Article Figures & Data
Figures
- Fig. 1.
Schematic representation of metformin transport in the kidney. OCT2 and MATE1 participate in the active secretion of metformin. Metformin is taken up from the blood via OCT2 and transported into the proximal tubule cell. Metformin is effluxed out of the proximal tubule cell via MATE1 and MATE2-K.
- Fig. 2.
Impact of RI on the dose dependency of metformin. Simulations were performed in Simcyp with oral metformin at 500, 1250, and 2000 mg. Simulations were performed in a male population with healthy and RI populations. Sim-healthy volunteers, Sim_RenalGFR_30-60, and Sim_RenalGFR_less_30 populations were used to represent GFRs of 100%, 50%, and 10%, respectively. Each simulation included 10 trials with 10 subjects in each.
- Fig. 3.
Impact of RI and drug transporter expression on the renal clearance of metformin. Simulations were performed in Simcyp with Sim-healthy volunteers, Sim_RenalGFR_30-60, and Sim_RenalGFR_less_30 populations to represent GFRs of 100%, 50%, and 10%, respectively. A dose of 2000 mg of metformin was administered in a fasted state to an exclusively male population. Expression of OCT2 and MATE1 was changed by altering Jmax ±2- or ±5-fold. Each simulation included 10 trials with 10 subjects in each.
- Fig. 4.
Effect of RI and inhibition on the renal clearance of metformin in males. Simulations were performed in Simcyp with Sim-healthy volunteers, Sim_RenalGFR_30-60, and Sim_RenalGFR_less_30 populations to represent GFRs of 100%, 50%, and 10%, respectively. A dose of 2000 mg of metformin was administered in a fasted state to an exclusively male population. Inhibition was incorporated through the parameter, R ([I]/Ki), which modified KM or Jmax for competitive and noncompetitive inhibition, respectively. R was varied from 0 to 100 to investigate varying levels of inhibition. Inhibition was applied to each transporter (OCT2/MATE1) separately. (A) Noncompetitive inhibition of OCT2. (B) Noncompetitive inhibition of MATE1. Each simulation included 10 trials with 10 subjects in each.
- Fig. 5.
Effect of RI and fraction unbound on the renal clearance of metformin with varying expression of OCT2 and MATE1 in males. Simulations were performed in Simcyp with Sim-healthy volunteers, Sim_RenalGFR_30-60, and Sim_RenalGFR_less_30 populations to represent GFRs of 100%, 50%, and 10%, respectively. A dose of 2000 mg of metformin was administered in a fasted state to an exclusively male population. Fraction unbound was varied from 0.1 to 1.0. Expression of OCT2 and MATE1 was altered by increasing or decreasing Jmax 2- or 5-fold. (A) Original expression (Jmax) of OCT2/MATE1. (B and D) ±2-fold expression (Jmax) of OCT2/MATE1. (C and E) ±5-fold expression (Jmax) of OCT2/MATE1. Each simulation included 10 trials with 10 subjects in each.
- Fig. 6.
Effect of RI and fraction unbound on the renal clearance of metformin with accompanying inhibition of OCT2. Simulations were performed in Simcyp with Sim-healthy volunteers (A), Sim_RenalGFR_30-60 (B), and Sim_RenalGFR_less_30 (C) populations to represent GFRs of 100%, 50%, and 10%, respectively. A dose of 2000 mg of metformin was administered in a fasted state to an exclusively male population. Fraction unbound was varied from 0.1 to 1.0. R ([I]/Ki), which modified KM and Jmax for uncompetitive inhibition. R was varied from 0 to 100 to investigate varying levels of inhibition. Each simulation included 10 trials with 10 subjects in each.
- Fig. 7.
Effect of RI and fraction unbound on the renal clearance of metformin with accompanying inhibition of MATE1. Simulations were performed in Simcyp with Sim-healthy volunteers (A), Sim_RenalGFR_30-60 (B), and Sim_RenalGFR_less_30 (C) populations to represent GFRs of 100%, 50%, and 10%, respectively. A dose of 2000 mg of metformin was administered in a fasted state to an exclusively male population. Fraction unbound was varied from 0.1 to 1.0. R ([I]/Ki), which modified KM and Jmax for uncompetitive inhibition. R was varied from 0 to 100 to investigate varying levels of inhibition. Each simulation included 10 trials with 10 subjects in each.
- Fig. 8.
Metformin plasma profiles for observed and simulated renally impaired populations. Observed plasma concentrations for metformin were plotted (black dots) for both moderate (A and B) and severe (C and D) renally impaired populations following an 850-mg oral dose of metformin obtained from Sambol et al. (1995). The mean, 5th, and 95th percentile data from simulations with Simcyp were then overlaid with the observed data for comparison. Simulations were performed with demographics and study conditions to match Sambol et al. (1995). The pictured simulations include the base Simcyp RI population and the most improved simulation as determined by improvement in the prediction/observed values for parameters given in Table 1. (A) Sim_RenalGFR_30-60. (B) Sim_RenalGFR_30-60 with 20% OCT2 expression (compared with normal expression). (C) Sim_RenalGFR_less_30 (D) Sim_RenalGFR_less_30 with OCT2 inhibition of R2 (competitive). Each simulation included 10 trials with 10 subjects in each.
- Fig. 9.
Ranitidine plasma profiles for observed and simulated renally impaired populations. Observed plasma concentrations for ranitidine were plotted (black dots) for both moderate (A and B) and severe (C and D) renally impaired populations following a 50-mg intravenous dose of ranitidine obtained from Koch et al. (1997). The mean, 5th, and 95th percentile data from simulations with Simcyp were then overlaid with the observed data for comparison. Simulations were performed with demographics and study conditions to match Koch et al. (1997). The pictured simulations include the base Simcyp RI population and the most improved simulation as determined by improvement in the prediction/observed values for parameters given in Table 2. (A) Sim_RenalGFR_30-60. (B) Sim_RenalGFR_30-60 with 10% OAT3 expression (compared with normal expression) and OAT3 inhibition of R4 (competitive). (C) Sim_RenalGFR_less_30. (D) Sim_RenalGFR_less_30 with 10% OAT3 expression (compared with normal expression), OAT3 inhibition of R4 (competitive), 20% OCT2 expression (compared with normal expression), and OCT2 inhibition of R2 (competitive). Each simulation included 10 trials with 10 subjects in each.
- Fig. 10.
Summary of the potential physiologic impact of RI on metformin and ranitidine. Simulations show that for the probe substrate metformin, a decrease in protein binding leads to an increase in CLR, whereas a decrease in GFR, DT expression, and TDIs all lead to a decrease in CLR. Inclusion of a decrease in DT expression and TDIs also leads to an improvement of clinical PK in RI populations for metformin and ranitidine.
Tables
- TABLE 1
Comparison of predicted and observed values for PK parameters for metformin
Simulation conditions are listed by rank order according to Σδall. δ is the absolute difference between one and the ratio of the predicted value of the parameter over the observed value, as defined by eq. 6 in the Materials and Methods section. Supplemental Table 39 provides actual parameter estimates as well as δ values.
δ Σδall ΣδR tmax Cmax AUC CLR Ae Healthy Sim healthy volunteers 0.191 0.007 0.172 0.162 0.062 0.595 0.224 Moderate RI Sim GFR 30–60 0.328 0.536 0.674 2.15 0.249 3.94 2.40 OCT2 20% 0.040 0.347 0.374 0.192 0.056 1.01 0.248 OCT2 20% OCT2 R2 0.152 0.262 0.185 0.303 0.234 1.14 0.537 OCT2 20% OCT1 10% 0.248 0.150 0.038 0.191 0.524 1.15 0.715 OCT2 20% OCT1 10% OCT2 R2 0.536 0.000 0.470 0.303 0.361 1.67 0.664 OCT2 R2 0.136 0.403 0.477 0.631 0.048 1.69 0.679 OCT1 10% OCT2 R2 0.088 0.243 0.197 0.631 0.565 1.72 1.20 OCT1 10% 0.232 0.439 0.559 2.15 0.654 4.04 2.81 Severe RI Sim GFR less than 30 0.282 0.463 0.563 1.10 0.036 2.45 1.14 OCT2 R2 0.012 0.310 0.278 0.018 0.186 0.806 0.204 OCT1 10% OCT2 R2 0.197 0.102 0.197 0.018 0.304 0.818 0.322 OCT2 20% 0.077 0.247 0.131 0.317 0.297 1.07 0.614 OCT2 20% OCT1 10% 0.347 0.008 0.608 0.318 0.248 1.53 0.566 OCT2 20% OCT2 R2 0.167 0.160 0.133 0.644 0.487 1.59 1.13 OCT1 10% 0.162 0.341 0.377 1.10 0.428 2.41 1.53 OCT2 20% OCT1 10% OCT2 R2 0.676 0.181 1.235 0.645 0.000 2.74 0.645 - TABLE 2
Comparison of predicted and observed values for PK parameters for ranitidine
Simulation conditions are listed by rank order according to Σδall. δ is the absolute difference between one and the ratio of the predicted value of the parameter over the observed value, as defined by eq. 6 in the Materials and Methods section. This table has been abbreviated to contain only the top-five simulations for each dose/RI combination. Supplemental Table 40 provides values for each simulation including actual parameter estimates as well as δ values.
Dose δ Σδall ΣδR AUC CL CLR Ae mg Healthy Sim-healthy volunteers 50 0.34 0.235 0.400 0.160 1.14 0.560 Sim-healthy volunteers 25 0.53 0.331 0.487 0.179 1.53 0.666 Moderate RI Sim GFR 30–60 50 0.083 0.090 0.360 0.256 0.789 0.616 OAT3 10% OAT3 R4 50 0.083 0.075 0.060 0.128 0.346 0.188 OAT3 10% 50 0.067 0.060 0.090 0.140 0.357 0.230 OAT3 R4 50 0.044 0.045 0.120 0.156 0.365 0.276 OCT2 R2 50 0.139 0.120 0.066 0.076 0.401 0.142 OCT2 20% 50 0.206 0.170 0.167 0.020 0.563 0.187 Severe RI Sim GFR less than 30 50 0.423 0.692 3.95 2.27 7.33 6.22 OCT2 20% OAT3 10% OCT2 R2 OAT3 R4 50 0.019 0.037 0.069 0.129 0.254 0.198 OCT2 20% OAT3 10% OCT2 R2 50 0.006 0.019 0.059 0.254 0.338 0.313 OCT2 20% OCT2 R2 OAT3 R4 50 0.035 0.019 0.221 0.396 0.671 0.617 OCT2 20% OAT3 10% OAT3 R4 50 0.058 0.037 0.377 0.527 1.00 0.904 OCT2 20% OAT3 10% 50 0.079 0.065 0.500 0.621 1.27 1.12 Sim GFR less than 30 25 0.396 0.670 20.3 11.5 32.9 31.8 OCT2 20% OAT3 10% OCT2 R2 OAT3 R4 25 0.065 0.055 2.98 3.34 6.44 6.32 OCT2 20% OAT3 10% OCT2 R2 25 0.039 0.028 3.52 3.82 7.41 7.34 OCT2 20% OCT2 R2 OAT3 R4 25 0.009 0.000 4.19 4.37 8.57 8.56 OCT2 20% OAT3 10% OCT2 R2 OAT3 R4 OATP1B3 R1 25 0.452 0.308 2.98 4.85 8.59 7.83 OCT2 20% OAT3 10% OCT2 R2 OATP1B3 R1 25 0.413 0.289 3.52 5.46 9.69 8.98
Data Supplement
- Supplemental Data -
Supplemental Tables 1 - 40
Supplementary Figure 1 - Structure of a general PBPK model used to describe the kinetics of metformin (center) and associated nested permeabilitylimited liver (Perf, left) and mechanistic kidney (Mech KiM, right) models
Supplementary Figure 2 - Effect of Renal Impairment (RI) and Inhibition on the Renal Clearance of Metformin in Males
Supplementary Figure 3 - Effect of Renal Impairment (RI) and Fraction Unbound on the Renal Clearance of Metformin with Accompanying Inhibition of OCT2
Supplementary Figure 4 - Effect of Renal Impairment (RI) and Fraction Unbound on the Renal Clearance of Metformin with Accompanying Inhibition of MATE1
Supplementary Figure 5 - Impact of Renal Impairment (RI) on the Dose Dependency of Metformin in Females
Supplementary Figure 6 - Impact of Renal Impairment (RI) and Drug Transporter Expression on the Renal Clearance of Metformin
Supplementary Figure 7 - Effect of Renal Impairment (RI) and Inhibition on the Renal Clearance of Metformin in Females
Supplementary Figure 8 - Effect of Changes in Renal Impairment (RI) and Fraction Unbound on the Renal Clearance of Metformin with Varying Expression of OCT2 and MATE1 in Females
- Supplemental Data -
