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Robert T. Foster - One of the best experts on this subject based on the ideXlab platform.
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cytochrome p450 3a and p glycoprotein drug drug interactions with Voclosporin
British Journal of Clinical Pharmacology, 2014Co-Authors: Spencer Ling, Robert B. Huizinga, Patrick R. Mayo, Richard Larouche, Derrick G. Freitag, Launa J. Aspeslet, Robert T. FosterAbstract: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.
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Cytochrome P450 3A and P‐glycoprotein drug–drug interactions with Voclosporin
British journal of clinical pharmacology, 2014Co-Authors: Spencer Ling, Robert B. Huizinga, Patrick R. Mayo, Richard Larouche, Derrick G. Freitag, Launa J. Aspeslet, Robert T. FosterAbstract: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.
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Population PKPD of Voclosporin in renal allograft patients
Journal of clinical pharmacology, 2013Co-Authors: Patrick R. Mayo, Spencer Ling, Robert B. Huizinga, Derrick G. Freitag, Launa J. Aspeslet, Robert T. FosterAbstract:The aims of this population-pharmacokinetic/pharmacodynamic (POP-PKPD) analysis of Voclosporin in renal allograft patients were to build a POP-PKPD model for Voclosporin and calcineurin activity (CNa) and identify clinically relevant covariates that could assist dosing of the drug. POP-PKPD modeling was performed using a stochastic approximation of the standard expectation maximization (SAEM) algorithm for nonlinear mixed-effects as implemented in Monolix™ 3.2. Voclosporin whole blood concentrations were obtained from de novo renal allograft patients and assayed using a validated LC/MS/MS assay. CNa was measured using a (32)P-radiolabeled assay. A two-compartment model with simultaneous sigmoid inhibitory Emax model was used to describe the PKPD relationship between Voclosporin concentration and CNa. The POP-PKPD model was then utilized to simulate an optimal initial dosing strategy. Eighty-seven patients were included in the POP-PKPD study. Population mean estimates (relative standard error, rse) for oral clearance (CL/F) and first compartment volume of distribution (V1), were 717 mL min(-1) (35%) and 2010 mL (17%), respectively. Maximum CNa Inhibition (Imax), effective concentration (C50), and baseline immunosuppression (S0) were 0.87 pmol/min/mg (8.0%), 123 ng/mL (10%), and 1.15 pmol/min/mg (4.0%), respectively. Covariate analyses demonstrated that age and body surface area significantly influenced CL/F: CLi=717(Agei/48.8)-0.57(BSAi/1.99)1.1, while serum triglycerides significantly altered S0: S0i=1.15(TRIGi/1.97)0.15.
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Pharmacokinetics of Voclosporin in renal impairment and hepatic impairment
Journal of clinical pharmacology, 2013Co-Authors: Spencer Ling, Robert B. Huizinga, Patrick R. Mayo, Derrick G. Freitag, Launa J. Aspeslet, Robert T. FosterAbstract: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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Voclosporin Food Effect and Single Oral Ascending Dose Pharmacokinetic and Pharmacodynamic Studies in Healthy Human Subjects
Journal of clinical pharmacology, 2013Co-Authors: Patrick R. Mayo, Spencer Ling, Robert B. Huizinga, Derrick G. Freitag, Launa J. Aspeslet, Robert T. FosterAbstract: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.
Robert B. Huizinga - One of the best experts on this subject based on the ideXlab platform.
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Differential Effects of Voclosporin and Tacrolimus on Insulin Secretion From Human Islets
Endocrinology, 2020Co-Authors: Jelena Kolic, Robert B. Huizinga, Leanne Beet, Peter Overby, Haoning Howard Cen, Evgeniy Panzhinskiy, Daren R Ure, Jennifer L Cross, James D. JohnsonAbstract:The incidence of new onset diabetes after transplant (NODAT) has increased over the past decade, likely due to calcineurin inhibitor-based immunosuppressants, including tacrolimus (TAC) and cyclosporin (CsA). Voclosporin (VCS), a next generation calcineurin inhibitor is reported to cause fewer incidences of NODAT but the reason is unclear. Whilst calcineurin signaling plays important roles in pancreatic β-cell survival, proliferation, and function, its effects on human β-cells remain understudied. In particular, we do not understand why some calcineurin inhibitors have more profound effects on the incidence of NODAT. We compared the effects of TAC and VCS on the dynamics of insulin secretory function, programmed cell death rate, and the transcriptomic profile of human islets. We studied two clinically relevant doses of TAC (10 ng/ml, 30 ng/ml) and VCS (20 ng/ml, 60 ng/ml), meant to approximate the clinical trough and peak concentrations. TAC, but not VCS, caused a significant impairment of 15 mM glucose-stimulated and 30 mM KCl-stimulated insulin secretion. This points to molecular defects in the distal stages of exocytosis after voltage-gated Ca 2+ entry. No significant effects on islet cell survival or total insulin content were identified. RNA sequencing showed that TAC significantly decreased the expression of 17 genes, including direct and indirect regulators of exocytosis (SYT16, TBC1D30, PCK1, SMOC1, SYT5, PDK4, and CREM), whereas VCS has less broad and milder effects on gene expression. Clinically relevant doses of TAC, but not VCS, directly inhibit insulin secretion from human islets, likely via transcriptional control of exocytosis machinery.
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differential effects of Voclosporin and tacrolimus on insulin secretion from human islets
bioRxiv, 2020Co-Authors: Jelena Kolic, Robert B. Huizinga, Leanne Beet, Peter Overby, Haoning Howard Cen, Evgeniy Panzhinskiy, Daren R Ure, Jennifer L Cross, James D. JohnsonAbstract:Context: The incidence of new onset diabetes after transplant (NODAT) has increased over the past decade, likely due to calcineurin inhibitor-based immunosuppressants, including tacrolimus (TAC) and cyclosporin (CsA). Voclosporin (VCS), a next generation calcineurin inhibitor is reported to cause fewer incidences of NODAT but the reason is unclear. Objective: Whilst calcineurin signaling plays important roles in pancreatic beta-cell survival, proliferation, and function, its effects on human beta-cells remain understudied. In particular, we do not understand why some calcineurin inhibitors have more profound effects on the incidence of NODAT. Methods: We compared the effects of TAC and VCS on the dynamics of insulin secretory function, programmed cell death rate, and the transcriptomic profile of human islets. We studied two clinically relevant doses of TAC (10 ng/ml, 30 ng/ml) and VCS (20 ng/ml, 60 ng/ml), meant to approximate the clinical trough and peak concentrations. Results: TAC, but not VCS, caused a significant impairment of 15 mM glucose-stimulated and 30 mM KCl-stimulated insulin secretion. This points to molecular defects in the distal stages of exocytosis after voltage-gated Ca2+ entry. No significant effects on islet cell survival or total insulin content were identified. RNA sequencing showed that TAC significantly decreased the expression of 17 genes, including direct and indirect regulators of exocytosis (SYT16, TBC1D30, PCK1, SMOC1, SYT5, PDK4, and CREM), whereas VCS has less broad and milder effects on gene expression. Conclusions: Clinically relevant doses of TAC, but not VCS, directly inhibit insulin secretion from human islets, likely via transcriptional control of exocytosis machinery.
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Tacrolimus, but not Voclosporin, inhibits insulin secretion from human islets at a clinical trough dose
2020Co-Authors: Jelena Kolic, Robert B. Huizinga, Leanne Beet, Peter Overby, Haoning Howard Cen, Evgeniy Panzhinskiy, Daren R Ure, Jennifer L Cross, James D. JohnsonAbstract:Context: The incidence of new onset diabetes after transplant (NODAT) has increased over the past decade. It has been suggested that NODAT is caused by exposure to calcineurin inhibitors, particularly tacrolimus (TAC). Voclosporin (VCS), a next generation calcineurin inhibitor is reported to cause fewer incidences of NODAT. Objective: Whilst calcineurin plays important roles in pancreatic β-cell survival, proliferation, and function, the effects of calcineurin inhibitors on human β-cells remain understudied. In particular, we do not understand why some inhibitors have more profound effects on the incidence of NODAT. Design: Here, we compared the effects of TAC and VCS on the dynamics of insulin secretory function, the programmed cell death rate, and the transcriptomic profile of human islets. We studied two clinically relevant doses of TAC (10 ng/ml, 30 ng/ml) and VCS (20 ng/ml, 60 ng/ml), meant to approximate the clinical trough and peak concentrations. Results: TAC, but not VCS, caused a significant impairment of 15 mM glucose-stimulated insulin secretion and 30 mM KCl-stimulated insulin secretion. This points to molecular defects in the distal stages of exocytosis after voltage-gated Ca2+ entry. No significant effects on islet cell survival or total islet insulin content were identified. RNA sequencing showed that TAC, and to a lesser extent VCS, decreased the expression of genes that regulate insulin exocytosis, trafficking, and processing, including SYT16, SYT5, PITPNM1, and PAM. Conclusions: TAC directly inhibits insulin secretion, likely via transcriptional control of exocytosis machinery. VCS was found to be gentler on isolated human islets than TAC.
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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.
Kidney international, 2018Co-Authors: Brad H. Rovin, Robert B. Huizinga, Neil Solomons, William F. Pendergraft, Mary Anne Dooley, James A. Tumlin, Juanita Romero-diaz, Lidia Lysenko, Sandra V. Navarra, Ihar AdzerikhoAbstract:Calcineurin inhibitors added to standard-of-care induction therapy for lupus nephritis (LN) may increase complete renal remission (CRR) rates. The AURA-LV study tested the novel calcineurin inhibitor Voclosporin for efficacy and safety in active LN. AURA-LV was a Phase 2, multicenter, randomized, double-blind, placebo-controlled trial of two doses of Voclosporin (23.7 mg or 39.5 mg, each twice daily) versus placebo in combination with mycophenolate mofetil (2 g/d) and rapidly tapered low-dose oral corticosteroids for induction of remission in LN. The primary endpoint was CRR at 24 weeks; the secondary endpoint was CRR at 48 weeks. Two hundred sixty-five subjects from 79 centers in 20 countries were recruited and randomized to treatment for 48 weeks. CRR at week 24 was achieved by 29 (32.6%) subjects in the low-dose Voclosporin group, 24 (27.3%) subjects in the high-dose Voclosporin group, and 17 (19.3%) subjects in the placebo group (OR=2.03 for low-dose Voclosporin versus placebo). The significantly greater CRR rate in the low-dose Voclosporin group persisted at 48 weeks, and CRRs were also significantly more common in the high-dose Voclosporin group compared to placebo at 48 weeks. There were more serious adverse events in both Voclosporin groups, and more deaths in the low-dose group compared to placebo and high-dose Voclosporin groups (11.2%, 1.1%, and 2.3%, respectively). These results suggest that the addition of low-dose Voclosporin to mycophenolate mofetil and corticosteroids for induction therapy of active LN results in a superior renal response compared to mycophenolate mofetil and corticosteroids alone, but higher rates of adverse events including death were observed.
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cytochrome p450 3a and p glycoprotein drug drug interactions with Voclosporin
British Journal of Clinical Pharmacology, 2014Co-Authors: Spencer Ling, Robert B. Huizinga, Patrick R. Mayo, Richard Larouche, Derrick G. Freitag, Launa J. Aspeslet, Robert T. FosterAbstract: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.
Launa J. Aspeslet - One of the best experts on this subject based on the ideXlab platform.
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cytochrome p450 3a and p glycoprotein drug drug interactions with Voclosporin
British Journal of Clinical Pharmacology, 2014Co-Authors: Spencer Ling, Robert B. Huizinga, Patrick R. Mayo, Richard Larouche, Derrick G. Freitag, Launa J. Aspeslet, Robert T. FosterAbstract: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.
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Cytochrome P450 3A and P‐glycoprotein drug–drug interactions with Voclosporin
British journal of clinical pharmacology, 2014Co-Authors: Spencer Ling, Robert B. Huizinga, Patrick R. Mayo, Richard Larouche, Derrick G. Freitag, Launa J. Aspeslet, Robert T. FosterAbstract: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.
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Population PKPD of Voclosporin in renal allograft patients
Journal of clinical pharmacology, 2013Co-Authors: Patrick R. Mayo, Spencer Ling, Robert B. Huizinga, Derrick G. Freitag, Launa J. Aspeslet, Robert T. FosterAbstract:The aims of this population-pharmacokinetic/pharmacodynamic (POP-PKPD) analysis of Voclosporin in renal allograft patients were to build a POP-PKPD model for Voclosporin and calcineurin activity (CNa) and identify clinically relevant covariates that could assist dosing of the drug. POP-PKPD modeling was performed using a stochastic approximation of the standard expectation maximization (SAEM) algorithm for nonlinear mixed-effects as implemented in Monolix™ 3.2. Voclosporin whole blood concentrations were obtained from de novo renal allograft patients and assayed using a validated LC/MS/MS assay. CNa was measured using a (32)P-radiolabeled assay. A two-compartment model with simultaneous sigmoid inhibitory Emax model was used to describe the PKPD relationship between Voclosporin concentration and CNa. The POP-PKPD model was then utilized to simulate an optimal initial dosing strategy. Eighty-seven patients were included in the POP-PKPD study. Population mean estimates (relative standard error, rse) for oral clearance (CL/F) and first compartment volume of distribution (V1), were 717 mL min(-1) (35%) and 2010 mL (17%), respectively. Maximum CNa Inhibition (Imax), effective concentration (C50), and baseline immunosuppression (S0) were 0.87 pmol/min/mg (8.0%), 123 ng/mL (10%), and 1.15 pmol/min/mg (4.0%), respectively. Covariate analyses demonstrated that age and body surface area significantly influenced CL/F: CLi=717(Agei/48.8)-0.57(BSAi/1.99)1.1, while serum triglycerides significantly altered S0: S0i=1.15(TRIGi/1.97)0.15.
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Pharmacokinetics of Voclosporin in renal impairment and hepatic impairment
Journal of clinical pharmacology, 2013Co-Authors: Spencer Ling, Robert B. Huizinga, Patrick R. Mayo, Derrick G. Freitag, Launa J. Aspeslet, Robert T. FosterAbstract: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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Voclosporin Food Effect and Single Oral Ascending Dose Pharmacokinetic and Pharmacodynamic Studies in Healthy Human Subjects
Journal of clinical pharmacology, 2013Co-Authors: Patrick R. Mayo, Spencer Ling, Robert B. Huizinga, Derrick G. Freitag, Launa J. Aspeslet, Robert T. FosterAbstract: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.
Patrick R. Mayo - One of the best experts on this subject based on the ideXlab platform.
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cytochrome p450 3a and p glycoprotein drug drug interactions with Voclosporin
British Journal of Clinical Pharmacology, 2014Co-Authors: Spencer Ling, Robert B. Huizinga, Patrick R. Mayo, Richard Larouche, Derrick G. Freitag, Launa J. Aspeslet, Robert T. FosterAbstract: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.
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Cytochrome P450 3A and P‐glycoprotein drug–drug interactions with Voclosporin
British journal of clinical pharmacology, 2014Co-Authors: Spencer Ling, Robert B. Huizinga, Patrick R. Mayo, Richard Larouche, Derrick G. Freitag, Launa J. Aspeslet, Robert T. FosterAbstract: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.
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Population PKPD of Voclosporin in renal allograft patients
Journal of clinical pharmacology, 2013Co-Authors: Patrick R. Mayo, Spencer Ling, Robert B. Huizinga, Derrick G. Freitag, Launa J. Aspeslet, Robert T. FosterAbstract:The aims of this population-pharmacokinetic/pharmacodynamic (POP-PKPD) analysis of Voclosporin in renal allograft patients were to build a POP-PKPD model for Voclosporin and calcineurin activity (CNa) and identify clinically relevant covariates that could assist dosing of the drug. POP-PKPD modeling was performed using a stochastic approximation of the standard expectation maximization (SAEM) algorithm for nonlinear mixed-effects as implemented in Monolix™ 3.2. Voclosporin whole blood concentrations were obtained from de novo renal allograft patients and assayed using a validated LC/MS/MS assay. CNa was measured using a (32)P-radiolabeled assay. A two-compartment model with simultaneous sigmoid inhibitory Emax model was used to describe the PKPD relationship between Voclosporin concentration and CNa. The POP-PKPD model was then utilized to simulate an optimal initial dosing strategy. Eighty-seven patients were included in the POP-PKPD study. Population mean estimates (relative standard error, rse) for oral clearance (CL/F) and first compartment volume of distribution (V1), were 717 mL min(-1) (35%) and 2010 mL (17%), respectively. Maximum CNa Inhibition (Imax), effective concentration (C50), and baseline immunosuppression (S0) were 0.87 pmol/min/mg (8.0%), 123 ng/mL (10%), and 1.15 pmol/min/mg (4.0%), respectively. Covariate analyses demonstrated that age and body surface area significantly influenced CL/F: CLi=717(Agei/48.8)-0.57(BSAi/1.99)1.1, while serum triglycerides significantly altered S0: S0i=1.15(TRIGi/1.97)0.15.
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Pharmacokinetics of Voclosporin in renal impairment and hepatic impairment
Journal of clinical pharmacology, 2013Co-Authors: Spencer Ling, Robert B. Huizinga, Patrick R. Mayo, Derrick G. Freitag, Launa J. Aspeslet, Robert T. FosterAbstract: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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Voclosporin Food Effect and Single Oral Ascending Dose Pharmacokinetic and Pharmacodynamic Studies in Healthy Human Subjects
Journal of clinical pharmacology, 2013Co-Authors: Patrick R. Mayo, Spencer Ling, Robert B. Huizinga, Derrick G. Freitag, Launa J. Aspeslet, Robert T. FosterAbstract: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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cytochrome p450 3a and p glycoprotein drug drug interactions with Voclosporin
British Journal of Clinical Pharmacology, 2014Co-Authors: Spencer Ling, Robert B. Huizinga, Patrick R. Mayo, Richard Larouche, Derrick G. Freitag, Launa J. Aspeslet, Robert T. FosterAbstract: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.
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Cytochrome P450 3A and P‐glycoprotein drug–drug interactions with Voclosporin
British journal of clinical pharmacology, 2014Co-Authors: Spencer Ling, Robert B. Huizinga, Patrick R. Mayo, Richard Larouche, Derrick G. Freitag, Launa J. Aspeslet, Robert T. FosterAbstract: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.
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Population PKPD of Voclosporin in renal allograft patients
Journal of clinical pharmacology, 2013Co-Authors: Patrick R. Mayo, Spencer Ling, Robert B. Huizinga, Derrick G. Freitag, Launa J. Aspeslet, Robert T. FosterAbstract:The aims of this population-pharmacokinetic/pharmacodynamic (POP-PKPD) analysis of Voclosporin in renal allograft patients were to build a POP-PKPD model for Voclosporin and calcineurin activity (CNa) and identify clinically relevant covariates that could assist dosing of the drug. POP-PKPD modeling was performed using a stochastic approximation of the standard expectation maximization (SAEM) algorithm for nonlinear mixed-effects as implemented in Monolix™ 3.2. Voclosporin whole blood concentrations were obtained from de novo renal allograft patients and assayed using a validated LC/MS/MS assay. CNa was measured using a (32)P-radiolabeled assay. A two-compartment model with simultaneous sigmoid inhibitory Emax model was used to describe the PKPD relationship between Voclosporin concentration and CNa. The POP-PKPD model was then utilized to simulate an optimal initial dosing strategy. Eighty-seven patients were included in the POP-PKPD study. Population mean estimates (relative standard error, rse) for oral clearance (CL/F) and first compartment volume of distribution (V1), were 717 mL min(-1) (35%) and 2010 mL (17%), respectively. Maximum CNa Inhibition (Imax), effective concentration (C50), and baseline immunosuppression (S0) were 0.87 pmol/min/mg (8.0%), 123 ng/mL (10%), and 1.15 pmol/min/mg (4.0%), respectively. Covariate analyses demonstrated that age and body surface area significantly influenced CL/F: CLi=717(Agei/48.8)-0.57(BSAi/1.99)1.1, while serum triglycerides significantly altered S0: S0i=1.15(TRIGi/1.97)0.15.
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Pharmacokinetics of Voclosporin in renal impairment and hepatic impairment
Journal of clinical pharmacology, 2013Co-Authors: Spencer Ling, Robert B. Huizinga, Patrick R. Mayo, Derrick G. Freitag, Launa J. Aspeslet, Robert T. FosterAbstract: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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Voclosporin Food Effect and Single Oral Ascending Dose Pharmacokinetic and Pharmacodynamic Studies in Healthy Human Subjects
Journal of clinical pharmacology, 2013Co-Authors: Patrick R. Mayo, Spencer Ling, Robert B. Huizinga, Derrick G. Freitag, Launa J. Aspeslet, Robert T. FosterAbstract: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.
