Pharmacokinetics of Asfotase Alfa in Adult Patients With Pediatric‐Onset Hypophosphatasia

Hypophosphatasia is a rare metabolic disease resulting from variant(s) in the gene‐encoding tissue‐nonspecific isozyme of alkaline phosphatase. In this 13‐week, phase 2a, multicenter, randomized, open‐label, dose‐response study (ClinicalTrials.gov: NCT02797821), the pharmacokinetics of asfotase alfa, an enzyme replacement therapy approved for the treatment of hypophosphatasia, was assessed in adult patients with pediatric‐onset hypophosphatasia. In total, 27 adults were randomly assigned 1:1:1 to a single subcutaneous dose of asfotase alfa (0.5, 2.0, or 3.0 mg/kg) during week 1. From week 3 to week 9, patients received 0.5, 2.0, or 3.0 mg/kg subcutaneously 3 times per week (equivalent to 1.5, 6.0, or 9.0 mg/kg/wk, respectively). Noncompartmental analysis revealed exposure (maximum concentration in the dosing interval and area under the concentration‐time curve from time 0 to infinity) to asfotase alfa increased between single‐ and multiple‐dose administration and with increasing doses; however, extensive interindividual variability was observed in the concentration‐time profiles within each dose cohort. Median terminal elimination half‐life was ≈5 days following multiple‐dose administration, with steady state achieved by approximately day 29. Dose‐normalized exposure data indicated that asfotase alfa activity was approximately dose‐proportional within the studied dose range. Additionally, dose‐normalized exposure was comparable across body mass index categories of <25, ≥25 to <30, and ≥30 kg/m(2), indicating that asfotase alfa dosing bioavailability was consistent in these patients, including those who were obese. These data, together with previously published pharmacodynamic results in this study population, support the use of asfotase alfa at the recommended dose of 6 mg/kg/wk in adults with pediatric‐onset hypophosphatasia.