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Pharmacology and pharmacokinetics

The affinity of linagliptin for the DPP-4 enzyme is high, which results in a
slow dissociation of this compound from its substrate. Compared with
vildagliptin, linagliptin has a 10-fold slower dissociation/off-rate. The
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very low dissociation of linagliptin complements the potency of this
drug, which is the highest in its class. Linagliptin has the highest selec-
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tivity for DPP-4 relative to DPP-8 and DPP-9 of all the DPP-4 inhibitors. 106-110
Linagliptin is 10,000 times more selective for DPP-4 than it is for either
DPP-8 or DPP-9. This has potential implications for the tolerability and
long-term safety of linagliptin, since the specific functions of DPP-8 and
DPP-9 have not yet been elucidated. A high selectivity for DPP-4 reduces
the likelihood of possible adverse effects related to the inadvertent
inhibition of DPP-8 and DPP-9. 111

Early clinical studies involving healthy volunteers demonstrated that
linagliptin is rapidly absorbed following oral administration of a 5 mg
dose. Peak plasma concentrations were reached after 1.5 hours. As a
consequence of the tight binding of linagliptin to its substrate it has a
long terminal half-life of more than 100 hours, but this does not contrib-
ute to the accumulation of the drug. The effective half-life for accumu-
lation of linagliptin is approximately 12 hours. After once-daily dosing,
steady-state plasma concentrations of 5 mg linagliptin are reached by
the third dose. The co-administration of a high-fat meal with lina-
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gliptin had no clinically relevant effects on pharmacokinetics; therefore
it may be administered with or without food.

Perhaps the most salient of linagliptin’s pharmacokinetic characteristics
is its primarily non-renal route of excretion. Renal excretion accounts for
only 5% of the dose. One main metabolite was detected during the
course of preclinical studies, but this was found to be pharmaco-
logically inactive. With its primarily non-renal route of elimination linagliptin
can be used in patients with any degree of renal or liver impairment or
cardiac insufficiency. No warnings/precautions, dose adjustments and
additional monitoring of renal or liver function are required in patients
treated with linagliptin.
Efficacy

Linagliptin was tested in a large clinical trial program involving >6,500
patients in more than 40 countries. These randomised, controlled studies
have shown that linagliptin reduces HbA in all stages of T2DM and in
1c
combination with all currently used treatment regimens. In addition, im-
provements in FPG, PPG and β-cell function have been demonstrated.
Key information from these studies is summarised in Table 6. As mono-
therapy, linagliptin has been shown to provide a significant and clini-

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