Mark Rogge

A Novel PEGylated Interferon Beta-1a for Multiple Sclerosis: Safety, Pharmacology, and Biology

This study clinically evaluated a novel PEGylated form of interferon beta‐1a (PEG‐IFN beta‐1a), a potential first‐line treatment for relapsing multiple sclerosis, in healthy volunteers. Two randomized, blinded phase I studies were conducted: a single‐dose study (n = 60) comparing subcutaneous or intramuscular PEG‐IFN beta‐1a (63, 125, or 188 μg) with intramuscular unmodified IFN beta‐1a 30 μg and a multiple‐dose study (n = 69) comparing subcutaneous PEG‐IFN beta‐1a dosed once every 2 or 4 weeks with placebo. Assessments included pharmacokinetic and pharmacodynamic (serum neopterin and 2′,5′‐OAS) measures, exploratory immune assessments, safety, and tolerability. A dose‐proportional increase in PEG‐IFN beta‐1a exposure was observed, with a 4‐fold greater exposure at 63 μg (6 million international units [MIU]) of PEG‐IFN beta‐1a than with 30 μg (6 MIU) intramuscular unmodified IFN beta‐1a. Increases in neopterin and 2′,5′‐OAS levels and changes in T helper cell pathway gene expression and lymphocyte subsets were greater and more sustained with PEG‐IFN beta‐1a than with unmodified IFN beta‐1a. PEG‐IFN beta‐1a was well tolerated, with only transient reductions in absolute neutrophils and some lymphocytes. Flu‐like symptoms were a commonly reported adverse event. These data support the continued clinical development of PEG‐IFN beta‐1a as a potentially effective treatment for patients with relapsing multiple sclerosis.

Pharmacokinetics and Pharmacodynamics of Interferon Beta-la (IFNβ-1a) in Healthy Volunteers after Intravenous, Subcutaneous or Intramuscular Administration

SummaryThe objective of this study was to define the single-dose pharmacokinetics and pharmacodynamics of interferon beta-la (IFNβ-1a) after various routes of administration. Three groups, each consisting of 8 healthy male and female subjects, received a single 60μg (12 million units) dose of IFNβ-1a by either a 30-minute intravenous infusion, or by subcutaneous or intramuscular injection. Serum interferon activity levels peaked immediately after the end of the intravenous infusion and thereafter fit a bioexponential decay model. The mean distribution and elimination half-lives were 4 minutes and 4 hours, respectively. The mean volume of distribution of the central compartment was 61.6L and the mean total clearance was 334 ml/h/kg. Interferon activity was consistently detectable in serum after intramuscular injection but not after subcutaneous injection. After intramuscular injection, peak serum interferon activity levels were approximately 40 U/ml and occurred 12 to 18 hours post-administration. The area under the curve for serum interferon activity was 2- to 3-fold higher after intramuscular injection than after subcutaneous injection. The pharmacodynamic response, as measured by changes in serum neopterin and β2-microglobulin concentrations, was also greatest after intramuscular injection, followed by subcutaneous, then intravenous administration. These results indicate that the optimal pharmacokinetic response is produced by intramuscular, rather than subcutaneous or intravenous, administration of IFNβ-1a.

Best practices for the use of itraconazole as a replacement for ketoconazole in drug–drug interaction studies

Ketoconazole has been widely used as a strong cytochrome P450 (CYP) 3A (CYP3A) inhibitor in drug–drug interaction (DDI) studies. However, the US Food and Drug Administration has recommended limiting the use of ketoconazole to cases in which no alternative therapies exist, and the European Medicines Agency has recommended the suspension of its marketing authorizations because of the potential for serious safety concerns. In this review, the Innovation and Quality in Pharmaceutical Developments Clinical Pharmacology Leadership Group (CPLG) provides a compelling rationale for the use of itraconazole as a replacement for ketoconazole in clinical DDI studies and provides recommendations on the best practices for the use of itraconazole in such studies. Various factors considered in the recommendations include the choice of itraconazole dosage form, administration in the fasted or fed state, the dose and duration of itraconazole administration, the timing of substrate and itraconazole coadministration, and measurement of itraconazole and metabolite plasma concentrations, among others. The CPLGs recommendations are based on careful review of available literature and internal industry experiences.

Population pharmacokinetics of recombinant factor VIII Fc fusion protein

Population pharmacokinetics (PK) of FVIII activity‐time profiles following recombinant factor VIII Fc fusion protein (rFVIIIFc) and recombinant factor VIII (rFVIII) dosing were evaluated in previously treated patients with severe hemophilia A (from two clinical trials). Potential covariates that may be determinants of variability in FVIII activity were identified. A 2‐compartment model adequately described the PK of both compounds. von Willebrand Factor (VWF) concentration was the major covariate for rFVIIIFc clearance, reflecting its protective role in FVIII activity clearance. The effect of body weight and hematocrit on the central volume of distribution of rFVIIIFc was minor. The results of these analyses confirmed that rFVIIIFc clearance (1.65 dL/h) is much lower than that of rFVIII (2.53 dL/h), while the steady state volumes of distribution were similar. The strong positive correlations between the PK parameters of rFVIIIFc and rFVIII suggest that individuals who have high time‐related PK characteristics with rFVIII are likely to have comparable characteristics with rFVIIIFc. Steady‐state activity‐time profiles for selected rFVIIIFc dosing regimens were simulated accounting for uncertainty in model parameters. These population PK analyses and simulations provide a comprehensive characterization of the PK of rFVIIIFc and rFVIII and may be useful for designing dosing regimens.

Pharmacokinetics of renally excreted drug dexpramipexole in subjects with impaired renal function

This phase I, open‐label, single‐dose study evaluated the pharmacokinetics, safety, and tolerability of renally excreted drug dexpramipexole in subjects with normal and impaired renal function, i.e. mild, moderate, severe renal impairment, or end‐stage renal disease (ESRD) requiring hemodialysis when matched by age and sex. Dexpramipexole area under the curves (AUCs), but not Cmax, were significantly increased with the severity of renal impairment after a single dose administration. The geometric mean ratio of dose‐normalized AUC(0–72) was 1.4, 1.7, 2.7, and 4.5, respectively, in mild, moderate, severe renal impairment, and ESRD subjects when compared to healthy subjects. There was a strong association between renal function (eGFR) and dexpramipexole CLr. The slope (90% confidence interval(CI)) of eGFR and renal clearance (CLr) in the regression model was 3.1 (2.4, 3.7). Dexpramipexole elimination in ESRD subjects during both dialysis and non‐dialysis (i.e., interval between dialysis) was insignificant. Single 75 mg and 150 mg doses of dexpramipexole were well tolerated, and the safety profile was comparable across renal function groups. Extensive drug accumulation may occur with repeated dosing in patients with significant renal impairment. It is recommended that dexpramipexole not to be given to patients with severe renal impairment or in those with ESRD.

Interferon beta assessment in non-Chinese and Chinese subjects: Pharmacokinetics and pharmacodynamic activity of an endogenous cytokine are not race dependent

Interferon beta‐1a (IFNβ‐1a) is a first‐line therapy for relapsing multiple sclerosis when administered as 30 mcg intramuscularly (IM) once weekly. This endogenous cytokine displays pharmacokinetic (PK) attributes consistent with a glycoprotein of 20‐kDa molecular weight that is administered IM. In this study, 24 healthy Chinese subjects (11 male, 13 female) each received 4 once‐weekly 60‐mcg IM doses of IFNβ‐1a. Serial blood samples were drawn for PK and pharmacodynamic (PD) assessments following the first and last dose of drug. Results were compared with historical data from a recent PK/PD assessment conducted in non‐Chinese subjects. Noncompartmental analysis revealed that no meaningful differences in either IFNβ‐1a exposure or response were apparent between the Chinese and non‐Chinese populations. Thus, it was concluded that no adjustment in dose regimen is warranted for future assessments of safety and efficacy in multiple sclerosis patients of Chinese origin.

Clinical Pharmacokinetics of Tonapofylline: Evaluation of Dose Proportionality, Oral Bioavailability, and Gender and Food Effects in Healthy Human Subjects

Tonapofylline is an antagonist of adenosine A1 receptor being developed for heart failure. In the present studies, pharmacokinetic characteristics, including dose proportionality, bioavailability, and effects of gender and food, were evaluated in healthy subjects receiving single‐dose tonapofylline (0.2–375 mg) in a parallel or crossover design. Following oral administration, tonapofylline concentrations mostly peaked within 3 hours and declined over time in a multiple phasic manner. Based on a power model, dose proportionality of peak concentration (Cmax), area under the time‐concentration curve for all values (AUCall), and area under the time‐concentration curve to infinity (AUCinf) was concluded in a clinical setting. The bioavailability of tonapofylline was 81.2% (90% confidence interval, 70.6%–93.5%). Following intravenous administration, the steady‐state volume of distribution of tonapofylline was estimated to be 756 mL/kg. The total clearance of tonapofylline was low (64.8 mL/h/kg), approximately 5% of hepatic blood flow. The terminal half‐life was variable within groups and ranged from 11.2 to 24.2 hours across the dose range. Female subjects showed significantly higher Cmax, AUCall, and AUCinf than male subjects (P < .05). Food decreased Cmax by approximately 39%, whereas it did not appear to affect AUCall and AUCinf. The intersubject variability of the pharmacokinetic parameters of tonapofylline was generally less than 30%. In these studies, a single dose of tonapofylline was safe and well tolerated.

Impaired bioavailability of interferon beta-1a when administered intramuscularly by needle-free injection.

Intramuscular (IM) or subcutaneous (SC) drug administration of small molecules and protein has been demonstrated by use of needle-free jet injection methods. One device that achieves needle-free parenteral administration, BIOJECTOR, is commercially available and was evaluated for IM delivery of interferon beta-1a. Recombinant human interferon beta-1a (IFN beta-1a) is a glycosylated protein containing 166 amino acids and has a molecular weight of 22.5 kDa. Needle-free jet injection of IFN beta-1a with the BIOJECTOR was assessed in a human Phase I trial. The study was a randomized, open-label crossover in which 12 healthy subjects each received 60 microg of IFN beta-1a as an IM injection by standard needle administration and by needle-free jet injection. Blood samples for pharmacokinetic (serum activity, PK) and pharmacodynamic (serum neopterin, PD) determinations were collected through 144 hours post-dose. Mean serum antiviral activity AUC values for needle-free and standard needle injection were 218 and 531 U x h/ml, respectively; corresponding C(max) values were 19.7 and 29.0 U/ml. Median T(max) following both treatments was 12 hours. The relative bioavailability of IFN beta-1a, needle-free to standard needle injection, was 41.1% with 90% confidence limits of 24.4% to 69.3%. Mean serum neopterin E(AUC) values for needle-free and standard needle injection were 114 and 325 ng x h/mL, respectively; corresponding E(max) values were 2.3 and 5.6 ng/mL. The ratio of serum neopterin E(AUC), needle-free to standard needle, was 34.9% with 90% confidence limits of 23.4% to 52.1%. Injection site reactions were substantially more frequent following needle-free injection; however, systemic side effects were less frequent. Intramuscular needle-free jet injection and needle-based injection of a 22.5-kDa glycoprotein do not produce equivalent systemic PK or PD responses.

A Semi‐Mechanistic Population Pharmacokinetic Model of Nusinersen: An Antisense Oligonucleotide for the Treatment of Spinal Muscular Atrophy

A pharmacokinetic (PK) model was developed for nusinersen, an antisense oligonucleotide (ASO) that is the first approved treatment for spinal muscular atrophy (SMA). The model was built with data from 92 nonhuman primates (NHPs) following intrathecal doses (0.3–7 mg) and characterized the PK in cerebrospinal fluid (CSF), plasma, total spinal cord, brain, and pons. The estimated volumes were 13.6, 937, 4.5, 53.8, and 2.11 mL, respectively. Global sensitivity analysis demonstrated that the CSF‐to‐plasma drug distribution rate (0.09 hour−1) is a major determinant of the maximum nusinersen concentration in central nervous system (CNS) tissues. Physiological age‐based and body weight‐based allometric scaling was implemented with exponent values of −0.08 and 1 for the rate constants and the volume of distribution, respectively. Simulations of the scaled model were in agreement with clinical observations from 52 pediatric phase I PK profiles. The developed model can be used to guide the design of clinical trials with ASOs.

Clinical pharmacology, creating current and future success in drug development

In response to an accelerating emergence of novel therapeutic platforms, regulatory development paradigms, and advances in analytical technology, the Clinical Pharmacology Leadership Group within the International Consortium for Innovation and Quality in Drug Development convened a Working Group to discuss these matters and formulate a vision of clinical pharmacology science for the next decade. The Working Group met throughout 2013/2014 and identified a number of critical needs and opportunities that, if addressed, will ensure that clinical pharmacology continues to provide core value to the drug development process. This Working Group did recognize prior commentaries on the state of clinical pharmacology and considered those expert opinions during the course of our discussions, such as those authored by Rawlins, Honig, and LaLonde. In contrast with these earlier commentaries, this effort intended to identify immediate and long-term opportunities and present solutions that are particularly related to drug development efforts. Over the past decade, there have been remarkable advances in the field of molecular biology that, with increased understanding of disease etiology, have resulted in the transition of increasing numbers of novel therapeutic classes into clinical development. Antibody–drug conjugates, immune therapy directed at oncology and inflammation targets, synthetic DNA engaging mRNA (antisense), proteosome modulation, and gene editing are just a few of the emerging therapeutic classes and treatment modalities that have benefited from these advances with several that have achieved approval and others either in or close to entering clinical development. Likewise, a number of nascent analytical technologies have matured into viable means for measuring drug/ metabolite concentration in the blood compartment and in some cases at the site of action. Biomarkers that demonstrate ligand:receptor interaction (target engagement) and pharmacological activity are becoming commonplace in many therapeutic areas. Although oncology has used imaging technology tomonitor target engagement andeffectwith great success, similar value is being realized in other therapeutic areas such as neurology and cardiology. The evolution of companion diagnostics has occurred in concert and will grow commensurate with our ability to differentiate both patients and disease. These advances have given us significant opportunities to move promising therapies into pivotal clinical trials with a better understanding of the likelihood of technical success and associated risks regarding safety and efficacy. The discipline of clinical pharmacology plays a pivotal role in optimizing novel therapeutic approaches while ensuring that development decisions are made based on an understanding of inherent likelihood of success and attendant risks.