Clinical determinants of calcineurin inhibitor disposition: a mechanistic review

Abstract

The calcineurin inhibitors (CNIs) tacrolimus and cyclosporine are widely used immunosuppressive drugs characterized by high pharmacokinetic and pharmacodynamic variability, both between and within patients. CNIs are highly lipophilic, poorly soluble, undergo extensive first-pass metabolism and are cleared by the liver. In both gut and liver, CNIs are substrates for the cytochrome P450 (CYP) enzymes 3A4 and 3A5 as well as the P-glycoprotein (P-gp) transporter, whose functions are determined by a complex interplay between genetic polymorphisms, the inductive or inhibitory effects of many drugs, herbs, food constituents and endogenous substances such as uremic toxins in case of end-stage renal disease. The current literature is reviewed for all common clinical determinants of variability in CNI disposition such as food intake, diarrhea and other intestinal pathology, anemia, hypoalbuminemia, hyperlipidemia, liver and kidney disease, aging, ethnicity, formulation and time post-transplant, focusing on the underlying mechanisms. Drugs and herb- and food constituents mainly interact with CNIs at the gut level by affecting bioavailability, with interactions generally being much more pronounced in case of oral compared with intravenous co-administration. Cyclosporine disposition is less susceptible to these interactions compared with tacrolimus, possibly because cyclosporine is itself a moderately strong CYP3A4- and strong P-gp inhibitor, blunting the effect of additional inhibitors. P-gp also has a major role in limiting distribution of CNI to tissues such as the brain, placenta, lymphocytes and kidney. Inactivating polymorphisms and inhibition of P-gp have the potential to significantly increase CNI exposure in these tissues with possible implications for toxicity and efficacy.

Practical Recommendations for Long-term Management of Modifiable Risks in Kidney and Liver Transplant Recipients

“…105 Expressers of the CYP3A5 enzyme (as is more often the case in black and Asian patients) do require higher dosages to reach therapeutic tacrolimus exposure. [105][106][107] The recently developed prolonged-release formulation in tablet form (also known as LCP-tacrolimus) is released and absorbed more distally in the gut. 105,106 This newer formulation of prolonged-release tacrolimus in tablets has shown some differences in terms of pharmacokinetics but longterm clinical outcome data is yet to be established.…”

“…[105][106][107] The recently developed prolonged-release formulation in tablet form (also known as LCP-tacrolimus) is released and absorbed more distally in the gut. 105,106 This newer formulation of prolonged-release tacrolimus in tablets has shown some differences in terms of pharmacokinetics but longterm clinical outcome data is yet to be established. 106 After absorption, tacrolimus diffuses extensively in blood cells and tissues.…”

“…There is extensive presystemic metabolism by the CYP3A enzymes in the gut wall and first-pass metabolism in liver, which limits its oral bioavailability. 105 Expressers of the CYP3A5 enzyme (as is more often the case in black and Asian patients) do require higher dosages to reach therapeutic tacrolimus exposure. [105][106][107] The recently developed prolonged-release formulation in tablet form (also known as LCP-tacrolimus) is released and absorbed more distally in the gut.…”

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“…8,9 Pharmacokinetics After oral administration, tacrolimus undergoes extensive first-pass effects via p-glycoprotein and intestinal and hepatic cytochrome P450 3A (CYP3A) enzymes. 10 Tacrolimus is primarily eliminated from the body in the bile by hepatic metabolism, and less than 1% of unchanged drug is excreted in the urine. 11 The oral bioavailability of tacrolimus is low and exhibits large intra-and interindividual variability, ranging from 4% to 89% (mean around 25% in liver and RT recipients and in patients with renal impairment).…”

Predictive Modeling of Tacrolimus Dose Requirements: “All That Is Gold Does Not Glitter”

“…The authors presume that the identified sets of gene variants (because of their distribution with oxidoreductase/monooxygenase activity) are causally linked to tacrolimus metabolism and thus exposure. It is important to note, however, that in the first 3 mo after transplantation, a number of clinical factors known to affect tacrolimus bioavailability closely covary with tacrolimus dosing and influence dose-corrected exposure, for example, graft function or dysfunction, gastrointestinal motility, hematocrit, albumin, corticosteroid tapering, and concomitant drugs (drug-drug interactions) (2). The fact that these factors were not corrected for increases the risk of overfitting the PLS1 models by modeling variability that is likely to be determined by clinical factors.…”