Development and validation of a LC/MS/MS method for quantifying the next generation calcineurin inhibitor, voclosporin, in human whole blood

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.

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“…Whole blood VCS concentrations were measured using a validated LC/MS/MS method . The limit of quantitation (LOQ) for VCS was 1 ng/mL.…”

Section: Methodsmentioning

confidence: 99%

Voclosporin Food Effect and Single Oral Ascending Dose Pharmacokinetic and Pharmacodynamic Studies in Healthy Human Subjects

Mayo¹,

Huizinga²,

Ling³

et al. 2013

The Journal of Clinical Pharmacology

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“…Twenty-four subjects were given voclosporin 0.4 mg kg −1 orally Q12H for 20 consecutive days (days [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20]. Subjects were to be given oral ketoconazole 400 mg once daily (QD) for 10 consecutive days (days [11][12][13][14][15][16][17][18][19][20] …”

Section: Ketoconazole Studymentioning

confidence: 99%

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

Ling¹,

Huizinga²,

Mayo³

et al. 2014

Br J Clin Pharmacol

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AIMSVoclosporin 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. METHODSVoclosporin 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. RESULTSKetoconazole 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). CONCLUSIONSAdministration 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. WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Calcineurin inhibitors are the gold standard for immunosuppression in transplantation.• Drug-drug interactions with cytochrome P450 inducers, inhibitors and substrates and with P-glycoprotein inhibitors and substrates in these drugs with narrow therapeutic windows may impact both safety and efficacy.• Knowledge of patient and drug factors that influence drug disposition enhances the optimal dosing and successful therapy with the drug. WHAT THIS STUDY ADDS• These results provide a rationale for avoiding the co-administration of voclosporin with strong CYP3A inhibitors and CYP3A inducers.• These results suggest that co-administration of voclosporin with substrates of CYP3A would not result in increased exposure to the substrate.• These results provide a rationale for conducting appropriate concentration and safety monitoring when voclosporin is co-administered with P-glycoprotein substrates and inhibitors.

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“…Whole blood concentrations of voclosporin were measured using a validated LC/MS/MS method by Isotechnika Pharma, Inc., Edmonton, Alberta, Canada. 8 Briefly, sample aliquots of 100 mL were processed utilizing a protein precipitation procedure that contained a mixture of methanol, ZnSO 4 , and deuterated voclosporin as internal standard. The supernatant was injected onto a Zorbax SB-C8, 2.1 mm Â 12.5 mm column (at 60°C), and washed with water-acetonitrile, to remove poorly retained components.…”

Section: Sample Analysismentioning

confidence: 99%

Pharmacokinetics of voclosporin in renal impairment and hepatic impairment

Ling¹,

Huizinga²,

Mayo³

et al. 2013

The Journal of Clinical Pharmacology

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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.

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Development and validation of a LC/MS/MS method for quantifying the next generation calcineurin inhibitor, voclosporin, in human whole blood

Cited by 13 publications

References 10 publications

Voclosporin Food Effect and Single Oral Ascending Dose Pharmacokinetic and Pharmacodynamic Studies in Healthy Human Subjects

Voclosporin Food Effect and Single Oral Ascending Dose Pharmacokinetic and Pharmacodynamic Studies in Healthy Human Subjects

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

Pharmacokinetics of voclosporin in renal impairment and hepatic impairment

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