Prednisolone

Pharmacodynamics

Network Meta Analyses

Drug Drug Interactions

Pharmacokinetics

Therapeutic Drug Monitoring

Prednisolone Pharmacokinetics

Prednisolone demonstrates favorable pharmacokinetic properties with reliable oral absorption and primarily hepatic metabolism, making it suitable for IBD therapy

Absorption

Rapidly and almost completely absorbed from the gastrointestinal tract with 80-100% bioavailability

Distribution:

Volume of distribution is approximately 0.5-2 L/kg

Protein binding:

70-90% bound to plasma proteins (primarily transcortin and albumin)
Free (unbound) fraction is pharmacologically active
Protein binding decreases at higher doses, increasing free drug concentration

Peak plasma concentration:

Achieved within 1-2 hours after oral administration

Plasma half-life:

2-4 hours (biological half-life: 12-36 hours)
- Discrepancy between plasma and biological half-life explains prolonged therapeutic effect

Metabolism:

Primarily hepatic via:
- Reduction of the 4,5 double bond and the ketone group at C-20
- Hydroxylation at various positions (6β, 16α)
- Conjugation with glucuronic and sulfuric acids
- CYP3A4 involvement in oxidative metabolism
Enterohepatic recirculation: Occurs to a limited extent, prolonging effect

Excretion:

Primarily renal (65-75%) with some biliary excretion (15-20%)
- Metabolites excreted primarily as glucuronides and sulfates
- Small amount (~5%) excreted unchanged in urine
Bioequivalence: 5mg of prednisolone approximately equals 4mg methylprednisolone or 0.75mg dexamethasone

Prednisolone Pharmacokinetics

Prednisolone exerts potent anti-inflammatory and immunosuppressive effects through multiple genomic and non-genomic mechanisms, addressing various inflammatory pathways dysregulated in IBD.

Cellular mechanism:

Diffuses across cell membranes and binds to cytoplasmic glucocorticoid receptors (GR)
Forms activated GR complexes that translocate to the nucleus
Binds to glucocorticoid response elements (GREs) in promoter regions

Genomic effects (require hours to days):

Transactivation: Increases transcription of anti-inflammatory proteins
- Lipocortin-1 (inhibits phospholipase A2)
- IL-10 (anti-inflammatory cytokine)
- IκB (inhibitor of NF-κB)
Transrepression: Decreases transcription of pro-inflammatory genes
- Inhibits NF-κB (major pro-inflammatory transcription factor)
- Suppresses AP-1 activity
- Reduces STAT activation

Non-genomic effects (rapid onset, minutes to hours):

Direct physicochemical interactions with cellular membranes
Cytosolic GR-mediated release of Src kinase
Specific interactions with membrane-bound GR

Immune cell effects in IBD:

T-cells: Reduces T-cell activation and proliferation; induces apoptosis of activated T-cells
B-cells: Decreases antibody production
Neutrophils: Inhibits chemotaxis, adhesion, and degranulation
Macrophages: Reduces phagocytosis and cytokine production
Eosinophils: Decreases survival and activation
Mast cells: Inhibits degranulation

Mucosal effects specific to IBD:

Decreases intestinal permeability
Stabilizes mucosal barrier function
Reduces epithelial cell apoptosis
Modulates tight junction protein expression

Molecular targets in IBD:

Suppresses TNF-α, IL-1β, IL-6, IL-8, IL-12, IL-23, and IFN-γ production
Inhibits COX-2 expression and subsequent prostaglandin synthesis
Reduces leukotriene production via lipocortin-mediated phospholipase A2 inhibition
Decreases expression of adhesion molecules (ICAM-1, VCAM-1, E-selectin)

Prednisolone Pivotal Studies

Upadacitinib exhibits dose-proportional pharmacokinetics with rapid absorption, high bioavailability, moderate protein binding, metabolism primarily via CYP3A4, and a half-life of approximately 9-14 hours allowing for once-daily dosing.

Ulcerative Colitis studies:

Truelove and Witts (BMJ, 1955): First landmark trial demonstrating efficacy of oral cortisone in acute UC
Baron et al. (BMJ, 1962): Established dose-response relationship of prednisolone in active UC
Lennard-Jones et al. (Gut, 1960): Demonstrated superiority of prednisolone over placebo for inducing remission
Powell-Tuck et al. (Gastroenterology, 1978): Confirmed efficacy of prednisolone enemas in distal UC
D'Haens et al. (Gastroenterology, 2001): Compared prednisolone with infliximab for steroid-refractory UC
CONSTRUCT trial (Lancet, 2016): Compared cyclosporine vs. infliximab in steroid-resistant acute severe UC

Crohn's Disease studies:

NCCDS (Summers et al., NEJM, 1979): First major controlled trial showing prednisolone efficacy
European Cooperative Crohn's Disease Study (ECCDS): Confirmed prednisolone superiority over placebo (66% vs. 30% remission rates)
Malchow et al. (Gastroenterology, 1984): Established prednisolone as standard therapy
GETAID studies (1990s): Defined optimal tapering schedules and predictors of response
Munkholm et al. (Gut, 1994): Long-term cohort study showing limited duration of benefit
SONIC trial (Colombel et al., NEJM, 2010): Included prednisolone as comparator/background therapy

Meta-analyses and systematic reviews:

Ford et al. (Cochrane Database, 2011): NNT of 3 for induction of remission in CD
Steinhart et al. (Am J Gastroenterol, 2003): Pooled analysis showing 60-70% response rates
Benchimol et al. (Cochrane Database, 2008): Confirmed efficacy for induction but not maintenance
Khan et al. (Cochrane Database, 2011): Meta-analysis of corticosteroids in UC

Steroid-sparing strategies:

REACT trial (Khanna et al., Lancet, 2015): Early combined immunosuppression to reduce steroid use
CALM study (Colombel et al., Lancet, 2018): Tight control approach to minimize steroid exposure
PREVENT trial (Sandborn et al., NEJM, 2019): Vedolizumab for steroid-free remission

Predictors of response:

GETAID studies: Identified C-reactive protein, disease duration, and colonoscopic severity as predictors
PRECISE studies: Established steroid-dependency as predictor of anti-TNF response
REACT2 trial: Early biomarker response predicts outcome of steroid therapy

Prednisolone Adverse Effects

Prednisolone therapy is associated with numerous potential adverse effects affecting multiple organ systems, with risk increasing with dose and duration of treatment.

Endocrine and metabolic:

Hyperglycemia and insulin resistance (30-40% of patients)
Cushingoid features (moon face, buffalo hump, central obesity): 70-80% with prolonged use
Adrenal suppression: Can persist for 6-12 months after discontinuation
Growth suppression in children: Dose and duration dependent
Dyslipidemia: Increased total and LDL cholesterol, triglycerides
Menstrual irregularities and reduced fertility
Hypernatremia and hypokalemia due to mineralocorticoid effects

Musculoskeletal:

Osteoporosis: 30-50% of long-term users; 2-3% annual bone loss
Avascular necrosis of femoral head: 3-5% of patients
Myopathy: Proximal muscle weakness in 50-60% of chronic users
Tendon rupture: Increased risk, especially Achilles tendon
Growth retardation in pediatric IBD patients

Gastrointestinal:

Peptic ulcer disease: 2-5% increased risk (higher with concomitant NSAIDs)
Pancreatitis: Rare but reported in case series
Fatty liver and hepatomegaly
In Crohn's disease specifically: Increased risk of abscess formation (OR 2.4), fistulae (RR 1.6)

Cardiovascular:

Hypertension: 20% with short-term use, up to 70% with chronic therapy
Fluid retention and edema: Common with higher doses
Dyslipidemia leading to accelerated atherosclerosis
Increased risk of thromboembolism (RR 2.0-3.2)

Neuropsychiatric:

Mood disturbances: Euphoria (10%), depression (20%), anxiety (20%)
Insomnia: 50-70% of patients
Psychosis: 5-6% with high-dose therapy
Cognitive impairment: "Steroid fog" reported in 30-40% of patients
Seizures: Lowered threshold, especially with rapid dosing changes

Dermatologic:

Acne: 30% of patients
Striae: 30-50% with prolonged use
Thin, fragile skin and easy bruising: Up to 40-50%
Impaired wound healing
Hirsutism: 5-10% of patients

Ocular:

Posterior subcapsular cataracts: 15-25% with long-term use
Glaucoma: 5-10% increase in intraocular pressure
Central serous chorioretinopathy: Rare but significant

Immunologic:

Increased risk of infections: Overall RR 1.6-2.5
Reactivation of latent tuberculosis
Increased risk of opportunistic infections (e.g., Pneumocystis jirovecii)
Impaired vaccine response: Live vaccines contraindicated

IBD-specific concerns:

Steroid dependency: 20-36% of UC patients, 28-33% of CD patients
Steroid resistance: 16-20% of UC, 20-30% of CD patients
Increased risk of intestinal perforation during severe disease
Potential masking of developing complications (abscess in CD)

Withdrawal effects:

Acute adrenal insufficiency with rapid discontinuation
Pseudorheumatism syndrome: Myalgias, arthralgias, malaise
Rebound inflammation exacerbating IBD symptoms
Psychological dependency in some patients

Prednisolone Drug Interactions

Prednisolone participates in numerous clinically significant drug interactions through pharmacokinetic and pharmacodynamic mechanisms that require monitoring and dose adjustments.

Pharmacokinetic interactions affecting prednisolone levels:

CYP3A4 inducers decrease prednisolone levels (30-50% reduction):
- Rifampin, rifabutin
- Phenytoin, carbamazepine, phenobarbital
- St. John's wort
CYP3A4 inhibitors increase prednisolone levels (40-200% increase):
- Ketoconazole, itraconazole, voriconazole
- Clarithromycin, erythromycin
- Ritonavir, cobicistat
- Grapefruit juice

Pharmacokinetic interactions with prednisolone affecting other drugs:

Oral anticoagulants: Variable effects on INR, requiring monitoring
Calcineurin inhibitors: Increased levels of cyclosporine and tacrolimus
Oral contraceptives: May increase ethinylestradiol levels
Calcium channel blockers: May increase levels of nifedipine, verapamil

Pharmacodynamic interactions:

NSAIDs: 4-fold increased risk of GI bleeding when combined
Antidiabetic agents: Antagonism requiring dose adjustments (insulin, sulfonylureas)
Diuretics:
- Thiazides and loop diuretics: Enhanced potassium loss
- Potassium-sparing diuretics: Reduced efficacy
Antihypertensives: Reduced efficacy due to fluid retention
Vaccines:
- Live vaccines contraindicated (increased risk of vaccine virus replication)
- Reduced efficacy of killed vaccines
Neuromuscular blockers: Enhanced effect of both depolarizing and non-depolarizing agent

IBD-specific treatment interactions:
- 5-ASA compounds: Generally safe combination; potential for increased efficacy
- Thiopurines (azathioprine, 6-MP): Increased efficacy but also immunosuppression
- Methotrexate: Increased efficacy as steroid-sparing agent; increased immunosuppression
- Anti-TNF agents:
  - No significant pharmacokinetic interactions
  - Increased risk of opportunistic infections (3-4 fold)
  - Reduced anti-drug antibody formation with concomitant steroids
- Integrin inhibitors (vedolizumab): No significant interactions reported
- IL-12/23 inhibitors (ustekinumab): No significant interactions reported
- JAK inhibitors (tofacitinib): No significant interactions reported
- Antibiotics commonly used in IBD: No significant interactions
Herb-drug interactions:
- St. John's wort: Significant reduction in prednisolone levels
- Licorice: Potentiates mineralocorticoid effects
- Ginseng: May increase steroid effects
- Echinacea: Theoretical risk of reducing immunosuppressive effects

Prednisolone Use in Pregnancy

Prednisolone can be used during pregnancy when clinically indicated for active IBD, with careful consideration of risks and benefits.

Safety classification:
- FDA pregnancy category C (pre-2015 classification)
- Australian category A (safe for use in pregnancy)
- Compatible with pregnancy according to ECCO guidelines
- Preferred corticosteroid during pregnancy due to placental metabolism
Maternal risks:
- Increased risk of gestational diabetes (OR 1.4-2.5)
- Exacerbation of pregnancy-induced hypertension
- Higher incidence of premature rupture of membranes (RR 1.5-2.2)
- Increased susceptibility to infections
- Potential for adrenal insufficiency during labor if chronically used

Heading 2

Fetal/neonatal considerations:
- Placental transfer:
  - Prednisolone crosses placenta at approximately 10-15% of maternal concentrations
  - 11β-hydroxysteroid dehydrogenase type 2 in placenta converts prednisolone to inactive prednisone
  - Lower fetal exposure compared to dexamethasone or betamethasone
- First trimester use:
  - Small increased risk of orofacial clefts (OR 1.3-3.0)
  - No consistent evidence for other congenital malformations
- Second/third trimester concerns:
  - No evidence for intrauterine growth restriction at doses <20mg/day
  - Theoretical risk of fetal adrenal suppression with high doses
  - Potential small reduction in birth weight (average 200g)
Lactation:
- Enters breast milk at approximately 5-25% of maternal serum levels
- Peak milk concentration occurs 2-3 hours after dosing
- Considered compatible with breastfeeding by American Academy of Pediatrics
- For doses >40mg, consider waiting 4 hours after dosing before breastfeeding
- No reported adverse effects in breastfed infants

IBD-specific considerations during pregnancy:
- Active disease poses greater risk to pregnancy than prednisolone therapy
- PIANO registry data (Mahadevan et al.): No increase in adverse pregnancy outcomes with steroids
- ECCO position statement: Better to treat active disease than withhold therapy
- TREAT registry: No significant concerns with use in pregnant IBD patients
- PIANO and DUMBO prospective studies: No increased congenital abnormalities
Dosing considerations:
- Use lowest effective dose for shortest duration
- Prefer prednisone/prednisolone over dexamethasone/betamethasone
- Consider stress-dose steroids during labor if used chronically
- Avoid rectal formulations during late pregnancy if possible
- Taper gradually post-partum if used chronically
Monitoring recommendations:
- Enhanced glucose monitoring (oral glucose tolerance test at 24-28 weeks)
- More frequent ultrasonography if high-dose or prolonged use
- Monitor blood pressure closely
- Consider fetal growth assessment in third trimester
- Pediatric notification if used near delivery

Prednisolone General References

Pivotal Studies and Meta-analyses

Ford AC, Bernstein CN, Khan KJ, et al. Glucocorticosteroid therapy in inflammatory bowel disease: systematic review and meta-analysis. Am J Gastroenterol. 2011;106(4):590-599. doi:10.1038/ajg.2011.70
Summers RW, Switz DM, Sessions JT Jr, et al. National Cooperative Crohn's Disease Study: results of drug treatment. Gastroenterology. 1979;77(4 Pt 2):847-869.
Truelove SC, Witts LJ. Cortisone in ulcerative colitis; final report on a therapeutic trial. Br Med J. 1955;2(4947):1041-1048. doi:10.1136/bmj.2.4947.1041
Steinhart AH, Ewe K, Griffiths AM, Modigliani R, Thomsen OO. Corticosteroids for maintenance of remission in Crohn's disease. Cochrane Database Syst Rev. 2003;(4). doi:10.1002/14651858.CD000301
Khan KJ, Dubinsky MC, Ford AC, Ullman TA, Talley NJ, Moayyedi P. Efficacy of immunosuppressive therapy for inflammatory bowel disease: a systematic review and meta-analysis. Am J Gastroenterol. 2011;106(4):630-642. doi:10.1038/ajg.2011.64

Pharmacology and Mechanisms

Barnes PJ. Mechanisms and resistance in glucocorticoid control of inflammation. J Steroid Biochem Mol Biol. 2010;120(2-3):76-85. doi:10.1016/j.jsbmb.2010.02.018
Buttgereit F, Scheffold A. Rapid glucocorticoid effects on immune cells. Steroids. 2002;67(6):529-534. doi:10.1016/s0039-128x(01)00171-4
Dubois-Camacho K, Ottum PA, Franco-Muñoz D, et al. Glucocorticosteroid therapy in inflammatory bowel diseases: From clinical practice to molecular mechanisms. Front Immunol. 2017;8:1210. doi:10.3389/fimmu.2017.01210
Barnes PJ. Glucocorticosteroids: current and future directions. Br J Pharmacol. 2011;163(1):29-43. doi:10.1111/j.1476-5381.2010.01199.x

Adverse Effects and Safety

Waljee AK, Wiitala WL, Govani S, et al. Corticosteroid use and complications in a US inflammatory bowel disease cohort. PLoS One. 2016;11(6). doi:10.1371/journal.pone.0158017
Lichtenstein GR, Feagan BG, Cohen RD, et al. Serious infection and mortality in patients with Crohn's disease: more than 5 years of follow-up in the TREAT registry. Am J Gastroenterol. 2012;107(9):1409-1422. doi:10.1038/ajg.2012.218
van der Goes MC, Jacobs JW, Bijlsma JW. The value of glucocorticoid co-therapy in different rheumatic diseases--positive and adverse effects. Arthritis Res Ther. 2014;16(Suppl 2). doi:10.1186/ar4686
Hoes JN, Jacobs JW, Boers M, et al. EULAR evidence-based recommendations on the management of systemic glucocorticoid therapy in rheumatic diseases. Ann Rheum Dis. 2007;66(12):1560-1567. doi:10.1136/ard.2007.072157
Buckley L, Guyatt G, Fink HA, et al. 2017 American College of Rheumatology Guideline for the Prevention and Treatment of Glucocorticoid-Induced Osteoporosis. Arthritis Rheumatol. 2017;69(8):1521-1537. doi:10.1002/art.40137