Brinda Tammara

A Multicenter, Randomized, Open‐Label, Pharmacokinetics and Safety Study of Pantoprazole Tablets in Children and Adolescents Aged 6 Through 16 Years With Gastroesophageal Reflux Disease

Children with gastroesophageal reflux disease (GERD) may benefit from gastric acid suppression with proton pump inhibitors such as pantoprazole. Effective treatment with pantoprazole requires correct dosing and understanding of the drugs kinetic profile in children. The aim of these studies was to characterize the pharmacokinetic (PK) profile of single and multiple doses of pantoprazole delayed‐release tablets in pediatric patients with GERD aged 6 to 11 years (study 1) and 12 to 16 years (study 2). Patients were randomly assigned to receive pantoprazole 20 or 40 mg once daily. Plasma pantoprazole concentrations were obtained at intervals through 12 hours after the single dose and at 2 and 4 hours after multiple doses for PK evaluation. PK parameters were derived by standard noncompartmental methods and examined as a function of both drug dose and patient age. Safety was also monitored. Pantoprazole PK was dose independent (when dose normalized) and similar to PK reported from adult studies. There was no evidence of accumulation with multiple dosing or reports of serious drug‐associated adverse events. In children aged 6 to 16 years with GERD, currently available pantoprazole delayed‐release tablets can be used to provide systemic exposure similar to that in adults.

Randomized, open-label, multicentre pharmacokinetic studies of two dose levels of pantoprazole granules in infants and children aged 1 month through <6 years with gastro-oesophageal reflux disease.

AbstractBackground and Objective: The primary objective of this study was to characterize the pharmacokinetic profile of pantoprazole delayed-release granules in infants and children aged 1 month to <6 years with gastro-oesophageal reflux disease (GORD). The studies described in this manuscript were conducted to fulfil the requirements of the paediatric written request for pantoprazole by the US FDA. Methods: Two randomized, open-label, multicentre studies were conducted in infants aged 1 month to <12 months (study 1) and children aged 1 year through <6 years (study 2) with GORD. Patients were randomly assigned to either the low-dose pantoprazole group (0.6mg/kg equivalent) or the high-dose pantoprazole group (1.2mg/kg equivalent) in a 1:1 fashion. Pantoprazole granules were administered approximately 30 minutes before breakfast for at least five consecutive doses. Blood samples were obtained at prespecified intervals. Plasma pantoprazole concentration-time data were analysed by non-compartmental methods. Descriptive statistics were calculated for pharmacokinetic parameters. Patients in study 2 additionally received pantoprazole for 28 days. Safety was monitored throughout. Results: In study 1, 43 patients were randomized; 42 were included in the single-dose pharmacokinetic evaluation (15 females, 27 males; mean postnatal age 6.3 months). In study 2,17 patients were randomized, and all were included in the single-dose pharmacokinetic evaluation (6 females, 11 males; mean age 3.2 years). In both studies, exposure increased with dose. Mean (standard deviation) maximum (peak) plasma concentration values for the low and high doses were 503 (506) ng/mL and 1318 (1307) ng/mL, respectively, in study 1, and 229 (196) ng/mL and 653 (645) ng/mL, respectively, in study 2. Area under the plasma concentration-time curve values for the low and high doses were 1046 (1043) ngh/mL and 3602 (3269) ng • h/mL, respectively, in study 1, and 293 (146) ng • h/mL and 2448 (2170) ng • h/mL, respectively, in study 2. There was a trend for increasing clearance with increasing age across the ages 1 month through <6 years. There was no evidence of drug accumulation after multiple doses. On-treatment adverse events (AEs) occurred in 19 of 43 patients in study 1 and in 11 of 17 patients in study 2. Serious AEs occurred in two patients in study 1 (gastroenteritis in one patient and acute gastroenteritis from rota virus infection resulting in discontinuation of one patient); the serious AEs resolved and were not considered by the investigators to be drug related. No other safety-related discontinuations occurred in either study. Conclusions: Exposure increased with increasing doses of pantoprazole granules, even though wide inter-individual variability was observed. Compared with that in adults receiving pantoprazole 40 mg, exposure obtained with the 1.2 mg/kg dose was similar in study 1 and slightly lower in study 2. Pantoprazole was generally well tolerated in infants and children aged 1 month through <6 years with GORD.

Effect of Disulfiram-Mediated CYP2E1 Inhibition on the Disposition of Vesnarinone

Vesnarinone is an orally administered inotropic agent that is metabolized in vitro by the cytochrome P450 (CYP) isozymes CYP3A4 and CYP2E1. The purpose of this study was to assess the contribution of CYP2E1 activity to the disposition of vesnarinone in humans by characterizing the pharmacokinetics before and after disulfiram‐mediated CYP2E1 inhibition. The pharmacokinetics of vesnarinone 60 mg were determined in normal healthy volunteers (N = 7) before and after daily disulfiram administration (250 mg). Chlorzoxazone 250 mg was also administered before, during, and after disulfiram administration to serve as a positive control for CYP2E1 inhibition. Disulfiram treatment decreased 6‐hydroxychlorzoxazone formation clearance by nearly 95% but effected only a modest decrease in vesnarinone apparent oral clearance (5.7 ± 1.0 vs. 5.0 ± 0.5 ml/min; p = 0.022). In contrast to the modest effect on the parent drug, disulfiram treatment substantially increased plasma concentrations of the primary metabolite OPC‐18692. The Cmax of OPC‐18692 was increased approximately 7‐fold, and the area under the plasma concentration‐time curve was increased 18‐fold (2.9 ± 0.9 vs. 53.7 ± 33.2 μg•h/ml; p = 0.006). The results indicate that CYP2E1 inhibition has only a modest, clinically insignificant effect on vesnarinone disposition but markedly increases plasma concentrations of the OPC‐18692 metabolite. The pharmacological properties of this metabolite have not been fully defined; thus, the clinical importance of this observation depends on whether this metabolite contributes to any of the toxicity associated with vesnarinone administration.

SAT0221 Efficacy and Safety of PF-04171327, a Novel Dissociated Agonist of the Glucocorticoid Receptor (DAGR): Results of a Phase 2, Randomized, Double-Blind Study

Background Glucocorticoids (GC) are widely used to treat rheumatic and other diseases, but adverse effects limit their full potential. Improvement of their benefit-risk ratio represents both a current need and an ongoing challenge. One promising option includes dissociated agonists of the glucocorticoid receptor (DAGR) with the efficacy of higher dose GCs and the safety profile of lower dose GCs. Objectives PF-04171327, a DAGR, represents a first-in-class compound under investigation for the treatment of rheumatoid arthritis. The aim was to test the above hypothesis that this novel drug preferentially exerts transrepression mediated effects thereby inducing potent therapeutic activity with reduced adverse effects. Methods 323 adult patients with active RA (≥6 TJC and 6 SJC plus CRP ≥0.7 mg/dL) receiving MTX were randomized to receive DAGR 1, 5, 10 or 15 mg, prednisone (pred) 5 or 10 mg, or placebo (PBO) QD for 8 weeks followed by a 4-week taper period, and an ACTH stimulation test at Week 13. Use of GCs within 6 weeks of screening was prohibited. Efficacy analyses included characterization of dose-response at Week 8 for primary and secondary efficacy endpoints: ACR20 and DAS28-4(CRP). Effects on bone formation (P1NP, osteocalcin) and resorption (uNTX/uCr, sCTX) biomarkers, fasting plasma glucose and HbA1c were assessed for safety in addition to AEs and laboratory tests. Results Based on ACR20 responses, DAGR 10 and 15 mg QD were superior (by 20% with 80% confidence) to PBO; and DAGR 15 mg QD was non-inferior (by a margin of 5% with 80% confidence) to pred 10 mg QD. DAS28-4(CRP) results were consistent with ACR20 responses. 1, 5, 10 and 15 mg QD doses of DAGR were comparable to pred 5mg QD in bone formation; with small decreases in HbA1c in these predominantly non-diabetes patients. No clear trends or dose-response were seen in bone resorption markers. Prompt HPA axis recovery was evident at Week 13 in all patients. All DAGR doses were well-tolerated (comparable to PBO and pred doses), with no safety signal identified. Conclusions The aggregate efficacy analysis demonstrated that both DAGR 10 and 15 mg QD have efficacy superior to PBO and comparable to pred 10 mg QD, with bone and glucose effects comparable to pred 5 mg QD. All DAGR doses were safe and well-tolerated. This 8-week RCT provides first clinical evidence to demonstrate that PF-04171327 increases the transrepression/transactivation ratio, thereby improving the GC benefit-risk ratio compared with prednisone in RA patients. Disclosure of Interest F. Buttgereit Grant/research support from: Pfizer, V. Strand Consultant for: Pfizer, E. Lee Grant/research support from: Pfizer, D. McCabe Employee of: Pfizer, S. Kolluri Employee of: Pfizer, B. Tammara Employee of: Pfizer, R. Rojo Employee of: Pfizer, J. Hey-Hadavi Employee of: Pfizer

The Pharmacokinetics of Toborinone in Subjects with Congestive Heart Failure and Concomitant Renal Impairment and/or Concomitant Hepatic Impairment

The pharmacokinetics of toborinone was studied in subjects with congestive heart failure (CHF) and concomitant renal and/or hepatic disease. At the time of admission, subjects were grouped based on estimated creatinine clearance and serum bilirubin. Glomerular filtration rate was assessed using iothalamate clearance. Hepatic function was assessed using the caffeine metabolism test and indocyanine green clearance. No significant differences were observed in mean toborinone pharmacokinetic parameters among the four study groups. Positive correlations were observed between toborinone clearance and the measured indices of renal and hepatic function: creatinine clearance, iothalamate renal clearance, paraxanthine/caffeine ratio, and indocyanine green clearance. Toborinone clearance decreased with decreasing creatinine clearance, decreasing glomerular filtration rate, decreasing demethylation metabolic activity, and decreasing hepatic blood flow, although no significant differences were observed in any mean toborinone pharmacokinetic parameters evaluated among the four study groups.

Lack of Effect of Rivipansel on QTc Interval in Healthy Adult African American Male Subjects

Rivipansel is a pan‐selectin inhibitor in phase 3 development for the treatment of vaso‐occlusive crises in patients with sickle cell disease. This single‐dose, randomized, 3‐period, 3‐treatment (400 mg moxifloxacin open‐label, 4 g rivipansel–blinded, and placebo‐blinded) crossover study evaluated the effect of rivipansel on the QT/QTc interval in 48 healthy male African American subjects (age, 21–53 years; weight, 60–115 kg). Time‐matched, placebo‐adjusted change from baseline QT interval using Fridericias correction method (QTcF) was determined using a repeated‐measures mixed‐effects model. The highest upper bound of the 2‐sided 90% confidence interval (CI) for QTcF change was 3.22 milliseconds 3 hours postdose. Moxifloxacin showed the anticipated QTcF effect, indicating that the study had adequate sensitivity to detect changes in the QTcF interval. The study concluded that no QTcF effect was demonstrated with rivipansel compared with placebo, as the upper bound of the 2‐sided 90%CI was less than 10 milliseconds at all times. Exposure–response modeling for rivipansel concentrations and change from baseline in QTcF data corroborated a lack of effect with rivipansel compared with placebo. Single doses of rivipansel 4 g by intravenous infusion over 20 minutes were well tolerated in this study.

Dissociated Agonist of Glucocorticoid Receptor or Prednisone for Active Rheumatoid Arthritis: Effects on P1NP and Osteocalcin Pharmacodynamics

Fosdagrocorat (PF‐04171327), a dissociated agonist of the glucocorticoid receptor, has potent anti‐inflammatory activity in patients with rheumatoid arthritis with reduced adverse effects on bone health. To identify fosdagrocorat doses with bone formation marker changes similar to prednisone 5 mg, we characterized treatment‐related changes in amino‐terminal propeptide of type I collagen (P1NP) and osteocalcin (OC) with fosdagrocorat (1, 5, 10, or 15 mg) and prednisone (5 or 10 mg) in a phase II randomized trial (N = 323). The time course of markers utilized a mixed‐effects longitudinal kinetic‐pharmacodynamic model. Median predicted changes from baseline at week 8 with fosdagrocorat 5, 10, and 15 mg were −18, −22, and −22% (P1NP), and −7, −13, and −17% (OC), respectively. Changes with prednisone 5 and 10 mg were −15% and −18% (P1NP) and −10% and −17% (OC). The probability of fosdagrocorat doses up to 15 mg being noninferior to prednisone 5 mg for P1NP and OC changes was >90%.

The effects of concomitant administration of theophylline and toborinone on the pharmacokinetics of both compounds in poor and extensive metabolizers via CYP2D6.

This study investigated the effects of the concomitant administration of theophylline and toborinone on the pharmacokinetics of both compounds in poor and extensive metabolizers via CYP2D6. In period 1, a single dose of 3.5 mg/kg theophylline was administered orally. In period 2, a single dose of 1.0 μg/kg/min toborinone was infused over 6 hours. In period 3, 3.5 mg/kg theophylline was coadministered with 1.0 μg/kg/min toborinone. Serial blood and pooled urine samples were collected before and after toborinone administration for the quantification of toborinone and its metabolites in plasma and urine. Serial blood samples were collected before and after theophylline administration for the quantification of theophylline and its metabolites in plasma. No significant differences were observed in toborinone pharmacokinetics between poor and extensive metabolizers via CYP2D6. Toborinone coadministration with theophylline did not result in a substantive effect on the disposition of theophylline and vice versa.

In Vitro and In Vivo Investigation of Potential for Complex CYP3A Interaction for PF-00251802 (Dagrocorat), a Novel Dissociated Agonist of the Glucocorticoid Receptor

The dissociated agonists of the glucocorticoid receptor are a novel class of agents in clinical development for rheumatoid arthritis. PF‐04171327 (fosdagrocorat) is a phosphate ester prodrug of PF‐00251802 (dagrocorat), a selective high‐affinity partial agonist of the glucocorticoid receptor, which is further metabolized to PF‐04015475. This study evaluated the cytochrome P450 (CYP)–mediated drug–drug interaction (DDI) potential of PF‐00251802 and PF‐04015475 in vitro and used model‐based prediction approaches to estimate clinical impact. PF‐00251802 is a reversible inhibitor of several CYPs, but modeling has suggested no clinically relevant interaction. PF‐00251802 and PF‐04015475 are time‐dependent inhibitors and inducers of CYP3A in vitro; PF‐00251802 is also a time‐dependent inhibitor of CYP2D6. Model‐based prediction suggested the potential for weak inhibition of CYP3A in vivo. A clinical DDI study was conducted with midazolam, a sensitive CYP3A substrate. A phase 1 open‐label, multiple‐dose study evaluated the effect of PF‐04171327 on midazolam pharmacokinetics and safety in 12 healthy volunteers. Administration of midazolam alone or concomitantly with PF‐04171327 resulted in equivalent pharmacokinetic profiles (AUCinf, 21.17 vs 20.28 ng·h/mL, respectively), indicating that PF‐04171327 had no net effect on CYP3A activity in vivo. These findings support the further development of PF‐00251802 and PF‐04171327 as potential treatments for patients with rheumatoid arthritis (NCT00987038).

Population Pharmacokinetics of Fosdagrocorat (PF‐04171327), a Dissociated Glucocorticoid Receptor Agonist, in Patients With Rheumatoid Arthritis

Dissociated agonists of the glucocorticoid receptor (DAGRs) show similar antiinflammatory effects but improved tolerability compared with standard glucocorticoid receptor (GR) agonists. The prodrug fosdagrocorat (PF‐04171327), with active DAGR metabolite PF‐00251802 (Metabolite‐1), is postulated to show superior efficacy over placebo and prednisone in patients with moderate to severe rheumatoid arthritis (RA). We investigated the population pharmacokinetics of active Metabolite‐1 and its active metabolite PF‐04015475 (Metabolite‐2) in patients with moderate to severe RA enrolled in a 12‐week, phase II, randomized, double‐blind study (NCT01393639). A simultaneous fit of a two‐compartment model for Metabolite‐1 and a one‐compartment model for Metabolite‐2 provided an adequate fit to the data. Significant covariates included weight, with an additional female effect on clearance of Metabolite‐1 (∼26%) and Metabolite‐2 (∼33%) compared with males. Age influenced clearance of Metabolite‐1. In combination, age, weight, and sex predicted >twofold differences in area under the concentration–time curve of Metabolite‐1 at the extremes.