Relationships between pharmacokinetics and rate of bone turnover after intravenous bisphosphonate (olpadronate) in patients with Paget's disease of bone

Abstract

Bisphosphonates are the treatment of choice of Paget's disease, but variable responses have been reported, and despite the availability of potent bisphosphonates, biochemical remission is not achieved in a substantial number of patients. This may, in part at least, be because of the influence of pharmacokinetics of bisphosphonates on their pharmacodynamics. That is the response of bone turnover to treatment. To address this issue, we examined the pharmacokinetics and pharmacodynamics of the bisphosphonate olpadronate given intravenously to 75 patients with Paget's disease, using a specific assay for olpadronate concentrations in serum and urine. The skeletal uptake of olpadronate varied greatly among patients and ranged between 10% and 90% of the administered dose. The two major determinants of skeletal uptake were renal function and prevalent rate of bone turnover. Serum and urinary data were well described by a physiology-based four-compartment pharmacokinetic model that takes into account the distribution of the bisphosphonate in the bone and its subsequent elimination. Bone turnover was suppressed to well within the normal range in virtually all patients. This, together with the absence of resolution of effect during 1 year, does not allow the construction of an adequate integrated pharmacokinetic/pharmacodynamic model. However, the pharmacokinetic model, described for the first time in Paget's disease, can accurately simulate the amount of bisphosphonate delivered to the skeleton with different dose regimens as well as the amount still present in bone after 1 year. Such approaches can lead to improved patient care and individualization of treatment of Paget's disease with bisphosphonates.