73 m2, and those whose occupation involved physical or manual labor (Supplementary Table 2). There was a significant increase in CK levels from baseline to month three in Māori and from baseline to month six in Pacific peoples (Table 4). No other variables were associated with a change in CK levels (Table 4). In the 79 participants with colchicine concentrations, there was no significant correlation between trough or peak colchicine concentrations and CK levels at month three (r = −0.17, P = 0.13; and r = −0.12, P = 0.30, respectively).
Table 4.
Change in CK from month 0 to month 3, and month 0 to month 6, in all trial participants*
| Colchicine | Placebo | |||
|---|---|---|---|---|
| n | Mean (95% CI) | n | Mean (95% CI) | |
| Change in CK from month 0 to month 3 | ||||
| Age | ||||
| <60 y | 53 | 0.90 (0.76–1.06) | 47 | 0.93 (0.80–1.08) |
| ≥60 y | 37 | 1.2 (1.0–1.43) | 43 | 0.96 (0.84–1.09) |
| Sex | ||||
| Female | 6 | 1.0 (0.74–1.31) | 6 | 0.92 (0.73–1.16) |
| Male | 84 | 1.01 (0.89–1.15) | 84 | 0.94 (0.85–1.05) |
| Ethnicity | ||||
| Māori | 12 | 1.27 (1.10–1.47) | 11 | 1.11 (0.74–1.67) |
| Pacific peoples | 12 | 1.16 (0.71–1.90) | 7 | 0.92 (0.89–1.28) |
| Non‐Māori/non‐Pacific peoples | 66 | 0.94 (0.82–1.09) | 72 | 0.92 (0.83–1.02) |
| eGFR | ||||
| <60 mL/min/1.73 m2 | 12 | 1.17 (0.87–1.17) | 13 | 1.13 (0.841.51) |
| ≥60 mL/min/1.73 m2 | 78 | 0.99 (0.86–1.13) | 77 | 0.91 (0.83–1.01) |
| BMI | ||||
| <30 | 37 | 1.01 (0.84–1.21) | 46 | 0.96 (0.84–1.11) |
| ≥30 | 49 | 1.03 (0.86–1.24) | 40 | 0.88 (0.78–0.98) |
| Statin | ||||
| Yes | 22 | 1.12 (0.86–1.46) | 27 | 1.01 (0.83–1.22) |
| No | 68 | 0.97 (0.84–1.13) | 63 | 0.92 (0.82–1.03) |
| Calcium channel blocker | ||||
| Yes | 9 | 1.07 (0.81–1.41) | 16 | 1.00 (0.78–1.27) |
| No | 81 | 1.00 (0.88–1.15) | 74 | 0.93 (0.84–1.04) |
| Physical or manual occupation | ||||
| Yes | 26 | 0.98 (0.78–1.24) | 29 | 0.85 (0.70–1.04) |
| No | 64 | 1.02 (0.88–1.19) | 61 | 0.99 (0.89–1.10) |
| Change in CK from month 0 to month 6 | ||||
| Age | ||||
| <60 y | 53 | 1.02 (0.82–1.28) | 45 | 1.02 (0.84–1.23) |
| ≥60 y | 38 | 1.15 (0.98–1.35) | 44 | 1.03 (0.89–1.19) |
| Sex | ||||
| Female | 7 | 1.2 (0.96–1.41) | 6 | 0.85 (0.56–1.30) |
| Male | 84 | 1.07 (0.91–1.25) | 83 | 1.03 (0.91–1.17) |
| Ethnicity | ||||
| Māori | 12 | 1.49 (1.15–1.94) | 10 | 1.18 (0.89–1.56) |
| Pacific peoples | 12 | 1.36 (1.00–1.85) | 8 | 0.87 (0.51–1.48) |
| Non‐Māori/non‐Pacific peoples | 67 | 0.97 (0.81–1.16) | 71 | 1.02 (0.89–1.17) |
| GFR | ||||
| <60 mL/min/1.73 m2 | 12 | 1.23 (0.94–1.63) | 16 | 0.85 (0.61–1.20) |
| ≥60 mL/min/1.73 m2 | 79 | 1.05 (0.89–1.24) | 73 | 1.06 (0.94–1.21) |
| BMI | ||||
| <30 | 34 | 1.08 (0.92–1.28) | 44 | 0.90 (0.75–1.11) |
| ≥30 | 51 | 1.09 (0.87–1.36) | 39 | 1.07 (0.95–1.21) |
| Statin | ||||
| Yes | 23 | 1.09 (0.89–1.34) | 28 | 1.01 (0.83–1.22) |
| No | 68 | 1.07 (0.89–1.28) | 61 | 1.03 (0.88–1.20) |
| Calcium channel blocker | ||||
| Yes | 10 | 1.12 (0.75–1.67) | 15 | 1.14 (0.81–1.58) |
| No | 81 | 1.07 (0.91–1.25) | 74 | 1.00 (0.88–1.14) |
| Physical or manual occupation | ||||
| Yes | 26 | 1.21 (0.94–1.55) | 28 | 1.00 (0.81–1.24) |
| No | 65 | 1.03 (0.86–1.23) | 61 | 1.03 (0.89–1.19) |
Data presented are the geometric mean ratios of CK between month 0 and month 3 or 6. BMI, body mass index; CI, confidence interval; CK, creatine kinase; eGFR, estimated glomerular filtration rate.
DISCUSSION
In this analysis of a randomized clinical trial of colchicine for gout flare prophylaxis, there was no significant association between trough or peak colchicine concentrations and occurrence of gout flares. There was also no consistent relationship between trough or peak colchicine concentrations and colchicine‐specific adverse events. However, both trough peak colchicine concentrations were higher in those with any adverse event in months four to six. Although trough and peak colchicine concentrations were higher in those taking a statin, there was no association with an increase in CK levels or muscle‐related adverse events.
From a clinical perspective TDM is likely to be more useful when colchicine is being used in the long term for prophylaxis while starting urate‐lowering therapy rather than in the short term for gout flares. However, we have shown that there is no reliable association between trough or peak colchicine concentrations and either efficacy, defined as gout flares, or colchicine‐specific adverse events. The lack of a relationship with efficacy is not necessarily unexpected because the majority of colchicine accumulates in neutrophils, and its therapeutic effects are mediated through its ability to bind within cells to tubulin monomers, thus preventing the formation of microtubule heterodimers, which are involved in cell division, signal transduction, regulation of gene expression, and migration. 16 It is possible that the higher dose of colchicine for prophylaxis of 0.5 mg twice daily may be more effective at preventing gout flares when starting allopurinol. Interestingly, both trough and peak colchicine concentrations were higher in those with any adverse event in months four to six. However, these results may be confounded by older age and worse renal function as markers of more comorbidities and higher risk of adverse events generally. In this prophylaxis study, colchicine was used at a lower dose and for a much longer duration (0.5 mg daily for six months) compared to the dose and duration for gout flare (1.2 mg stat followed by 0.6 mg after one hour). This likely, at least in part, explains the lower peak concentrations observed in our study as compared to a previous study of the higher dose in healthy volunteers, as the longer duration of therapy could allow more penetration of colchicine into cells and tissues. 2
Of interest we have shown that both trough and peak colchicine concentrations are higher in those individuals receiving a statin. The interaction between colchicine and statins is well recognized, as both are substrates and inhibitors of CYP3A4 and P‐glycoprotein. Approximately 5% of colchicine is metabolized by CYP3A4 into inactive metabolites, with the majority of colchicine excreted via the liver and kidneys mediated by P‐glycoprotein. Simvastatin and atorvastatin are substrates of the CYP3A4 enzyme and P‐glycoprotein and are thus subject to interactions with colchicine, resulting in increased colchicine concentrations. 17 In comparison, pravastatin and rosuvastatin are not substrates of CYP enzymes, and hence the concomitant use of CYP inhibitors or inducers, such as colchicine, does not affect them. Our finding that colchicine concentrations are higher in those receiving a statin is therefore not unexpected. Of more importance to patients and health care providers is whether there are clinically meaningful adverse events associated with the combination of colchicine and a statin. Both colchicine and statins can cause myopathy. There are four statin‐associated myopathy clinical phenotypes: rhabdomyolysis, myalgia or mild hyperCKemia (defined as less than five times the upper limit normal), self‐limited toxic statin myopathy, and myositis, which is typically an immune‐mediated necrotizing myopathy with anti–3‐hydroxy‐3‐methylglutaryl‐coenzyme A reductase antibodies. The number of participants in our study was too small to undertake reliable analysis of those taking a statin and colchicine; however, there was no increase in muscle‐related adverse events, including myalgia, in the whole group receiving colchicine compared to those receiving placebo. More recent larger studies have shown no increased risk of colchicine‐related adverse events in those also receiving a statin. 18 , 19 For example, in a study of 674 people with gout, 486 received colchicine alone and 188 received colchicine and a statin. The incidence of myopathy was 2.7% in those taking both drugs, compared to 1.4% in those taking colchicine alone (P = 0.33). 18 Multivariable analysis revealed an increased risk of myopathy in those with chronic kidney disease (hazard ratio [HR] 29.06), liver cirrhosis (HR 10.68), higher colchicine doses (HR 20.96), and concomitant CYP3A4 inhibitor use (HR 12.02). However, concomitant use of statins was not associated with increased risk of myopathy, even after adjustment for confounders (HR 1.12). 18 In keeping with our findings of no increased risk of myopathy or muscle‐related adverse events, we observed no significant increase in CK levels over six months in those taking colchicine. It is important to recognize that there is variation in CK levels depending on age, renal function, physical activity, and ethnicity. Given the findings of our study and other recent studies, regular monitoring of CK may not be required; rather, targeted measurement of CK levels in individuals with muscle symptoms may be more appropriate.
Strengths of this study include analysis of a randomized clinical trial with consistent measurement of adverse events and blood tests, together with comprehensive concomitant medication data collection. Limitations are that the study was not powered to detect rare adverse events due to colchicine and that the study design did not allow analysis of the safety of higher doses of colchicine or longer durations. The study was not designed as a formal pharmacokinetics study. It is important to note that there is substantial variation in colchicine bioavailability in healthy individuals, with additional variation possible in people with gout, because of polypharmacy and genetic variants in transporters, among other factors. In addition, there is widespread distribution of colchicine into cells and tissues, where its anti‐inflammatory effects are exerted, compared to the much lower levels observed in plasma. The inability to assess drug concentration in tissues where colchicine exerts its anti‐inflammatory effects, such as leucocytes, as well as calculate the volume of distribution is a limitation. The samples collected did not allow us to accurately calculate volume of distribution or area under the curve, and there is wide variation in these parameters, as shown in a small study in healthy volunteers in which total body colchicine clearance was approximately doubled and the area under the curve was approximately four times less for healthy individuals compared with older individuals. 20 Finally, the sampling may have missed the true peak concentrations in some individuals.
In conclusion, colchicine concentrations are not associated with gout flare prophylaxis efficacy, and there is no consistent relationship between colchicine concentrations and colchicine‐specific adverse events. Although colchicine concentrations increase with concomitant statin use, this does not result in muscle‐related adverse events. These findings indicate that colchicine TDM is of limited value in routine clinical practice.
AUTHOR CONTRIBUTIONS
All authors contributed to at least one of the following manuscript preparation roles: conceptualization AND/OR methodology, software, investigation, formal analysis, data curation, visualization, and validation AND drafting or reviewing/editing the final draft. As corresponding author, Dr Stamp confirms that all authors have provided the final approval of the version to be published and takes responsibility for the affirmations regarding article submission (eg, not under consideration by another journal), the integrity of the data presented, and the statements regarding compliance with institutional review board/Declaration of Helsinki requirements.
Supporting information
Disclosure form.
Appendix S1: Supplementary Information
ACKNOWLEDGMENTS
Open access publishing facilitated by University of Otago, as part of the Wiley ‐ University of Otago agreement via the Council of Australian University Librarians.
ACTRN Trial identifier: 12618001179224.
Supported by the Health Research Council of New Zealand and Arthritis New Zealand.
Additional supplementary information cited in this article can be found online in the Supporting Information section (https://acrjournals.onlinelibrary.wiley.com/doi/10.1002/acr.25548).
Author disclosures are available at https://onlinelibrary.wiley.com/doi/10.1002/acr.25548.
REFERENCES
- 1. FitzGerald JD, Dalbeth N, Mikuls T, et al. 2020 American College of Rheumatology guideline for the management of gout. Arthritis Care Res (Hoboken) 2020;72(6):744–760. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2. Terkeltaub RA, Furst DE, Bennett K, et al. High versus low dosing of oral colchicine for early acute gout flare: twenty‐four‐hour outcome of the first multicenter, randomized, double‐blind, placebo‐controlled, parallel‐group, dose‐comparison colchicine study. Arthritis Rheum 2010;62(4):1060–1068. [DOI] [PubMed] [Google Scholar]
- 3. Kuncl RW, Duncan G, Watson D, et al. Colchicine myopathy and neuropathy. N Engl J Med 1987;316(25):1562–1568. [DOI] [PubMed] [Google Scholar]
- 4. Wallace SL, Singer JZ, Duncan GJ, et al. Renal function predicts colchicine toxicity: guidelines for the prophylactic use of colchicine in gout. J Rheumatol 1991;18(2):264–269. [PubMed] [Google Scholar]
- 5. Mikuls TR, MacLean CH, Olivieri J, et al. Quality of care indicators for gout management. Arthritis Rheum 2004;50(3):937–943. [DOI] [PubMed] [Google Scholar]
- 6. Rees F, Jenkins W, Doherty M. Patients with gout adhere to curative treatment if informed appropriately: proof‐of‐concept observational study. Ann Rheum Dis 2013;72(6):826–830. [DOI] [PubMed] [Google Scholar]
- 7. Gómez‐Lumbreras A, Boyce RD, Villa‐Zapata L, et al. Drugs that interact with colchicine via inhibition of cytochrome P450 3A4 and P‐glycoprotein: a signal detection analysis using a database of spontaneously reported adverse events (FAERS). Ann Pharmacother 2023;57(10):1137–1146. [DOI] [PubMed] [Google Scholar]
- 8. US Food and Drug Administration . FDA Colcrys label 2020. Accessed August 28, 2023. https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/022352s026lbl.pdf [Google Scholar]
- 9. Wacher VJ, Wu CY, Benet LZ. Overlapping substrate specificities and tissue distribution of cytochrome P450 3A and P‐glycoprotein: implications for drug delivery and activity in cancer chemotherapy. Mol Carcinog 1995;13(3):129–134. [DOI] [PubMed] [Google Scholar]
- 10. Vrachatis DA, Papathanasiou KA, Giotaki SG, et al. Repurposing colchicine's journey in view of drug‐to‐drug interactions. A review. Toxicol Rep 2021;8:1389–1393. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11. Kintz P, Jamey C, Tracqui A, et al. Colchicine poisoning: report of a fatal case and presentation of an HPLC procedure for body fluid and tissue analyses. J Anal Toxicol 1997;21(1):70–72. [DOI] [PubMed] [Google Scholar]
- 12. Molad Y. Update on colchicine and its mechanism of action. Curr Rheumatol Rep 2002;4(3):252–256. [DOI] [PubMed] [Google Scholar]
- 13. Karatza E, Ismailos G, Karalis V. Colchicine for the treatment of COVID‐19 patients: efficacy, safety, and model informed dosage regimens. Xenobiotica 2021;51(6):643–656. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14. Stamp L, Horne A, Mihov B, et al. Is colchicine prophylaxis required with start‐low go‐slow allopurinol dose escalation in gout? A non‐inferiority randomised double‐blind placebo‐controlled trial. Ann Rheum Dis 2023;82(12):1626–1634. [DOI] [PubMed] [Google Scholar]
- 15. Taylor W, Dalbeth N, Saag KG, et al. Flare rate thresholds for patient assessment of disease activity states in gout. J Rheumatol 2021;48(2):293–298. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16. Terkeltaub RA. Colchicine update: 2008. Semin Arthritis Rheum 2009;38(6):411–419. [DOI] [PubMed] [Google Scholar]
- 17. Davis MW, Wason S. Effect of steady‐state atorvastatin on the pharmacokinetics of a single dose of colchicine in healthy adults under fasted conditions. Clin Drug Investig 2014;34(4):259–267. [DOI] [PubMed] [Google Scholar]
- 18. Kwon OC, Hong S, Ghang B, et al. Risk of colchicine‐associated myopathy in gout: influence of concomitant use of statin. Am J Med 2017;130(5):583–587. [DOI] [PubMed] [Google Scholar]
- 19. Alfehaid LS, Farah S, Omer A, et al. Drug‐drug interactions and the clinical tolerability of colchicine among patients with COVID‐19: a secondary analysis of the COLCORONA Randomized Clinical Trial. JAMA Netw Open 2024;7(9):e2431309. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20. Rochdi M, Sabouraud A, Girre C, et al. Pharmacokinetics and absolute bioavailability of colchicine after i.v. and oral administration in healthy human volunteers and elderly subjects. Eur J Clin Pharmacol 1994;46(4):351–354. [DOI] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Disclosure form.
Appendix S1: Supplementary Information