Paul Jordan

Pharmacokinetics and Pharmacodynamics of Intravenous and Subcutaneous Continuous Erythropoietin Receptor Activator (C.E.R.A.) in Patients with Chronic Kidney Disease

Continuous Erythropoietin Receptor Activator (C.E.R.A.) is a new agent that is in development for the treatment of anemia with extended administration intervals in patients who have chronic kidney disease (CKD), both those on and those not on dialysis. This was an open-label, randomized, multicenter, two-period, crossover study in erythropoiesis-stimulating agentnaïve patients who had CKD and anemia and were receiving peritoneal dialysis. After a 1-wk run-in period, 16 patients were randomly assigned to receive a single administration of intravenous C.E.R.A. 0.4 microg/kg (n = 8) or subcutaneous C.E.R.A. 0.8 microg/kg (n = 8). Six weeks after the first administration of C.E.R.A. (4-wk assessment, 2-wk washout), the route of administration was switched so that all patients received single administrations of both intravenous C.E.R.A. 0.4 microg/kg and subcutaneous C.E.R.A. 0.8 microg/kg. C.E.R.A. had a prolonged and comparable half-life after intravenous (mean 134 h) and subcutaneous (mean 139 h) administration. Reticulocyte counts peaked at a median of 8 d after intravenous and subcutaneous administration with no difference in the time course between administration routes. This resulted in similar mean values for the area under the reticulocyte count-time curve (1191 x 10(9) and 1193 x 10(9).d per L, respectively) and the maximum absolute increase in reticulocyte counts (36 x 10(9) and 41 x 10(9)/L, respectively). C.E.R.A. has a prolonged and comparable half-life after intravenous or subcutaneous injection, suggesting that extended administration intervals may be feasible in patients with CKD.

Inhibition of 11β-HSD1 with RO5093151 for non-alcoholic fatty liver disease: a multicentre, randomised, double-blind, placebo-controlled trial

BACKGROUND The prevalence of non-alcoholic fatty liver disease is increasing worldwide and an effective and safe pharmacological treatment is needed. We investigated whether inhibition of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1, also known as HSD11B1) by RO5093151 could safely and effectively decrease liver-fat content in patients with this disorder. METHODS We did this phase 1b trial at four centres in Germany and Austria. Participants with non-alcoholic fatty liver disease (defined as (1)H magnetic resonance spectroscopy liver-fat content >5·56%), insulin resistance (homoeostatic model assessment of insulin resistance [HOMA-IR] of at least 2·0 mmol/L·mU/L), BMI greater than 27 kg/m(2), and aged 35-65 years were randomly assigned by interactive voice response system in a 1:1 ratio, stratified for triglyceride concentration (<1·7 mmol/L or ≥1·7 mmol/L), to oral RO5093151 (200 mg twice daily) or matching placebo for 12 weeks. The main exclusion criteria were other liver diseases, aspartate aminotransferase or alanine aminotransferase concentrations of more than two and a half times the upper limit of normal, history of diabetes or bariatric surgery, and use of weight lowering drugs. Participants and investigators were masked to assignment throughout the study. The primary endpoint was change in liver-fat content from baseline to week 12. Efficacy analysis was by modified intention to treat, including all patients who received at least one dose of study drug and had a baseline and follow-up measurement of liver-fat content. Safety analyses included all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, number NCT01277094. FINDINGS We did this trial between Jan 13, 2011, and March 28, 2012. 41 patients were randomly assigned to RO5093151 and 41 to placebo. 35 patients in the RO5093151 group and 39 in the placebo group were included in the efficacy analysis. Mean liver-fat content decreased in the RO5093151 group (from 16·75% [SD 8·67] to 14·28% [8·89]), but not in the placebo group (from 18·53% [10·00] to 18·46% [10·78], p=0·02 for between group difference). 26 participants (65%) in the RO5093151 group had adverse events, compared with 21 (53%) in the placebo group. The most common adverse events were gastrointestinal disorders (12 patients [30%] in the RO5093151 group vs seven [18%] in the placebo group), and infections and infestations (eight [20%] vs nine [23%]). Nervous system disorders occurred in significantly more patients in the RO5093151 group than in the placebo group (nine [23%] vs two [5%]; p=0·02); all other differences in adverse events were non-significant. One participant (3%) in the placebo group and three participants (8%) in the RO5093151 group had serious adverse events. All serious adverse events were deemed unrelated to study treatment. INTERPRETATION Inhibition of 11β-HSD1 by RO5093151 was effective and safe in reducing liver-fat content, suggesting that targeting of 11β-HSD1 might be a promising approach for the treatment of non-alcoholic fatty liver disease. FUNDING F Hoffmann-La Roche.

A Comparison of the Theoretical Relationship between HDL Size and the Ratio of HDL Cholesterol to Apolipoprotein A-I with Experimental Results from the Women's Health Study

BACKGROUND HDL size and composition vary among individuals and may be associated with cardiovascular disease and diabetes. We investigated the theoretical relationship between HDL size and composition using an updated version of the spherical model of lipoprotein structure proposed by Shen et al. (Proc Natl Acad Sci U S A 1977;74:837-41.) and compared its predictions with experimental data from the Womens Health Study (WHS). METHODS The Shen model was updated to predict the relationship between HDL diameter and the ratio of HDL-cholesterol (HDL-C) to apolipoprotein A-I (ApoA-I) plasma concentrations (HDL-C/ApoA-I ratio). In the WHS (n = 26 772), nuclear magnetic resonance spectroscopy (NMR) was used to measure the mean HDL diameter (d(mean,NMR)) and particle concentration (HDL-P); HDL-C and ApoA-I (mg/dL) were measured by standardized assays. RESULTS The updated Shen model predicts a quasilinear increase of HDL diameter with the HDL-C/ApoA-I ratio, consistent with the d(mean,NMR) values from WHS, which ranged between 8.0 and 10.8 nm and correlated positively with the HDL-C/ApoA-I ratio (r = 0.608, P < 2.2 × 10(-16)). The WHS data were further described by a linear regression equation: d(WHS) = 4.66 nm + 12.31(HDL-C/Apo-I), where d(WHS) is expressed in nanometers. The validity of this equation for estimating HDL size was assessed with data from cholesteryl ester transfer protein deficiency and pharmacologic inhibition. We also illustrate how HDL-P can be estimated from the HDL size and ApoA-I concentration. CONCLUSIONS This study provides a large-scale experimental examination of the updated Shen model. The results offer new insights into HDL structure, composition and remodeling and suggest that the HDL-C/ApoA-I ratio might be a readily available biomarker for estimating HDL size and HDL-P.

Pharmacokinetic and Pharmacodynamic Properties of Methoxy Polyethylene Glycol‐Epoetin Beta Are Unaffected by the Site of Subcutaneous Administration1

C.E.R.A. (methoxy polyethylene glycol‐epoetin beta), a continuous erythropoietin receptor activator, differs from traditional erythropoiesis‐stimulating agents in its pharmacokinetic and receptor binding properties. This phase I, randomized, open‐label, single‐center, single‐dose, 3‐way crossover study in 42 healthy volunteers compared the pharmacokinetic and pharmacodynamic profile of C.E.R.A. 3.0 μg/kg after subcutaneous injection into the abdomen, arm, or thigh. The pharmacokinetic profile was similar at all 3 injection sites, with a prolonged apparent elimination half‐life from 160 to 164 hours, area under the concentration–time curve from 4088 to 4323 ngṁh/mL, and clearance/bioavailability from 0.64 to 0.68 mL/h/kg. C.E.R.A. produced a sustained erythropoietic response, and the pharmacodynamic profile (area under the reticulocyte count–time curve and maximum increase in reticulocyte count) was similar for all sites. C.E.R.A. was generally well tolerated, regardless of the administration site. This study suggests that C.E.R.A. has the potential to offer a choice of injection sites in clinical practice. The long half‐life may permit effective anemia management with extended dosing intervals. Phase III clinical studies support the role of C.E.R.A. in managing anemia in patients with chronic kidney disease.

Thorough QT/QTc Study of Ritonavir-Boosted Saquinavir Following Multiple-Dose Administration of Therapeutic and Supratherapeutic Doses in Healthy Participants

The effect of saquinavir‐boosted ritonavir at therapeutic (1000/100 mg twice daily [bid]) and supratherapeutic (1500/100 mg bid) doses was evaluated in a double‐blind, placebo‐ and positive‐controlled (moxifloxacin 400 mg) 4‐way crossover thorough QT/QTc study. Least squares mean estimated study‐specific QTc (QTcS) change from dense predose baseline (ddQTcSdense) was the primary endpoint. Greatest mean increase in ddQTcSdense occurred 12 hours postdose for the 1000/100‐mg group (18.9 ms) and 20 hours for the 1500/10‐mg group (30.2 ms). The upper 1‐sided 95% confidence interval was >20 ms from 2 to 20 hours postdose in both groups. ddQTcBdense and ddQTcFdense were similar to ddQTcSdense. No QTcS, QTcF, or QTcB measurements were >500 ms. One participant receiving 1000/100 mg and 3 receiving 1500/100 mg had a maximum ddQTcSdense >60 ms. More participants with ≥1 adverse event received saquinavir/ritonavir. PubMed search and Roche postmarketing data did not reveal publications or reports directly presenting the effect of saquinavir on QT/QTc or causing torsade de pointes.

Subcutaneous injection pain with C.E.R.A., a continuous erythropoietin receptor activator, compared with darbepoetin alfa.

ABSTRACT Objective: This study assessed injection site pain following subcutaneous (SC) administration with a continuous erythropoietin receptor activator (C.E.R.A.), compared with darbepoetin alfa in healthy adults. Methods: In a randomized, placebo-controlled, single-centre, single-blind, three-way crossover study, subjects received one of six treatment sequences (ABC/ACB/BAC/BCA/CBA/CAB) involving SC injection of (A) C.E.R.A. 50 μg, (B) darbepoetin alfa 50 μg, or (C) placebo on days 1, 29, and 57. An initial pilot phase (n = 12) was used to determine the sample size for the confirmatory phase (n = 72), and data were combined for the final analysis (n = 84). Main outcome measures: The primary endpoint was pain on the 100 mm visual analog scale (VAS) immediately after dosing. Secondary endpoints included VAS at 1 hour after dosing and pain on the six-point verbal rating scale (VRS) immediately and at 1 hour after dosing. Results: C.E.R.A. was associated with significantly less pain immediately after SC injection compared with darbepoetin alfa: least squares mean VAS 21.5 (95% confidence interval [CI]: 17.5, 25.5) versus 33.4 (95% CI: 28.4, 38.4) ( p < 0.0001). Incidence of pain on the VRS was lower with C.E.R.A. compared with darbepoetin alfa immediately after dosing ( p < 0.0001). One hour after administration, most subjects had no VRS pain. A study limitation is the small sample size and the findings need to be confirmed in a large trial of chronic kidney disease patients. Conclusions: SC injection with C.E.R.A. is significantly less painful than SC darbepoetin alfa in healthy adults. Treatment of anemia in chronic kidney disease with SC injection of C.E.R.A. may provide a lower pain burden compared with darbepoetin alfa.

Bayesian adaptive designs in single ascending dose trials in healthy volunteers

AIM Recent publications indicate a strong interest in applying Bayesian adaptive designs in first time in humans (FTIH) studies outside of oncology. The objective of the present work was to assess the performance of a new approach that includes Bayesian adaptive design in single ascending dose (SAD) trials conducted in healthy volunteers, in comparison with a more traditional approach. METHODS A trial simulation approach was used and seven different scenarios of dose-response were tested. RESULTS The new approach provided less biased estimates of maximum tolerated dose (MTD). In all scenarios, the number of subjects needed to define a MTD was lower with the new approach than with the traditional approach. With respect to duration of the trials, the two approaches were comparable. In all scenarios, the number of subjects exposed to a dose greater than the actual MTD was lower with the new approach than with the traditional approach. CONCLUSIONS The new approach with Bayesian adaptive design shows a very good performance in the estimation of MTD and in reducing the total number of healthy subjects. It also reduces the number of subjects exposed to doses greater than the actual MTD.

The effect of severe hepatic impairment on the pharmacokinetics and haematological response of C.E.R.A.

ABSTRACT Aim: To examine the effect of severe hepatic impairment (HI) on the pharmacokinetics (PK) and pharmacodynamics (PD) of the continuous erythropoietin receptor activator, C.E.R.A. Methods: A non-randomised, multicentre, single-dose, open-label study in patients with HI (n = 12) and healthy subjects (n = 12). After 2 weeks of screening, participants received a single intravenous dose of C.E.R.A. (200 µg), and were then followed for ≈8 weeks. The area under the concentration–time curve (AUC) from drug administration to last measurable concentration (AUClast), and maximum C.E.R.A. concentration (Cmax) were calculated to assess PK. The baseline-corrected area under the effect curve over 22 days (AUEcorr) for reticulocyte count was the primary PD parameter. Results: The PK profile was similar in patients and healthy subjects (AUClast: 6678 vs 6985 ng*h/mL; Cmax: 63 vs 75 ng/mL) C.E.R.A. produced a sustained erythropoietic response in bothgroups, with increases in reticulocyte counts peaking 7–9 days post-dose and returning to baseline by Day 22. Although mean AUEcorr was 64% lower in patients, this may have been an artefact of higher baseline reticulocyte counts. Lower reticulocyte responses in patients did not translate into lower responses for haemoglobin, haematocrit or erythrocytes, suggesting that HI had no clinically relevant effect on the PD of C.E.R.A. C.E.R.A. was well tolerated. Four AEs (none considered drug related) were reported in three patients (mild myocardial ischaemia; mild pyrexia and liver transplant; severe bacterial peritonitis [serious AE]); no AEs were reported in healthy subjects. Conclusions: Severe HI has no clinically relevant effect on PK parameters or haematological response after single-dose C.E.R.A.

Aleglitazar, a balanced PPARα/γ agonist, has no clinically relevant pharmacokinetic interaction with high-dose atorvastatin or rosuvastatin

Background: Aleglitazar, a dual PPAR-α/γ agonist, combines the lipid benefits of fibrates and the insulin-sensitizing benefits of thiazolidinediones. Objective: To investigate the pharmacokinetic effects of co-administration of atorvastatin or rosuvastatin with aleglitazar. Research design and methods: In a two-cohort, open-label, randomised, three-period crossover study, 44 healthy subjects received once-daily oral doses of aleglitazar 300 μg, statin (atorvastatin 80 mg or rosuvastatin 40 mg) and aleglitazar co-administered with each statin for 7 days. Plasma concentrations of each drug were measured and pharmacokinetic parameters determined on day 7 in each period. Main outcome measures: Peak observed plasma concentration (Cmax) and total exposures (AUC0 – 24) of aleglitazar, atorvastatin and rosuvastatin. Results: Cmax and AUC0 – 24 to aleglitazar were similar, whether administered alone or in combination with a statin. Total exposure to either statin was unaffected by co-administration with aleglitazar. Cmax treatment ratios for both statins exceeded the conventional no-effect boundary (1.25) when administered with aleglitazar. Conclusions: Co-administration of aleglitazar with a statin does not alter the pharmacokinetic profile of either drug.

Sequentially updating the likelihood of success of a Phase 3 pivotal time-to-event trial based on interim analyses or external information

ABSTRACT When performing a pivotal clinical trial, it may be of interest to assess the probability of success (PoS) of that trial. Initially evaluated when the trial is designed, PoS can be updated as the trial progresses and new information about the drug effect becomes available. Such information can be external to the trial, such as results from trials conducted in parallel, or internal, such as continuing after an interim analysis. We develop a framework to update PoS based on such internal and external information for a time-to-event endpoint and illustrate it using a realistic development program for a new molecule.