Immunotherapy

Question 1

Cyclosporine (Sandimmune, Neoral)

Answer 1

Description

• Immunosuppressive cyclic peptide produced by the fungus Beauveria nivea
• Immunosuppressive effect was discovered in 1972, approved by FDA in 1983
• Used to prevent organ rejection after transplant; TX for rheumatoid arthritis, psoriasis, inflammatory bowel disease

Mechanism of action

• Calcineurin inhibitor (CNI); binds to cyclophilin, complex binds to calcineurin and inhibits phosphatase activity of calcineurin; this prevents the dephosphorylation and translocation of a transcription factor (NF-AT) that stimulates cytokine gene expression
• Result is inhibition of T cell activation and decreased release of IL-2, IL-3, IL-4, TNF-a, IFN-g

Pharmacokinetics

• Given PO or IV for immunosupression at 2.5-15 mg/kg QD; narrow therapeutic window
• Opthalmic formulation 0.05% or 0.1% (Restasis®) is used to increase tear production that has been suppressed by inflammation, usually 1 gtt BID
• Metabolized by CYP3A4 (→ drug interactions!), metabolites mostly excreted in bile

Adverse reactions

• Nephrotoxicity (20-38%); CNI induce interstitial fibrosis and vasoconstriction of afferent arterioles, leading to tubular necrosis
• CV: hypertension (8-28%)
• Hirsutism (10-21%) occurs in both ♂ and ♀ receiving systemic cyclosporine
• Gingival hyperplasia (4-16%)
• CNS: tremor (10-12%)
• Opthalmic application may causes burning (17%)
• Hyperglycemia (< 2%) (uniquely low)

Precautions

• Therapeutic drug monitoring; maintain trough level of ~ 150-200 ng/mL (narrow therapeutic window, balance nephrotoxicity w/ organ rejection)
• Hepatic disease, renal disease, hypertension

Question 2

Tacrolimus (Prograf)

Answer 2

Description

• Immunosuppressive derived from the fungus Streptomyces tsukubaensis
• Used to prevent organ rejection after transplant; psoriasis, atopic dermatitis

Mechanism of action

• Calcineurin inhibitor (CNI); forms complex with FK binding protein, complex binds to calcineurin and inhibits phosphatase activity of calcineurin; this prevents the dephosphorylation and translocation of a transcription factor (NF-AT) that stimulates cytokine gene expression; 50-100X more potent than cyclosporine
• Result is inhibition of T cell activation and decreased release of IL-2, IL-3, IL-4, TNF-a, IFN-g

Pharmacokinetics

• Given IV or PO; PO absorption is highly variable, necessitating individualized regimens
• Extensively metabolized by CYP3A4 (→ drug interactions!), metabolites mostly excreted in bile
• Concentrated in the pancreas and may inhibit pancreatic insulin secretion

Adverse reactions (worse than cyclosporine)

• Nephrotoxicity (40-52%); CNI induce interstitial fibrosis and vasoconstriction of afferent arterioles, leading to tubular necrosis
• CV: hypertension (38-50%)
• CNS: tremor (48-56%), insomnia (32-64%), headache (37-64%)
• GI: NVD (32-59%), elevated LFTs
• Hyperglycemia (33-47%)

Precautions

• Diabetes
• Therapeutic drug monitoring, target blood concentration is ~ 5-20 ng/mL
• Hepatic disease, renal disease, hypertension

Question 3

Sirolimus (Rapamune, Cypher)

Answer 3

Description

• Macrocyclic lactone produced by Streptomyces hygroscopicus
• Used to prevent rejection after renal transplant, not recommended for liver or lung transplants

Mechanism of action

• Binds to FK binding protein, complex then binds to and inhibits mTOR, a key kinase involved in upstream regulation of protein synthesis, cell growth, proliferation; inhibits progression from G1 to S phase of the cell cycle
• Cytostatic: T cells still produce IL-2 but fail to proliferate

Pharmacokinetics

• Supplied as a solution or tabs for PO administration, commonly 2-5 mg QD
• Cypher® is a sirolimus-eluting stent used to inhibit restenosis after stenting to treat coronary artery occlusion; 80% of sirolimus is released in 30 days and the rest in 90 days
• CYP3A4 substrate (→ drug interactions!), metabolites mostly excreted in bile
• Long, ~ 60 hr half-life

Adverse reactions

• PULM: dyspnea (22-30%), pharyngitis (16-21%)
• HEME: myelosuppression (13-37%) (thrombocytopenia, leukopenia)
• GI: NVD (19-42%), hepatotoxicity, elevated LFTs
• MET: hyperlipidemia (35-57%), hypertriglyceridemia, electrolyte imbalances (11-23%), edema (54-64%)
• Nephrotoxicity; may potentiate CNI-induced nephrotoxicity

Precautions

• Therapeutic drug monitoring, target concentration is 12-24 ng/mL (necessary to monitor levels for tacrolimus and cyclosporine too)

Question 4

Azathioprine (Imuran)

Answer 4

Description

• Historically, first drug to be used for immunosuppression after transplantation
• Cytotoxic antimetabolite-class agent; prodrug of 6-mercaptopurine (6-MP)
• Used to prevent rejection of kidney transplants and to reduce symptoms of rheumatoid arthritis and Crohn’s disease; 6-MP itself is used as an antileukemia agent

Mechanism of action

• Azathioprine → 6-MP → 6-thioguanine → 6-thioguanine nucleotides, which are incorporated into DNA and RNA → impaired function
• 6-MP and 6-thioguanine also interfere with several enzymes in the de novo purine nucleotide biosynthetic pathway, resulting in depletion of purine nucleotides, decreased ATP and GTP, decreased glycoproteins, etc.

Pharmacokinetics

• Administered as PO or IV, good oral absorption; usual maintenance dose is 1-3 mg/kg QD
• 6-MP is inactivated by oxidation (by xanthine oxidase) and methylation (by thiopurine S-methyltransferase); excretion is mostly renal

Adverse reactions

• HEM: myelosuppression (up to 50%), with potentially severe leukopenia
• GI: NVD (12%), abdominal pain, elevated LFTs
• Rashes

Precautions

• Thiopurine methyltransferase deficiency (~ 10%) → enhanced toxicity (genetically slow metabolism)
• TX with allopurinol → enhanced toxicity
• Pregnancy Risk Category D

Question 5

Mycophenolate mofetil (CellCept)

Answer 5

Description

• Prodrug; semisynthetic derivative of mycophenolic acid obtained from Penicillium species
• Used concomitantly with or as an alternative to cyclosporine or tacrolimus to prevent organ rejection after renal, cardiac, or liver transplants; recommendation is mycophenolate mofetil + cyclosporine + corticosteroid
• Less bone marrow suppression than azathioprine

Mechanism of action

• Mycophenolic acid is a reversible inhibitor of inosine monophosphate dehydrogenase, inhibits the de novo pathway of guanosine biosynthesis that is critical to lymphocyte proliferation and activation, resulting in blunted T and B cell responses
• Selective for lymphocytes; other cells are able to recover purines via a separate salvage pathway and are thus able to escape the effect

Pharmacokinetics

• Supplied as PO and IV formulations; both routes offer essentially complete bioavailability of mycophenolic acid
• Usual dose is 1 g BID for kidney and liver transplants, 1.5 g BID for heart transplants (high dose)
• The inactive phenolic glucuronide is the main metabolite; excreted almost entirely in the urine

Adverse reactions

• GI: NVD (13-36%), abdominal pain
• CNS: headache (16-54%)
• CV: hypertension (28-77%)
• HEM: myelosuppression (9-35%) (less than azathioprine)
• DERM: acne (10%) rash (8%)

Precautions

• Chronic renal insufficiency (GFR < 25 mL/min) (excreted almost entirely in urine)
• Pregnancy Risk Category D

Question 6

Muromonab-CD3 (Orthoclone OKT3)

Answer 6

Description

• Murine monoclonal antibody directed against CD3 protein on surface of T cells
• First monoclonal antibody to be FDA-approved (1985)
• Used to block acute rejection of heart, liver, kidney transplants and to deplete T cells from donor bone marrow prior to transplantation

Mechanism of action

• Binds to T cell receptor-associated CD3 complex, causes initial activation and cytokine release, followed by blockade, apoptosis, and depletion of T cells

Pharmacokinetics

• Supplied as 1 mg/mL solution for IV bolus administration, usual dose is 5 mg QD for 10-14 days
• T cells begin to disappear from blood within minutes and reappear ~ 1 week after therapy is halted

Adverse reactions

• Triggers cytokine release syndrome: fever (73%), chills (59%), headache, tremor, dyspnea (21%), chest pain (14%), NVD (12%); syndrome subsides after first day and can be minimized by pretreatment with glucocorticoids, acetaminophen, or diphenhydramine
• Seizures (1-5%)
• Rare, but potentially fatal, anaphylaxis

Precautions

• Allergy to mouse proteins
• CV: heart failure, hypertension, hypotension
• Epilepsy

Question 7

Basiliximab (Simulect)

Answer 7

Description

• “Nondepleting” immunosuppressive agent
• Anti-CD25 antibody; recombinant human-mouse IgG vs. IL-2 receptor-CD25 complex (targets only activated T cells w/ CD25)
• Used for prophylaxis of acute rejection following kidney transplant, combined with cyclosporine and a glucocorticoid

Mechanism of action

• IL-2 receptor antagonist; binds with high affinity (KD ~ 0.1 nM) to CD25, the IL-2 receptor a chain on activated T cells, preventing activation by IL-2
• CD25 is only expressed on activated T cells, so basiliximab is does not cause widespread depletion of T cells

Pharmacokinetics

• Supplied as a lyophylized powder that is reconstituted for IV administration
• 20 mg is given IV as a bolus injection or as an infusion over 20-30 min
• First 20 mg dose is given 2 hr prior to surgery
• Second 20 mg dose is given 4 days after transplantation
• Elimination half-life is ~ 7 days; normal T cell numbers return in 7-14 days

Adverse reactions

• Incidence and severity much lower than muromonab-CD3
• GI (10%): NVD, pain
• MET: electrolyte imbalances (3-10%)
• CV (3-10%): hypertension, arrhythmias
• Rare, potentially fatal anaphylaxis

Precautions

• Pediatric patients < 35 kg are given half-doses
• Allergy to mouse proteins

Question 8

Adalimumab (Humira)

Answer 8

Description

• Fully humanized monoclonal antibody
• Immunosuppressive human IgG vs. TNF-a
• TX for rheumatoid arthritis, Crohn’s disease, ankylosing spondylitis, psoriasis

Mechanism of action

• Binds to TNF-a, preventing its interactions with p55 and p75 cell surface TNF receptors; decreases biological activity of TNF-a (cytokine depletor)
• Clinical response is ↓ levels of pro-inflammatory cytokines such as IL-1 and IL-6, ↓ leukocyte migration, ↓ activation of neutrophils and eosinophils, ↓ fibroblast proliferation, ↓ synthesis of prostaglandins, ↓ matrix metalloproteinases that produce tissue remodeling responsible for cartilage destruction

Pharmacokinetics

• Supplied in prefilled syringes containing 20 mg or 40 mg for SC injection
• Usual maintenance dose is 40 mg Q 2 weeks
• Elimination half-life is 10-20 days (mean ~ 14 days)

Adverse reactions

• Mild injection site reactions
• Headache (12%)
• Rash (12%)
• CV: hypertension (5%)
• MET: hyperlipidemia (6-7%)

Precautions

• Chronic or recurrent infection; tuberculosis
• Travel to regions where mycoses or tuberculosis are endemic