Acido Micofenólico en Síndrome · Acido Micofenólico en Síndrome Nefrótico: ¿Una Buena...

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

Disclosures • Lamentablemente, no hablo español. • I have no financial relationships to disclose within the past

120 months relevant to my presentation

MPA Monitoring

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

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

Review of mechanism of action and pharmacokinetics

of MMF

MPA Monitoring

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

Mycophenolic Acid (MPA) MPA Monitoring

O

OH O

COOH

OCH3

CH3

CH3

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

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

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

MPA Monitoring

UGT1A9-275T>A/-2152C>T Polymorphisms

N=104 renal transplant patients

MPA PK Profiles in 104 Paediatric Renal Transplant Recipients

MPA Pharmacokinetics

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)

Dose Normalized AUC varies with concomitant medication

Filler G et al. Pediatr Nephrol 2000; 14:100-104.

MPA Monitoring

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.

What evidence is out there about MMF and NS?

MPA Monitoring

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


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


MPA Clearance: Other factors MPA and SSNS

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


A Closer Look at SRNS

MMF and NS

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).




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

Estimation of AUC from MPA C0 MMF for Nephrotic Syndrome

Impact of Albumin MMF for Nephrotic Syndrome


• 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.


Factors affecting MPA CL/F

MMF and NS

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

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

Kearns GL et al. N Engl J Med. 2003;349:1157-67

Drug Dosing

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

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)

MPA Clearance: Other factors

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

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

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

Acido Micofenólico en Síndrome · Acido Micofenólico en Síndrome Nefrótico: ¿Una Buena...

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