SERUM KINETICS, BIOAVAILABILITY AND BONE SCANNING OF TC-99M-LABELED SODIUM OLPADRONATE IN PATIENTS WITH DIFFERENT RATES OF BONE TURNOVER

The activity of olpadronate labelled with technetium-99m(Tc-99m) was m onitored in plasma and urine samples after single oral (925 MBq Tc-99m /10 mg, coadministered with 50 mg cold drug) and intravenous (925 MBq Tc-99m/5 mg) administrations to two groups of patients with different rates of bone turnover. The first group comprised high bone turnover ( HBTO) patients suffering from Paget's bone disease; the second group c omprised patients with normal to low bone turnover (NBTO) having the d iagnosis of rheumatoid arthritis and secondary osteoporosis. Kinetic v ariables were correlated with anthropomorphometric variables, biologic al markers of bone metabolism and plasma proteins. Data were also obta ined after repeatedly dosing the HBTO patients. Additionally, Paget's bone and healthy bone (PB/HB) uptake before and after low-dose oral tr eatment were assessed by means of scintigraphy. Results showed that mo st of the kinetic variables did not differ between the two groups of p atients, except for a greater V-ss and smaller blood area under the cu rve AUC in the patients with HBTO. After a repeated-dose administratio n period, the blood AUC activity and Whole Body Retention (WBR) of the HBTO patients tended to be similar to those of the NBTO patients. In both groups, after oral dosing, the C-max was 20 times lower than the C-0.5 after i.v. injection, and the oral bioavailability ranged from 3 % to 4%. Finally, the plasma t(1/2)B ranged from 9 to 14 h. Correlatio n coefficients were obtained from multiple regression analysis; kineti c variables showed very low correlations with anthropomorphometric mea surements. In contrast the V-ss and WBR were significantly correlated with serum alkaline phosphatase levels and the V-ss also with urine hy droxyproline levels. Plasma protein concentration was also correlated with excretion parameters such as CL(p) and plasma t(1/2)B after an or al dose. Scintigraphic studies in the HBTO group allowed bone selectiv ity to be seen through skeletal drug uptake. The 15 Pagetic lesions an alysed in the HBTO group showed a decrease in PB/HB ratio from 3.8 in the basal study to 2.7 after olpadronate administration for 30 days at the rate of 50 mg/day. In conclusion, the kinetic profile of Tc-99m-l abelled olpadronate, mainly AUC and WBR, showed a dependence upon bone metabolism and seemed unrelated to body size variables. HBTO patients showed a lower blood AUC but a higher V-ss. Both variables may have b een reflecting the fact that the drug binds selectively with calcified tissues and, in turn,with the target compartment. Scintigraphy confir med the labelled-compound bone selectivity as a desirable feature for a bone-scanning agent.