Download A systems pharmacology model of SGLT2 and SGLT1 inhibition to

A
systems
pharmacology
model
of
SGLT2/SGLT1
inhibition
to
understand
mechanism and quantification of urinary glucose
excretion (UGE) after treatment with gliflozins.
Tatiana Yakovleva, Kirill Zhudenkov, Victor Sokolov
Moscow, 2016
Renal glucose reabsorption mechanism
About 99% of the filtrate is reabsorbed as it passes through the nephron and the remaining 1%
becomes urine. The filtrate includes water, small molecules, and ions that easily pass through
the filtration membrane.
Glomerular filtration rate (GFR) is the amount of filtrate produced every minute.
• GFR is 180 liters per day.
• Glucose GFR: 180 g/day.
• In normal conditions glucose is
completely reabsorbed in
kidneys.
• If the capacity of sodium-glucose
linked transporters (SGLT2 and
SGLT1) is exceeded, glucose
appears in the urine.
SGLT2 is believed responsible for 80–90% of renal glucose reabsorption, and SGLT1 for the rest
10–20% in healthy humans [De Fronzo et al., 2012]
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SGLTs and diabetes
Inhibition of glucose reabsorption results in plasma
glucose lowering, which is beneficent for diabetic
subjects.
Gliflozins are the inhibitors of SGLT2/1
transporters, widely used as anti-T2D therapy.
Problem:
• According to in vitro experiments, gliflozins administration leads to almost complete
inhibition of SGLT2;
• in vitro data is showed that about 90% of glucose reabsorbed by SGLT2;
However, the clinical observations are demonstrated that only 30–50% of inhibition in glucose
reabsorption was achieved under the treatment with potent SGLT2 inhibitors.
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Questions
How to explain the mechanism underlying this apparent
discrepancy in clinical data?
How to estimate the relative contributions of SGLT2/SGLT2 in
the glucose reabsorption in vivo?
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Modelling strategy
For explanation of the mechanism underlying apparent discrepancy in UGE clinical data and
estimate the relative contribution of SGLT1 and SGLT2, the QSP model was developed based on
two previously published model:
•
•
•
•
•
•
•
oral drug administration
plasma degradation
transport between plasma
and peripheral
compartment
glomerular filtration
secretion from plasma to
the lumen
reverse reabsorption
urinary excretion
•
•
kidney glucose reabsorption
competitive inhibition of
SGLT1 and SGLT2 by gliflozins
These models were combined and readdressing based on experimental data on 24-hours
urinary glucose excretion for healthy subjects after treatment with Dapagliflozin, Canagliflozin
and Empagliflozin.
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The model structure. Drug distribution.
The QSP model is based on the system of ordinary differential equations (ODEs).
The model describes plasma PK profiles, kidney
distribution, and excretion for three gliflozins:
• dapagliflozin (2-compartment PK model),
• canagliflozin (1-compartment PK model),
• empagliflozin (1-compartment PK model);
The following data were used for the models
verification:
Plasma PK profile
24-hours amount
of drug in urine
GFR = 120 ml/min (7.2 L/h)
𝑄𝑢𝑟𝑖𝑛𝑒 = 0.055 L/h
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The model structure. Glucose fluxes.
• Glucose flux from plasma to lumen
• Urinary glucose excretion
• Kidney glucose reabsorption
Kidney glucose reabsorption process was described
based on approach from [Lu et al., 2014].
The inhibitor competes with glucose for SGLT1 and
SGLT2, and hence competitively inhibits glucose
reabsorption:
GFR = 120 ml/min (7.2 L/h)
𝑄𝑢𝑟𝑖𝑛𝑒 = 0.055 L/h
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SGLT1 and SGLT2 affinity
Parameters of glucose affinity for SGLT1/SGLT2 were taken from the literature
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IC50 and Vmax estimation
Vmax parameters and corresponding IC50 for each of the drugs were fitted simultaneously
based on the 24-hours UGE data after treatment with gliflozins.
Total SGLT2 and SGLT1 reabsorption capacity did not exceed the physiological threshold of
maximum glucose reabsorption (140 mmol/h):
𝑉𝑚𝑎𝑥𝑆𝐺𝐿𝑇1 = 140 − 𝑉𝑚𝑎𝑥𝑆𝐺𝐿𝑇2
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Urinary Glucose Excretion after treatment. Fitting results
Dapagliflozin
Canagliflozin
Empagliflozin
Maximum contributions of SGLT2 (Vmax2) and SGLT1 (Vmax1) to the total renal
glucose reabsorption under conditions of saturation with glucose were fitted to 87%
and 13%, respectively, which correlates closely with in vitro experimental data on
transporter contributions (80-90% and 10-20%) [De Fronzo et al., 2012]
𝑉𝑟𝑒𝑎𝑏𝑠 =
𝑽𝒎𝒂𝒙 ∗ 𝐺𝑙𝑢𝑐𝑜𝑠𝑒𝑙𝑢𝑚𝑒𝑛
𝐷𝑟𝑢𝑔𝑙𝑢𝑚𝑒𝑛
𝐾𝑚 ∗ 1 +
+ 𝐺𝑙𝑢𝑐𝑜𝑠𝑒𝑙𝑢𝑚𝑒𝑛
𝐼𝐶50
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SGLT2/SGLT1 contribution to the in vivo reabsorption rate
Following gliflozins treatment, contributions from each of the transporters change depending on
the dose of the inhibitor used and has a 35% value for the treatment with the registered doses
for all considered drugs.
Dapagliflozin
Canagliflozin
Empagliflozin
- - - - Particular drug registered doses: 10 mg for dapagliflozin, 300 mg for canagliflozin, 25 mg for empagliflozin
• High dosages of drugs lead to strong inhibition of SGLT2, but not of SGLT1, because the IC50
for SGLT1 is several times higher vs. the IC50 for SGLT2.
• Therefore, contributions of SGLT1 towards the overall reabsorption process increases with
dosages of gliflozins.
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Conclusions
• Observed 24-hours UGE levels are dependent on corresponding IC50 values
for SGLT2 and SGLT1, as well as lumen concentrations for each of the drugs;
• The maximum contribution of SGLT2 and SGLT1 to renal glucose reabsorption
were estimated as 87% and 13% respectively;
• The relative contribution of SGLT2 and SGLT1 to renal glucose reabsorption
without drug administration for healthy subjects with normal renal function
was predicted to be around 77% and 23% respectively;
• The contribution of SGLT2 to renal glucose reabsorption is about 35% given
treatment with the three gliflozins at registered doses.
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Discussion & Future plans
The QSP model of SGLT2/SGLT1 inhibition allowed us to describe the relationship
between UGE and renal glucose reabsorption processes and estimate relative
contributions of transporters towards the total renal glucose reabsorption rate.
We found that SGLT1 contribution towards total glucose reabsorption increases with
dosages of gliflozins, which could be a compensatory mechanism underlying the
apparent discrepancy in UGE levels, as observed across gliflozins compounds.
At that moment the model describes the glucose reabsorption processes only for
healthy subjects with normal renal function. It will be interesting to extend the
prediction capacity of the model for the diabetes subjects and patients with renal
function impairment.
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Thanks for your attention!
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Backup
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Drug PK model scheme
The model describes:
• oral drug administration (F, k_abs, tlag);
• plasma degradation (k_deg);
• transport between plasma and
peripheral compartment (Q_prf);
• glomerular filtration (GFR, fup);
• secretion from plasma to the lumen of
the kidney’s proximal tubules (k_sec,
fup);
• reverse reabsorption (k_reab, fup);
• urinary excretion (Q_urine).
[Demin et al., 2014]
Subjects with normal renal function: GFR is 120 ml/min.
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Introduction of glucose filtration, reabsorption and UGE
We expanded a previously-published model [Front Pharmacol. 2014 Oct 13;5:218] by
introducing kidney glucose filtration by GFR, reabsorption by SGLT2/SGLT1, and urine excretion.
• Glucose flux from plasma to lumen was described based on GFR rate for normal subjects
(120 ml/min) and average plasma glucose concentration for healthy subjects (5 mmol/L);
• Urinary flux for glucose was described using the same constant of urine formation Q_urine:
UGE rate = Q_urine * Glucose_lumen; {mmol/h};
• Kidney glucose reabsorption process was described based on approach, which was proposed
in [Front Pharmacol. 2014 Dec 10;5:274].
The inhibitor competed with glucose for SGLT1/2, and hence competitively inhibited glucose
reabsorption:
where Rj* - glucose reabsorption rate for each of the transporters (SGLT1/SGLT2),
Cglu,j – concentration of Glucose in lumen
Km – denotes glucose affinity for SGLT1 or SGLT2
Cdrug,j – drug concentration in lumen
Ki – corresponding affinity of the inhibitor to SGLTs.
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