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Kazano

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Kazano

CLINICAL PHARMACOLOGY

Mechanism of Action

Alogliptin and Metformin hydrochloride

KAZANO combines 2 antihyperglycemic agents with complementary and distinct mechanisms of action to improve glycemic control in patients with type 2 diabetes: alogliptin, a selective inhibitor of DPP-4, and metformin HCl, a member of the biguanide class.

Alogliptin

Increased concentrations of the incretin hormones such as glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are released into the bloodstream from the small intestine in response to meals. These hormones cause insulin release from the pancreatic beta cells in a glucose-dependent manner but are inactivated by the DPP-4 enzyme within minutes. GLP-1 also lowers glucagon secretion from pancreatic alpha cells, reducing hepatic glucose production. In patients with type 2 diabetes, concentrations of GLP-1 are reduced but the insulin response to GLP-1 is preserved. Alogliptin is a DPP-4 inhibitor that slows the inactivation of the incretin hormones, thereby increasing their bloodstream concentrations and reducing fasting and postprandial glucose concentrations in a glucose-dependent manner in patients with type 2 diabetes mellitus. Alogliptin selectively binds to and inhibits DPP-4 but not DPP-8 or DPP-9 activity in vitro at concentrations approximating therapeutic exposures.

Metformin hydrochloride

Metformin is a biguanide that improves glucose tolerance in patients with type 2 diabetes, lowering both basal and postprandial plasma glucose. Metformin decreases hepatic glucose production, decreases intestinal absorption of glucose, and improves insulin sensitivity by increasing peripheral glucose uptake and utilization. Metformin does not produce hypoglycemia in patients with type 2 diabetes or in healthy subjects except in special circumstances [see WARNINGS AND PRECAUTIONS] and does not cause hyperinsulinemia. With metformin therapy, insulin secretion remains unchanged while fasting insulin levels and day-long plasma insulin response may actually decrease.

Pharmacodynamics

Alogliptin

Single-dose administration of alogliptin to healthy subjects resulted in a peak inhibition of DPP-4 within 2 to 3 hours after dosing. The peak inhibition of DPP-4 exceeded 93% across doses of 12.5 mg to 800 mg. Inhibition of DPP-4 remained above 80% at 24 hours for doses greater than or equal to 25 mg. Peak and total exposure over 24 hours to active GLP-1 were 3- to 4-fold greater with alogliptin (at doses of 25 - 200 mg) than placebo. In a 16-week, double-blind, placebo-controlled study, alogliptin 25 mg demonstrated decreases in postprandial glucagon while increasing postprandial active GLP-1 levels compared to placebo over an 8-hour period following a standardized meal. It is unclear how these findings relate to changes in overall glycemic control in patients with type 2 diabetes mellitus. In this study, alogliptin 25 mg demonstrated decreases in 2-hour postprandial glucose compared to placebo (-30 mg/dL versus 17 mg/dL, respectively).

Multiple-dose administration of alogliptin to patients with type 2 diabetes also resulted in a peak inhibition of DPP-4 within 1 to 2 hours and exceeded 93% across all doses (25 mg, 100 mg, and 400 mg) after a single dose and after 14 days of once-daily dosing. At these doses of alogliptin, inhibition of DPP-4 remained above 81% at 24 hours after 14 days of dosing.

Pharmacokinetics

Absorption and Bioavailability

Alogliptin and Metformin hydrochloride

In bioequivalence studies of KAZANO, the area under the curve (AUC) and maximum concentration (Cmax) of both the alogliptin and the metformin component following a single dose of the combination tablet were bioequivalent to the alogliptin 12.5 mg concomitantly administered with metformin HCl 500 or 1000 mg tablets under fasted conditions in healthy subjects. Administration of KAZANO with food resulted in no change in total exposure (AUC) of alogliptin and metformin. Mean peak plasma concentrations of alogliptin and metformin were decreased by 13% and 28%, respectively, when administered with food. There was no change in time to peak plasma concentrations (Tmax) for alogliptin under fed conditions, however, there was a delayed Tmax for metformin of 1.5 hr. These changes are not likely to be clinically significant.

Alogliptin

The absolute bioavailability of alogliptin is approximately 100%. Administration of alogliptin with a high-fat meal resulted in no change in total and peak exposure to alogliptin. Alogliptin may therefore be administered with or without food.

Metformin hydrochloride

The absolute bioavailability of metformin following administration of a 500-mg metformin HCl tablet given under fasting conditions is approximately 50 to 60%. Studies using single oral doses of metformin HCl tablets 500 mg to 1500 mg, and 850 mg to 2550 mg, indicate that there is a lack of dose proportionality with increasing doses, which is due to decreased absorption rather than an alteration in elimination. Food decreases the extent of and slightly delays the absorption of metformin, as shown by approximately a 40% lower mean peak plasma concentration (Cmax), a 25% lower area under the plasma concentration versus time curve (AUC), and a 35-minute prolongation of time to peak plasma concentration (Tmax) following administration of a single 850-mg tablet of metformin HCl with food, compared to the same tablet strength administered fasting. The clinical relevance of these decreases is unknown.

Distribution

Alogliptin

Following a single, 12.5 mg intravenous dose of alogliptin to healthy subjects, the volume of distribution during the terminal phase was 417 L, indicating that the drug is well distributed into tissues.

Alogliptin is 20% bound to plasma proteins.

Metformin hydrochloride

The apparent volume of distribution (V/F) of metformin following single oral doses of immediate release metformin HCl tablets 850 mg averaged 654 ± 358 L. Metformin is negligibly bound to plasma proteins. Metformin partitions into erythrocytes, most likely as a function of time. At usual clinical doses and dosing schedules of metformin, steadystate plasma concentrations of metformin are reached within 24 to 48 hours and are generally < 1 mcg/mL. During controlled clinical trials, which served as the basis for approval for metformin, maximum metformin plasma levels did not exceed 5 mcg/mL, even at maximum doses.

Metabolism

Alogliptin

Alogliptin does not undergo extensive metabolism and 60% to 71% of the dose is excreted as unchanged drug in the urine.

Two minor metabolites were detected following administration of an oral dose of [14C] alogliptin, N-demethylated, M-I ( < 1% of the parent compound), and N-acetylated alogliptin, M-II ( < 6% of the parent compound). M-I is an active metabolite and is an inhibitor of DPP-4 similar to the parent molecule; M-II does not display any inhibitory activity towards DPP-4 or other DPP-related enzymes. In vitro data indicate that CYP2D6 and CYP3A4 contribute to the limited metabolism of alogliptin.

Alogliptin exists predominantly as the (R)-enantiomer ( > 99%) and undergoes little or no chiral conversion in vivo to the (S)-enantiomer. The (S)-enantiomer is not detectable at the 25 mg dose.

Metformin hydrochloride

Intravenous single-dose studies in healthy subjects demonstrate that metformin is excreted unchanged in the urine and does not undergo hepatic metabolism (no metabolites have been identified in humans) nor biliary excretion.

Excretion and Elimination

Alogliptin

The primary route of elimination of [14C] alogliptin-derived radioactivity occurred via renal excretion (76%) with 13% recovered in the feces, achieving a total recovery of 89% of the administered radioactive dose. The renal clearance of alogliptin (9.6 L/hr) indicates some active renal tubular secretion and systemic clearance was 14.0 L/hr.

Metformin hydrochloride

Renal clearance is approximately 3.5 times greater than creatinine clearance, which indicates that tubular secretion is the major route of metformin elimination. Following oral administration, approximately 90% of the absorbed drug is eliminated via the renal route within the first 24 hours, with a plasma elimination half-life of approximately 6.2 hours. In blood, the elimination half-life is approximately 17.6 hours, suggesting that the erythrocyte mass may be a compartment of distribution.

Special Populations

Renal Impairment

Alogliptin and Metformin hydrochloride

Use of KAZANO in patients with renal impairment increases the risk for lactic acidosis. Because KAZANO contains metformin, KAZANO is contraindicated in patients with renal impairment [see CONTRAINDICATIONS and WARNINGS AND PRECAUTIONS].

Hepatic Impairment

KAZANO is not recommended in patients with hepatic impairment. KAZANO contains metformin and use of metformin in patients with hepatic impairment has been associated with some cases of lactic acidosis [see WARNINGS AND PRECAUTIONS].

Alogliptin

Total exposure to alogliptin was approximately 10% lower and peak exposure was approximately 8% lower in patients with moderate hepatic impairment (Child-Pugh Grade B) compared to healthy subjects. The magnitude of these reductions is not considered to be clinically meaningful. Patients with severe hepatic impairment (Child-Pugh Grade C) have not been studied.

Metformin hydrochloride

No pharmacokinetic studies of metformin have been conducted in subjects with hepatic impairment.

Gender

Alogliptin

No dose adjustment is necessary based on gender. Gender did not have any clinically meaningful effect on the pharmacokinetics of alogliptin.

Metformin hydrochloride

Metformin pharmacokinetic parameters did not differ significantly between normal subjects and patients with type 2 diabetes when analyzed according to gender. Similarly, in controlled clinical studies in patients with type 2 diabetes, the antihyperglycemic effect of metformin hydrochloride tablets was comparable in males and females.

Geriatric

KAZANO contains metformin which is contraindicated in patients with renal impairment [see WARNINGS AND PRECAUTIONS]. Due to declining renal function in the elderly, measurement of creatinine clearance should be obtained prior to initiation of therapy. Do not use KAZANO if renal function is not within normal range.

Alogliptin

No dose adjustment is necessary based on age. Age did not have any clinically meaningful effect on the pharmacokinetics of alogliptin.

Metformin hydrochloride

Limited data from controlled pharmacokinetic studies of metformin in healthy elderly subjects suggest that total plasma clearance of metformin is decreased, the half-life is prolonged, and Cmax is increased, compared to healthy young subjects. From these data, it appears that the change in metformin pharmacokinetics with aging is primarily accounted for by a change in renal function.

Pediatrics

Studies characterizing the pharmacokinetics of alogliptin in pediatric patients have not been performed.

Race

Alogliptin

No dose adjustment of alogliptin is necessary based on race. Race (White, Black and Asian) did not have any clinically meaningful effect on the pharmacokinetics of alogliptin.

Metformin hydrochloride

No studies of metformin pharmacokinetic parameters according to race have been performed. In controlled clinical studies of metformin in patients with type 2 diabetes, the antihyperglycemic effect was comparable in Whites (n=249), Blacks (n=51), and Hispanics (n=24).

Drug Interactions

Alogliptin and Metformin hydrochloride

Administration of alogliptin 100 mg once daily with metformin HCl 1000 mg twice daily for 6 days had no meaningful effect on the pharmacokinetics of alogliptin or metformin.

Specific pharmacokinetic drug interaction studies with KAZANO have not been performed, although such studies have been conducted with the individual components of KAZANO (alogliptin and metformin).

Alogliptin

In Vitro Assessment of Drug Interactions

In vitro studies indicate that alogliptin is neither an inducer of CYP1A2, CYP2B6, CYP2C9, CYP2C19, and CYP3A4, nor an inhibitor of CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP3A4 and CYP2D6 at clinically relevant concentrations.

In Vivo Assessment of Drug Interactions

Effects of Alogliptin on the Pharmacokinetics of Other Drugs

In clinical studies, alogliptin did not meaningfully increase the systemic exposure to the following drugs that are metabolized by CYP isozymes or excreted unchanged in urine (Figure 1). No dose adjustment of alogliptin is recommended based on results of the described pharmacokinetic studies.

Figure 1: Effect of Alogliptin on the Pharmacokinetic Exposure to Other Drugs

Effect of Alogliptin on the Pharmacokinetic Exposure to Other Drugs - Illustration

*warfarin was given once daily at a stable dose in the range of 1 mg to10 mg. Alogliptin had no significant effect on the prothrombin time (PT) or International Normalized Ratio (INR).
**caffeine (1A2 substrate), tolbutamide (2C9 substrate), dextromethorphan (2D6 substrate), midazolam (3A4 substrate), and fexofenadine (P-gp substrate) were administered as a cocktail.

Effects of Other Drugs on the Pharmacokinetics of Alogliptin

There are no clinically meaningful changes in the pharmacokinetics of alogliptin when alogliptin is administered concomitantly with the drugs described below (Figure 2).

Figure 2: Effect of Other Drugs on the Pharmacokinetic Exposure of Alogliptin

Effect of Other Drugs on the Pharmacokinetic Exposure of Alogliptin - Illustration

Metformin hydrochloride

Pharmacokinetic drug interaction studies have been performed on metformin (Tables 4 and 5).

Table 4: Effect of Coadministered Drug on Plasma Metformin Systemic Exposure

Coadministered Drug Dose of Coadministered Drug* Dose of Metformin HCl* Geometric Mean Ratio (ratio with/without coadministered drug) No effect = 1.00
AUC† Cmax
No dosing adjustments required for the following:
Glyburide 5 mg 500 mg‡ 0.98§ 0.99§
Furosemide 40 mg 850 mg 1.09§ 1.22§
Nifedipine 10 mg 850 mg 1.16 1.21
Propranolol 40 mg 850 mg 0.9 0.94
Ibuprofen 400 mg 850 mg 1.05§ 1.07§
Cationic drugs eliminated by renal tubular secretion may reduce metformin elimination: use with caution [see WARNINGS AND PRECAUTIONS and DRUG INTERACTIONS]
Cimetidine 400 mg 850 mg 1.4 1.61
Carbonic anhydrase inhibitors may cause metabolic acidosis: use with caution [see WARNINGS AND PRECAUTIONS and DRUG INTERACTIONS]
Topiramate 100 mg¶ 500 mg¶ 1.25¶ 1.17
*aii meuormin anu coauminibiereu uruus were given as single doses
†AUC = AUC0-∞
‡metformin hydrochloride extended-release tablets 500 mg
§Ratio of arithmetic means
¶At steady state with topiramate 100 mg every 12 hours and metformin 500 mg every 12 hours; AUC = AUC0-12h

Table 5: Effect of Metformin on Coadministered Drug Systemic Exposure

Coadministered Drug Dose of Coadministered Drug* Dose of Metformin HCl* Geometric Mean Ratio (ratio with/without coadministered drug) No effect = 1.00
AUC† Cmax
No dosing adjustments required for the following:
Glyburide 5 mg 500 mg‡ 0.78§ 0.63§
Furosemide 40 mg 850 mg 0.87§ 0.69§
Nifedipine 10 mg 850 mg 1.10‡ 1.08
Propranolol 40 mg 850 mg 1.01‡ 0.94
Ibuprofen 400 mg 850 mg 0.97¶ 1.01¶
Cimetidine 400 mg 850 mg 0.95‡ 1.01
*All metformin and coadministered drugs were given as single doses
†AUC = AUC0-∞
‡AUC0-24 hr reported
§Ratio of arithmetic means, p-value of difference < 0.05
¶Ratio of arithmetic means

Clinical Studies

The coadministration of alogliptin and metformin has been studied in patients with type 2 diabetes inadequately controlled on either diet and exercise alone, on metformin alone or metformin in combination with a thiazolidinedione.

There have been no clinical efficacy studies conducted with KAZANO; however bioequivalence of KAZANO with coadministered alogliptin and metformin tablets was demonstrated, and efficacy of the combination of alogliptin and metformin has been demonstrated in three Phase 3 efficacy studies.

A total of 4716 patients with type 2 diabetes were randomized in 4 double-blind, placebo- or active-controlled clinical safety and efficacy studies conducted to evaluate the effects of KAZANO on glycemic control. The racial distribution of patients exposed to study medication was 65% White, 20% Asian, 8% Black, and 7% other racial groups. The ethnic distribution was 23% Hispanic. Patients had an overall mean age of approximately 55 years (range 21 to 80 years). In patients with type 2 diabetes, treatment with KAZANO produced clinically meaningful and statistically significant improvements in A1C versus comparator. As is typical for trials of agents to treat type 2 diabetes, the mean reduction in A1C with KAZANO appears to be related to the degree of A1C elevation at baseline.

Alogliptin and Metformin Coadministration in Patients with Type 2 Diabetes Inadequately Controlled on Diet and Exercise

In a 26-week, double-blind, placebo-controlled study, a total of 784 patients inadequately controlled on diet and exercise alone (mean baseline A1C=8.4%) were randomized to 1 of 7 treatment groups: placebo; metformin HCl 500 mg or metformin HCl 1000 mg twice daily, alogliptin 12.5 mg twice daily, or alogliptin 25 mg daily; alogliptin 12.5 mg in combination with metformin HCl 500 mg or metformin HCl 1000 mg twice daily. Both coadministration treatment arms (alogliptin 12.5 mg + metformin HCl 500 mg and alogliptin 12.5 mg + metformin HCl 1000 mg) resulted in significant improvements in A1C (Figure 3) and FPG when compared with their respective individual alogliptin and metformin component regimens (Table 6). Coadministration treatment arms demonstrated improvements in 2-hour postprandial glucose (PPG) compared to alogliptin alone or metformin alone (Table 6). A total of 12% of patients receiving alogliptin 12.5 mg + metformin HCl 500 mg, 3% of patients receiving alogliptin 12.5 mg + metformin HCl 1000 mg, 17% of patients receiving alogliptin 12.5 mg, 23% of patients receiving metformin HCl 500 mg, 11% of patients receiving metformin HCl 1000 mg and 39% of patients receiving placebo required glycemic rescue.

Improvements in A1C were not affected by gender, age, race, or baseline BMI. The mean decrease in body weight was similar between metformin alone and alogliptin when coadministered with metformin. Lipid effects were neutral.

Table 6: Glycemic Parameters at Week 26 for Alogliptin and Metformin Alone and in Combination in Patients with Type 2 Diabetes

  Placebo Alogliptin 12.5 mg twice daily Metformin HCl 500 mg twice daily Metformin HCl 1000 mg twice daily Alogliptin 12.5 mg + Metformin HCl 500 mg twice daily Alogliptin 12.5 mg + Metformin HCl 1000 mg twice daily
A1C (%)* N=102 N=104 N=103 N=108 N=102 N=111
Baseline (mean) 8.5 8.4 8.5 8.4 8.5 8.4
Change from baseline (adjusted mean†) 0.1 -0.6 -0.7 -1.1 -1.2 -1.6
Difference from metformin (adjusted mean† with 95% confidence interval) - - - - -0.6‡ (-0.9, -0.3) -0.4‡ (-0.7, -0.2)
Difference from alogliptin (adjusted mean† with 95% confidence interval) - - - - -0.7‡ (-1.0, -0.4) -1.0‡ (-1.3, -0.7)
% Patients (n/N) achieving A1C < 7%§ 4% (4/102) 20% (21/104) 27% (28/103) 34% (37/108) 47%‡ (48/102) 59%‡ (66/111)
FPG (mg/dL)* N=105 N=106 N=106 N=110 N=106 N=112
Baseline (mean) 187 177 180 181 176 185
Change from baseline (adjusted mean†) 12 -10 -12 -32 -32 -46
Difference from metformin (adjusted mean† with 95% confidence interval) - - - - -20‡ (-33, -8) -14‡ (-26, -2)
Difference from alogliptin (adjusted mean† with 95% confidence interval) - - - - -22‡ (-35, -10) -36‡ (-49, -24)
2-Hour PPG (mg/dL)¶ N=26 N=34 N=28 N=37 N=31 N=37
Baseline (mean) 263 272 247 266 261 268
Change from baseline (adjusted mean†) -21 -43 -49 -54 -68 -86‡
Difference from metformin (adjusted mean† with 95% confidence interval) - - - - -19 (-49, 11) -32‡ (-58, -5)
Difference from alogliptin (adjusted mean† with 95% confidence interval) - - - - -25 (-53, 3) -43‡ (-70, -16)
*Intent-to-treat population using last observation on study prior to discontinuation of double-blind study medication or sulfonylurea rescue therapy for patients needing rescue.
†Least squares means adjusted for treatment, geographic region and baseline value.
‡ p < 0.05 when compared to metformin and alogliptin alone
§Compared using logistic regression.
¶Intent to treat population using data available at Week 26

Figure 3: Change From Baseline A1C at Week 26 with Alogliptin and Metformin Alone and Alogliptin in Combination with Metformin

Change From Baseline A1C - Illustration

Alogliptin and Metformin Coadministration in Patients with Type 2 Diabetes Inadequately Controlled on Metformin Alone

In a 26-week double-blind, placebo-controlled study, a total of 527 patients already on metformin (mean baseline A1C=8%) were randomized to receive alogliptin 12.5 mg, alogliptin 25 mg, or placebo once daily. Patients were maintained on a stable dose of metformin HCl (median daily dose=1700 mg) during the treatment period. Alogliptin 25 mg in combination with metformin resulted in statistically significant improvements from baseline in A1C and FPG at Week 26, when compared to placebo (Table 7). A total of 8% of patients receiving alogliptin 25 mg and 24% of patients receiving placebo required glycemic rescue. Improvements in A1C were not affected by gender, age, race, baseline BMI, or baseline metformin dose.

The mean decrease in body weight was similar between alogiptin 25 mg and placebo when given in combination with metformin. Lipid effects were also neutral.

Table 7: Glycemic Parameters at Week 26 in a Placebo-Controlled Study of Alogliptin as Add-on Therapy to Metformin*

  Alogliptin 25 mg + Metformin Placebo + Metformin
A1C (%) N=203 N=103
  Baseline (mean) 7.9 8
  Change from baseline (adjusted mean†) -0.6 -0.1
  Difference from placebo (adjusted mean† with 95% confidence interval) -0.5‡ (-0.7, -0.3)
  % of patients (n/N) achieving A1C ≤ 7%‡ 44% (92/207)‡ 18% (19/104)
FPG (mg/dL) N=204 N=104
  Baseline (mean) 172 180
  Change from baseline (adjusted mean†) -17 0
  Difference from placebo (adjusted mean† with 95% confidence interval) -17‡ (-26, -9)
*Intent-to-treat population using last observation on study.
†Least squares means adjusted for treatment, baseline value, geographic region, and baseline metformin dose.
‡p < 0.001 compared to placebo.

Alogliptin Add-on Therapy in Patients with Type 2 Diabetes Inadequately Controlled on the Combination of Metformin and Pioglitazone

In a 52-week, active-comparator study, a total of 803 patients inadequately controlled (mean baseline A1C=8.2%) on a current regimen of pioglitazone 30 mg and metformin were randomized to either receive the addition of once daily alogliptin 25 mg or the titration of pioglitazone 30 mg to 45 mg following a 4-week single-blind, placebo run-in period. Patients were maintained on a stable dose of metformin HCl (median daily dose=1700 mg). Patients who failed to meet pre-specified hyperglycemic goals during the 52-week treatment period received glycemic rescue therapy.

In combination with pioglitazone and metformin, alogliptin 25 mg was shown to be statistically superior in lowering A1C and FPG compared with the titration of pioglitazone from 30 to 45 mg at Week 26 and at Week 52 (Table 8). A total of 11% of patients in the alogliptin 25 mg in combination with pioglitazone 30 mg and metformin treatment group and 22% of patients in the up titration of pioglitazone in combination with metformin treatment group required glycemic rescue. Improvements in A1C were not affected by gender, age, race, or baseline BMI.

The mean increase in body weight was similar in both treatment arms. Lipid effects were neutral.

Table 8: Glycemic Parameters at Week 52 in an Active-Controlled Study of Alogliptin as Add-on Combination Therapy to Metformin and Pioglitazone*

  Alogliptin 25 mg + Pioglitazone 30 mg+ Metformin Pioglitazone 45 mg + Metformin
A1C (%) N=397 N=394
Baseline (mean) 8.2 8.1
Change from Baseline (adjusted mean†) -0.7 -0.3
Difference from Pioglitazone 45 mg + Metformin* (adjusted mean† with 95% confidence interval) -0.4‡ (-0.5, -0.3)
% of Patients (n/N) achieving A1C ≤ 7% 33% (134/404)§ 21% (85/399)
FPG (mg/dL)‡ N=399 N=396
Baseline (mean) 162 162
Change from Baseline (adjusted mean†) -15 -4
Difference from Pioglitazone 45 mg + Metformin (adjusted mean† with 95% confidence interval) -11§ (-16, -6)
* Intent-to-treat population using last observation on study.
† Least squares means adjusted for treatment, baseline value, geographic region, and baseline metformin dose.
‡ Non-inferior and statistically superior to metformin plus pioglitazone at the 0.025 1-sided significance level.
§p < 0.001 compared to pioglitazone 45 mg + metformin.

Last reviewed on RxList: 2/11/2013
This monograph has been modified to include the generic and brand name in many instances.

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