Effect of Cyclosporine on the Pharmacokinetics of Colchicine in Healthy Subjects

Wason, Suman; DiGiacinto, Jennifer L.; Davis, Matthew W.

doi:10.3810/pgm.2012.07.2579

Cited by 20 publications

(18 citation statements)

References 30 publications

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“…Cyclosporine inhibits intestinal efflux transporters (BCRP, multidrug resistance‐associated protein 2 and P‐gp) in vitro , and has the potential to increase fraction absorbed (Fa) of substrate drugs like colchicine, pravastatin, and saquinavir in humans . PF‐04991532 is a low‐to‐moderate permeable (Caco‐2 permeability ~ 2.5 × 10 −6 cm/second) BCRP substrate but not transported by P‐gp and multidrug resistance‐associated protein 2 based on our in vitro studies.…”

Section: Discussionmentioning

confidence: 89%

Effect of Hepatic Organic Anion‐Transporting Polypeptide 1B Inhibition and Chronic Kidney Disease on the Pharmacokinetics of a Liver‐Targeted Glucokinase Activator: A Model‐Based Evaluation

Bergman

Mathialagan

et al. 2019

Clin Pharma and Therapeutics

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PF‐04991532 ((S)‐6‐(3‐Cyclopentyl‐2‐(4‐(trifluoromethyl)‐1H‐imidazol‐1‐yl) propanamido) nicotinic acid) is a glucokinase activator designed to achieve hepato‐selectivity via organic anion‐transporting polypeptides (OATP)s, so as to minimize systemic hypoglycemic effects. This study investigated the effect of OATP1B1/1B3 inhibition and renal impairment on PF‐04991532 oral pharmacokinetics. Cyclosporine (600 mg single dose) increased mean area under the plasma curve (AUC) of PF‐04991532 by approximately threefold in healthy subjects. In a renal impairment study, PF‐04991532 AUC values were ~ 2.3‐fold greater in subjects with mild, moderate, and severe kidney dysfunction, compared with healthy subjects. Physiologically‐based pharmacokinetic (PBPK) model parameterizing hepatic and renal transporter‐mediated disposition based on in vitro inputs, and verified using first‐in‐human data, indicated the key role of OATP‐mediated hepatic uptake in the systematic and target‐tissue exposure of PF‐04991532. Mechanistic evaluation of the clinical data suggest reduced hepatic OATPs (~ 35%) and renal organic anion transporter (OAT)3 (80–90%) function with renal impairment. This study illustrates the adequacy and utility of the PBPK approach in assessing the impact of drug interactions and kidney dysfunction on transporter‐mediated disposition.

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Section: Discussionmentioning

confidence: 89%

Effect of Hepatic Organic Anion‐Transporting Polypeptide 1B Inhibition and Chronic Kidney Disease on the Pharmacokinetics of a Liver‐Targeted Glucokinase Activator: A Model‐Based Evaluation

Bergman

Mathialagan

et al. 2019

Clin Pharma and Therapeutics

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“…[6][7][8] Cyclosporine is a known inhibitor of P-glycoprotein, and CYP3A4 and coadministration will result in increased colchicine exposure and decreased hepatic and renal elimination. 9 This may lead to colchicine toxicity, presenting as gastrointestinal symptoms, liver dysfunction, polyneuropathy, myopathy, rhabdomyolysis, arrythmias, and/or pancytopenia. 10 Our patient developed signs and symptoms of myopathy soon after the colchicine initiation, which quickly resolved after discontinuation.…”

Section: Discussionmentioning

confidence: 99%

Colchicine-Induced Myopathy in a Tacrolimus-Treated Renal Transplant Recipient

Bhat

Reddy

Pillai

et al. 2016

American Journal of Therapeutics

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Renal transplant recipients are prone to develop drug toxicities because of polypharmacy and drug-drug interactions. Colchicine is often used for the treatment of gout in these patients as nonsteroidal medications are contraindicated. In addition, patients are often on corticosteroids and frequent, periodic, dose escalation for gouty flare may lead to side effects. Colchicine-induced myopathy has been very well described in the literature. Several cases of colchicine toxicity have been reported in cyclosporine-treated patients due to a drug-drug interaction. We report a 62-year-old African American renal transplant recipient who had been doing well on tacrolimus-based immunosuppression and was started on colchicine (0.6 mg twice daily) for gouty flare. A few days later, he was found to have a 4-fold increase in aspartate aminotransferase and an elevated creatine phosphokinase. Although this interaction is very well known with cyclosporine, it has not yet been reported in patients on tacrolimus.

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“…Supporting this, cyclosporine inhibits ABCG2 in vitro,88 hyperuricemia and gout can be induced by cyclosporine,89 and there is an interaction between cyclosporine and colchicine90 (colchicine is commonly used to treat gout attacks and is able to correct the dysfunctional internalization of ABCG2 141K36). Collectively, these observations suggest that ABCG2 may be influenced by off-target effects of cyclosporine.…”

Section: Abcg2: a Regulator Of Acute Gouty Inflammation?mentioning

confidence: 93%

ABCG2 polymorphisms in gout: insights into disease susceptibility and treatment approaches

Cleophas¹,

Joosten²,

Stamp³

et al. 2017

PGPM

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As a result of the association of a common polymorphism (rs2231142, Q141K) in the ATP-binding cassette G2 (ABCG2) transporter with serum urate concentration in a genome-wide association study, it was revealed that ABCG2 is an important uric acid transporter. This review discusses the relevance of ABCG2 polymorphisms in gout, possible etiological mechanisms, and treatment approaches. The 141K ABCG2 urate-increasing variant causes instability in the nucleotide-binding domain, leading to decreased surface expression and function. Trafficking of the protein to the cell membrane is altered, and instead, there is an increased ubiquitin-mediated proteasomal degradation of the variant protein as well as sequestration into aggresomes. In humans, this leads to decreased uric acid excretion through both the kidney and the gut with the potential for a subsequent compensatory increase in renal urinary excretion. Not only does the 141K polymorphism in ABCG2 lead to hyperuricemia through renal overload and renal underexcretion, but emerging evidence indicates that it also increases the risk of acute gout in the presence of hyperuricemia, early onset of gout, tophi formation, and a poor response to allopurinol. In addition, there is some evidence that ABCG2 dysfunction may promote renal dysfunction in chronic kidney disease patients, increase systemic inflammatory responses, and decrease cellular autophagic responses to stress. These results suggest multiple benefits in restoring ABCG2 function. It has been shown that decreased ABCG2 141K surface expression and function can be restored with colchicine and other small molecule correctors. However, caution should be exercised in any application of these approaches given the role of surface ABCG2 in drug resistance.

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Effect of Cyclosporine on the Pharmacokinetics of Colchicine in Healthy Subjects

Abstract: www.ClinicalTrials.gov identifier NCT00983931 (http://clinicaltrials.gov/ct2/show/NCT00983931).

Cited by 20 publications

References 30 publications

Effect of Hepatic Organic Anion‐Transporting Polypeptide 1B Inhibition and Chronic Kidney Disease on the Pharmacokinetics of a Liver‐Targeted Glucokinase Activator: A Model‐Based Evaluation

Effect of Hepatic Organic Anion‐Transporting Polypeptide 1B Inhibition and Chronic Kidney Disease on the Pharmacokinetics of a Liver‐Targeted Glucokinase Activator: A Model‐Based Evaluation

Colchicine-Induced Myopathy in a Tacrolimus-Treated Renal Transplant Recipient

ABCG2 polymorphisms in gout: insights into disease susceptibility and treatment approaches

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