Drugs affecting MPA pharmacokinetics
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Serum creatinine dynamics and diuresis over 5-7 postoperative days
(before MPA PK assessment)
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Hypoalbuminemia at baseline of MPA PK assessment
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Postoperative complications, acute rejection, infectious,
cardiovascular, metabolic or hepatic co-morbidity that may affect MPA
PK and/or exposure to calcineurin inhibitors (CNI)
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Drugs that interfere (apart from CNI) with ABCG2 – by
inclusion-exclusion criteria pertinent to drugs affecting MPA PK (some
are common) and comorbidities (i.e., no need for treatments)
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Drugs affecting CNI pharmacokinetics – by inclusion-exclusion
criteria pertinent to drugs affecting MPA PK (some are common) and
comorbidities (i.e., no need for treatments)
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Factors controlled for by matching/statistical
adjustment |
Type of MPA formulation
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Estimated creatinine clearance at baseline of MPA PK assessment
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Type of CNI
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CNI trough concentrations at baseline of MPA PK assessment
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Age and body mass index
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Polymorphisms: UGT1A9 -2152/-275 diplotypes; UGT2B7 -161
genotype; ABCB1 2677 / 3435 / 1236 diplotypes; SLC01B1
521 genotype; ABCC2 -24 genotype; ABCC2 1249 genotype
(recipient and donor)
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Measured factors, but not included in
matching/adjustment |
CYP3A4*22 and CYP3A5*3 polymorphisms: a) only a few
subjects overall had variant alleles. Considering that CYP3A4/5 are
practically irrelevant for MPA PK, adjustments for these two
polymorphisms are practically meaningless; b) potential impact of
these two polymorphisms on exposure to CNIs is accounted for by
matching in respect to CNI trough concentrations.
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Prednisone-equivalent doses: a) doses were closely similar between
ABCG2 421C>A variant carriers and wild-type
controls considering raw data (Table 2). After matching, weighted
medians, quartiles and ranges were closely similar in 11 variant
carriers (40, 30-50, 30-60 mg/day, respectively) matched to 43
wild-type controls (30, 30-40, 20-75 mg/day, respectively); b) effects
of glucocorticoids on exposure to MPA are minor/irrelevant
[1,2,5]; c) possible effects on CNI troughs (e.g., CYP-induction)
are accounted for by matching in respect to CNI trough concentrations.
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