Lupkynis (Voclosporin)
voclosporin
Indications
| Indication | Approved Population | Therapy Type | Status |
|---|---|---|---|
| Active lupus nephritis | Adults (≥18 years) | Combination with MMF + corticosteroids | FDA Approved |
Voclosporin is the first oral therapy approved specifically for lupus nephritis in the United States (January 22, 2021). It is a second-generation calcineurin inhibitor with a dual mechanism: immunosuppression through calcineurin inhibition and direct podocyte stabilisation. The 2024 ACR lupus nephritis guideline and 2023 EULAR recommendations both support voclosporin as an add-on option for proliferative lupus nephritis alongside MMF and low-dose glucocorticoids. Safety and efficacy have not been established in combination with cyclophosphamide, and this combination is not recommended.
Non-lupus glomerulonephritis (e.g., FSGS, membranous nephropathy): Preclinical rationale exists based on podocyte-stabilising properties; no clinical trials in these populations. Evidence quality: Very low.
Renal transplant rejection prophylaxis: Early-phase studies were conducted in this population but voclosporin was not pursued for transplant indications. Evidence quality: Low.
Voclosporin Dosing
Standard Adult Dosing
| Clinical Scenario | Starting Dose | Maintenance Dose | Maximum Dose | Notes |
|---|---|---|---|---|
| Active lupus nephritis — standard regimen | 23.7 mg (3 capsules) PO BID | 23.7 mg PO BID (adjust per eGFR) | 23.7 mg BID | Take fasted, 12 h apart (min 8 h); swallow whole Use with MMF 2 g/day + corticosteroid taper |
| Mild-moderate hepatic impairment (Child-Pugh A or B) | 15.8 mg (2 capsules) PO BID | 15.8 mg PO BID | 15.8 mg BID | Dose reduction required Severe hepatic impairment (Child-Pugh C): avoid use |
| Severe renal impairment at baseline (eGFR ≤45 used only if benefit > risk) | 15.8 mg (2 capsules) PO BID | 15.8 mg PO BID | 15.8 mg BID | Not recommended if baseline eGFR ≤45 unless benefit exceeds risk Not studied in this population |
| With moderate CYP3A4 inhibitor (verapamil, fluconazole, diltiazem) | 15.8 mg AM / 7.9 mg PM | 15.8 mg AM / 7.9 mg PM | 15.8 mg AM / 7.9 mg PM | Asymmetric dosing due to CYP3A4 interaction Strong CYP3A4 inhibitors are CONTRAINDICATED |
eGFR-Based Dose Adjustments
| eGFR Change from Baseline | Action | Follow-Up | Re-escalation | Notes |
|---|---|---|---|---|
| eGFR <60 AND reduced >20% but <30% | Reduce by 7.9 mg BID | Reassess eGFR in 2 weeks | Increase by 7.9 mg BID when eGFR ≥80% of baseline; do not exceed starting dose | If still >20% reduced at 2 wk, reduce again by 7.9 mg BID |
| eGFR <60 AND reduced ≥30% | Discontinue | Reassess eGFR in 2 weeks | Consider restarting at 7.9 mg BID only if eGFR returns to ≥80% of baseline | 71% of GFR decreases occurred within first 3 months |
| BP >165/105 mmHg or hypertensive emergency | Discontinue | Initiate antihypertensive therapy | Reassess after BP controlled | Do not initiate voclosporin if baseline BP >165/105 |
Each capsule is 7.9 mg, so the standard dose is 3 capsules twice daily. Capsules must be swallowed whole on an empty stomach. Avoid grapefruit and grapefruit juice throughout treatment (CYP3A4 inhibition). If a dose is missed, take it within 4 hours; beyond 4 hours, skip to the next scheduled dose. If no therapeutic benefit is observed by 24 weeks, consider discontinuation. Unlike traditional calcineurin inhibitors in transplant, routine therapeutic drug monitoring is not required for voclosporin in lupus nephritis — dose adjustments are eGFR-driven rather than trough-concentration-driven.
Pharmacology
Mechanism of Action
Voclosporin is a next-generation calcineurin inhibitor derived from cyclosporine A through chemical modification at the amino acid-1 position. Like cyclosporine, it forms a complex with cyclophilin A that binds to and inhibits calcineurin, a calcium- and calmodulin-dependent phosphatase. This prevents dephosphorylation of NFAT (Nuclear Factor of Activated T-Cells), blocking T-cell activation, proliferation, and pro-inflammatory cytokine production. However, voclosporin exhibits approximately 3–4-fold greater potency for calcineurin inhibition compared to cyclosporine, with more predictable pharmacokinetics and improved metabolic stability. Crucially for lupus nephritis, voclosporin also directly stabilises podocyte actin cytoskeleton and stress fibres, providing a non-immunological renal-protective effect that complements its immunosuppressive action. This dual mechanism — immunosuppression plus podocyte stabilisation — distinguishes voclosporin from traditional calcineurin inhibitors in the lupus nephritis setting.
ADME Profile
| Parameter | Value | Clinical Implication |
|---|---|---|
| Absorption | Oral; median Tmax 1.5 h (range 1–4 h) fasted; bioavailability estimated ~57% (comparable to conventional cyclosporine); food significantly reduces Cmax and AUC | Must be taken on empty stomach consistently; no loading dose needed; linear PK over therapeutic range supports fixed dosing without routine TDM |
| Distribution | Vss/F = 2,154 L; protein binding 97%; partitions extensively into red blood cells (concentration- and temperature-dependent) | Very large apparent Vd reflects extensive tissue distribution; RBC partitioning means whole-blood concentrations differ significantly from plasma levels |
| Metabolism | Predominantly CYP3A4 (sensitive substrate); major metabolite (IM9) = 16.7% of total exposure, ~8-fold less potent than parent; pharmacologic activity mainly attributed to parent molecule | Strong CYP3A4 inhibitors contraindicated; moderate inhibitors require dose reduction. Improved metabolic profile vs cyclosporine — single dominant metabolite with low activity reduces metabolite-driven toxicity |
| Elimination | Effect-indicative t½ ~7 h; steady state in 6 days with ~2-fold accumulation; 92.7% recovered in faeces (5% unchanged), 2.1% in urine | 12-hourly dosing maintains therapeutic exposure; predominantly faecal elimination means renal impairment has modest effect on PK (1.5–1.7-fold increase in severe RI) |
Side Effects
| Adverse Effect | Incidence | Clinical Note |
|---|---|---|
| GFR decreased | 26% (vs 9% placebo) | Most common AE; 71% occurred within first 3 months; 78% resolved/improved with dose modification; 14% led to permanent discontinuation |
| Hypertension | 19% (vs 9% placebo) | CNI class effect; monitor BP q2wk for first month then as indicated; may require antihypertensive therapy |
| Diarrhea | 19% (vs 13% placebo) | Evaluate for concurrent MMF contribution; manageable with supportive care |
| Headache | 15% (vs 8% placebo) | Part of neurotoxicity spectrum; distinguish from PRES if severe or accompanied by visual changes |
| Anemia | 12% (vs 6% placebo) | Multifactorial in LN population; monitor CBC; consider PRCA in refractory cases |
| Cough | 11% (vs 2% placebo) | Notable excess over placebo; evaluate for infection |
| Urinary tract infection | 10% (vs 6% placebo) | Immunosuppression-related; treat promptly |
| Adverse Effect | Incidence | Clinical Note |
|---|---|---|
| Upper abdominal pain | 7% (vs 2%) | Evaluate for GI pathology; consider MMF contribution |
| Dyspepsia | 6% (vs 3%) | Take on empty stomach as directed |
| Alopecia | 6% (vs 3%) | Distinguish from lupus-related hair loss |
| Renal impairment | 6% (vs 3%) | Part of nephrotoxicity spectrum; eGFR-guided dose adjustment critical |
| Abdominal pain | 5% (vs 2%) | Assess for pancreatitis if severe |
| Mouth ulceration | 4% (vs 1%) | May overlap with MMF-associated stomatitis |
| Fatigue | 4% (vs 1%) | Assess for anaemia and disease activity contribution |
| Tremor | 3% (vs 1%) | CNI neurotoxicity; dose-related; consider reduction |
| Acute kidney injury | 3% (vs 1%) | Differentiate from LN flare; consider nephrotoxicity workup |
| Decreased appetite | 3% (vs 1%) | Monitor nutritional status |
| Adverse Effect | Estimated Frequency | Typical Onset | Required Action |
|---|---|---|---|
| Serious infections (pneumonia, gastroenteritis, UTI) | 11.9 per 100 PY (vs 12.0 placebo) | Any time | Boxed warning; monitor closely; consider interruption for new serious infections |
| Nephrotoxicity (acute and/or chronic) | 37.1 per 100 PY (GFR decreased; vs 11.3 placebo) | 71% within first 3 months | Follow eGFR-based dose algorithm; discontinue if ≥30% decrease from baseline with eGFR <60; persistent decrease warrants chronic CNI nephrotoxicity evaluation |
| Serious hypertension | 2.1 per 100 PY (vs 0.4 placebo) | Any time; monitor closely in first month | Discontinue if BP >165/105 or hypertensive emergency; initiate antihypertensive therapy |
| Serious neurotoxicity (PRES, seizure, delirium) | 3.9 per 100 PY (vs 0.9 placebo) | Variable | Monitor for neurological symptoms; reduce dose or discontinue if neurotoxicity occurs; MRI if PRES suspected |
| Malignancy (lymphoma, skin cancer) | 1.7 per 100 PY (vs 0 placebo) | Risk increases with duration | Boxed warning; examine skin regularly; advise sun protection (SPF ≥30); consider risk-benefit of continuation |
| Hyperkalemia | 2.1 per 100 PY (vs 0.8 placebo) | Any time; higher risk with ACEi/ARBs/K-sparing diuretics | Monitor serum potassium periodically; avoid or closely monitor concomitant agents that raise potassium |
| QTc prolongation | 0.9 per 100 PY | Dose-dependent | Monitor ECG and electrolytes in high-risk patients; avoid concomitant QT-prolonging drugs |
| Opportunistic infections (CMV, disseminated HZ) | 1.3 per 100 PY (vs 0.9 placebo) | Any time | Screen for and treat promptly; consider prophylaxis in high-risk patients |
GFR decrease is the most common adverse reaction (26% vs 9% placebo) and the most critical to manage. Most episodes occur early (71% within the first 3 months), are hemodynamic in nature, and respond to protocol-guided dose reduction. The key is adherence to the eGFR monitoring schedule: every 2 weeks for the first month, every 4 weeks through year 1, and quarterly thereafter. Prompt dose reduction for >20% eGFR decline prevents progression to chronic CNI nephrotoxicity. Persistent eGFR decline despite dose adjustment should prompt histological evaluation to distinguish CNI nephrotoxicity from LN progression.
Drug Interactions
Voclosporin is a sensitive CYP3A4 substrate, a weak P-gp inhibitor, and an inhibitor of OATP1B1/1B3 transporters. These properties create clinically significant interactions that require close attention. Unlike traditional CNIs in transplant settings, voclosporin in lupus nephritis does not use routine therapeutic drug monitoring — instead, interaction management relies on dose adjustments and avoidance.
Monitoring
- eGFRBaseline, q2wk ×1 mo, q4wk ×1 yr, then quarterly
RoutineMost critical parameter. Establish accurate baseline before starting. Dose-adjust per eGFR algorithm. GFR decreased in 26% of patients vs 9% placebo. Most reversible with early intervention. - Blood pressureBaseline, q2wk ×1 mo, then as indicated
RoutineHypertension in 19% vs 9% placebo. Do not initiate if BP >165/105. Discontinue if hypertensive emergency. Note: diltiazem/verapamil used as antihypertensives also require voclosporin dose reduction. - Serum potassiumBaseline, periodically during treatment
RoutineHyperkalemia (2.1 per 100 PY vs 0.8 placebo). Higher risk with ACE inhibitors, ARBs, potassium-sparing diuretics. - LN disease activityEvery 3–6 months
RoutineMonitor UPCR, serum albumin, complement, anti-dsDNA. Target UPCR ≤0.5 mg/mg. If no therapeutic benefit by 24 weeks, consider discontinuation. - Infection surveillanceEvery visit
RoutineInfections reported in 135.2 per 100 PY (vs 107.4 placebo). Screen for URI, UTI, herpes zoster, opportunistic infections (CMV). Boxed warning for serious infections. - Skin examinationAt initiation, then annually
RoutineBoxed warning for malignancy. CNI use increases risk of skin cancers and lymphoma. Advise sun avoidance, protective clothing, broad-spectrum SPF ≥30. - Neurological statusIf symptoms arise
Trigger-basedNeurotoxicity (including PRES, seizure, tremor) reported at 38.9 per 100 PY vs 21.6 placebo. Evaluate new headache, visual changes, confusion, or tremor promptly. - ECGAt baseline in high-risk patients
Trigger-basedQTc prolongation is dose-dependent. Monitor in patients with bradycardia, hypokalemia/hypomagnesemia, congenital long QT, or on other QT-prolonging medications.
Contraindications & Cautions
Absolute Contraindications
- Concomitant use of strong CYP3A4 inhibitors (ketoconazole, itraconazole, clarithromycin): Significantly increases voclosporin exposure, raising the risk of acute and chronic nephrotoxicity.
- History of serious or severe hypersensitivity reaction (including anaphylaxis) to voclosporin or any excipients.
Relative Contraindications (Specialist Input Recommended)
- Baseline eGFR ≤45 mL/min/1.73 m²: Not recommended unless benefit exceeds risk; not studied in this population. If used, start at 15.8 mg BID.
- Baseline BP >165/105 mmHg or hypertensive emergency: Do not initiate voclosporin until BP is controlled.
- Severe hepatic impairment (Child-Pugh C): Use is not recommended.
- Concomitant cyclophosphamide: Safety and efficacy not established with this combination.
Use with Caution
- Pregnancy: Avoid use. The formulation contains dehydrated ethanol (21.6 mg per capsule, 129.4 mg total daily dose). Embryotoxic and fetocidal in animal studies at 15x MRHD. MMF co-administration also carries independent fetal harm risk.
- Known malignancy risk factors: CNIs increase the risk of lymphoma and skin cancers (boxed warning). Use the lowest effective dose for the shortest duration needed.
- Risk of hyperkalemia: Use caution with potassium-sparing diuretics, ACE inhibitors, and ARBs.
- Geriatric patients: No adequate data; use with caution.
Increased risk for developing malignancies and serious infections with voclosporin or other immunosuppressants that may lead to hospitalisation or death. Lymphomas and other malignancies, particularly of the skin, may occur. The risk appears to be related to the intensity and duration of immunosuppression rather than to any specific agent. Serious infections, including bacterial, viral, fungal, and protozoal infections (including opportunistic infections), have been reported and may be fatal.
Patient Counselling
Purpose of Therapy
Voclosporin is a capsule taken twice daily to treat active lupus nephritis (kidney inflammation caused by lupus). It works by calming the overactive immune system and directly protecting the kidney’s filtering cells. It is always used together with mycophenolate and low-dose steroids. The goal is to reduce protein in the urine, protect kidney function, and prevent kidney damage. Clinical trials showed that patients receiving voclosporin were nearly twice as likely to achieve a complete renal response compared to standard therapy alone.
How to Take
Take 3 capsules (23.7 mg) twice daily, approximately 12 hours apart, on an empty stomach. Swallow capsules whole — do not open, crush, or chew them. Avoid grapefruit and grapefruit juice entirely while on treatment. If you miss a dose and it has been less than 4 hours, take it right away. If more than 4 hours have passed, skip to your next scheduled dose — never double up.
Sources
- Aurinia Pharma U.S., Inc. LUPKYNIS (voclosporin) prescribing information. Revised October 2025. FDA LabelPrimary source for all dosing, safety, eGFR adjustment algorithms, pharmacokinetic, and clinical trial data in this monograph.
- Rovin BH, Teng YKO, Ginzler EM, et al. Efficacy and safety of voclosporin versus placebo for lupus nephritis (AURORA 1): a double-blind, randomised, multicentre, placebo-controlled, phase 3 trial. Lancet. 2021;397(10289):2070-2080. doi:10.1016/S0140-6736(21)00578-XPivotal Phase 3 trial: CRR at 52 weeks 40.8% vs 22.5% placebo (OR 2.7; P<0.001) with background MMF + low-dose steroids.
- Saxena A, Ginzler EM, Gibson K, et al. Safety and efficacy of long-term voclosporin treatment for lupus nephritis in the phase 3 AURORA 2 clinical trial. Arthritis Rheumatol. 2024;76(1):59-67. doi:10.1002/art.426573-year extension data showing sustained efficacy and consistent long-term safety; 20.1% sustained CRR with voclosporin vs 11.8% placebo.
- Rovin BH, Solomons N, Engela L, et al. A randomized, controlled double-blind study comparing the efficacy and safety of dose-ranging voclosporin with placebo in achieving remission in patients with active lupus nephritis (AURA-LV). Kidney Int. 2019;95(1):219-231. doi:10.1016/j.kint.2018.08.025Phase 2 trial establishing dose selection (23.7 mg BID); CRR at 24 weeks significantly higher with low-dose voclosporin.
- Fanouriakis A, Kostopoulou M, Andersen J, et al. EULAR recommendations for the management of systemic lupus erythematosus: 2023 update. Ann Rheum Dis. 2024;83(1):15-29. doi:10.1136/ard-2023-224762EULAR guideline supporting voclosporin or belimumab as add-on to MMF for active proliferative lupus nephritis.
- Sammaritano LR, Askanase A, Bermas BL, et al. 2024 American College of Rheumatology (ACR) guideline for the screening, treatment, and management of lupus nephritis. Arthritis Rheumatol. 2025;77(9):1115-1135. doi:10.1002/art.432122024 ACR lupus nephritis guideline recommending triple therapy (MMF + voclosporin or belimumab + steroids) for proliferative LN.
- Rovin BH, Ayoub IM, Chan TM, et al. KDIGO 2024 clinical practice guideline for the management of lupus nephritis. Kidney Int. 2024;105(1 Suppl):S1-S69. doi:10.1016/j.kint.2023.09.002KDIGO guideline endorsing voclosporin-containing triple therapy for Class III/IV LN alongside MMF and glucocorticoids.
- Kuglstatter A, Mueller F, Kusber R, et al. Structural basis for the cyclophilin A binding affinity and immunosuppressive potency of E-ISA247 (voclosporin). Acta Crystallogr D Biol Crystallogr. 2011;67(Pt 2):119-123. doi:10.1107/S0907444910051905X-ray crystallography revealing how the amino acid-1 modification in voclosporin enhances cyclophilin A binding and calcineurin inhibition.
- Faul C, Donnelly M, Merscher-Gomez S, et al. The actin cytoskeleton of kidney podocytes is a direct target of the antiproteinuric effect of cyclosporine A. Nat Med. 2008;14(9):931-938. doi:10.1038/nm.1857Foundational study demonstrating that calcineurin inhibitors protect podocyte cytoskeleton independent of immunosuppression, supporting voclosporin’s dual mechanism.
- Huizinga RB, Yahya R, Engel S, et al. Population pharmacokinetics of voclosporin in patients with lupus nephritis. Clin Pharmacokinet. 2022;61(12):1737-1751. doi:10.1007/s40262-022-01179-2Population PK analysis confirming predictable voclosporin pharmacokinetics in LN with no clinically meaningful effect of age, sex, race, or body weight.
- Ling SY, Huizinga RB, Mayo PR, et al. Clinical pharmacokinetics and pharmacodynamics of voclosporin. Clin Pharmacokinet. 2023;62(5):633-654. doi:10.1007/s40262-023-01246-2Comprehensive PK/PD review: effect-indicative t½ ~7 h, 97% protein binding, Vss/F 2,154 L, CYP3A4 sensitivity, and exposure-response relationships.