SCIENTIFIC DISCUSSION
`
`Introduction
`
`
`
` 1
`
`•
`
`•
`
`
`The pathophysiology of Type 2 diabetes mellitus (T2DM) is characterised by deficient insulin activity
`arising from decreased insulin secretion secondary to beta cell failure, and/or compromised insulin
`action in peripheral target tissues (insulin resistance). This abnormal metabolic state is exacerbated by
`excess hepatic glucose production and altered metabolism of proteins and lipids, which along with
`hyperglycaemia, contribute to microvascular and macrovascular complications.
`T2DM accounts for approximately 85% to 95% of diabetes cases in developed regions like the
`European Union. Age and weight are established risk factors for T2DM. The majority of patients
`with T2DM are overweight or obese. Diet modification and exercise is the first line of treatment for
`T2DM. Pharmacologic intervention with one oral antidiabetic drug (OAD) is usually the next step in
`treatment. After 3 to 9 years of OAD monotherapy, patients typically require an additional
`intervention. The recommended first line treatment is metformin, which restrains hepatic glucose
`production and decreases peripheral insulin resistance. Sulphonylureas, which are insulin
`secretagogues, may be used as an alternative to patients intolerant to metformin, or as an addition to
`metformin. Other second line oral treatment alternatives include alpha-glucosidase inhibitors,
`meglitinides and thiazolidinediones. Although being efficient in attenuating hyperglycaemia, all of
`these treatment alternatives have more or less serious side effects and there is a need for development
`of efficient drugs without metabolic or other side effects.
`
`Vildagliptin belongs to a new class of oral anti-diabetic drugs and is a selective and reversible
`inhibitor of Dipeptidyl peptidase 4 (DPP-4), the enzyme which inactivates the incretin hormones,
`glucagon-like peptide-1 (GLP-1), and glucose-dependent insulinotropic polypeptide (GIP), hormones
`which significantly contribute to the maintenance of glucose homeostasis.
`
`The therapeutic indication granted is: Treatment of type 2 diabetes mellitus as dual oral therapy in
`combination with
`• metformin, in patients with insufficient glycaemic control despite maximal tolerated dose of
`monotherapy with metformin,
`a sulphonylurea, in patients with insufficient glycaemic control despite maximal tolerated dose
`of a sulphonylurea and for whom metformin is inappropriate due to contraindications or
`intolerance,
`a thiazolidinedione, in patients with insufficient glycaemic control and for whom the use of a
`thiazolidinedione is appropriate.
`
`
`The recommended dose is 100 mg daily administered either once daily or divided into two doses of 50
`mg given in the morning and evening, except for the combined use with a sulphonylurea, where the
`recommended dose is 50 mg given in the morning.
`
` 2
`
`
`
`Quality aspects
`
`
`Introduction
`
`Galvus an immediate release dosage form is presented as tablets containing 50 mg and 100 mg of
`vildagliptin as active substance. The other ingredients are microcrystalline cellulose, lactose
`anhydrous, sodium starch glycolate and magnesium stearate.
`
`The film-coated tablets are marketed in aluminium/aluminium (PA/Al/PVC//Al) blisters.
`
`Active Substance
`
`The active substance is vildagliptin. Its chemical name is (S)-1-[2-(3-Hydroxyadamantan-1-ylamino)
`acetyl]pyrrolidine-2-carbonitrile according to the IUPAC nomenclature.
`Vildagliptin is a white to slightly yellowish or slightly greyish crystalline powder and no polymorphs
`or solvates have been identified so far. Vildagliptin is non-hygroscopic and freely soluble in water and
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`polar organic solvents. The above-mentioned active substance has one chiral centre and is used as a
`single enantiomer (S).
`
` •
`
` Manufacture
`
`
`Vildagliptin is synthesised in two reactions steps followed by purification (recrystallisation). The
`manufacturing process for vildagliptin has been adequately described. Critical parameters have been
`identified and adequate in-process controls included. Specifications for starting materials, reagents,
`and solvents have been provided. Adequate control of critical steps and intermediates has been
`presented.
`Structure elucidation has been performed by elemental analysis, ultraviolet spectroscopy, infrared
`absorption spectroscopy, 1H-NMR spectroscopy, 13C-NMR spectroscopy, and mass spectroscopy. The
`molecular weight was determined by elemental analysis which is in agreement with the expected
`molecular weight. The proposed molecular structure was confirmed by X-ray powder diffraction and
`X-ray single crystal structural analysis.
`
` •
`
` Specification
`
`
`The vildagliptin specifications include tests for appearance (slightly yellowish or slightly greyish
`powder), particle size (by laser light diffraction), identification (by IR-KBr, IR-ATR and X-ray
`diffraction), Related substances (HPLC and IC), R-enantiomer of vildagliptin (HPLC), residual
`solvents (Head-space GC), loss on drying (thermogravimetry), sulphated ash, heavy metals, clarity of
`solution, colour of solution, assay (by HPLC) and microbiological limit tests.
`It was verified that all specifications reflect the relevant quality attributes of the active substance. The
`analytical methods, which were used in the routine controls, were well described and their validations
`are in accordance with the relevant ICH Guidelines.
`Impurities were described, classified as process related impurities and possible degradation products,
`and qualified. Residual solvents were satisfactorily controlled in the active substance according to the
`relevant ICH requirements. Certificates of analyses for the active substances were provided and all
`batch analysis results comply with the specifications and show a good uniformity from batch to batch.
`
` •
`
` Stability
`
`
`The stability results from long-term accelerated and stress studies were completed according to ICH
`guidelines demonstrated adequate stability of the active substance. The active substance is not
`susceptible to degradation under the influence of light and temperature exposure. The results of the
`long-term and accelerated studies fulfil the proposed specification and for that reason support the
`proposed retest period.
`
`Medicinal Product
`
` •
`
` Pharmaceutical Development
`
`
`All information regarding the choice of the active substance and the excipients are sufficiently
`justified.
`Galvus tablets were developed five tablet strengths which were used in clinical trials. However, only
`two tablet strengths (50 mg and 100 mg) will be marketed.
`The main aim of the applicant was to develop robust final formulation that would be suitable for
`routine manufacturing at the production scale for that reason different formulation containing different
`excipients were investigated and optimised.
`Having investigated different formulations the applicant selected for commercialisation a direct
`compression tablet formulation.
`Lactose monohydrate is manufactured from bovine milk. The supplier confirms that the milk used in
`the manufacture of the lactose is sourced from healthy animals under the same conditions as for
`human consumption.
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`• Manufacture of the Product
`
`The proposed commercial manufacturing process involves standard technology using standard
`manufacturing processes such as mixing, blending and compressing.
`Furthermore, the equipment used is commonly available in the pharmaceutical industry. It was
`demonstrated that there are no critical steps in the manufacturing process.
`The batch analysis results show that the medicinal product can be manufactured reproducibly
`according the agreed finished product specifications.
`
` •
`
` Product Specification
`
`
`The finished product specifications were established according the ICH guidelines and include the
`following tests: appearance, identification (TLC and HPLC), mean mass, dissolution, water (Karl
`Fischer), degradation products (HPLC), uniformity of dosage units by mass variation (Ph Eur), or,
`alternatively, uniformity of dosage units by content uniformity (Ph Eur), assay (HPLC) and microbial
`limits (Ph Eur).
`All analytical procedures that were used for testing the drug product were properly described.
`Moreover, all relevant methods were satisfactorily validated in accordance with the relevant ICH
`guidelines.
`Batch analysis data on three stability batches and three production scale batches (validation batches)
`confirm satisfactory uniformity of the product at release.
`
`
`The stability studies were conducted according to the relevant ICH guidelines. Three full production
`scale batches of each strength, as well as a supportive production batch of 100 mg have been stored at
`long term and accelerated conditions in the proposed market packaging.
`One production batch per strength was stored under elevated temperature conditions for 3 months and
`at ICH conditions, and under low temperature conditions for 6 months and for photostability at ICH
`conditions.
`Based on the available stability data, the proposed shelf life and storage conditions as stated in the
`SPC are acceptable.
`
`Discussion on chemical, pharmaceutical and biological aspects
`
`Information on development, manufacture, control of the active substance and the finished product
`have been presented in a satisfactory manner and justified in accordance with relevant CHMP and ICH
`guidelines. The results of tests carried out indicate satisfactory consistency and uniformity of the
`finished product. Therefore, this medicinal product should have a satisfactory and uniform
`performance in the clinic.
`
`
`
`Non-clinical aspects
`
`3.
`
`Introduction
`
`All pivotal toxicology and safety studies were performed in accordance with GLP regulations.
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`
`Pharmacology
`
` •
`
` Primary pharmacodynamics
`
`
`In vitro studies
`The non-clinical pharmacology program has demonstrated that vildagliptin is a selective and potent
`inhibitor of DPP-4. The IC50 value for inhibition of human DPP-4 is about 3 nM and similar activity
`was observed with the rat enzyme, demonstrating the lack of species selectivity. Vildagliptin showed
`some activity at the related enzymes DPP-8 and DPP-9 (Ki values of 506 nM and 65 nM,
`respectively). Although these values are 253 and 32 times higher than the Ki for DPP-4, activity at
`Cmax in humans (2.3 μM) is likely. No assays exist allowing evaluation of DPP-8/DPP-9 inhibition in
`vivo. The possibility of activity at one or both of these targets is considered a safety concern in
`relation to the occurrence of skin lesions in monkeys (see below). No, or minimal, inhibition was seen
`with other related enzymes.
`
`In vivo studies
`In vivo pharmacodynamic studies were performed in rats and monkeys. These studies demonstrated
`the in vivo inhibition of DPP-4 and increased plasma levels of GLP-1. Studies in diabetic rats and in
`insulin-resistant monkeys demonstrated a glucose-lowering effect of vildagliptin. Chronic effects of
`vildagliptin were studied in pre-diabetic and insulin-treated diabetic monkeys. Beneficial effects were
`observed on HbA1c, fasting insulin, fibrinogen and PAI-1.
`
`Vildagliptin increased β-cell mass in neonatal rats, and improved β-cell function in streptozotocin-
`induced diabetic mice. These data could suggest that vildagliptin has the potential to mitigate the
`progressive loss of islet function in type 2 diabetes patients.
`
` •
`
` Secondary pharmacodynamics
`
`
`Vildagliptin showed no significant effect on gastric emptying in monkeys. This is in contrast to what
`has been observed with exogenously-administered GLP-1 and GLP-1 analogues.
`
`As discussed above, activity at the related enzymes DPP-8 and/or DPP-9 can not be excluded at
`clinical exposures. Concerns related to secondary pharmacology can also arise from the importance of
`DPP-4 in enzymatic and non-enzymatic functions other than inhibiting the inactivation of GLP-1 and
`GIP.
`
`DPP-4 (CD26) is present as a cell surface molecule on immune cells and has been characterised as an
`important costimulatory molecule in immune activation. Although some studies applying DPP-4
`inhibitors have suggested a role for the enzyme activity for the immune function, other studies have
`suggested costimulation to be unrelated to the enzyme activity. The studies performed with
`vildagliptin and discussed in the dossier support the view that the immune function of CD26 is
`independent of its enzyme activity.
`
`There are no indications for safety issues related to other DPP-4 substrates than GLP-1 and GIP.
`
`Potential effects on the immune system, resulting in an increased risk for infections and on substance
`P and neurokinin resulting in an increased risk of angioedema are discussed in the Risk Management
`Plan. No increased risk has been observed during clinical development for any of these adverse events.
`
` •
`
` Safety pharmacology programme
`
`
`Safety pharmacology studies have been conducted to evaluate neuropharmacological, respiratory and
`cardiovascular effects of vildagliptin in animals.
`Cardiovascular changes were observed in dogs at high doses, occasionally resulting in mortality.
`Possible mechanisms were examined in an extensive battery of in vitro and in vivo studies of
`cardiovascular parameters. These effects are possibly related to inhibition of SCN5A sodium channels
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`which was observed in in vitro studies. Based on dog exposure data (Cmax > 7-fold higher at NOAEL
`than seen at maximum dose in humans) and the in vitro IC50 for sodium channels (365 μM versus
`clinical Cmax of 2 μM), a clinical effect is unlikely. However, conduction disturbances were further
`investigated in humans.
`
` •
`
` Pharmacodynamic drug interactions
`
`
`The effects of combinations of vildagliptin with the rapid-onset insulinotropic agent, nateglinide
`(Starlix) and with the insulin sensitizer, pioglitazone (Actos) were assessed in Zucker fatty rats and
`resulted in an additive or more than additive effect on several plasma glucose-related parameters.
`
`Pharmacokinetics
`
`Vildagliptin was rapidly absorbed with a high bioavailability in all species. There were no important
`differences in pharmacokinetic parameters between the tested animal species and humans.
`
`Vildagliptin showed low binding to plasma proteins in all species (<10%). In a whole body
`autoradiography study in rats, vildagliptin-related radioactivity was widely distributed to most tissues.
`Drug-related radioactivity was bound to melanin. There was a low passage for drug-related
`radioactivity across the blood-brain barrier. No radioactivity was detected in any tissue at 48 h post-
`dose. Studies in pregnant rats and rabbits demonstrated placental transfer of vildagliptin.
`
`
`The parent compound was one of the major circulating components in all species and all metabolites
`observed in humans were also found in the animal species. Hydrolysis was the main mechanism of
`vildagliptin metabolism in all species and exposure to the major metabolites was broadly similar in the
`rat, dog and human. In humans, the predominant metabolic pathway was hydrolysis at the cyano
`moiety to form a carboxylic acid metabolite (M20.7/LAY151), accounting for approximately 55% of
`circulating drug-related material following an oral dose. M20.7 was the main metabolite both in the rat
`(54%) and the dog (33%). In the rabbit, another hydrolysis product M15.3 was the main metabolite
`(53%).
`
`Vildagliptin is produced as a pure S-enantiomer. A clinical study showed that chiral conversion in vivo
`is unlikely.
`
`Urinary excretion was the main route in all species except the rat, where equal amounts were excreted
`with urine and feces. Milk transfer of vildaglitin and metabolites were demonstrated in the rat, which
`is therefore mentioned in the SPC section 4.6, with a milk/plasma ratio for total radioactivity of 4.
`
`In vitro studies demonstrated that vildagliptin is unlikely to exhibit a potential for pharmacokinetic
`drug interactions. Vildagliptin did not inhibit Pgp or any of a series of CYP enzymes. There was no
`evidence for enzyme induction.
`
`Toxicology
`
` •
`
` Single dose toxicity
`
`
`Vildagliptin exhibits low acute toxicity. In mice and rats no toxicological signs were observed after a
`single oral dose of 2000 mg/kg.
`
` •
`
` Repeat dose toxicity (with toxicokinetics)
`
`
`Repeat dose toxicity studies were performed in rats (up to 26 weeks) and dogs (up to 52 weeks). These
`models are considered relevant, based on the lack of species specificity for the pharmacological
`activity of vildagliptin, and the similarities in metabolism to humans.
`
`The main toxicological effect noted in rats was the accumulation of clusters of foamy alveolar
`macrophages in the lung. Similar observations were made in mice. This finding was proposed to be
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`due to an exaggerated pharmacological effect of DPP-4 inhibition in the rat. The clinical relevance of
`the lung findings in rats cannot be fully excluded. There is a considerable safety margin (5 x human
`AUC at NOAEL) and the findings are considered of limited importance.
`
`The most consistent toxicological finding in the dog was the appearance of gastrointestinal symptoms,
`particularly soft faeces, mucoid faeces, diarrhea and at higher doses, faecal blood. These signs were
`observed at relatively low systemic exposures (observed already at lowest dose representing 2 x
`human AUC). GI findings were not observed in any other species and according to the applicant no GI
`disorders have been observed in clinical trials. The CHMP was of the opinion, that these findings are
`unlikely to be of clinical importance.
`
` •
`
` Genotoxicity
`
`
`The data from genotoxicity studies conducted with vildagliptin in several standard genotoxicity tests
`do not indicate a genotoxic potential.
`
` •
`
` Carcinogenicity
`
`
`Life-time carcinogenicity studies were performed in mice and rats. No evidence for a carcinogenic
`potential was observed in the rat. An increased incidence of hemangiosarcomas was observed at the
`highest dose in female rats while in male rats, the incidence was slightly decreased. Given the mouse
`findings discussed below, a relation to treatment cannot be fully excluded. In the mouse there was an
`increased incidence of hemangiosarcomas and mammary carcinoma. The increased incidence of
`hemangiosarcoma in mice occurred only in organs where this tumour occurs as a relatively common
`spontaneous finding in the mouse (liver, spleen, uterus etc.). It is suggested that a predisposition to
`spontaneous hemangiosarcoma at the affected site is needed for vildagliptin to promote an increased
`incidence. A study in the mouse demonstrated that vildagliptin inhibits VEGF-induced angiogenesis.
`Based on these mechanistic data the applicant proposes a mechanism whereby inhibition of VEGF-
`induced angiogenesis over a long period exerts selection pressure in favour of endothelium that
`proliferates independently of VEGF and hence increases the likelihood of endothelial neoplasia. There
`was a disproportionate increase in hemangiosarcoma involving the liver in treated male mice at ≥ 250
`mg/kg/day. At the same time there was a decreased incidence of hepatocellular carcinoma in male
`mice. The applicant hypothesizes that hemangiosarcomas may originate within early hepatocellular
`tumours or preneoplastic lesions followed by obliteration of the hepatocellular tumour and its
`replacement with the more aggressive hemangiosarcoma. There is a substantial safety margin
`(exposure margin at NOAEL = 16). It was considered that vildagliptin is likely to act by promoting
`development of a tumour form that appears commonly mice, and that the data do not suggest an
`increased risk for hemangiosarcoma development in humans where this tumour form is uncommon.
`The fact that the incidences of other common spontaneous tumours were not increased by vildagliptin
`treatment supports the view that a more general tumour promoting effect of vildaglitin is unlikely. The
`applicant will further study the mechanism for tumour development in the liver of mice, and the
`findings were considered by the CHMP not to represent a significant risk to humans.
`
`In the case of mammary adenocarcioma, the applicant suggested that tumours noted in the mouse
`carcinogenicity study are likely the result of an effect on the pituitary-gonadal axis that is unlikely to
`be of relevance to humans. In mammary tissue from mice treated with vildagliptin for 53 weeks there
`was a dramatic upregulation of genes related to milk production, such as casein-beta, casein-gamma
`and lactalbumin, suggesting that hormonally-driven changes are occurring in the mammary gland of
`mice treated with vildagliptin. The CHMP was of the opinion that these effects are unlikely to be of
`relevance to humans.
`
` •
`
` Reproduction Toxicity
`
`
`Vildagliptin showed no effects on fertility, reproductive performance or early embryonic development
`in the rat. Embryo-foetal toxicity was evaluated in rats and rabbits. In the rat, an increased incidence of
`wavy ribs was observed at ≥ 225 mg/kg/day, in association with reduced maternal body weight
`parameters. Although classified as a malformation, literature data suggest that wavy ribs in the rat may
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`be reversible. In rabbits, decreased foetal weight and skeletal variations indicative of developmental
`delays were noted in rabbits at 150 mg/kg/day, in the presence of severe maternal toxicity (including
`mortality). It is concluded that vildagliptin is not selectively embryotoxic and does not exhibit a
`teratogenic potential. In the peri- and postnatal toxicity study in rats, maternal toxicity was observed at
`all doses. Transient decrease in F1 generation body weight and a decreased number of central beam
`breaks in open-field motor activity tests were observed at ≥ 150 mg/kg/day.
`
` •
`
` Local tolerance
`
`
`Local tolerance of vildagliptin was investigated as part of the intravenous toxicity. No local effects due
`to vildagliptin were observed in either species. A skin irritation study conducted in rabbits did not
`indicate any dermal irritant properties.
`
` •
`
` Other toxicity studies
`
`
`Vildagliptin showed no effect on the immune response in KLH-immunised rats. As discussed in the
`section on Pharmacology, the lack of immunotoxicity supports the view that the immune function of
`DPP-4/CD26 is independent of its enzymatic activity.
`
`No toxicity studies with metabolites were performed. The main human metabolites were present at
`similar amounts in the toxicology species. In patients with renal impairment, the exposure to the
`pharmacologically inactive metabolite LAY151 may be increased up to 6 times. There are no
`indications for any toxicity related to the metabolite and no further studies are warranted.
`
`Drug impurities requiring toxicological qualification were tested in repeat-dose toxicity and
`genotoxicity studies with a vildagliptin preparation spiked with the impurities at levels of 2-3%. There
`were no findings suggesting a change in toxicity profile.
`
`Available data indicate that the administration of DPP-4 inhibitors to monkeys results in dose and
`duration-dependent increases in necrotic lesions of the tail, digits, ears, nose and scrotum. The
`mechanism is unknown and such lesions have not been described in humans, rats or dogs. Data from
`the safety pharmacology study in monkeys suggest that vildagliptin may cause skin lesions in the
`monkey. A 13-week toxicology in cynomolgus monkeys shows occurrence of necrotic lesions with a
`lack of safety margin and lack of reversibility at higher doses. The skin lesions are proposed to result
`from peripheral vasoconstriction.The skin lesions were observed at doses that produced a tachycardic
`and a prohypertensive action indicating a sympathomimetic effect of vildagliptin at these doses in
`monkeys.The applicant argues that these findings were related to DPP4 inhibition, and that monkeys
`are much more sensitive to DPP4 inhibition than humans. The lack of skin lesions with sitagliptin in
`rhesus monkeys speaks against this proposal suggesting that other factors may be involved in causing
`the skin lesions result, such as inhibition of DPP8 and or DPP9, the occurance of which in vivo is not
`known.
`
`Based on mechanistic considerations, no firm conclusion on the relevance of the skin lesions in
`monkeys for clinical safety can be drawn at this time. The CHMP considered these findings acceptable
`for a market authorisation, considering the clinical safety documented so far, and appropriate means
`taken by the applicant to identify any signals in the post-marketing phase. Further studies on the
`mechanism of skin lesions in the monkeys will be performed as follow-up measures. In addition to
`describing the findings in SPC section 5.3, a warning is included in section 4.4 with a reference to
`section 5.3.
`
`Ecotoxicity/environmental risk assessment
`
`The environmental risk assessment does not indicate any important risk to the environment.
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`Clinical aspects
`
`
`4.
`
`Introduction
`
`Vildagliptin is a selective and reversible inhibitor of DPP-4, and thus belongs to a new class of oral
`anti-diabetic drugs.
`
`The applicant received repeated Scientific Advice from the CHMP on 21 November 2003, 24 June
`2004 and on 22 October 2004. The Scientific Advice focused on clinical aspects, including study
`design, documentation of cardiac safety, and discussion of study endpoints.
`
`During the clinical development program, there were 2 events of note:
`1. The 100 mg dose was initially discontinued by amendment in 2 phase II dose selection studies
`(because of cardiac findings in dogs at very high exposures, which were subsequently mitigated) and
`resumed in phase III studies.
`2. Unreliable HbA1c assessments in 6 key phase III studies and the 1 phase III dose regimen study
`required reanalysis in retention samples. As some patients had no retention samples for re-analysis,
`and others did not reach the entry requirements for HbA1c upon re-analysis, replacement patients were
`recruited in each study prior to database lock and patients without reliable baseline values or required
`entry values were excluded from the full analysis in accordance with ICH guidance.
`
`The therapeutic indication for vildaglitpin claimed by the applicant was treatment of T2DM:
`• As monotherapy, in patients inadequately controlled by diet and exercise for whom metformin
`is inappropriate because of intolerance or contraindications,
`• As dual oral therapy with metformin, a sulfonylurea, or a thiazolidinedione, in patients with
`insufficient glycaemic control despite maximal tolerated doses of monotherapy with these
`agents,
`In combination with insulin.
`
`•
`
`
`During the evaluation of the MAA, the CHMP had concerns about the proposed monotherapy
`indication, as well as about the proposed use in combination with insulin. The applicant initially
`proposed a further restriction of the combination usage with insulin but finally withdrew this part of
`the indication. In addition, on 5 July 2007, the applicant also withdrew the part of the indication
`proposing vildagliptin as monotherapy in patients inadequately controlled by diet and exercise for
`whom metformin is inappropriate because of intolerance or contraindications, thus addressing the
`remaining concerns by the CHMP.
`
`The therapeutic indication finally granted is therefore: treatment of T2DM, as dual oral therapy in
`combination with
`• metformin, in patients with insufficient glycaemic control despite maximal tolerated dose of
`monotherapy with metformin,
`a sulphonylurea, in patients with insufficient glycaemic control despite maximal tolerated dose
`of a sulphonylurea and for whom metformin is inappropriate due to contraindications or
`intolerance,
`a thiazolidinedione, in patients with insufficient glycaemic control and for whom the use of a
`thiazolidinedione is appropriate.
`
`•
`
`•
`
`
`The recommended dose is 100 mg daily administered either once daily or divided into two doses of 50
`mg given in the morning and evening, except for the combined use with a sulphonylurea, where the
`recommended dose is 50 mg given in the morning.
`
`No study in the paediatric population was performed and therefore the use in this population is not
`recommended. Experience in patients aged 75 years and older is limited and caution should be
`exercised with the use in this population.
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`GCP
`
`The Clinical trials were performed in accordance with GCP as claimed by the applicant.
`
`The applicant has provided a statement to the effect that clinical trials conducted outside the
`community were carried out in accordance with the ethical standards of Directive 2001/20/EC.
`
`Pharmacokinetics
`
` A
`
` total of 38 clinical pharmacology studies enrolling approximately 1014 subjects have been
`conducted with vildagliptin to evaluate PK, dose-response, PK/PD relationship, mode of action and
`potential for drug-drug interactions.
`
`Vildagliptin is analyzed in plasma and urine using a specific LC-MS method. The analytical methods
`are adequate for accurate determination of vildagliptin (LAF237) and its major inactive metabolite
`LAY151 in human biological fluids.
`
` •
`
` Absorption
`
`
`Bioavailability: Vildagliptin is rapidly absorbed with a median tmax of about 1.5 hr after oral dosing
`and has a mean absolute oral bioavailability of 85%. An in vitro study with Caco-2 cell monolayer
`suggests that vildagliptin is a substrate of P-gp, with low affinity, however.
`
`The rate of absorption is reduced when vildagliptin final marketing tablets are taken with a high fat
`meal and there is also a slight reduction of extent of absorption as reflected by an increase in tmax from
`1.75 h under fasting conditions to 2.5 h after a high fat meal, a 19% decrease in Cmax and 10% decrease
`in AUC. These effects are not considered clinically relevant. Galvus can be taken with or without food
`(mentioned in the SPC, section 4.2).
`
`Bioequivalence: Formulations used in early studies included a solution and a pilot capsule
`formulation, respectively. Subsequent phase I and II clinical studies used a tablet formulation (market
`formulation, MF). The capsule was shown to be of similar bioavailability to the Phase 2 MF tablet.
`Subsequent pivotal Phase 3 studies employed the FMI (final marketing image) formulation, which was
`also used in subsequent PK, PK/PD and mechanistic studies. Bioequivalence has been shown between
`the Phase 2 MF tablet and the FMI tablet.
`
`The mean AUC in patients with Type 2 diabetes mellitus at the therapeutic dose (2160 ± 520
`ng·hr/mL, N=71) was comparable to healthy subjects (2275 ± 459 ng·hr/mL, N=150).
`
` •
`
` Distribution
`
`
`The protein binding of vildagliptin to human plasma is low (9.3%). Vildagliptin distributes equally
`between plasma and red blood cells. The volume of distribution (Vss) is 70.7±16.1 L, indicating
`distribution to the extravascular tissue compartment. Drug-drug interactions linked to protein
`displacement are not expected.
`
` •
`
` Elimination
`
`
`Vildagliptin is eliminated mainly by metabolism and subsequent urinary excretion of metabolites.
`After administration of 14C-vildagliptin 100 mg oral solution 85.4±4.4% of the dose was excreted in
`urine and 14.8±3.5% in faeces. About 33% of dose was excreted in urine as unchanged vildagliptin
`after intravenous administration. Mean total plasma clearance (CL) determined after intravenous
`administration of 25 mg was 40.6±8.97 L/hr and renal clearance (CLR) 13.0±2.35 L/hr (> 216 ml/min).
`Hence, tubular secretion by active transport proteins is involved in vildagliptin elimination to some
`extent. The mean plasma elimination half-life (t1/2) of vildagliptin oral administration was about 2-3 h
`at doses of 50-100 mg.
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`© EMEA 2007
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`The metabolism of vildagliptin has been well characterised. It is extensive since only 1/3 of the dose is
`recovered as unchanged drug. Compound M20.7 or LAY151 is the major and inactive metabolite with
`plasma exposure 3-fold that of vildagliptin. Glucuronidation is only a minor pathway accounting for
`less than 5% of the initial dose and oxidation accounts only for 1.6% of the dose. Multiple t