Hereditary transthyretin-mediated amyloidosis is an inherited, rapidly progressive, life-threatening disease caused by mutated transthyretin (TTR) protein. Patisiran is a small interfering RNA (siRNA) formulated in a lipid nanoparticle that inhibits hepatic TTR protein synthesis by RNA interference. We have developed an indirect-response pharmacokinetic-pharmacodynamic model relating plasma siRNA (ALN-18328) levels to serum TTR reduction across five clinical studies. A sigmoidal function described this relationship, with estimated Hill coefficient of 0.548, and half maximal inhibitory concentration (IC50), IC80, and IC90 values of 9.45, 118.5, and 520.5 ng/mL, respectively. Following patisiran 0.3 mg/kg every 3 weeks (q3w), steady-state plasma ALN-18328 exposures were between IC80 and IC90, yielding average serum TTR reductions of 80%-90% from baseline. Covariate analysis indicated similar TTR reduction across evaluated intrinsic and extrinsic factors, obviating the need for dose adjustment. Modeling results support the recommended patisiran dosing schedule of 0.3 mg/kg q3w, with a maximum dose of 30 mg for patients weighing ≥100 kg.
Keywords: hereditary transthyretin-mediated amyloidosis; patisiran; polyneuropathy; population pharmacokinetic–pharmacodynamic modeling; small interfering RNA.