GLYXAMBI
The
results of the bioequivalence study in healthy subjects demonstrated
that GLYXAMBI (25 mg empagliflozin/5 mg linagliptin) combination tablets
are bioequivalent to coadministration of corresponding doses of empagliflozin
and linagliptin as individual tablets. Administration of the fixed-dose
combination with food resulted in no change in overall exposure of
empagliflozin or linagliptin; however, the peak exposure was decreased
39% and 32% for empagliflozin and linagliptin, respectively. These
changes are not likely to be clinically significant.
Absorption
Empagliflozin
The pharmacokinetics of empagliflozin
has been characterized in healthy volunteers and patients with type
2 diabetes and no clinically relevant differences were noted between
the two populations. After oral administration, peak plasma concentrations
of empagliflozin were reached at 1.5 hours post-dose. Thereafter,
plasma concentrations declined in a biphasic manner with a rapid distribution
phase and a relatively slow terminal phase. The steady state mean
plasma AUC and Cmax were 1870 nmol·h/L and
259 nmol/L, respectively, with 10 mg empagliflozin once daily treatment,
and 4740 nmol·h/L and 687 nmol/L, respectively, with 25 mg empagliflozin
once daily treatment. Systemic exposure of empagliflozin increased
in a dose-proportional manner in the therapeutic dose range. The
single-dose and steady-state pharmacokinetic parameters of empagliflozin
were similar, suggesting linear pharmacokinetics with respect to time.
Administration of 25 mg empagliflozin
after intake of a high-fat and high-calorie meal resulted in slightly
lower exposure; AUC decreased by approximately 16% and Cmax decreased by approximately 37%, compared to fasted
condition. The observed effect of food on empagliflozin pharmacokinetics
was not considered clinically relevant and empagliflozin may be administered
with or without food.
Linagliptin
The absolute bioavailability
of linagliptin is approximately 30%. High-fat meal reduced Cmax by 15% and increased AUC by 4%; this effect is not
clinically relevant. Linagliptin may be administered with or without
food.
Distribution
Empagliflozin
The apparent
steady-state volume of distribution was estimated to be 73.8 L based
on a population pharmacokinetic analysis. Following administration
of an oral [14C]-empagliflozin solution
to healthy subjects, the red blood cell partitioning was approximately
36.8% and plasma protein binding was 86.2%.
Linagliptin
The mean apparent volume of distribution at steady state following
a single intravenous dose of linagliptin 5 mg to healthy subjects
is approximately 1110 L, indicating that linagliptin extensively distributes
to the tissues. Plasma protein binding of linagliptin is concentration-dependent,
decreasing from about 99% at 1 nmol/L to 75% to 89% at ≥30 nmol/L,
reflecting saturation of binding to DPP-4 with increasing concentration
of linagliptin. At high concentrations, where DPP-4 is fully saturated,
70% to 80% of linagliptin remains bound to plasma proteins and 20%
to 30% is unbound in plasma. Plasma binding is not altered in patients
with renal or hepatic impairment.
Metabolism
Empagliflozin
No major metabolites of empagliflozin
were detected in human plasma and the most abundant metabolites were
three glucuronide conjugates (2-O-, 3-O-, and 6-O-glucuronide). Systemic
exposure of each metabolite was less than 10% of total drug-related
material. In vitro studies suggested that the primary
route of metabolism of empagliflozin in humans is glucuronidation
by the uridine 5'-diphospho-glucuronosyltransferases UGT2B7, UGT1A3,
UGT1A8, and UGT1A9.
Linagliptin
Following oral administration,
the majority (about 90%) of linagliptin is excreted unchanged, indicating
that metabolism represents a minor elimination pathway. A small fraction
of absorbed linagliptin is metabolized to a pharmacologically inactive
metabolite, which shows a steady-state exposure of 13.3% relative
to linagliptin.
Elimination
Empagliflozin
The apparent terminal elimination half-life of empagliflozin
was estimated to be 12.4 h and apparent oral clearance was 10.6 L/h
based on the population pharmacokinetic analysis. Following once-daily
dosing, up to 22% accumulation, with respect to plasma AUC, was observed
at steady-state, which was consistent with empagliflozin half-life.
Following administration of an oral [14C]-empagliflozin solution to healthy subjects, approximately 95.6%
of the drug-related radioactivity was eliminated in feces (41.2%)
or urine (54.4%). The majority of drug-related radioactivity recovered
in feces was unchanged parent drug and approximately half of drug-related
radioactivity excreted in urine was unchanged parent drug.
Linagliptin
Following administration of an oral [14C]-linagliptin dose to healthy subjects, approximately 85% of the
administered radioactivity was eliminated via the enterohepatic system
(80%) or urine (5%) within 4 days of dosing. Renal clearance at steady
state was approximately 70 mL/min.
Specific Populations
Renal Impairment
GLYXAMBI:
Studies characterizing the pharmacokinetics of empagliflozin
and linagliptin after administration of GLYXAMBI in renally impaired
patients have not been performed [see Dosage and Administration
(2.2)].
Empagliflozin: In patients
with mild (eGFR: 60 to less than 90 mL/min/1.73 m2), moderate (eGFR: 30 to less than 60 mL/min/1.73 m2), and severe (eGFR: less than 30 mL/min/1.73 m2) renal impairment and subjects with kidney failure/end stage renal
disease (ESRD) patients, AUC of empagliflozin increased by approximately
18%, 20%, 66%, and 48%, respectively, compared to subjects with normal
renal function. Peak plasma levels of empagliflozin were similar
in subjects with moderate renal impairment and kidney failure/ESRD
compared to patients with normal renal function. Peak plasma levels
of empagliflozin were roughly 20% higher in subjects with mild and
severe renal impairment as compared to subjects with normal renal
function. Population pharmacokinetic analysis showed that the apparent
oral clearance of empagliflozin decreased, with a decrease in eGFR
leading to an increase in drug exposure. However, the fraction of
empagliflozin that was excreted unchanged in urine, and urinary glucose
excretion, declined with decrease in eGFR.
Linagliptin: An open-label
pharmacokinetic study evaluated the pharmacokinetics of linagliptin
5 mg in male and female patients with varying degrees of chronic renal
impairment. The study included 6 healthy subjects with normal renal
function (creatinine clearance [CrCl] ≥80 mL/min), 6 patients with
mild renal impairment (CrCl 50 to <80 mL/min), 6 patients with
moderate renal impairment (CrCl 30 to <50 mL/min), 10 patients
with type 2 diabetes and severe renal impairment (CrCl <30 mL/min),
and 11 patients with type 2 diabetes and normal renal function. Creatinine
clearance was measured by 24-hour urinary creatinine clearance measurements
or estimated from serum creatinine based on the Cockcroft-Gault formula.
Under steady-state conditions,
linagliptin exposure in patients with mild renal impairment was comparable
to healthy subjects.
In patients with moderate renal impairment under steady-state conditions,
mean exposure of linagliptin increased (AUCτ,ss by 71% and Cmax by 46%) compared with healthy
subjects. This increase was not associated with a prolonged accumulation
half-life, terminal half-life, or an increased accumulation factor.
Renal excretion of linagliptin was below 5% of the administered dose
and was not affected by decreased renal function. Patients with type
2 diabetes and severe renal impairment showed steady-state exposure
approximately 40% higher than that of patients with type 2 diabetes
and normal renal function (increase in AUCτ,ss by 42% and Cmax by 35%). For both type 2
diabetes groups, renal excretion was below 7% of the administered
dose.
These findings
were further supported by the results of population pharmacokinetic
analyses.
Hepatic Impairment
GLYXAMBI: Studies characterizing the pharmacokinetics of empagliflozin and
linagliptin after administration of GLYXAMBI in hepatically impaired
patients have not been performed.
Empagliflozin: In subjects
with mild, moderate, and severe hepatic impairment according to the
Child-Pugh classification, AUC of empagliflozin increased by approximately
23%, 47%, and 75% and Cmax increased by approximately
4%, 23%, and 48%, respectively, compared to subjects with normal hepatic
function.
Linagliptin:
In patients with mild hepatic impairment (Child-Pugh class
A) steady-state exposure (AUCτ,ss) of linagliptin
was approximately 25% lower and Cmax,ss was
approximately 36% lower than in healthy subjects. In patients with
moderate hepatic impairment (Child-Pugh class B), AUCss of linagliptin was about 14% lower and Cmax,ss was approximately 8% lower than in healthy subjects. Patients with
severe hepatic impairment (Child-Pugh class C) had comparable exposure
of linagliptin in terms of AUC0-24 and approximately
23% lower Cmax compared with healthy subjects.
Reductions in the pharmacokinetic parameters seen in patients with
hepatic impairment did not result in reductions in DPP-4 inhibition.
Effects of Age, Body
Mass Index, Gender, and Race
Empagliflozin: Based on the population PK analysis, age, body mass index (BMI),
gender and race (Asians versus primarily Whites) do not have a clinically
meaningful effect on pharmacokinetics of empagliflozin [see
Use in Specific Populations (8.5)].
Linagliptin: Based on the population PK analysis, age, body mass index (BMI),
gender and race do not have a clinically meaningful effect on pharmacokinetics
of linagliptin [see Use in Specific Populations (8.5)].
Pediatric
Studies characterizing the pharmacokinetics of empagliflozin or
linagliptin after administration of GLYXAMBI in pediatric patients
have not been performed.
Drug Interactions
Pharmacokinetic drug
interaction studies with GLYXAMBI have not been performed; however,
such studies have been conducted with the individual components of
GLYXAMBI (empagliflozin and linagliptin).
Empagliflozin
In vitro Assessment of Drug Interactions
In vitro data suggest that the primary
route of metabolism of empagliflozin in humans is glucuronidation
by the uridine 5'-diphospho-glucuronosyltransferases UGT2B7, UGT1A3,
UGT1A8, and UGT1A9. Empagliflozin does not inhibit, inactivate, or
induce CYP450 isoforms. Empagliflozin also does not inhibit UGT1A1.
Therefore, no effect of empagliflozin is anticipated on concomitantly
administered drugs that are substrates of the major CYP450 isoforms
or UGT1A1. The effect of UGT induction (e.g., induction by rifampicin
or any other UGT enzyme inducer) on empagliflozin exposure has not
been evaluated.
Empagliflozin
is a substrate for P-glycoprotein (P-gp) and breast cancer resistance
protein (BCRP), but it does not inhibit these efflux transporters
at therapeutic doses. Based on in vitro studies,
empagliflozin is considered unlikely to cause interactions with drugs
that are P-gp substrates. Empagliflozin is a substrate of the human
uptake transporters OAT3, OATP1B1, and OATP1B3, but not OAT1 and OCT2.
Empagliflozin does not inhibit any of these human uptake transporters
at clinically relevant plasma concentrations and, therefore, no effect
of empagliflozin is anticipated on concomitantly administered drugs
that are substrates of these uptake transporters.
In vivo Assessment
of Drug Interactions
No dose adjustment of empagliflozin is recommended when coadministered
with commonly prescribed medicinal products based on results of the
described pharmacokinetic studies. Empagliflozin pharmacokinetics
were similar with and without coadministration of metformin, glimepiride,
pioglitazone, sitagliptin, linagliptin, warfarin, verapamil, ramipril,
and simvastatin in healthy volunteers and with or without coadministration
of hydrochlorothiazide and torsemide in patients with type 2 diabetes
(see Figure 1). The observed increases in overall exposure (AUC)
of empagliflozin following coadministration with gemfibrozil, rifampicin,
or probenecid are not clinically relevant. In subjects with normal
renal function, coadministration of empagliflozin with probenecid
resulted in a 30% decrease in the fraction of empagliflozin excreted
in urine without any effect on 24-hour urinary glucose excretion.
The relevance of this observation to patients with renal impairment
is unknown.
Figure
1 Effect of Various Medications on the Pharmacokinetics of Empagliflozin
as Displayed as 90% Confidence Interval of Geometric Mean AUC and
Cmax Ratios [reference lines indicate 100%
(80% - 125%)]
aempagliflozin, 50 mg, once daily; bempagliflozin, 25 mg, single dose; cempagliflozin, 25 mg, once daily; dempagliflozin,
10 mg, single dose
Empagliflozin had no clinically relevant
effect on the pharmacokinetics of metformin, glimepiride, pioglitazone,
sitagliptin, linagliptin, warfarin, digoxin, ramipril, simvastatin,
hydrochlorothiazide, torsemide, and oral contraceptives when coadministered
in healthy volunteers (see Figure 2).
Figure 2 Effect of Empagliflozin on
the Pharmacokinetics of Various Medications as Displayed as 90% Confidence
Interval of Geometric Mean AUC and Cmax Ratios
[reference lines indicate 100% (80% - 125%)]
aempagliflozin,
50 mg, once daily; bempagliflozin, 25 mg,
once daily; cempagliflozin, 25 mg, single
dose; dadministered as simvastatin; eadministered as warfarin racemic mixture; fadministered as Microgynon®; gadministered as ramipril
Linagliptin
In vitro Assessment of Drug Interactions
Linagliptin is a weak to moderate inhibitor of CYP isozyme
CYP3A4, but does not inhibit other CYP isozymes and is not an inducer
of CYP isozymes, including CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6,
2E1, and 4A11.
Linagliptin
is a P-glycoprotein (P-gp) substrate, and inhibits P-gp mediated transport
of digoxin at high concentrations. Based on these results and in vivo drug interaction studies, linagliptin is considered
unlikely to cause interactions with other P-gp substrates at therapeutic
concentrations.
In vivo Assessment of Drug Interactions
Strong inducers of CYP3A4 or P-gp (e.g., rifampin) decrease
exposure to linagliptin to subtherapeutic and likely ineffective concentrations.
For patients requiring use of such drugs, an alternative to linagliptin
is strongly recommended. In vivo studies indicated
evidence of a low propensity for causing drug interactions with substrates
of CYP3A4, CYP2C9, CYP2C8, P-gp and organic cationic transporter (OCT).
No dose adjustment of linagliptin is recommended based on results
of the described pharmacokinetic studies.
Table 3 Effect of Coadministered Drugs on Systemic
Exposure of Linagliptin| aMultiple dose (steady
state) unless otherwise noted |
| bSingle dose |
| cAUC = AUC(0 to 24 hours)
for single dose treatments and AUC = AUC(TAU) for multiple dose treatments |
| QD = once daily |
| BID = twice daily |
| TID = three times daily |
| Coadministered Drug | Dosing of Coadministered Druga | Dosing of Linagliptina | Geometric Mean Ratio
(ratio with/without
coadministered drug)
No effect = 1.0 |
| AUCc | Cmax |
| No dosing adjustments required for linagliptin when given with the
following coadministered drugs: |
Metformin | 850 mg TID | 10 mg QD | 1.20 | 1.03 |
Glyburide | 1.75 mgb | 5 mg QD | 1.02 | 1.01 |
Pioglitazone | 45 mg QD | 10 mg QD | 1.13 | 1.07 |
Ritonavir | 200 mg BID | 5 mgb | 2.01 | 2.96 |
The efficacy of linagliptin may be
reduced when administered in combination with strong inducers of CYP3A4
or P-gp (e.g., rifampin). Use of alternative treatments is strongly
recommended [see Drug Interactions (7.2)]. |
Rifampin | 600 mg QD | 5 mg QD | 0.60 | 0.56 |
Table 4 Effect of Linagliptin on Systemic Exposure
of Coadministered Drugs| aMultiple dose (steady
state) unless otherwise noted |
| bSingle dose |
| cAUC = AUC(INF) for single
dose treatments and AUC = AUC(TAU) for multiple dose treatments |
| dAUC=AUC(0-168) and Cmax=Emaxfor pharmacodynamic end
points |
| INR = International Normalized Ratio |
| PT = Prothrombin Time |
| QD = once daily |
| TID = three times daily |
Coadministered
Drug | Dosing of
Coadministered Druga | Dosing of
Linagliptina | Geometric
Mean Ratio
(ratio with/without coadministered drug)
No effect = 1.0 |
| AUCc | Cmax |
No dosing adjustments required for
the following coadministered drugs: |
Metformin | 850 mg TID | 10 mg QD | metformin | 1.01 | 0.89 |
Glyburide | 1.75 mgb | 5 mg QD | glyburide | 0.86 | 0.86 |
Pioglitazone | 45 mg QD | 10 mg QD | pioglitazone metabolite M-III metabolite M-IV | 0.94 0.98 1.04 | 0.86 0.96 1.05 |
Digoxin | 0.25 mg QD | 5 mg QD | digoxin | 1.02 | 0.94 |
Simvastatin | 40 mg QD | 10 mg QD | simvastatin
simvastatin acid | 1.34 1.33 | 1.10 1.21 |
Warfarin | 10 mgb | 5 mg QD | R-warfarin S-warfarin INR PT | 0.99 1.03 0.93d 1.03d | 1.00 1.01 1.04d 1.15d |
Ethinylestradiol and levonorgestrel | ethinylestradiol 0.03 mg and levonorgestrel
0.150 mg QD | 5 mg QD | ethinylestradiol levonorgestrel | 1.01 1.09 | 1.08 1.13 |
