Paper: Pharmacokinetic Evaluation of Astagraf XL® and Prograf® in Renal Transplant Candidates Following Laparoscopic Sleeve Gastrectomy (2016 ACCP Virtual Poster Symposium)

Wednesday, May 18, 2016

Alicia Lichvar, PharmD¹, Abbie Leino, PharmD¹, Tiffany Kaiser, PharmD¹, Tomoyuki Mizuno, PhD², Tsuyoshi Fukuda, PhD², Uwe Christians, MD, PhD³, Rita Alloway, PharmD¹, Alexander Vinks, PhD², E. Steve Woodle, MD¹ and Tayyab Diwan, MD¹
1University of Cincinnati, Cincinnati, OH
2Cincinnati Children's Hospital, Cincinnati, OH
3University of Colorado, Aurora, CO

Poster

Introduction: Impact of laparoscopic sleeve gastrectomy (LGS) on immunosuppressive drug pharmacokinetics (PK) is unknown.

Objectives: To evaluate PK following LSG for two tacrolimus (FK) formulations (Astagraf XL® and Prograf®) with mycophenolate mofetil (MMF) in end stage renal disease patients awaiting renal transplantation (RTx) across genotypes.

Study Design: Open-label, randomized, two-way crossover PK study.

Methods: RTx candidates who were >3 months post-LSG were randomized to Astagraf XL® 8mg (1 dose) or Prograf® 4mg (2 doses 12h apart) in combination with MMF 1gm (2 doses 12h apart). 24-hour PK profiles were analyzed by LC-MS and compared. Genotyping was performed for MDR1/ABCB1, CYP3A4, and CYP3A5. PK differences across genotypes were compared. Astagraf XL® bioequivalence to Prograf® was assessed by 90%CI for LSMeans ratio of AUC_0-24and Cmax.

Results: 23 patients completed the study: male (56.5%), Caucasian (56.5%) with a mean age of 50.8 years (+11.4). Table 1 includes PK and bioequivalence results. CYP5A5*1 genotype conferred lower AUC_0-24 values in Prograf® (73.8ng*h/mL vs. 180.5ng*h/mL, p<0.001) and Astagraf XL® (116.8ng*h/mL vs. 150.8ng*h/mL, p=0.008). CYP5A5*1 genotype also conferred higher CL/F values in Prograf® (108.5L/h vs. 44.5L/h, p<0.001) and Astagraf XL® (68.51L/h vs. 53.1L/h, p=0.008). CYP3A4*22 and ABCB1 did not impact tacrolimus PK. Ideal (R²=0.15) and actual (R²=0.229) body weights poorly correlated with FK AUC_0-24.

Conclusions: Single dose PK analysis revealed Astagraf XL® and Prograf® were bioequivalent. CYP3A51* allele influences PK parameters of FK formulations in an LSG population. Alternative starting doses of Prograf® and Astagraf® following transplant are not necessary.

Table 1.

Parameter

Astagraf XL®

Prograf®

p

AUC_0-24(ng*h/mL)

129.8 (34.3–292.7)

138.7 (26.5–356.2)

0.50

CL/F (L/h)

61.6 (51.9–73.8)

57.7 (42.1–106.0)

0.88

C_max (ng/mL)

13.9 (6.0–31.0)

18.9 (4.0–35.2)

0.04

C_min (ng/mL)

2.6 (0.7–6.27)

0-12h: 2.4 (1.52–6.9)
12-24h: 3.9 (1.5–10.7)

0.09
0.004

Reference/ Test formulation

Ratio of geometric means (%)

90%CI

AUC_0-24

Prograf®/ Astagraf XL®

103.49

89.6–119.6

C_max

Prograf®/ Astagraf XL®

92.53

80.45–106.43

Parameter	Astagraf XL®	Prograf®	p
AUC_0-24(ng*h/mL)	129.8 (34.3–292.7)	138.7 (26.5–356.2)	0.50
CL/F (L/h)	61.6 (51.9–73.8)	57.7 (42.1–106.0)	0.88
C_max (ng/mL)	13.9 (6.0–31.0)	18.9 (4.0–35.2)	0.04
C_min (ng/mL)	2.6 (0.7–6.27)	0-12h: 2.4 (1.52–6.9) 12-24h: 3.9 (1.5–10.7)	0.09 0.004
	Reference/ Test formulation	Ratio of geometric means (%)	90%CI
AUC_0-24	Prograf®/ Astagraf XL®	103.49	89.6–119.6
C_max	Prograf®/ Astagraf XL®	92.53	80.45–106.43

71 Pharmacokinetic Evaluation of Astagraf XL® and Prograf® in Renal Transplant Candidates Following Laparoscopic Sleeve Gastrectomy