TREND statement checklist.

<div><p>Background</p><p>Fabry disease (FD) is an X-linked lysosomal disorder leading to multiorgan dysfunction, including renal impairment and the risk of significant accumulation for renally excreted drugs. Migalastat, an approved therapy in FD patients with amenable variants, is primarily eliminated in urine; however, its use had not been studied in patients with end-stage renal disease (ESRD) receiving dialysis therapy. This study investigated the pharmacokinetics (PK), dialyzability, and tolerability of 123 mg migalastat in non-FD subjects with ESRD on stable hemodialysis/hemodiafiltration (EudraCT 2018-003684-57). Results were analyzed by population PK and physiologically based PK (PBPK) modeling and intended to propose dose regimens resulting in negligible migalastat trough levels in plasma and comparable concentrations above the threshold in target tissues in FD patients with ESRD.</p><p>Methods</p><p>Subjects with ESRD received 123 mg migalastat 24 hours before dialysis and, following an 8-day washout, immediately before dialysis. Matched controls with normal renal function (NRF) received migalastat 123 mg. Migalastat concentrations were measured in plasma, urine, and dialysate, and modeled to select regimens providing similar disposition to NRF.</p><p>Results</p><p>Migalastat was extracted by hemodialysis/hemodiafiltration (74%/72%). PBPK modeling predicted that 123 mg every other week (QOW) with regular dialysis 2–3 times weekly in ESRD subjects produced: a fraction of time above EC<sub>50</sub> similar to FD patients with NRF; adequate C<sub>max</sub> for intracellular trafficking of mutant α-galactosidase A to the lysosome; and C<sub>trough</sub> levels near the lower limit of quantification (LLOQ) similar to NRF subjects receiving 123 mg every other day. Migalastat 82 mg weekly produced a greater fraction of time above EC<sub>50</sub> and longer duration of concentrations above the LLOQ, potentially resulting in accumulation in tissues.</p><p>Conclusion</p><p>Migalastat was well extracted by hemodialysis/hemodiafiltration. Migalastat 123 mg QOW is the proposed dose regimen for further evaluation in FD patients with ESRD, which could inform expansion of treatment options.</p><p>Trial registration</p><p>Trial registration: EU Clinical Trials Register, EudraCT number <a href="https://eudract.ema.europa.eu/" target="_blank">2018-003684-57</a>.</p></div>