Pharmacokinetics of voclosporin in renal impairment and hepatic impairment

Abstract

Voclosporin is a novel calcineurin inhibitor intended for prevention of organ graft rejection and treatment of lupus nephritis. These studies evaluated the effect of renal or hepatic impairment on pharmacokinetics of voclosporin. Thirty-three subjects were enrolled into 1 of 4 groups based on renal function as defined by creatinine clearance and 18 subjects were enrolled into 1 of 3 groups based on hepatic function defined by Child-Pugh classes. Voclosporin 0.4 mg/kg was administered orally. Geometric mean ratios (renal/hepatic impairment-to-normal) and 90% confidence intervals for Cmax and AUC were calculated. A default no-effect interval of 80-125% was set. Although 90% confidence intervals exceeded the no-effect intervals for both parameters, individual Cmax and AUC plots indicate almost complete overlapping range of values for mild and moderate renal impairment and normal subjects. Severe renal impairment resulted in a 1.5-fold increase in AUC without an increase in Cmax . Mild to moderate hepatic impairment resulted in a 1.5- to 2-fold increase in voclosporin exposure. Voclosporin can be administered safely to patients with mild to moderate renal impairment without dose modification. Appropriate safety monitoring with concentration-based adjustments in transplantation are recommended for patients with severe renal impairment, and for patients with hepatic impairment.

<p>Pharmacokinetic Disposition Difference Between Cyclosporine and Voclosporin Drives Their Distinct Efficacy and Safety Profiles in Clinical Studies</p>

“…The PK data of voclosporin included the single ascending doses from 0.25 to 4.5 mg/kg, 10 multiple doses of 0.4 mg/kg in an organ impairment study and a control cohort in a drug–drug interaction study. 11 , 12 The PK data for cyclosporine included PK studies of single doses of cyclosporine in healthy Caucasians (350, 700 and 1400 mg) 9 and drug–drug interaction studies with cyclosporine dosed at 300 and 400 mg. 12 , 13…”

Next-generation calcineurin inhibitors in development for the prevention of organ rejection

“…50 Similarly, other data indicate that 40% CN inhibition is achieved with VCS at an AUC of 226 ng × hour/mL, but with a 15% rise in serum creatinine occurs only at a VCS AUC of 3448 ng × hour/mL. 22,50 Ling et al 22 concluded that mild to moderate hepatic impairment resulted in a 1.5-to 2-fold increase in VCS exposure. VCS can be administered safely to patients with mild to moderate renal impairment without dose modification.…”

“…VCS is a novel CNI intended for the prevention of organ graft rejection and treatment of lupus nephritis. 22 It has a strong immunosuppressant effect by reversible inhibition of T-lymphocyte proliferation and release of cytokines through blocking the cytoplasmic calcium dependent phosphatase. 15 Inside lymphocytes, voclosporin binds to immunophilins forming complexes that inhibit CN.…”

Voclosporin: First Approval

“…There were no clinically relevant effect of age, bodyweight, gender, race, serum albumin, total bilirubin and eGFR on the pharmacokinetics of voclosporin [4,13]. Voclosporin C max and AUC in patients with mild [creatinine clearance (CL cr ) 60-89 mL/min as estimated by Cockcroft-Gault] and moderate (CL cr 30-59 mL/min) renal impairment were similar to those in subjects with normal renal function (CL cr ≥ 90 mL/min) [4,14]. In patients with severe (CL cr < 30 mL/min) renal impairment, voclosporin C max and AUC increased by 1.5-and 1.7-fold, respectively.…”