THERAPEUTIC DRUG MONITORING

CASE 34-7, QUESTION 5: E.P.’s tacrolimus concentrations are measured by whole blood HPLC mass

spectrometry. Why is it important to monitor E.P.’s tacrolimus concentrations and how should his tacrolimus

therapy be monitored?

Because of the large interpatient and intrapatient variability, the narrow

therapeutic index, and the large number of potential drug interactions associated with

this agent, tacrolimus concentrations should be monitored in patients receiving

therapy. Concentrations are monitored to prevent toxicity, optimize efficacy, and

assess patient adherence to the prescribed regimen. A relationship exists between

concentration, efficacy, and toxicity.

62 The primary monitoring parameter used

clinically is the trough concentration because trough concentrations correlate well

with overall total body exposure (AUC). The target trough range is 5 to 12 ng/mL for

the first 3 months and 4 to 10 ng/mL thereafter, but this can vary with each transplant

center’s protocols and type of transplant. Most centers are now using mass

spectrometry to monitor all immunosuppressant concentrations. HPLC with mass

spectrometry is a more reliable method of analysis that does not cross-react with

metabolites; therefore, only parent drug is quantitated.

63

As in all cases, pharmacokinetic data must be interpreted in conjunction with the

patient’s clinical condition. In addition, deference always must be given to trends

established by multiple tacrolimus concentrations over that of a single concentration.

ADVERSE DRUG REACTIONS

CASE 34-7, QUESTION 6: What are the major adverse effects associated with tacrolimus and what clinical

parameters should be monitored in E.P.?

Nephrotoxicity, which usually is the limiting adverse effect of tacrolimus, has been

reported in more than 50% of patients in some studies.

64 This high incidence may be

related to the higher dosages used in earlier trials. Fortunately, dose reduction

usually reverses the acute nephrotoxicity. Because IV administration of tacrolimus

during the first week has been associated with acute renal failure in 20% of patients,

very few centers use this route or rapidly convert

p. 736

p. 737

to oral therapy. Presumably, liver recipients with poor graft function have a very

low tacrolimus clearance and are at a greater risk for acute renal failure.

64

In a

multicenter study involving 529 patients, the efficacy and toxicity of tacrolimus was

compared with cyclosporine in liver transplant recipients. Both agents increased

serum creatinine and decreased glomerular filtration rate comparably.

65 Thus, E.P.’s

renal function should be monitored closely.

Major neurologic toxicities (e.g., confusion, seizures, dysarthria, persistent coma)

occur in approximately 10% of patients. Minor neurologic toxicities occur in

approximately 20% to 60% of patients and include tremors, headache, and sleep

disturbances.

65 Hypertension (40%) is another common finding in patients treated

with tacrolimus. A greater number of tacrolimus-treated patients, however, are able

to discontinue or limit their use of antihypertensives as compared with cyclosporine.

Other adverse effects include diarrhea, nausea, vomiting and anorexia, alopecia,

hypomagnesemia, hyperkalemia, hemolytic uremic syndrome, alopecia, increased

susceptibility to infection and malignancy, and hyperglycemia. Hyperglycemia is

reported to occur more often with tacrolimus than cyclosporine. This is most likely to

be seen in patients with higher tacrolimus levels, higher steroid doses, and in

African-Americans. With reduction in tacrolimus and steroid doses, hyperglycemia

may reverse or decrease in severity. Hirsutism and gingival hyperplasia, which occur

with cyclosporine, are not seen with tacrolimus use.

Generic Tacrolimus

In August 2009, the FDA approved the first generic tacrolimus. Since that time, there

are up to five commercially available generic products. There has been continued

controversy and debate regarding the bio- and clinical equivalence of generic

tacrolimus products, with studies providing evidence on both sides of this argument.

However, recently completed FDA-solicited multicenter crossover studies

conducted in organ transplant recipients have demonstrated bioequivalence. The use

of generic tacrolimus has become fairly routine across most transplant centers,

although clinicians continue to caution against frequent changing of different

manufacturers.

66

Tacrolimus ER

Two new products, which are once-daily extended-release formulations of

tacrolimus, have recently been approved for use in the United States (Astragraf XL

and Envarsus XR). Studies demonstrate a 1:1 conversion from the normal-release

product yields lower peak concentrations, but similar 24 hour AUCs when using

Astragraf XL. Randomized clinical trials demonstrate similar rates of acute rejection,

graft loss, and death between tacrolimus ER and normal-release formulations;

however, specifically within female liver transplant recipients, there was a

significant higher rate of death in the ER formulation group, which led the FDA to

add a black box warning to the label for Astragraf XL. A number of small follow-up

studies have also demonstrated improved adherence to the once-daily formulation,

although this is a controversial area of debate amongst clinicians. The conversion

from immediate-release tacrolimus to Envarsus XR is 1:0.8; meaning 80% of the

preconversion daily dose of tacrolimus of immediate release should be given when

using the Envarsus XR formulation.

67,68

Rejection

CASE 34-7, QUESTION 7: E.P. was discharged from the hospital. He went to stay with his brother and was

followed up with laboratory tests obtained 3 times a week. The following laboratory values were obtained 2

weeks later:

AST, 36 IU/L

ALT, 52 IU/L

GGT, 65 IU/L

Total/direct (T/D) bilirubin, 1.0/0.3 mg/dL

and another week later:

AST, 158 IU/L

ALT, 322 IU/L

GGT, 321 IU/L

T/D bilirubin, 3.6/3.2 mg/dL

E.P. was readmitted to the transplant center because his LFT rise suggested acute liver dysfunction, and a

percutaneous needle liver biopsy was obtained to determine the cause. On admission, he complained of

lethargy, severe headaches, a mild tremor, and some pain over the area of the transplanted liver. E.P. also

stated that he had not felt like eating for the last 2 to 3 days. The pathologist interpreted the liver biopsy as

moderate rejection, and E.P. was given a 500-mg IV bolus of methylprednisolone followed by rapidly tapered

doses of IV methylprednisolone: 50 mg every 6 hours for four doses; 40 mg every 6 hours for four doses; 30

mg every 6 hours for four doses; 20 mg every 6 hours for four doses; 20 mg every 12 hours for two doses; then

back to the pretaper oral prednisone dose. Three days into the recycle, E.P.’s liver enzyme values had not

improved and rabbit antithymocyte globulin therapy was initiated. Laboratory values after 10 days of

thymoglobulin IV 1.5 mg/kg/day were as follows:

AST, 35 IU/L

ALT, 108 units/L

GGT, 169 units/L

T/D bilirubin, 1.0/0.6 mg/dL

The 12-hour tacrolimus trough level at the end of the treatment course was 15.2 ng/mL. E.P. was discharged

and sent home with the following medications: tacrolimus 5 mg PO BID; prednisone 20 mg PO daily; clonidine

0.3 mg PO BID; felodipine 10 mg PO daily; furosemide 20 mg PO daily; co-trimoxazole one tablet daily

Mondays, Wednesdays, and Fridays; and valganciclovir 450 mg PO daily. What subjective and objective

evidence of liver rejection is present in E.P.?

Hyperacute rejection rarely occurs with liver transplantation; when this occurs,

treatment is supportive and retransplantation is required.

69 Unlike other organs,

however, the liver may function adequately, but survival is lower when the organ is

transplanted across blood types (ABO incompatible) or in patients that are

presensitized to the HLA antigens.

70