Introduction/Aims
Duchenne muscular dystrophy (DMD) is caused by mutations in the DMD gene resulting in the absence of dystrophin. Casimersen is a phosphorodiamidate morpholino oligomer designed to ...bypass frameshift DMD mutations and produce internally truncated, yet functional, dystrophin protein in patients amenable to exon 45 skipping. Our primary study objective was to evaluate safety and tolerability of casimersen; the secondary objective was to characterize the plasma pharmacokinetics.
Methods
This multicenter, phase 1/2 trial enrolled 12 participants (aged 7‐21 years, who had limited ambulation or were nonambulatory) and comprised a 12‐week, double‐blind dose titration, then an open‐label extension for up to 132 weeks. During dose titration, participants were randomized 2:1 to weekly casimersen infusions at escalating doses of 4, 10, 20, and 30 mg/kg (≥2 weeks per dose), or placebo.
Results
Participants received casimersen for a mean 139.6 weeks. Treatment‐emergent adverse events (TEAEs) occurred in all casimersen‐ and placebo‐treated participants and were mostly mild (over 91.4%) and unrelated to casimersen or its dose. There were no deaths, dose reductions, abnormalities in laboratory parameters or vital signs, or casimersen‐related serious AEs. Casimersen plasma concentration increased with dose and declined similarly for all dose levels over 24 hours postinfusion. All pharmacokinetic parameters were similar at weeks 7 and 60.
Discussion
Casimersen was well tolerated in participants with DMD amenable to exon 45 skipping. Most TEAEs were mild, nonserious, and unrelated to casimersen. Plasma exposure was dose proportional with no suggestion of plasma accumulation. These results support further studies of casimersen in this population.
Abstract
Introduction/Aims
Duchenne muscular dystrophy (DMD) is caused by mutations in the
DMD
gene resulting in the absence of dystrophin. Casimersen is a phosphorodiamidate morpholino oligomer ...designed to bypass frameshift
DMD
mutations and produce internally truncated, yet functional, dystrophin protein in patients amenable to exon 45 skipping. Our primary study objective was to evaluate safety and tolerability of casimersen; the secondary objective was to characterize the plasma pharmacokinetics.
Methods
This multicenter, phase 1/2 trial enrolled 12 participants (aged 7‐21 years, who had limited ambulation or were nonambulatory) and comprised a 12‐week, double‐blind dose titration, then an open‐label extension for up to 132 weeks. During dose titration, participants were randomized 2:1 to weekly casimersen infusions at escalating doses of 4, 10, 20, and 30 mg/kg (≥2 weeks per dose), or placebo.
Results
Participants received casimersen for a mean 139.6 weeks. Treatment‐emergent adverse events (TEAEs) occurred in all casimersen‐ and placebo‐treated participants and were mostly mild (over 91.4%) and unrelated to casimersen or its dose. There were no deaths, dose reductions, abnormalities in laboratory parameters or vital signs, or casimersen‐related serious AEs. Casimersen plasma concentration increased with dose and declined similarly for all dose levels over 24 hours postinfusion. All pharmacokinetic parameters were similar at weeks 7 and 60.
Discussion
Casimersen was well tolerated in participants with DMD amenable to exon 45 skipping. Most TEAEs were mild, nonserious, and unrelated to casimersen. Plasma exposure was dose proportional with no suggestion of plasma accumulation. These results support further studies of casimersen in this population.
•Nusinersen is an antisense oligonucleotide approved for treating SMA.•Unforeseen circumstances have the potential to cause delayed or missed doses.•Using population PK modeling and simulation, we ...analyzed the impact of a delayed or missed dose on nusinersen CSF exposures.•Nusinersen CSF exposures were strongly dependent on the duration of dosing interruption and the phase in the regimen when it occurred.•Administration of the delayed dose, followed by the subsequent dose as originally scheduled, rapidly restored steady-state concentration.
Nusinersen is an antisense oligonucleotide approved for the treatment of spinal muscular atrophy. The drug is given intrathecally at 12 mg, beginning with 3 loading doses at 2-week intervals, a fourth loading dose 30 days thereafter, and maintenance doses at 4-month intervals. This population pharmacokinetic model was developed to clarify how to maintain targeted nusinersen exposure after an unforeseen one-time delay or missed dose. Simulations demonstrated that the impact of a one-time delay in dosing or a missed dose on median cerebrospinal fluid exposures depended on duration of interruption and the regimen phase in which it occurred. Delays in loading doses delayed reaching the peak trough concentration by approximately the duration of the interruption. Resumption of the regimen as soon as possible resulted in achieving steady state trough concentration upon completion of the loading phase. A short delay (30–90 days) during the maintenance phase led to prolonged lower median cerebrospinal fluid concentration if all subsequent doses were shifted by the same 4-month interval. However, administration of the delayed dose, followed by the subsequent dose as originally scheduled, rapidly restored trough concentration. If a dose must be delayed, patients should return to the original dosing schedule as soon as possible.
Objectives
Raltegravir is a human immunodeficiency virus (HIV)‐1 integrase strand transfer inhibitor currently marketed at a dose of 400 mg twice daily (BID). Raltegravir for once‐daily regimen (QD) ...at a dose of 1200 mg is under development. The effect of calcium carbonate and magnesium/aluminium hydroxide antacids on the pharmacokinetics of a 1200 mg dose of raltegravir was assessed in this study.
Methods
An open‐label, four‐period, four‐treatment, fixed‐sequence study in 20 HIV‐infected patients was performed. Patients needed to be on raltegravir as part of a stable treatment regimen for HIV, and upon entry into the trial received 5 days of 1200 mg raltegravir as pretreatment, before they entered the four‐period study: 1200 mg of raltegravir alone (period 1), calcium carbonate antacid as TUMS® Ultra Strength (US) 1000 and 1200 mg raltegravir given concomitantly (Period 2), magnesium/aluminium hydroxide antacid as 20 ml MAALOX® Maximum Strength substitute MS given 12 h after administration of 1200 mg raltegravir (period 3), and calcium carbonate antacid as TUMS® US 1000 given 12 h after administration of 1200 mg raltegravir (period 4). Patients received their dose of 1200 mg QD raltegravir during the intervals between periods to re‐establish steady state. AUC0–24, C24, Cmax and Tmax were calculated from the individual plasma concentrations of 1200 mg QD raltegravir after administration alone or with a calcium carbonate antacid or with a staggered dose of a calcium carbonate antacid or magnesium/aluminium hydroxide antacid. Adverse events, in addition to laboratory safety tests (haematology, serum chemistry and urinalysis), 12‐lead electrocardiograms and vital signs were assessed.
Key findings
All treatments were well tolerated in the study. Metal‐cation antacids variably affected the pharmacokinetics of 1200 mg QD raltegravir. When calcium carbonate antacid was given with 1200 mg raltegravir concomitantly, the geometric mean ratio (GMR) and its associated 90% confidence interval (90% CI) for AUC0–24, Cmax and C24 h were 0.28 (0.24, 0.32), 0.26 (0.21, 0.32) and 0.52 (0.45, 0.61), respectively. When calcium carbonate antacid and magnesium/aluminium hydroxide were given 12 h after raltegravir 1200 mg QD dosing, the GMR (90% CI) values for AUC0–24 and Cmax were 0.90 (0.80, 1.03), 0.98 (0.81, 1.17), and 0.86 (0.73, 1.03), 0.86 (0.65, 1.15), respectively. However, significant reduction in the trough concentrations of raltegravir was observed: C24 h 0.43 (0.36, 0.51) in the presence of calcium carbonate antacids and 0.42 (0.34, 0.52) in presence of magnesium/aluminium hydroxide, respectively.
Conclusions
Overall, the use of metal‐cation antacids with 1200 mg QD raltegravir is not recommended.
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