In this study, pharmacokinetic simulations were performed to determine what dosing regimens, with colchicine oral solution in different levels of reduced renal clearance, support plasma levels to be within the safe and efficacious therapeutic range (0.5–3 ng/mL). Our analysis shows that in patients with normal to mildly impaired renal function, dosing with the currently recommended colchicine dose of 0.6 mg QD would contain the steady state colchicine plasma concentration within the therapeutic range (Fig. 2a). For patients in the moderate renal impairment group based on simulation from Fig. 2b, a dose of 0.48 mg (4 mL) QD of colchicine oral solution or 0.5 mg of colchicine tablet (in countries where available) will result in steady state concentrations contained within the target range. For patients in the severe renal impairment group, dosing 0.3 mg (2.5 mL) QD of colchicine oral solution seems to be optimal (Fig. 2c) as the steady state levels are contained in the target range, and this concurs with the dosing recommendation on the product label. QOD dosing with 0.6 mg tablet/capsule formulations has been used by clinicians, but QOD dosing may pose adherence challenges to the colchicine regimen in a patient population with already low compliance rates compared to daily dosing [20]. In addition, 0.6 mg QOD regimen will essentially leave patients with moderate renal impairment essentially untreated half the time as their colchicine levels will be below the lower therapeutic range of 0.5 ng/mL in the second half of the dosing interval based on the simulation (Fig. 2b).

Colchicine’s cellular effects depend predominantly on its ability to bind tubulin, particularly within leukocytes [7]. Although the anti-inflammatory effects of colchicine are largely determined by intracellular leukocyte accumulation, and serum concentrations may relate inadequately to efficacy, serum levels are useful to model drug safety which may depend on colchicine actions in cells other than or in addition to leukocytes [21]. At steady state, the safe upper limit of colchicine concentration is generally considered to be 3.0 ng/mL [12]. The plasma half-life of colchicine is prolonged in patients with renal failure, especially in those with combined renal and liver diseases [22]. Patients with renal or liver diseases who take colchicine should be monitored carefully for possible toxic effects of the drug. The ACR guidelines recommend exercising caution and instituting colchicine dose adjustment in renal impairment at the discretion of the treating clinician [6]. Pharmacodynamic studies confirm that doses of 0.5 mg BID and 0.6 mg QD do not sustain serum levels beyond this threshold in healthy individuals, and that doses of 0.5 mg QD do not sustain serum levels beyond this range even in patients with mild to moderate renal impairment or with concomitant use of most interacting medications [13].

Apart from avoiding the use of colchicine with adversely interacting drugs, colchicine dose reductions should be considered in patients with renal or hepatic impairment, and in the elderly. Some recommendations suggest reducing the colchicine dose by 50% in patients with creatinine clearance below 50 mL/min [23]. However, there is a paucity of data and very little guidance regarding colchicine dosing regimens for patients with gout and CKD. In addition, as most studies on colchicine have excluded individuals with CKD, there is insufficient data to inform on the safety and efficacy of colchicine in these patients [24]. In patients with gout and CKD, it is challenging to maintain optimum sU levels, as uric acid is largely excreted renally. As a result of decreased renal function, hyperuricemia is more common in patients with moderate-severe CKD [3]. An eGFR of 60 mL/min/1.73 m2 (the borderline between mild and moderate renal impairment) appears to be a threshold for the dramatic increase in the prevalence of gout, with the risk of gout increasing 10-fold in patients with moderate CKD [3]. Colchicine doses of 0.5 mg or 0.6 mg orally QD or BID are recommended per international and ACR guidelines, respectively, for prophylaxis use in treatment of gout, in subjects with normal renal function, with downward dose adjustments recommended for patients with moderate to severe renal impairment or due to potential drug–drug interactions [5, 6]. Unfortunately, there is a substantial knowledge gap around the safe use and dosing of colchicine in patients with both gout and CKD [25, 26].

Prior to the availability of colchicine oral solution, there existed an unmet need in treatment of gout in patients with CKD (particularly in stage ≥ 3) as non-steroidal anti-inflammatory drugs (NSAIDs), corticosteroids, and other anti-inflammatory drugs are relatively contraindicated for gout prophylaxis in CKD [27, 28]. NSAIDs can negatively impact kidney function and prolonged use is not recommended for patients with eGFR below 60 mL/min/1.73 m2 [26, 27]. Similarly, known risks associated with prolonged use of corticosteroids include effects on glycemic control, weight gain, and cardiovascular adverse effects [28].

Use of solid dosage forms of colchicine may be challenging when dose reductions are needed, such as for renal impairment or drug–drug interactions. Colchicine oral solution offers a convenient choice for patients with CKD and gout as precise dosing is possible. The availability of colchicine oral solution as a liquid formulation allows for precise dosing adjustments using a graduated oral syringe to help balance efficacy with the risk of toxicities.

Modeling assumptions were made. The level of renal impairment was based on creatinine clearance, which is assumed to be directly proportional to the impairment in colchicine clearance and estimated parameters of clearance for patients with mild, moderate, and severe renal impairment used in simulation. We did not perform analyses on sex and therefore could not determine if there were any differences in men vs. women.