Serum kinetics, bioavailability and bone scanning of 99mTc-labelled sodium olpadronate in patients with different rates of bone turnover

Abstract

The activity of olpadronate labelled with technetium-99m(99mTc) was monitored in plasma and urine samples after single oral (925 MBq 99mTc/10 mg, coadministered with 50 mg cold drug) and intravenous (925 MBq 99mTc/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 comprised patients with normal to low bone turnover (NBTO) having the diagnosis of rheumatoid arthritis and secondary osteoporosis. Kinetic variables were correlated with anthropomorphometric variables, biological markers of bone metabolism and plasma proteins. Data were also obtained after repeatedly dosing the HBTO patients. Additionally, Paget's bone and healthy bone (PB/HB) uptake before and after low-dose oral treatment were assessed by means of scintigraphy. Results showed that most of the kinetic variables did not differ between the two groups of patients, except for a greater Vss and smaller blood area under the curve AUC in the patients with HBTO. After a repeated-dose administration 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 Cmax was 20 times lower than the C0.5 after i.v. injection, and the oral bioavailability ranged from 3% to 4%. Finally, the plasma t1/2 beta ranged from 9 to 14 h. Correlation coefficients were obtained from multiple regression analysis; kinetic variables showed very low correlations with anthropomorphometric measurements. In contrast the Vss and WBR were significantly correlated with serum alkaline phosphatase levels and the Vss also with urine hydroxyproline levels. Plasma protein concentration was also correlated with excretion parameters such as CLP and plasma t1/2 beta after an oral dose. Scintigraphic studies in the HBTO group allowed bone selectivity to be seen through skeletal drug uptake. The 15 Pagetic lesions analysed 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 99mTc-labelled 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 Vss. Both variables may have been reflecting the fact that the drug binds selectively with calcified tissues and, in turn, with the target compartment. Scintigraphy confirmed the labelled-compound bone selectivity as a desirable feature for a bone-scanning agent.

Relationships Between Pharmacokinetics and Rate of Bone Turnover After Intravenous Bisphosphonate (Olpadronate) in Patients With Paget's Disease of Bone

“…For adequate description of PK, the bone compartment, the target of bisphosphonate concentration and action should be considered. Previous studies tried to address these issues with the use of radiolabeled bisphosphonates or the determination of the so‐called bisphosphonate space that estimates skeletal uptake of the bisphosphonate by the simultaneous measurements of glomerular filtration using Tc‐labeled hexamethylene diphosphonate (HMDP) and Cr‐EDTA (13, 14) . Although such studies provide valuable information of clinical PK of bisphosphonates, estimations are indirect and uncertain.…”

Efficacy and Safety of Bisphosphonate Therapy in Children with Osteogenesis Imperfecta: A Systematic Review

“…In one study [17] not NTx but urine C-telopeptide and deoxypiridinoline were assessed. Furthermore, the low bioavailability of the administrated oral BPs (0.65% for risedronate [49] and 3-4% for olpadronate [50]) might explain in part these nonsignificant changes in resorptive markers. Although higher doses of oral BPs could lead to a stronger bone metabolism effect [33], wide variations between the different types of BPs regarding the biological activity on bone tissue should be taken into consideration in the interpretation of resorptive markers.…”

Ibandronate: A Clinical Pharmacological and Pharmacokinetic Update

“… t 1/2 , elimination half‐life (t 1/2 ); VD, volume of distribution; CLR, renal clearance; ss, steady state. References: ibandronate (data on file), tiludronate, 48 zoledronate, 49 , 50 alendronate, 46 , 51 incadronate, 43 olpandronate, 52 risedronate, 47 , 53 pamidronate, 44 , 45 , 54 , 55 and clodronate 56 …”