Breakfast significantly reduced the MRT of oxybutynin and N-desethyloxybutynin.

Gastrointestinal absorption of bisphosphonates is highly variable from individual to individual (between-subject variation) and from day to day (within-subject variation), a fact that creates problems both in research and in clinical use of these drugs. We conducted a randomized, two-period cross-over pharmacokinetic (phase I) study to assess the relative bioavailability of two different clodronate preparations: an 800 mg tablet and a 400 mg capsule. Urinary excretion of clodronate correlates with gastrointestinal absorption. To minimize the confounding effect of the high variability of gastrointestinal absorption, we chose as the primary parameter the cumulative amount of clodronate excreted into urine (A e0-t ) during 9 days (7 days of treatment, 2 days of follow-up). The 90% confidence interval calculated for the population medians of A e0-t was 0.83-1.09, well within the 90% confidence interval stipulated for bioequivalence for the area under the curve values (0.80 -1.25). This new procedure for pooling urinary excretion data offered a clear advantage over previous methods, and thus could presumably be used to study other drugs as well that are not metabolized and may show highly variable gastrointestinal absorption. (J Bone Miner Res 1997;12:66-71) INTRODUCTION C LODRONATE (dichloromethylene bisphosphonate) belongs to the bisphosphonates, compounds structurally related to the naturally occurring pyrophosphate, which regulates mineralization of bone matrix. In bisphosphonates, the P-O-P bond of pyrophosphate is replaced by a P-C-P bond, which makes them resistant to enzymatic hydrolysis. Clodronate, like other bisphosphonates, because it inhibits osteoclastic bone resorption, is used clinically in the therapy of hypercalcemia and bone resorption due to malignancy. (1,2) Clodronate, with its high water solubility and extensive ionization, is poorly penetrative through biological membranes. This leads to poor absorption from the gastrointestinal tract, a common characteristic of all bisphosphonates; clodronate's bioavailability is about 2% of the oral dose. The plasma protein binding of the drug is low, i.e., about 30%. (3) The peak serum concentration after a single oral dose is reached in 0.5 h, which may point to site-specific absorption in the (upper) gastrointestinal tract. Absorption occurs to some extent in the stomach and to a larger extent in the small intestine. It is greatly diminished when the drug is given with meals, especially in the presence of calcium and iron.(1,2) Elimination of clodronate from serum is characterized by two clearly distinguished phases: the distribution phase with a half-life of about 2 h (4,5) and a very slow second elimination phase, (3,5,6) which results from its strong binding to bone. (3,6) About 20 -30% of the intravenously administered dose remains in the body (in bone). (3,4,6) When bisphosphonates are given in clinically effective doses, there seems to be no saturation in their total skeletal uptake in humans.(1,2) The bone-unbound portion of the absorbed or...

The pharmacokinetic parameters describing the fate of one intravenous clodronate (disodium dichloromethane diphosphonate) dose was studied in 24 normal subjects and in 24 patients with different degrees of renal insufficiency. The aim of the study was to derive data for adjustment of dosage in relation to renal function. Disodium clodronate in serum and urine samples was analyzed by capillary gas chromatography with mass-selective detection. The renal clearance (CLR) of clodronate was highly dependent on renal function and declined successively with declining glomerular filtration rate (GFR). Plasma clearance (CLP) declined, too, but to a lesser degree than CLR. The impairment of renal function resulted in decreased cumulative urinary elimination of clodronate and increased total areas under the serum concentration-time curve (AUC0-infinity). Hence, as the renal elimination of clodronate diminishes with decreasing GFR, there is a related retention of the substance. As a result of the present study, the following dosages are recommended: creatinine clearance (CLCr) from 50 to 80 ml/minute, 75-100% of normal dose; CLCr 12-50 ml/minute, 50-75% of normal dose; and ClCr < 12 ml/minute, 50% of normal dose. The results must be interpreted with caution in patients with malignancy and severe skeletal disease, in whom the nonrenal clearance may vary markedly.

Estramustine phosphate is generally used as a second-line treatment in patients with advanced prostate cancer. The bone metastases due to the cancer are often treated simultaneously with clodronate in order to relieve the bone pain. Therefore, the interaction of clodronate (800 mg orally four times daily) and estramustine phosphate (280 mg orally twice daily) on their bioavailability was studied in twelve patients with prostate carcinoma and bone metastases. The drugs were first given separately, each to six patients, for five days, and then concomitantly for the same period. The bioavailabilities of the drugs were calculated on the last day of each treatment period. When clodronate was given alone, its concentrations in serum and AUC for one dose interval (6 hr) did not differ from those obtained with the drug given concomitantly with estramustine phosphate, nor did the combination of estramustine phosphate change the excretion of clodronate in urine. The serum concentrations of estramustine phosphate were elevated by about 80% when the drug was given together with clodronate. The AUC for one dose interval (12 hr) was also significantly higher for estramustine phosphate with clodronate than without clodronate. The urinary excretion of estrone, a major metabolite of estramustine phosphate, was also significantly higher after the admission with clodronate. The results suggest that clodronate increases the oral bioavailability of estramustine phosphate.

Introduction Multiple myeloma (MM) is the second most common hematological malignancy in Europe and the US. The median survival after diagnosis is approximately 4-5 years (Röllig et al The Lancet 2015), with recent improvement observed in younger (Kyle et al Expert Rev Hematol 2014) and older patients (Kumar et al Leukemia 2013). The improvement in outcomes of MM patients is largely due to the introduction of autologous stem cell transplant (ASCT) and novel treatments including proteasome inhibitors and immunomodulators. Norwegian guidelines state that the preferred frontline treatment for MM patients under 65-70 years old is ASCT, but this option may be limited by comorbidity. Here, we report results from a retrospective, non-interventional study using data collected at the MM registry at Oslo University Hospital (OUS), Norway. The aim was to describe patient and disease characteristics, overall survival (OS), and potential predictors of death for the study population in Norway. Methods The study period was from 1 Jan 2008 to 31 Dec 2015. Patients (n=169) aged 18 years or older at MM diagnosis and who were treated at OUS (ASCT or not) or in 1 of 5 regional hospitals (ASCT only, with ASCT received at OUS and other treatments received locally), during the study period, were included. Study entry was defined as date of MM diagnosis and follow-up started from study entry. End of follow-up occurred at the first of: end of study period, loss to follow-up, or death. Variables used were part of routine practice. Descriptive analysis was done at diagnosis for the overall population, for patients who received ASCT (n=100), and for those who did not receive ASCT at any time during the study period (n=69). At treatment line 1, Cox models were used to identify potential predictors for OS. Results In the study, 55.6% of patients were diagnosed with MM at OUS and 25 of those patients (14.8% of total population) received ASCT. Patients who did not receive ASCT were older and included a larger percentage of women than in the transplant cohort (mean age non-ASCT 73.1±11.2 with 55.1% women and for ASCT 55.5±6.7 years with 45.0% women). More MM patients were diagnosed with Bence Jones (BJ) (21.9% of patients) or IgG type myeloma (54.4% of patients) than IgA type (20.1% of patients) (Table 1). Of transplant patients, more were of International Staging System (ISS) stage I or stage II than stage III MM, though 35.0% of patients were of unknown stage. Most non-transplant patients had unknown ISS stage, followed by stages II and III and the least number of patients were of stage I. Of the CRAB symptoms at diagnosis, most ASCT patients showed no hypercalcemia (80.0%), no renal impairment (90.0%), or no anemia (68.0%), and 34.0% presented with skeletal destruction (Table 1). Similarly, most non-transplant patients had no hypercalcemia (87.0%) and no renal impairment (79.7%) at diagnosis. Anemia and skeletal destruction were not measured in 24.6% of non-transplant patients. Of those with recorded results, more non-transplant patients had skeletal destruction than not and approximately the same number of non-transplant patients presented with anemia than not. High-risk cytogenic abnormalities, a criterion of the revised (R)-ISS, was unknown for most patients (80.5%). Median OS from start of treatment line 1 was 75.93 (90% confidence interval (CI): 68.23 to not reached) months for transplant patients and 34.20 (90% CI: 25.57-42.16) months for non-transplant patients. Variables including age group, sex, CRAB symptoms at diagnosis, type of first therapy, and type of MM at diagnosis were included in the Cox models per cohort, if they had a missingness of <20%. Hypercalcemia at diagnosis was a significant predictor for OS for the transplant cohort, while anemia at diagnosis gave a decreased risk of death. Hypercalcemia as well belonging to the older age groups (e.g., 61-70 years and 71-80 years) were significant predictors of death for the non-transplant patients (Table 2). Conclusions For MM patients in Norway, overall survival was much greater for patients receiving transplant in the first line. Hypercalcemia at diagnosis predicted death for both transplant and non-transplant cohorts and anemia at diagnosis was identified as a decreased risk of death for transplant patients, but not well-recorded for non-transplant patients. Belonging to an older age group (>71 or 80 years old) also was a significant predictor of death, but only for non-transplant patients. Disclosures Schjesvold: Oncopeptides: Consultancy; Celgene: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy; Takeda: Consultancy, Honoraria; Bayer: Consultancy; Amgen: Consultancy, Honoraria, Research Funding; Adaptive: Consultancy; Janssen: Consultancy, Honoraria, Research Funding; Abbvie: Honoraria; Novartis: Honoraria. Jenna:Janssen-Cilag: Other: Employee of StatFinn & EPID Research, contracted by Janssen-Cilag. Sõnajalg:Janssen-Cilag: Other: Employee of StatFinn & EPID Research, contracted by Janssen-Cilag. Leval:Janssen-Cilag: Employment. Rana:Janssen-Cilag: Employment. Castren-Kortekangas:Janssen-Cilag: Employment. Borgsten:Janssen-Cilag: Employment.