acido micofenólico en síndrome · acido micofenólico en síndrome nefrótico: ¿una buena...
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Acido Micofenólico en Síndrome Nefrótico: ¿Una Buena opción? Guido Filler MD, PhD, FRCPC October 2018 ACONEPE Barranquilla, Colombia, 11-Oct-2018
Presented by: Guido Filler, MD, PhD, FRCPC
Chair/Chief, Department of Paediatrics Department of Paediatrics
Schulich School of Medicine and Dentistry
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Disclosures • Lamentablemente, no hablo español. • I have no financial relationships to disclose within the past
120 months relevant to my presentation
MPA Monitoring
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Was sind Spurenelemente? •Spurenelemente sind bekannte Substanzen, welche sehr niedrige Konzentrationen in Geweben und biologischen Flüssigkeiten haben.
•Dazu gehören Schwermetalle wie Cadmium, Chrom, Nickel, Vanadium, Kupfer, Blei, Mangan, Selen und Zink.
•Die meisten haben eine Altersabhängigkeit mit den niedrigsten Konzentrationen im ersten Lebensjahr.
Spurenelemente in der Niereninsuffizienz
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LHSC
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Objectives
• To understand drug disposition and ontogeny of mycophenolate mofetil, its active compound mycophenolic acid (MPA) and its metabolites
• To learn how MPA monitoring can improve clinical outcomes
• Strategies to optimization of MMF therapy for nephrotic syndrome
MMF for Nephrotic Syndrome
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Review of mechanism of action and pharmacokinetics
of MMF
MPA Monitoring
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Mycophenolate Mofetil (MMF)
• Prodrug, converted to the active form, Mycophenolic acid (MPA) by an esterase
• inhibitor of inosine monophosphate dehydrogenase (IMPDH)
• This is the rate-limiting enzyme in de novo synthesis of guanosine nucleotides.
• T- and B-cells depend on this pathway more than other cells
MPA Monitoring
O
OH O
COOH
OCH3
CH3
CH3
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Mycophenolic Acid (MPA) MPA Monitoring
O
OH O
COOH
OCH3
CH3
CH3
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Dosing and Features of MMF
• The drug was developed for the use with concomitant Cyclosporine
• A typical dose in adults would be 1 g bid in combination with Cyclosporine
• Equivalent dosing for children was determined to be 600 mg/m2 bid (Ettenger R, 1997)
• Stronger immunosuppressive effect in comparison with Azathioprine
MPA Monitoring
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Metabolic pathways of MPA in humans
O
OH O
COOH
OCH3
CH3
CH3
O
O O
COOH
OCH3
CH3
CH3
O COOH OH
HO HO
O
OH O
OCH3
CH3
CH3
C
O
O
O
O O
COOH
OCH3
CH3
CH3
mycophenolic acid
acyl glucuronide ( AcMPAG )
7-O-glucoside (M-1 )
7-O-glucuronide MPAG
M-3
CYP P450
UDP-glucuronosyl transferase
UDP-glucuronosyl transferase
UDP-glucosyl transferase
Shipkova et al British J Pharmacol: 1999; 126: 1075
MPA Monitoring
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Mycophenolic Acid (MPA)
• Can be measured on commercial platforms by various techniques, including EMIT, FPIA and HPLC (used to be gold standard) techniques, and more recently using MS-MS.
MPA Monitoring
O
OH O
COOH
OCH3
CH3
CH3
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MPA Monitoring
UGT1A9-275T>A/-2152C>T Polymorphisms
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N=104 renal transplant patients
MPA PK Profiles in 104 Paediatric Renal Transplant Recipients
MPA Pharmacokinetics
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Correlation Between MPA AUC and Abbreviated AUC from C1, 2 and 6
Filler G, Mai I. Ther Drug Monit 2000; 22:169-73.
0 50 100 150 200 0
50
100
150 10.75+0.98·C1 + 2.38·C2 + 4.86·C6
r2 = 0.8390
AUC (µg·h/ml)
Abbr
evia
ted
AUC
from
C
1, C
2 an
d C
6 (µ
g·h/
ml)
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Dose Normalized AUC varies with concomitant medication
Filler G et al. Pediatr Nephrol 2000; 14:100-104.
MPA Monitoring
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Is the trough level so bad if only concomitant Tac is considered?
MPA Monitoring
Todorova E. et al. Pediatr Transplant. 2015 Nov;19(7):669-74.
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What evidence is out there about MMF and NS?
MPA Monitoring
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Open label studies
1. Bagga A, Hari P, Moudgil A, Jordan SC (2003) Mycophenolate mofetil and prednisolone therapy in children with steroid-dependent nephrotic syndrome. Am J Kidney Dis 42:1114–1120 2. Novak I, Frank R, Vento S, Vergara M, Gauthier B, Trachtman H (2005) Efficacy of mycophenolate mofetil in pediatric patients with steroid-dependent nephrotic syndrome. Pediatr Nephrol 20:1265–1268 3. Hogg RJ, Fitzgibbons L, Bruick J, Bunke M, Ault B, Baqi N, Trachtman H, Swinford R (2006) Mycophenolate mofetil in children with frequently relapsing nephrotic syndrome: a report from the Southwest Pediatric Nephrology Study Group. Clin J Am Soc Nephrol 1:1173–1178 4. Okada M, Sugimoto K, Yagi K, Yanagida H, Tabata N, Takemura T (2007) Mycophenolate mofetil therapy for children with intractable nephrotic syndrome. Pediatr Int 49:933–937 5. Fujinaga S, Ohtomo Y, Umino D, Takemoto M, Shimizu T, Yamashiro Y, Kaneko K (2007) A prospective study on the use of mycophenolate mofetil in children with cyclosporine-dependent nephrotic syndrome. Pediatr Nephrol 22:71–76 6. Afzal K, Bagga A, Menon S, Hari P, Jordan SC (2007) Treatment with mycophenolate mofetil and prednisolone for steroid-dependent nephrotic syndrome. Pediatr Nephrol 22:2059–2065 7. Baudouin V, Alberti C, Lapeyraque AL, Bensman A, Andre JL, Broux F, Cailliez M, Decramer S, Niaudet P, Deschenes G, Jacqz-Aigrain E, Loirat C (2012) Mycophenolate mofetil for steroid-dependent nephrotic syndrome: a phase II Bayesian trial. Pediatr Nephrol 27:389–396 8. Banerjee S, Pahari A, Sengupta J, Patnaik SK (2013) Outcome of severe steroid-dependent nephrotic syndrome treated with mycophenolate mofetil. Pediatr Nephrol 28:93–97 9. Wang J, Mao J, Chen J, Fu H, Shen H, Zhu X, Liu A, Shu Q, Du L (2016) Evaluation of mycophenolate mofetil or tacrolimus in children with steroid sensitive but frequently relapsing or steroid-dependent nephrotic syndrome. Nephrology (Carlton) 21:21–27
MMF for Nephrotic Syndrome
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Open label studies
• MMF mostly used as a steroid-sparing agent, more so in SDNS than SRNS
• In most studies, patient have previously been treated with other immunosuppressive agents
• Different clinical endpoints, making comparison difficult • However, MMF has been beneficial in all studies
– Lower rate of relapses – Lower rate of steroid requirements
• MMF was equally or less effective than Tacrolimus in two uncontrolled trials
• Inconsistent use of TDM
MMF for Nephrotic Syndrome
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MPA Clearance: Other factors MPA and SSNS
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Randomized controlled trials
• MPA trough levels 2-5 ng/mL, higher than transplant, in the studies by Dorresteijn and Gellermann
• Better outcomes on Cyclosporine or Tacrolimus with regards to relapse rate in two, difference not significant in Gellermann’s study
• Post-hoc analysis of Gellermann’s study revealed that MPA AUC < 50 mg*h/L was associated with relapses
• Main side effect of calcineurin inhibitors: Nephrotoxicity
MMF for Nephrotic Syndrome
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Randomized controlled trials
• MPA trough levels 2-5 ng/mL, higher than transplant, in the studies by Dorresteijn and Gellermann
• Better outcomes on Cyclosporine or Tacrolimus with regards to relapse rate in two, difference not significant in Gellermann’s study
• Post-hoc analysis of Gellermann’s study revealed that MPA AUC < 50 mg*h/L was associated with relapses
• Main side effect of calcineurin inhibitors: Nephrotoxicity
MMF for Nephrotic Syndrome
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A Closer Look at SRNS
MMF and NS
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SRNS (FSGS) study from London
• Retrospective cohort study • 182 MPA pre-dose trough levels (1-45/patient,
HPLC/MS/MS) in 10 patients aged 0.9-18 years with SRNS treated with MMF.
• Apparent MPA clearances (CL/F) were calculated from the dose/estimated AUC.
• Median apparent clearance was 22.63 L/h (IQR 17.1, 32.47). Significant correlations were found between MPA Cl/F and serum albumin (r=-0.47), microalbuminuria (+0.54), Triglycerides (+0.33), and Cholesterol (+0.32).
MMF for Nephrotic Syndrome
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MMF for Nephrotic Syndrome
SRNS (FSGS) study from London
Patient
Sex, race
Age at Dx
Histological Dx,
Genetic if available
GFR at biopsy [mL/min]
Min Alb
Max mAb:Cr [mg/mmol]
Age at start of MMF
Time from dx to MMF
Indication for MMF
GFR at MMF [mL/min/ 1.73 m2]
Starting MMF dose[mg/m2/d]
Max MMF dose
[mg/m2/d]
# MPA Levels
Avg. MPA Level [mg/L]
Max CyA dose [mg/kg/d]
Max CyA trough level [ng/mL]
Last GFR (mL/min)
Regimen responsible for remission
1
M, ME
6y
FSGS, NPHS1
149
28
894.6
11y
5y
To induce remission
157
960
1230
8
1.87
N/A
N/A
118
Steroids + MMF
2
F, AA
3y
FSGS, NPHS1
128
21
475.7
5y
2y
To induce remission
119
770
1100
15
1.99
8.7
789
83
CyA + MMF
3
M, C
13m
FSGS, CD2AP and NPHS2, both UTR
60
10
2922.7
14m
1m
CyA sparing
60
2400
2400
20
2.13
25
263
107
Rituximab
4
M, C
7y
FSGS, no mutations
144
11
5821.0
8y
1y
CyA sparing
93
847
1208
45
1.90
18
560
121
CyA + Rituximab
5
F, C
11y
FSGS, NPHS1
111
19
290.3
12y
9m
To induce remission
78
813
813
17
4.25
6.1
357
135
CyA + MMF
6
M, AS
2y
FSGS, NPHS1
61
19
1890.1
7y
5y
CyA sparing
88
768
2047
19
2.93
10.6
428
121
Steroid retrial after Rituximab
7
F, C
6y
FSGS, no mutation
88
11
>limit
7y
9m
To induce remission
31
1170
2706
38
0.84
14.7
715
12
No remission
8
F, C
3y
FSGS, no genetics
119
12
546.6
8y
5y
To induce remission
127
1096
1626
13
4.48
14.5
420
106
Rituximab
9
M, AS
16m
MN, no mutation
154
17
1937.6
6y
5y
CyA sparing
264
1200
1674
3
2.03
10.6
361
146
CyA
10
M, C
8y
HSP, no genetics
121
18
1594.0
8y
2w
To induce remission
90
1221
1221
4
3.12
N/A
N/A
90
Steroids + MMF
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Estimation of AUC from MPA C0 MMF for Nephrotic Syndrome
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Impact of Albumin MMF for Nephrotic Syndrome
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MMF for Nephrotic Syndrome
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MMF for Nephrotic Syndrome
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MMF for Nephrotic Syndrome
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SRNS (FSGS) study from London
• CL/F increased from a minimum of 2.4 L/h for the highest albumin levels to a maximum of 59.9 for albumin levels < 25g/L.
• Similarly, the apparent MPA clearance increased significantly with higher triglycerides and lower hematocrit.
• This study confirms a significant increase of the apparent clearance of MPA with low serum albumin, microalbuminuria, proteinuria, high triglycerides, and low hematocrit.
• The 20-fold increase of the apparent clearance suggests that MMF unresponsiveness in the nephrotic state may be related to MPA underexposure.
MMF for Nephrotic Syndrome
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Factors affecting MPA CL/F
MMF and NS
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What is ontogeny of drug disposition?
• Ontogeny: the origin and development of an organism from the fertilized egg to its mature form (also Ontogenesis or Morphogenesis)
• Multiple organs that affect drug disposition undergo developmental changes – gastrointestinal function – integumentary development – extracellular water (affects volume of distribution) – body fat (important for drugs with distribution in fat) – developmental changes in renal function – capacity of key metabolic enzymes
Drug Dosing
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Specifics of drug metabolism in the growing body
Kearns GL et al. N Engl J Med. 2003;349:1157-67
Metabolic capacity Water distribution GI function
Skin thickness etc. Renal function
Drug Dosing
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Kearns GL et al. N Engl J Med. 2003;349:1157-67
Drug Dosing
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Age dependency of dose required for an AUC of 60 ug x h/mL in children on Tacrolimus and
Mycophenolate Mofetil (MMF)
0 5 10 15 20 25 0
5
10
15
20
25
30
35
p
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Results ANOVA/Kruskal Wallis
n = 37
12 years
p
Dose Normalized MPA trough levels [mg/kg]
Median (IQR)
0.0526
(0.0882-0.286)
0.110
(0.0705-0.157)
0.134
(0.0692-0.226)
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MPA Clearance: Other factors
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Summary
• MPA levels are easily obtained, covered and the trough level is not that bad with concomitant tacrolimus or no calcineurin inhibitor.
• The pharmacokinetics of MPA are highly variable, both in adults as well as in children, and somewhat unpredictable.
• MPA Clearance affected by haemoglobin, albumin and triglycerides.
• There is evidence that MPA AUC > 50 mg x h/L is needed to maintain remission.
• Small children are particularly at risk for under-dosing.
MPA Monitoring
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Conclusions
• MMF therapy is an excellent option to maintain remission in FRNS and SDNS.
• MMF therapy in NS should be monitored using TDM.
• An MPA trough level > 2 mg/L is essential. • Efficacy of MMF in SRNS better in remission
than for relapse, possibly owing to massive increase of MPA CL/F
MPA Monitoring
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Número de diapositiva 1Número de diapositiva 2Número de diapositiva 3Número de diapositiva 4Número de diapositiva 5Número de diapositiva 6ObjectivesNúmero de diapositiva 8Mycophenolate Mofetil (MMF)Mycophenolic Acid (MPA)Dosing and Features of MMFMetabolic pathways of MPA in humansMycophenolic Acid (MPA)Número de diapositiva 14Número de diapositiva 15Correlation Between MPA AUC and Abbreviated AUC from C1, 2 and 6Dose Normalized AUC varies with concomitant medicationIs the trough level so bad if only concomitant Tac is considered?Número de diapositiva 19Open label studiesOpen label studiesNúmero de diapositiva 22Randomized controlled trialsRandomized controlled trialsNúmero de diapositiva 25SRNS (FSGS) study from LondonSRNS (FSGS) study from LondonEstimation of AUC from MPA C0Impact of AlbuminNúmero de diapositiva 30Número de diapositiva 31Número de diapositiva 32SRNS (FSGS) study from LondonNúmero de diapositiva 34What is ontogeny of drug disposition?Specifics of drug metabolism in the growing bodyNúmero de diapositiva 37Age dependency of dose required for an AUC of �60 ug x h/mL in children on Tacrolimus and Mycophenolate Mofetil (MMF)Número de diapositiva 39Número de diapositiva 40SummaryConclusionsNúmero de diapositiva 43Número de diapositiva 44