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Pharmacokinetics of orally administered immunosuppressive drugs in adults

Pharmacokinetics of orally administered immunosuppressive drugs in adults
Drug (US brand name) Oral bioavailability Effect of food on absorption Metabolism and clearance* Enzyme/transporter inhibition* Half-life in hours (range)
Antimetabolites
Mycophenolate mofetil (MMF, CellCept) 80.7% (renal transplant patients)
94% (healthy volunteers)
  • High-fat meal: ↓Cmax by 40%; AUC is unchanged
  • Should be taken on an empty stomach or at a consistent time each day in relation to meals to improve GI tolerability
  • Giving total daily dose in three or four equally divided doses may improve GI tolerability
 Rapidly hydrolyzed to its active metabolite mycophenolic acid (MPA), which is further metabolized by UGT to the inactive metabolite mycophenolic acid glucuronide (MPAG), which is excreted primarily via urine; MPA undergoes enterohepatic recirculation, and secondary increases in MPA levels are seen 6 to 12 hours after a dose of MMF None known

17.9 (11.4 to 24.4) (MPA)

MPAG can accumulate in renal failure
Mycophenolate sodium, enteric coated (Myfortic)Δ 72% (renal transplant patients)
  • High-fat meal: ↓Cmax by 33%; AUC is unchanged
  • Should be taken on an empty stomach
 Rapidly hydrolyzed to the active metabolite mycophenolic acid (MPA), which is further metabolized by UGT to the inactive metabolite mycophenolic acid glucuronide (MPAG), which is excreted primarily via urine; MPA undergoes enterohepatic recirculation, and secondary increases in MPA levels are seen 6 to 8 hours after a dose of mycophenolate sodium None known

12 (8 to 16) (MPA)

MPAG can accumulate in renal failure
Calcineurin inhibitors
Cyclosporine non-modified (Sandimmune) Generally poor and unpredictable:
  • 10 to 89% (renal transplant patients)
  • <10% (liver transplant patients)
  • High-fat meal: ↑(highly variable)
  • Should be taken at a consistent time each day in relation to meals

Metabolized by CYP3A4 to reduced activity and inactive metabolites (eg, M1, M9, M4N) cleared fecally via bile

Substrate of P-gp		 Inhibitor of P-gp, BCRP, OATP1B1/1B3

19 (10 to 27)

Prolonged in hepatic impairment
Cyclosporine modified (microemulsion) (Neoral) 23 to 50% better absorbed than non-modified formulation in renal and liver transplant patients, respectively
  • High-fat meal: ↓Cmax by 33% and ↓AUC by 13%
  • Should be taken at a consistent time each day in relation to meals

8.4 (5 to 18)

Prolonged in hepatic impairment
Tacrolimus immediate-release capsule (Prograf) 7 to 32%
  • High-fat meal: ↓Cmax by 77% and ↓AUC by 37%
  • High-carbohydrate meal: ↓Cmax by 65% and ↓AUC by 28%
  • Should be taken on an empty stomach

Metabolized by CYP3A4/5 to active (eg, 13-O-demethyl) and inactive metabolites cleared fecally via bile

Substrate of P-gp		 May be an inhibitor of P-gp; supportive data are limited to in-vitro effects (ie, clinical effect is unknown)

12 (2 to 36)

Prolonged in severe hepatic impairment
Tacrolimus extended-release capsule (Astagraf XL) 12 to 19%
  • High-fat meal: ↓Cmax by 77% and ↓AUC by 25%
  • Should be taken preferably on an empty stomach at least 1 hour before a meal or at least 2 hours after a meal

38 (35 to 41)

Prolonged in severe hepatic impairment
Tacrolimus extended-release tablet (Envarsus XR) 50% better absorbed than immediate-release capsule
  • High-fat meal: ↓Cmax by 22% and ↓AUC by 55%
  • Evening administration: ↓AUC by 15%
  • Should be taken on an empty stomach

31 (23 to 39)

Prolonged in severe hepatic impairment
mTOR inhibitors
Everolimus (Zortress) 30%
  • High-fat meal: ↓Cmax by 60%; ↓AUC by 16%
  • Should be taken at a consistent time each day in relation to meals

Metabolized by CYP3A4 to six weakly active metabolites that are excreted primarily via feces

Substrate of P-gp		 None known

30 (19 to 41)

Prolonged in hepatic impairment
Sirolimus (Rapamune) 18% (tablet)
14% (oral solution)
  • High-fat meal: ↑AUC by 23 to 35%
  • Should be taken at a consistent time each day in relation to meals

Metabolized by CYP3A4 to seven metabolites (some have weak activity) that are excreted primarily via feces

Substrate of P-gp		 None known

62 (46 to 78)

Prolonged in hepatic impairment
Careful therapeutic drug monitoring (TDM) of systemic calcineurin inhibitors and mTOR inhibitors is essential due to the narrow margin between adequate immunosuppression and toxicity. Blood concentration monitoring is necessary for any change in formulation (including switch between generics or brands) and between methods of administration (eg, oral, sublingual, intravenous) to determine the need for dose alteration. Refer to accompanying text.

AUC: area under the 24-hour serum concentration × time plot; Cmax: maximum concentration; CYP3A4: cytochrome P450 3A4; GI: gastrointestinal; MMF: mycophenolate mofetil; MPA: mycophenolic acid (active form of mycophenolate); MPAG: mycophenolic acid glucuronide (inactive metabolite of mycophenolic acid); mTOR inhibitors: mammalian (mechanistic) target of rapamycin inhibitors; P-gp: P-glycoprotein efflux membrane transporters (multi-drug efflux pump); UGT: uridine diphosphate (UDP) glucuronosyltransferase.

* The classification of immunosuppressive drug effects on drug metabolism are based upon US Food and Drug Administration (FDA) guidance.[1,2] Other sources may use a different classification system resulting in some agents being classified differently. Weak inhibitor effects are not listed. Clinically significant interactions can occasionally occur due to weak inhibitors, particularly if the target drug has a narrow therapeutic margin. Refer to the drug interactions program included within UpToDate for a full review of potential interactions.

¶ Standard deviation 6.5 hours per US manufacturer.

Δ To convert from mycophenolate mofetil (MMF, CellCept) 1000 mg every 12 hours, switch to mycophenolate sodium enteric coated (Myfortic) 720 mg every 12 hours.
References:
  1. US Food and Drug Administration. Clinical drug interaction studies — Cytochrome P450 enzyme- and transporter-mediated drug interactions guidance for industry, January 2020. Available at: https://www.fda.gov/regulatory-information/search-fda-guidance-documents/clinical-drug-interaction-studies-cytochrome-p450-enzyme-and-transporter-mediated-drug-interactions (Accessed on June 5, 2020).
  2. Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers. US Food and Drug Administration. Available at: www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers.

Prepared with data from: UpToDate Lexidrug. More information available at https://online.lexi.com/.

Additional data from:
  1. US prescribing information available at https://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm.
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