Effect of canagliflozin, a sodium glucose co-transporter 2 inhibitor, on the pharmacokinetics of oral contraceptives, warfarin, and digoxin in healthy participants

Devineni, Damayanthi; Manitpisitkul, Prasarn; Vaccaro, Nicole; Bernard, Apexa; Skee, Donna; Mamidi, Rao N. V. S.; Tian, Hong; Weiner, Sveta; Stieltjes, Hans; Sha, Sue; Rothenberg, Paul

doi:10.5414/cp202157

Cited by 15 publications

(20 citation statements)

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“…Although there was no clinical drug-drug interaction study conducted with a co-administered CYP2B6 substrate, based on Simcyp physiologically based PK simulation results, no clinically relevant drug-drug interactions with CYP2B6 substrates were expected (mean C max and AUC ratios of bupropion were 112 % and 113 %, respectively). Despite being a highly plasma protein bound (98.35-99.2 %) drug, canagliflozin did not have a clinically meaningful effect on the PK of other drugs that are highly bound to plasma proteins such as glyburide (98 %) [13,26], warfarin (99.5 %) [14,27], or simvastatin (95 %) [13,28]. In summary, for common medications that patients with T2DM may be treated with (such as statins [simvastatin], anti-hyperglycemic agents [metformin and sulfonylureas], or diuretics [hydrochlorothiazide]), no interactions with canagliflozin were observed.…”

Section: Effect Of Canagliflozin On Other Drugsmentioning

confidence: 97%

“…Canagliflozin had no clinically relevant effects on the PK of metformin (OCT2 substrate) [13], the individual components of an oral contraceptive (containing ethinyl estradiol and levonorgestrel, CYP3A4 substrates) [14], simvastatin (substrate of CYP3A4 and OATP1B1) [13], glyburide and warfarin (CYP2C9 substrates) [13,14], digoxin (P-glycoprotein [P-gp] substrate) [14], hydrochlorothiazide [16], acetaminophen (unpublished data), and teneligliptin [25] (Table 2). Therefore, meaningful interactions would not be expected for other CYP3A4, CYP2C9, P-gp, OAT1B1, and OCT2 substrates.…”

Section: Effect Of Canagliflozin On Other Drugsmentioning

confidence: 97%

“…Canagliflozin did not inhibit expression of most CYP450 enzymes (CYP1A2, 2A6, 2C9, 2C19, 2D6, and 2E1, IC50 [ 100 lM) in human liver microsomes, and weakly inhibited CYP2B6 (16 lM), CYP2C8 (75 lM), CYP2C9 (80 lM), and CYP3A4 (27 lM) [13,14]. Although the IC 50 values for CYP2C8 and 2B6 indicated a potential for canagliflozin to inhibit these isozymes, only a few potentially co-administered drugs are metabolized by these pathways (drugs metabolized by CYP2C8 including pioglitazone, repaglinide, rosiglitazone, tolbutamide, and drugs metabolized by CYP2B6 including bupropion, cyclophosphamide, clopidogrel, efavirenz).…”

Section: In Vitro Assessment Of Drug Interactionsmentioning

confidence: 98%

“…Canagliflozin was a substrate of P-glycoprotein (P-gp), multidrug resistance protein 2 (MRP2) transporters, and breast cancer resistance protein (BCRP) [14,18] and was not a substrate of solute-linked carrier uptake transporters such as organic anion transporter 1 (OAT1), OAT3, organic anion transporting polypeptide 1B1 (OATP1B1), OATP1B3, and organic cation transporter 1 (OCT1), OCT2. Canagliflozin was a potentially weak inhibitor of P-gp and MRP2 and did not inhibit OATP1B3, OATP1B1, BCRP, OAT1, OAT3, and OCT1 and OCT2 transporters.…”

Section: In Vitro Assessment Of Drug Interactionsmentioning

confidence: 99%

“…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 Canagliflozin On Other Drugsmentioning

confidence: 97%

Section: Effect Of Canagliflozin On Other Drugsmentioning

confidence: 97%

Section: In Vitro Assessment Of Drug Interactionsmentioning

confidence: 98%

Section: In Vitro Assessment Of Drug Interactionsmentioning

confidence: 99%

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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Effect of food on the pharmacokinetics of canagliflozin, a sodium glucose co‐transporter 2 inhibitor, and assessment of dose proportionality in healthy participants

Devineni

Manitpisitkul

Murphy

et al. 2014

Clinical Pharm in Drug Dev

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Canagliflozin, an orally active inhibitor of sodium glucose co-transporter 2, is approved for the treatment of type-2 diabetes mellitus. The effect of food on the pharmacokinetics of 300 mg canagliflozin, and dose proportionality of 50, 100, and 300 mg canagliflozin, were evaluated, in two studies, in healthy participants. Study 1 used a randomized, 2-way crossover design: canagliflozin 300 mg/day was administered under fasted (Period-1) and fed (Period-2) conditions or vice versa. Study 2 was a 3-way crossover: participants were randomized to receive three single-doses of canagliflozin (50, 100, and 300 mg), one in each period. In both studies, treatment periods were separated by washout intervals of 10-14 days, and pharmacokinetics assessed up to 72 hours postdose of each treatment period. No clinically relevant food effects on canagliflozin exposure parameters were observed: 90% confidence intervals (CIs) for the fed/fasted geometric mean ratios of AUC∞ (ratio: 100.51; 90% CI: 89.47-112.93) and Cmax (ratio: 108.09; 90% CI: 103.45-112.95) were entirely within bioequivalence limits (80-125%). Plasma canagliflozin exposures were dose-proportional as the 90% CI of the slope of the regression line for dose-normalized AUC∞ and Cmax fell entirely within the prespecified limits of -0.124 to 0.124. No clinically significant safety issues were noted, and canagliflozin was generally well-tolerated.

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Lack of Drug‐Drug Interaction Between Filgotinib, a Selective JAK1 Inhibitor, and Oral Hormonal Contraceptives Levonorgestrel/Ethinyl Estradiol in Healthy Volunteers

Begley

Anderson

Watkins

et al. 2020

Clinical Pharm in Drug Dev

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Filgotinib (FIL) is a potent and selective JAK1 inhibitor in clinical development for treatment of severe inflammatory diseases. A drug‐drug interaction study to evaluate the potential effect of FIL on the pharmacokinetics (PK) of the oral contraceptive levonorgestrel (LEVO)/ethinyl estradiol (EE) was conducted. This was a phase 1, open‐label, randomized, crossover study in healthy female subjects (N = 24). Subjects received a single dose of LEVO (150 μg)/EE (30 μg) alone (reference), or in combination with multiple‐dose FIL (200 mg once daily for 15 days; test). Intensive PK sampling was conducted, and safety was assessed throughout the study. PK interactions were evaluated using 90% confidence intervals of the geometric least squares mean ratios of the test versus reference treatments. All 24 subjects enrolled completed study treatments. Coadministration of FIL with the oral contraceptive did not alter the PK of LEVO and EE; the 90% confidence intervals of the geometric least squares mean ratios were contained within bioequivalence bounds (80%‐125%). Exposures of FIL were consistent with observed clinical exposure data. Study treatments were generally well tolerated. All adverse events were mild. Coadministration with FIL did not alter the PK of LEVO/EE, and hormonal contraceptives can serve as an effective contraception method for subjects on FIL treatment.

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Effect of canagliflozin, a sodium glucose co-transporter 2 inhibitor, on the pharmacokinetics of oral contraceptives, warfarin, and digoxin in healthy participants

Abstract: Canagliflozin can be coadministered with OC, warfarin, or digoxin without dose adjustments. All treatments were well-tolerated.

Cited by 15 publications

References 0 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

Effect of food on the pharmacokinetics of canagliflozin, a sodium glucose co‐transporter 2 inhibitor, and assessment of dose proportionality in healthy participants

Lack of Drug‐Drug Interaction Between Filgotinib, a Selective JAK1 Inhibitor, and Oral Hormonal Contraceptives Levonorgestrel/Ethinyl Estradiol in Healthy Volunteers

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