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KING FAISAL SPECIALIST HOSPITAL Riyadh, Saudi Arabia

The Patterns of Cyclosporine Sandimmun and Neoral Parent Compound and Metabolites in Renal Transplant patients with and without liver disease. KING FAISAL SPECIALIST HOSPITAL Riyadh, Saudi Arabia Alfurayh O, Abutaleb N, Almeshari K, Shaibani K, Taher S, Hussain R. The objectives:

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KING FAISAL SPECIALIST HOSPITAL Riyadh, Saudi Arabia

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  1. The Patterns of Cyclosporine Sandimmun and Neoral Parent Compound and Metabolites in Renal Transplant patients with and without liver disease KING FAISAL SPECIALIST HOSPITAL Riyadh, Saudi Arabia Alfurayh O, Abutaleb N, Almeshari K, Shaibani K, Taher S, Hussain R

  2. The objectives: To study: 1. The patterns and concentrations of CSA metabolites (primary) in renal transplant patients with and without chronic liver disease. 2. The effect of microemulsion technology on the pattern of CSA parent compound and its metabolites in both renal transplant patient groups.

  3. Patients and Methods : We analysed our data from an earlier study on CSA pharmacokinetics (PK) in stable renal transplant patients with and without chronic liver disease (CLD). 16 patients with normal liver function tests and negative serology for HCV and HBV constituted the non-CLD (N-CLD) group.14 CLD patients were selected with high liver enzymes (ALT> 1.5 X normal > 6 mo.) and +ve for HCV or HBV. Same dose was maintained upon collecting blood samples (at 0,.5, 1, 1.5, 2, 3, 4, 5, 6, 9, 10, 12 h post dosing ) for PK profile (HPLC Assay) of PC and the primary metabolites (AM1, AM9 & AM4N) on Sandimmun (SM) and Neoral (NL).

  4. Results: Basic PK parameters of PC in both study groups SM NL N-CLD CLD p N-CLD CLD p CSA Dose 3.09 1.82 0.005 Same Dosage AUC 2161 1405 0.013 3220 1984 0.003 Cmax 615 385 0.017 934 554 0.001 T max 2.4 2.1 0.37 1.8 1.9 0.92 Relative bioavailability, RF 1.67+ 0.77 1.49+ 0.52 0.46 AUC/dose 1506 1694 0.36 2206 2379 0.47

  5. SM NL N-CLD CLD p N-CLD CLD p AM1 : AUC/Dose 1425+836 2500+1415 0.02 200+1084 3263+1032 0.003 Cmax/Dose 196+122 297+178 0.08 258+118 396+147 0.008 AM 9 : AUC/Dose 562+144 808+125 0.02 853+158 1131+173 0.03 Cmax 103+66 1 37+46 0.05 159+96 203+59 0.05 AM4N : AUC/Dose 85+97 68+50 0.55 114+33 94+51 0.21 Cmax/Dose 29+14 26+6 0.79 40+4 34+7 0.49 Basic PK parameters of PC in both study groups

  6. Basic PK parameters of PC in both study groups SM NL N-CLD CLD p N-CLD CLD p AM1 : AUC/Dose 142525000.02 2001 32630.003 Cmax/Dose 196 297 0.08 258 3960.008 AM 9 : AUC/Dose 562 808 0.02 853 1131 0.03 Cmax 103 137 0.05 159 203 0.05 AM4N : AUC/Dose 85 68 0.55 114 94 0.21 Cmax/Dose 29 26 0.79 40 34 0.49

  7. Basic PK parameters of CSA metabolites in both study groups SM NL N-CLD CLD p N-CLD CLD p AUC of PMT 2813 2585 0.57 4076 3564 0.30 AUC/Dose of PMT 2071 3370 0.015 2969 4488 0.004 PC/PMT *:AUC ratio 81% 54% 0.002 87% 60% 0.005 *PMT= primary metabolites

  8. Parent compound and metabolites rise by 2 hrs post dosing SM NL N-CLD CLD p N-CLD CLD p PC increment (ug/l) over C0: 352 269 0.33 683 3520.0002 PMT increment (ug/l)over C0: 115 139 0.53 310 243 0.16 PC/dose increment (ug/l) over C0: 263 320 0.42 478 430 0.43 PMT/dose increment (ug/l) over C0: 198.6 360 0.006 375 556 0.005

  9. Parent compound and primary metabolites during absorptive phase of AUC: SM NL N-CLD CLD p N-CLD CLD p PC/PMT (at peak) 1.69 1.12 0.04 1.96 1.32 0.015 (ug/l) AUC/dose of PMT 779 1239 0.02 697 1115 0.003 (ug/l) PMT = primary metabolites, PC = parent compound

  10. Relative Metabolites Concentrations : SM NL N-CLD CLD p N-CLD CLD p AM1 68% 72% 0.11 65.5% 72.2% 0.006 AM9 28% 26% 0.30 30.0% 25.6% 0.02 AM4N3.9% 2.4% 0.06 4.5% 2.3% 0.001

  11. Correlation between CSA dose and AUC’s of PC and primary metabolites: AUC of: SM NL PC 0.65* 0.87* AM1 0.13 0.36 AM9 0.48* 0.70* AM4N 0.31 0.82* *p<0.05

  12. AUC’s ratios SM NL PC/PMT 0.51* 0.49* AM1/PMT - 0.5 * - 0.61* AM9/PMT 0.50* 0.56* AM4N/PMT 0.39 0.55* *p<0.05 Correlation between CSA dose and the relative concentration of individual metabolites

  13. SM NL PC 57.1% 60.5% AM1 35.4% 36.3% AM9 41.5% 47.3% M4N 65.1% 77.8% The proportions of AUC’s in the first four hours of the dosing interval

  14. Relative Metabolites Concentrations at 3 Hours post Dosing: • SM NL • N-CLD CLD p N-CLD CLD p • AM160% 64% 0.23 56% 65% 0.002 • AM 9 33% 31% 0.37 35% 30% 0.019 • AM4N 6.6% 5.1% 0.26 8.1% 4.4% 0.001 • Correlation between CSA dose and the relative • concentration of AM1 at 3 hours post dosing: • Correlation Coeffecient : -0.37 (p = 0.046) on SM • -0.72 (p = 0.000) on NL

  15. The observed range of relative concentration of AM1: • At C3: From 42% to 82% • At C0 : From 80% to 100%

  16. SM NL N-CLD CLD p N-CLD CLD p AM1 62% 61% 0.31 60% 63% 0.48 AM 9 31% 33% 0.48 33% 32% 0.80 AM 9 6.7% 6.0% 0.39 7.3% 5.3% 0.17 Relative metabolites concentrations at 3 hours post dosing in the subgroups with equal dose (1.06 vs. 1.05 mg/kg) :

  17. SM NL N-CLD CLD p N-CLD CLD p AM1 59% 68% 0.08 53% 68% 0.00005 AM 9 35% 28% 0.11 38% 29% 0.001 AM4N 6.6% 3.9% 0.23 9.0% 3.3% 0.002 Relative Metabolites Concentrations at 3 Hours post Dosing after excluding patients with similar dosage from the two study groups:

  18. PK Profile of CSA Parent Compound on SM and NL 700 600 Neoral Sandimmun 500 400 300 200 100 0 C 0.5 C 1.5 C 10 C 12 C 0 C 1 C 2 C 3 C 4 C 5 C 6 C 9

  19. PK Profiles of AM1 on SM and NL 320 Neoral Sandimmun 280 240 200 160 120 80 C 3 C 4 C 5 C 6 C 9 C 10 C 12 C 1.5 C 0.5

  20. PK Profile of AM9 on SM and NL

  21. PK Profile of AM4N on SM and NL 45 Neoral 35 Sandimmun 25 15 5 -5 C0 C1 C2 C3 C4 C5 C6 C9 C10 C12 C.5 C1.5

  22. Correlation between CSA dose and the relative concentration of individual metabolites in the first four hours of the dosing interval AUC’s ratiosSMNL PC/PMT 0.37* 0.85* AM1/PMT - 0.42* - 0.62* AM9/PMT 0.38* 0.59* M4N/PMT 0.30 0.58* *p<0.05

  23. PC / Metabolites Ratio During Dosing Interval (On NL): Ratio PC/AM1 AUC N-CLD CLD p • in first 4h 2.21 1.29 0.0002 • in last 8 h 0.83 0.58 0.15 • Ratio of PC/AM9 AUC in first 4 h 3.62 2.74 0.01 in last 8 h 2.17 1.84 0.41 Ratio of PC/AM4N AUC in first 4 h 16.81 18.90 0.30 in last 8 h 69.0 94.72 0.32

  24. SM NL N-CLD CLD p N-CLD CLD p AM 1 0.124 0.076 0.32 0.196 0.167 0.55 AM 9 0.39 0.21 0.003 0.35 0.24 0.04 AM4N can not be determined accurately Terminal Slopes of CSA metabolites:

  25. Gender effect on relative parent compound and metabolites concentrations among N-CLD patients: SM NL Male Female p Male Female p No. 8 8 8 8 CSA Dose 2.3 2.6 0.32 same dose maintained AUC ratio of PC/PMT 73.6% 88.0% 0.29 76.2% 98.5% 0.099 At C4 : AM1/PMT66% 59% 0.04 62% 59% 0.39 AM 9/PMT 29% 35% 0.03 30% 33% 0.15

  26. Gender effect on relative parent compound and metabolites concentrations among N-CLD patients: At C3 : SM NL Male Female p Male Female p AM4N / PMT 5.4% 7.9% 0.2 8.1% 8.1% 0.98

  27. Conclusions: 1. Despite the effects of the reported “narrow G I window” for CSA absorption, the higher hepatic first pass effect and despite the lesser degree of cholestasis, patients with normal liver function expressed higher gain (from NL) in the PC absorption. The effect of higher dosing (& so higher rate of absorption) in saturating the G I enzyme provides a clear explanation.

  28. Conclusions: 1. Renal transplant patients with normal liver function expressed higher gain (from NL) in the PC absorption. The effect of higher dosing (& so higher rate of absorption) in saturating the G I enzyme provides a clear explanation.

  29. 2. Improved PC absorption constituted the main reason for improved bioavailability on NL among N-CLD patients.. While the slower elimination (after an improved absorption) has resulted in an almost comparable RF value in CLD patients.

  30. 3. AM1 constitutes the main CSA metabolite throughout the dosing interval (range 42% to 100%). During the absorptive phase, however, the other two primary metabolites are formed at relatively high rates. It seems that saturation of the first pathway of CSA metabolism ( hydroxylation at a.a No. 1) at this phase has resulted in higher utilization of the alternative primary metabolic pathways.

  31. This conclusion provides an explanation for the already demonstrated wide fluctuation in the pattern of CSA metabolites among transplant patients.

  32. 4. Metabolites exist at higher concentration in CLD patients throughout the dosing interval. Both higher metabolite production (initially by gut) and slower elimination account for such finding.

  33. RF correlation with %AUC in last 8 h: SM NL N-CLD CLD N-CLD CLD PC -0.15/0.57 0.80/0.001 -0.08/0.77 0.53/0.051 AM1 -0.20/0.45 0.62/0.02 0.16/0.55 0.53/0.05 AM9 -.33/0.22 0.70/0.005 0.27/0.31 0.24/0.40 AM4N -.27/.32 0.76/0.004 -0.27/0.32 0.34/0.25

  34. Dose (mg/kg) correlated with: AUC ratio PC/PMT (r= 0.56,p=0.001on SM & 0.51,0.004 on NL) AUC/dose of PMT(r=-0.53,p=0.003 on SM & -0.62, 0.000 on NL) AUC/dose of PC+PMT (r = -0.55,p=0.002 on SM & 0.61,0.000 on NL)

  35. AUC increment (AUC on NL / AUC on SM) of CSA PC and Metabolites N-CLD CLD p PC 1.67 1.49 0.46 AM1 1.53 1.45 0.08 AM9 1.81 1.44 0.26 AM4N 1.76 1.44 0.52 *p<0.05

  36. AUC increment (AUC on NL / AUC on SM) of CSA PC and Metabolites N-CLD CLD p PC 1.67 1.49 0.46 AM1 1.53 1.45 0.08 AM9 1.81 1.44 0.26 AM4N 1.76 1.44 0.52 *p<0.05

  37. Parent Compound and Metabolism on Sandimmun at 12 hour Trough Level AM1 AM1 AM9 AM9 AM4N P.C. P.C. CLD N-CLD

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