L04A: Immunosuppressants
L04A holds the immunosuppressants, drugs that dampen the immune response. WHO sorts them into level-4 groups, mostly by what they block.
How do immunosuppressants work?
- Calcineurin inhibitors (L04AD) include ciclosporin (L04AD01) and tacrolimus (L04AD02). Tacrolimus binds FK-binding protein 12 in T lymphocytes, and the complex binds calcineurin. This keeps NFAT (nuclear factor of activated T cells) from being dephosphorylated and moving to the nucleus, which ultimately inhibits interleukin-2 production and T-cell activation [1].
- mTOR inhibitors (L04AH), such as everolimus (L04AH02), block growth-driven signals in the T-cell response to donor antigens (alloantigen), at a later stage than the calcineurin inhibitors [2].
- Mycophenolic acid (L04AA06) inhibits inosine monophosphate dehydrogenase (IMPDH), which eventually stops T and B lymphocytes from proliferating [3].
- TNF-α inhibitors (L04AB) act on the cytokine tumor necrosis factor α. Infliximab (L04AB02) and adalimumab (L04AB04) are monoclonal antibodies against it [4]. Etanercept (L04AB01) is a soluble TNF receptor fusion protein [5].
- Interleukin inhibitors (L04AC) include tocilizumab (L04AC07).
- JAK inhibitors (L04AF) have their own section below.
L04AF: Janus-associated kinase (JAK) inhibitors
Introduction
Janus Kinase (JAK) inhibitors are a class of drugs that target the Janus Kinase family of enzymes. Janus Kinases are a family of cytoplasmic tyrosine kinases that transduce cytokine-mediated signals via the JAK-STAT pathway [6].
The Janus Kinases are:
- JAK1
- JAK2
- JAK3
- TYK2
Janus kinase inhibitors can be classed in several overlapping classes: they are immunomodulators, they are DMARDs (disease-modifying antirheumatic drugs), and they are a subclass of tyrosine kinase inhibitors.
Mechanism of action
JAK-inhibitors work by modifying the immune system via cytokine activity inhibition. The JAK enzymes interact with the intracellular part of distinct cytokine receptors, and are thus involved in the signaling pathways of multiple pro-inflammatory cytokines, such as IL-2, 4, 7, 9, 13, 15, 21 and 23. By inhibiting JAK enzymes, JAK inhibitors can modulate the immune response and reduce inflammation. JAK inhibitors are used to treat a variety of autoimmune and inflammatory diseases, including rheumatoid arthritis, psoriasis, and inflammatory bowel disease [6].
Examples of JAK inhibitors
First generation JAK inhibitors:
- Tofacitinib (L04AF01, JAK1/3 inhibitor)
- Ruxolitinib (JAK1/2 inhibitor; WHO classifies it with the antineoplastic JAK inhibitors, L01EJ01)
Second generation JAK inhibitors:
- Upadacitinib (L04AF03, designed to be selective for JAK1)
Efficacy
Transplantation
In kidney transplantation, a low mycophenolic acid AUC has been associated with more biopsy-proven acute rejection. Targeting an AUC over 12 hours of 30 to 60 mg·h/L is likely to minimize the risk of acute rejection. Limited sampling strategies and Bayesian forecasting can estimate this AUC without a full concentration-time profile [3].
For tacrolimus, lower exposure has been related to acute rejection. It is monitored by whole-blood trough concentrations, which correlate with AUC [1].
Rheumatoid arthritis and psoriasis
The diseases themselves are described in the primers on rheumatoid arthritis and psoriasis.
In the phase 2 and 3 rheumatoid arthritis studies of upadacitinib (L04AF03), efficacy was the proportion of patients reaching an ACR20, ACR50 or ACR70 response (American College of Rheumatology 20%, 50% or 70% improvement), or a DAS28-CRP (Disease Activity Score for 28 joints with C-reactive protein) disease activity threshold. These categorical endpoints were described over time with continuous-time Markov models, and the proportion of responders increased with plasma exposure [7].
Models of the Psoriasis Area and Severity Index (PASI) are covered in the psoriasis primer.
Safety
Tacrolimus has a narrow therapeutic index, and higher exposure has been related to toxicity, including kidney damage (nephrotoxicity), hypertension, nervous system toxicity (neurotoxicity) and high blood sugar (hyperglycemia). Patients who express CYP3A5 have lower dose-adjusted tacrolimus trough concentrations than non-expressers, and the Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline recommends a 1.5 to 2 times higher starting dose for them [1].
Everolimus appears to be less nephrotoxic than ciclosporin and tacrolimus. Its adverse effects include high blood triglycerides (hypertriglyceridemia), high blood cholesterol (hypercholesterolemia), opportunistic infections, a low platelet count (thrombocytopenia) and a low white blood cell count (leukopenia). Its trough concentration correlates well with AUC and is used for monitoring [2].
For mycophenolic acid, gastrointestinal adverse events may be dose related. Leukopenia and anemia have been associated with high exposure in some studies but not in others [3].
In four phase 3 studies in rheumatoid arthritis, tocilizumab, an antibody against the interleukin-6 receptor, lowered neutrophil and platelet counts, which returned to baseline once the drug was eliminated. In a population model, neutrophils were a direct function of the unbound soluble interleukin-6 receptor, and platelets followed a transit-compartment life-span model [8].
In the upadacitinib studies, safety endpoints were modeled with logistic regression, and shallow exposure-response relationships were found for serious infections, grade 3 or worse low lymphocyte count (lymphopenia), and hemoglobin decreases of more than 2 g/dL [7]. For the antibodies approved in rheumatoid arthritis, the relationship between concentration and adverse effects is poorly documented [4].