Cytochrome P450 3A and P-glycoprotein drug-drug interactions with voclosporin.

AIMS: Voclosporin is a novel calcineurin inhibitor intended for prevention of organ graft rejection and treatment of lupus nephritis. Pharmacokinetic drug interactions between voclosporin and a CYP3A inhibitor, inducer and substrate and a P-glycoprotein inhibitor and substrate were evaluated. METHODS: Voclosporin 0.4 mg kg(-1) was administered to 24 subjects in each of five studies, as follows: every 12 h (Q12H) alone and concomitantly with ketoconazole 400 mg once daily (QD); single dose before and single dose after rifampin 600 mg QD; Q12H where midazolam 7.5 mg was administered as a single dose alone before voclosporin and with last the dose of voclosporin; Q12H alone and concomitantly with verapamil 80 mg every 8 h; and Q12H with digoxin 0.25 mg QD. The noncompartmental pharmacokinetic parameters maximal concentration (Cmax ) and area under the concentration-time curve (AUC) were obtained, and geometric least squares mean ratios and 90% confidence intervals were evaluated. RESULTS: Ketoconazole increased voclosporin Cmax (6.4-fold) and AUC (18-fold); rifampin reduced voclosporin AUC (0.9-fold); voclosporin did not change exposure of midazolam or α-hydroxy-midazolam; verapamil increased voclosporin Cmax (2.1-fold) and AUC (2.7-fold); and voclosporin increased digoxin Cmax (0.5-fold), AUC (0.25-fold) and urinary excretion (0.2-fold). CONCLUSIONS: Administration of voclosporin concomitantly with strong inhibitors and inducers of CYP3A resulted in increased and decreased exposures, respectively, and should be considered contraindicated. Drug-drug interactions involving voclosporin and CYP3A substrates are not expected. Administration of voclosporin concomitantly with inhibitors and substrates of P-glycoprotein resulted in increased voclosporin and substrate exposures, respectively. Appropriate concentration and safety monitoring is recommended with co-administration of voclosporin and P-glycoprotein substrates and inhibitors.

Voclosporin food effect and single oral ascending dose pharmacokinetic and pharmacodynamic studies in healthy human subjects.

Voclosporin (VCS) is a novel calcineurin (CN) inhibitor intended for prevention of organ graft rejection and treatment of lupus nephritis. These studies evaluated the single ascending dose pharmacokinetics (PK) and pharmacodynamics (PD, CN activity) of VCS and the effect of food. VCS was administered orally in single doses of 0.25 through 4.5 mg/kg in 62 subjects in the single ascending dose study and as a single oral 1.5 mg/kg dose to 18 subjects after fasting, consumption of a low-fat and high-fat meal. Non-compartmental PK, PD, and PKPD correlation were evaluated. Following single oral doses, systemic exposure increased in a linear manner and demonstrated 1:1 dose-proportional, first-order linear PK above 1.5 mg/kg. VCS inhibited CN activity in a dose-related fashion with maximal inhibition peaking at 3.0 mg/kg. PKPD correlation indicated an EC50 of 78.3 ± 6.8 ng/mL. Administration of VCS with a low-fat and high-fat meal decreased C(max) by 29% and 53%, respectively, and AUC(inf) by 15% and 25%, respectively. Following ascending single doses of VCS, exposure increased in a linear fashion. A food effect on exposure was demonstrated, with a more pronounced effect following a high-fat meal. VCS concentrations were also found to correlate with CN activity.

ISA247: quality of life results from a phase II, randomized, placebo-controlled study.

BACKGROUND: Psoriasis is a chronic skin condition that can negatively affect a patient's quality of life (QoL), often hindering social functioning. ISA247, a novel psoriatic agent, has shown clinical efficacy in moderate to severe psoriasis sufferers, but its effect on QoL is currently not reported. OBJECTIVE: The objective of this study was to assess the effect of ISA247 on the QoL in patients with stable, plaque-type psoriasis. METHODS: A phase II, randomized, double-blind, placebo-controlled, parallel-group, multicenter study assessed the effects of ISA247 doses of 0.5 mg/kg/d (n = 77) or 1.5 mg/kg/d (n = 83) compared with placebo (n = 41) for 12 weeks. QoL was assessed using the Dermatology Life Quality Index (DLQI) and Psoriasis Disability Index (PDI) scales. RESULTS: ISA247 treatment (pooled groups) significantly improved QoL scores as assessed by both the DLQI and the PDI compared with those receiving placebo (p < .05). Treatment with the higher dose of 1.5 mg/kg/d demonstrated a significantly greater response to many of the QoL scales compared with the 0.5 mg/kg/d group (p < .05). CONCLUSIONS: ISA247 appears to improve the QoL while also providing effective treatment for chronic, moderate to severe, plaque-type psoriasis.

A new agent for the treatment of noninfectious uveitis: rationale and design of three LUMINATE (Lux Uveitis Multicenter Investigation of a New Approach to Treatment) trials of steroid-sparing voclosporin.

Uveitis is an inflammatory, putative Th1-mediated autoimmune disease that affects various parts of the eye and is a leading cause of visual loss. Currently available therapies are burdened with toxicities and/or lack definitive evidence of efficacy. Voclosporin, a rationally designed novel calcineurin inhibitor, exhibits a favorable safety profile, a strong correlation between pharmacokinetic and pharmacodynamic response, and a wide therapeutic window. The LUMINATE (Lux Uveitis Multicenter Investigation of a New Approach to TrEatment) clinical development program was initiated in 2007 to assess the safety and efficacy of voclosporin for the treatment, maintenance, and control of all forms of noninfectious uveitis. If LUMINATE is successful, voclosporin will become the first Food and Drug Administration-approved corticosteroid-sparing agent for this condition.