Pharmacokinetics, pharmacodynamics, and safety of peginterferon beta-1a in subjects with normal or impaired renal function

Abstract

Peginterferon beta-1a was efficacious in a Phase 3 relapsing multiple sclerosis trial, and its safety profile was consistent with other beta interferons. This study evaluated the impact of renal impairment on the pharmacokinetics and pharmacodynamics (neopterin elevation; a biomarker of pharmacological activity induced by interferon beta-1a) of peginterferon beta-1a following a single subcutaneous dose at 63 μg (n = 5) or 125 μg (n = 30). The results showed a fractional increase in area-under-the-concentration-time curve (AUC [30-53%]) and peak serum concentration (Cmax [26-42%]) in subjects with mild, moderate, and severe renal impairment, versus healthy subjects; AUC and Cmax were similar for healthy subjects and end-stage-renal-disease patients receiving hemodialysis. Pharmacokinetic simulation showed that the steady state concentration overlapped in the majority of healthy subjects and subjects with severe renal impairment. Neopterin baseline, peak concentration, and AUC increased as renal function decreased. Peginterferon beta-1a was well tolerated in all groups. These results do not warrant peginterferon beta-1a dose adjustment in subjects with renal impairment.

Trial registration: ClinicalTrials.gov NCT01119781.

Keywords: clinical trial; multiple sclerosis; pegylation.

© 2014, The American College of Clinical Pharmacology.

Figures

Figure 1

Mean (±SD) serum concentration of peginterferon beta-1a (a and b) and neopterin (c and d) after a single subcutaneous dose of 125 µg peginterferon beta-1a in healthy subjects (circle), subjects with mild (square), moderate (triangle), or severe (inverted triangle) renal impairment, or subjects with end-stage renal disease (ESRD) undergoing hemodialysis (diamond). Data for healthy subjects and individuals with mild, moderate, or severe renal impairment are shown on parts a and c. Data for healthy subjects and individuals with ESRD are shown on parts b and d. Vertical broken lines in parts b and d indicate time window of hemodialysis for subjects with ESRD.

Figure 2

Simulated PK profiles at steady state for subjects with normal renal function or with severe renal impairment. The dashed lines from top to bottom represent the 95th, 50th, and 5th concentration percentiles of the concentration profile in healthy subjects, respectively; the solid lines represent the 95th, 50th, and 5th concentration percentiles of the concentration profile in subjects with severe renal impairment, respectively; the dotted line represents the lower limit of quantitation (LLOQ; 31.3 pg/mL).

Figure 3

Simulated PK profiles for ESRD subjects under different schedules for hemodialysis. (a) Schedule 1: prior to peginterferon beta-1a dosing and at 3, 5, and 7 days post-dose (representing the schedule of the current study); (b) Schedule 2: at 2, 4, 6, and 9 days post-dose; (c) Schedule 3: at 1, 3, 5, and 8 days post-dose; (c) Schedule 4: at 0.5 hours, 3, 5, 7, and 10 days post-dose. Solid line: simulation peginterferon beta-1a concentration; dashed line: LLOQ (31.3 pg/mL); arrows: hemodialysis events.