Effects of rifampin, cyclosporine A, and probenecid on the pharmacokinetic profile of canagliflozin, a sodium glucose co-transporter 2 inhibitor, in healthy participants

Devineni, Damayanthi; Vaccaro, Nicole; Murphy, Joe; Curtin, Christopher R.; Mamidi, Rao N. V. S.; Weiner, Sveta; Wang, Shean‐Sheng; Ariyawansa, Jay; Stieltjes, Hans; Wajs, Ewa; Prospero, Nicholas A. Di; Rothenberg, Paul

doi:10.5414/cp202158

Cited by 39 publications

(42 citation statements)

References 36 publications

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“…Because canagliflozin undergoes glucuronidation by two different UGT enzymes and glucuronidation is a high-capacity/low-affinity system, clinically relevant interactions of other drugs on canagliflozin PK via inhibition of glucuronidation are unlikely to occur [29]. Cyclosporine, an inhibitor of P-gp, CYP3A, and several drug transporters including MRP2, had no clinically relevant effect on the PK of canagliflozin [15]. Therefore, no meaningful interactions would be expected with other inhibitors of P-gp.…”

Section: Effect Of Other Drugs On Canagliflozinmentioning

confidence: 94%

“…Probenecid (nonselective inhibitor of UGT enzymes and drug transporters, 500 mg bid), increased systemic exposure of canagliflozin (C max , 13 % and AUC 24h , 21 %) when administered concomitantly [15]. Because canagliflozin undergoes glucuronidation by two different UGT enzymes and glucuronidation is a high-capacity/low-affinity system, clinically relevant interactions of other drugs on canagliflozin PK via inhibition of glucuronidation are unlikely to occur [29].…”

Section: Effect Of Other Drugs On Canagliflozinmentioning

confidence: 95%

“…Coadministration of rifampin (a nonselective inducer of several UGT enzymes and drug transporters, 600 mg qd) decreased the plasma concentrations of canagliflozin (300 mg qd) (C max by 28 % and AUC ? by 51 %) in healthy participants, which may decrease the efficacy of canagliflozin [15]. If a combined inducer of UGT enzymes and drug transporters (e.g., rifampicin, phenytoin, barbiturates, phenobarbital, ritonavir, carbamazepine, efavirenz, St John's wort [Hypericum perforatum]) must be co-administered in a patient along with canagliflozin (100 mg), glycosylated hemoglobin (HbA 1c ) should be monitored with consideration to increasing the canagliflozin dose to 300 mg qd if additional glycemic control is needed [15].…”

Section: Effect Of Other Drugs On Canagliflozinmentioning

confidence: 97%

“…Clinical pharmacology studies were conducted in healthy participants and patients with T2DM to characterize the PK and PD of canagliflozin [11,12], and in healthy participants to investigate potential drug-drug interactions [13][14][15][16], the effect on QT interval/QT interval corrected for heart rate (QT/QTc) [17], and the potential effects of intrinsic factors in patients with hepatic or renal impairment [18].…”

Section: Overviewmentioning

confidence: 99%

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Clinical Pharmacokinetic, Pharmacodynamic, and Drug–Drug Interaction Profile of Canagliflozin, a Sodium-Glucose Co-transporter 2 Inhibitor

Devineni

Polidori

2015

Clin Pharmacokinet

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The sodium-glucose co-transporter 2 (SGLT2) inhibitors represent novel therapeutic approaches in the management of type 2 diabetes mellitus; they act on kidneys to decrease the renal threshold for glucose (RTG) and increase urinary glucose excretion (UGE). Canagliflozin is an orally active, reversible, selective SGLT2 inhibitor. Orally administered canagliflozin is rapidly absorbed achieving peak plasma concentrations in 1-2 h. Dose-proportional systemic exposure to canagliflozin has been observed over a wide dose range (50-1600 mg) with an oral bioavailability of 65 %. Canagliflozin is glucuronidated into two inactive metabolites, M7 and M5 by uridine diphosphate-glucuronosyltransferase (UGT) 1A9 and UGT2B4, respectively. Canagliflozin reaches steady state in 4 days, and there is minimal accumulation observed after multiple dosing. Approximately 60 % and 33 % of the administered dose is excreted in the feces and urine, respectively. The half-life of orally administered canagliflozin 100 or 300 mg in healthy participants is 10.6 and 13.1 h, respectively. No clinically relevant differences are observed in canagliflozin exposure with respect to age, race, sex, and body weight. The pharmacokinetics of canagliflozin remains unaffected by mild or moderate hepatic impairment. Systemic exposure to canagliflozin is increased in patients with renal impairment relative to those with normal renal function; however, the efficacy is reduced in patients with renal impairment owing to the reduced filtered glucose load. Canagliflozin did not show clinically relevant drug interactions with metformin, glyburide, simvastatin, warfarin, hydrochlorothiazide, oral contraceptives, probenecid, and cyclosporine, while co-administration with rifampin modestly reduced canagliflozin plasma concentrations and thus may necessitate an appropriate monitoring of glycemic control. Canagliflozin increases UGE and suppresses RTG in a dose-dependent manner, thereby lowering the plasma glucose levels and reducing the glycosylated hemoglobin levels through an insulin-independent mechanism of action. The 300-mg dose provides near-maximal effects on RTG throughout the full 24-h dosing interval, whereas the effect of the 100-mg dose on RTG is near-maximal for approximately 12 h and is modestly attenuated during the overnight period. The observed pharmacokinetic/pharmacodynamic profile of canagliflozin in patients with type 2 diabetes mellitus supports a once-daily dosing regimen.

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Section: Effect Of Other Drugs On Canagliflozinmentioning

confidence: 94%

Section: Effect Of Other Drugs On Canagliflozinmentioning

confidence: 95%

Section: Effect Of Other Drugs On Canagliflozinmentioning

confidence: 97%

Section: Overviewmentioning

confidence: 99%

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Clinical Pharmacokinetic, Pharmacodynamic, and Drug–Drug Interaction Profile of Canagliflozin, a Sodium-Glucose Co-transporter 2 Inhibitor

Devineni

Polidori

2015

Clin Pharmacokinet

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“…The pharmacokinetic profile of canagliflozin is similar in healthy individuals and patients with T2DM, and supports once-daily dosing [22][23][24]27,[48][49][50]. No clinically meaningful interactions were observed between canagliflozin and glyburide, metformin, simvastatin, probenecid, cyclosporine A, oral contraceptives and warfarin in healthy individuals [51][52][53]. There was an increase in the area under the curve (AUC) and mean peak drug concentration (C max ) of digoxin (20 and 36%, respectively) when co-administered with canagliflozin 300 mg; therefore, patients taking canagliflozin with concomitant digoxin should be monitored appropriately [43].…”

Section: • • Pharmacokinetics and Pharmacodynamics Of Canagliflozinmentioning

confidence: 95%

Canagliflozin for the treatment of adults with Type 2 diabetes

Meininger¹,

Canovatchel²,

Polidori³

et al. 2015

Diabetes Management

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Canagliflozin is an SGLT2 inhibitor approved for the treatment of adults with Type 2 diabetes mellitus (T2DM). A comprehensive Phase III program evaluated canagliflozin in a broad range of patients with T2DM on various background therapies; studies were also conducted in special populations, including older patients and those with moderate renal impairment. Canagliflozin provided clinically meaningful reductions in HbA1c, bodyweight and blood pressure versus placebo and active comparators in studies up to 104 weeks. Canagliflozin was generally well tolerated, with increased incidences of adverse events related to the mechanism of action, including genital mycotic infections and osmotic diuresisrelated adverse events. Overall, canagliflozin appears to be a useful treatment option for patients with inadequately controlled T2DM. Practice points• Type 2 diabetes mellitus (T2DM) is a chronic and progressive metabolic disease, with growing prevalence worldwide.• SGLT2 inhibitors are a new class of oral antihyperglycemic agents with an insulin-independent mechanism of lowering the renal threshold for glucose and increasing urinary glucose excretion, thereby lowering plasma glucose.• Canagliflozin is an SGLT2 inhibitor approved in the USA, EU and other countries as adjunct to diet and exercise for the treatment of adults with hyperglycemia.• Canagliflozin has been evaluated in ~10,000 patients with T2DM in placebo-and active-controlled Phase III studies of up to 104 weeks, including special populations (e.g., older patients, patients with moderate renal impairment and patients with elevated cardiovascular risk).• In placebo-controlled, Phase III studies, canagliflozin improved glycemic control and lowered bodyweight and blood pressure in a broad range of patients with T2DM on a variety of background antihyperglycemic agents, including older patients, patients with moderate renal impairment and patients with elevated cardiovascular risk.• In active-controlled, Phase III studies, canagliflozin 300 mg demonstrated superiority to glimepiride and sitagliptin 100 mg in HbA1c lowering as add-on to metformin at 52 weeks; canagliflozin 300 mg also demonstrated superiority to sitagliptin 100 mg in HbA1c lowering as add-on to metformin and sulfonylurea over 52 weeks.• Canagliflozin was generally well tolerated, with increased incidences of adverse effects related to the mechanism of action (e.g., genital mycotic infections, urinary tract infections, osmotic diuresis-related adverse events, volume depletion-related adverse events); the incidence of hypoglycemia was low with canagliflozin in patients not on background sulfonylurea or insulin.

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Inhibitory effects of sulfonylureas and non‐steroidal anti‐inflammatory drugs on in vitro metabolism of canagliflozin in human liver microsomes

Algeelani¹,

Alkhelb²,

Greenblatt

2018

Biopharm & Drug Disp

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Canagliflozin, used to treat type 2 diabetes mellitus (T2DM), is commonly co-administered with sulfonylureas. The objective of the present study was to evaluate the possible inhibitory effect of sulfonylureas and non-steroidal anti-inflammatory drugs (NSAIDs) on canagliflozin metabolism in vitro. Three sulfonylurea derivatives were evaluated as inhibitors: chlorpropamide, glimepiride and gliclazide. Two other NSAIDs were used as positive control inhibitors: niflumic acid and diclofenac. The rate of formation of canagliflozin metabolites was determined by HPLC analysis of in vitro incubations of canagliflozin as a substrate with and without inhibitors, using human liver microsomes (HLMs). Among sulfonylureas, glimepiride showed the most potent inhibitory effect against canagliflozin M7 metabolite formation, with an IC value of 88 μm, compared to chlorpropamide and gliclazide with IC values of more than 500 μm. Diclofenac inhibited M5 metabolite formation more than M7, with IC values of 32 μm for M5 and 80 μm for M7. Niflumic acid showed no inhibition activity against M5 formation, but had relatively selective inhibitory potency against M7 formation, which is catalysed by UGT1A9, with an IC value of 1.9 μm and an inhibition constant value of 0.8 μm. A clinical pharmacokinetic interaction between canagliflozin and sulfonylureas is unlikely. However, a possible clinically important drug interaction between niflumic acid and canagliflozin has been identified.

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Effects of rifampin, cyclosporine A, and probenecid on the pharmacokinetic profile of canagliflozin, a sodium glucose co-transporter 2 inhibitor, in healthy participants

Cited by 39 publications

References 36 publications

Clinical Pharmacokinetic, Pharmacodynamic, and Drug–Drug Interaction Profile of Canagliflozin, a Sodium-Glucose Co-transporter 2 Inhibitor

Clinical Pharmacokinetic, Pharmacodynamic, and Drug–Drug Interaction Profile of Canagliflozin, a Sodium-Glucose Co-transporter 2 Inhibitor

Canagliflozin for the treatment of adults with Type 2 diabetes

Inhibitory effects of sulfonylureas and non‐steroidal anti‐inflammatory drugs on in vitro metabolism of canagliflozin in human liver microsomes

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