Patrick R. Mayo

The PROMISE Study: A Phase 2b Multicenter Study of Voclosporin (ISA247) Versus Tacrolimus in De Novo Kidney Transplantation

Voclosporin (VCS, ISA247) is a novel calcineurin inhibitor being developed for organ transplantation. PROMISE was a 6‐month, multicenter, randomized, open‐label study of three ascending concentration‐controlled groups of VCS (low, medium and high) compared to tacrolimus (TAC) in 334 low‐risk renal transplant recipients. The primary endpoint was demonstration of noninferiority of biopsy proven acute rejection (BPAR) rates. Secondary objectives included renal function, new onset diabetes after transplantation (NODAT), hypertension, hyperlipidemia and pharmacokinetic–pharmacodynamic evaluation. The incidence of BPAR in the VCS groups (10.7%, 9.1% and 2.3%, respectively) was noninferior to TAC (5.8%). The incidence of NODAT for VCS was 1.6%, 5.7% and 17.7% versus 16.4% in TAC (low‐dose VCS, p = 0.03). Nankivell estimated glomerular filtration rate was respectively: 71, 72, 68 and 69 mL/min, statistically lower in the high‐dose group, p = 0.049. The incidence of hypertension and adverse events was not different between the VCS groups and TAC. VCS demonstrated an excellent correlation between trough and area under the curve (r2= 0.97) and no difference in mycophenolic acid exposure compared to TAC. This 6‐month study shows VCS to be as efficacious as TAC in preventing acute rejection with similar renal function in the low‐ and medium‐exposure groups, and potentially associated with a reduced incidence of NODAT.

Effect of passive smoking on theophylline clearance in children.

The author investigated the effects of passive tobacco smoking on the metabolism of theophylline in a pediatric population. In a retrospective analysis of 201 children admitted to a pediatric unit for asthma, 31 were identified with an acute exacerbation of asthma of noninfectious origin in which environmental exposure to tobacco smoke could be established. The parents were known smokers with a minimum 1-pack-per-day habit. An age-and gender-matched control population of children was then identified who had an acute exacerbation of asthma without any environmental exposure to tobacco smoke. In addition, the patients in both groups received the same dose of intravenous aminophylline for a minimum of 48 hours to ensure steady-state conditions. Total body clearance of theophylline was significantly elevated in the children exposed to environmental tobacco smoke (1.36 ± 0.09 vs. 0.90 ± 0.04 mL/min per kg, p < 0.0001). Steady-state serum levels were significantly lower in the passive smoking group (55.3 ± 2.8 vs. 73.2 ± 3.3 p < 0.00001) for those receiving nearly identical intravenous doses. The length of hospital stay was longer in the group exposed to passive smoke (4.4 ± 2.6 vs. 2.9 ± 1.3 days, p < 0.05). The clearance of theophylline is greater in asthmatic children exposed to passive tobacco smoke than in asthmatic children not exposed to passive tobacco smoke. These findings suggest that passive smoking may increase the clearance of other drugs metabolized in a manner similar to theophylline.

Application of a neural network for gentamicin concentration prediction in a general hospital population

Neural network (NN) computation is computer modeling based in part on simulation of the structure and function of the brain. These modeling techniques have been found useful as pattern recognition tools. In the present study, data including age, sex, height, weight, serum creatinine concentration, dose, dosing interval, and time of measurement were collected from 240 patients with various diseases being treated with gentamicin in a general hospital setting. The patient records were randomly divided into two sets: a training set of 220 patients used to develop relationships between input and output variables (peak and trough plasma concentrations) and a testing set (blinded from the NN) of 20 to test the NN. The network model was the back-propagation, feed-forward model. Various networks were tested, and the most accurate networks for peak and trough (calculated as mean percent error, root mean squared error of the testing group, and tau value between observed and predicted values) were reported. The results indicate that NNs can predict gentamicin serum concentrations accurately from various input data over a range of patient ages and renal function and may offer advantages over traditional dose prediction methods for gentamicin.

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.

Pharmacokinetics of voclosporin in renal impairment and hepatic impairment

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.

Population PKPD of voclosporin in renal allograft patients

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 32P‐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 .

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 Cmax by 29% and 53%, respectively, and AUCinf 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.

Clinical prediction survival of advanced cancer patients by palliative care: a multi-site study

AIMS This study examined (1) accuracy of clinician prediction of survival (CPS) by palliative practitioners on first assessment with the use of standardised palliative tools, (2) factors affecting accuracy, (3) potential impact on clinical care. METHODS A multi-site prospective study (n=1530) was used. CPS was divided into four time periods (<=2wks, >2 to 6wks, >6 to 12wks and >12wks). Multivariate analysis was assessed on six predictor variables. RESULTS Overall, median survival of the sample was only 5 weeks. CPS category was accurate only 38.6% of the time, with 44.6% patients dying before the predicted time period. Of six candidate variables, on multivariate analysis only (i) the clinical time periods themselves and (ii) Palliative Performance Scale <=50 predicted for prognostic accuracy. CONCLUSION CPS, even by palliative practitioners, remains overly optimistic with the existence of the horizon effect. This raises the question in that these individuals may have been potentially overtreated.