Mean Effective Half-life Research Articles

Pharmacokinetics, safety, and tolerability of the novel tetrameric gadolinium-based MRI contrast agent gadoquatrane in healthy Chinese and Japanese men: Two randomized dose-escalation studies including concentration–QTc modeling

PurposeTo investigate the pharmacokinetics, safety, and tolerability of the novel tetrameric high-relaxivity gadolinium-based contrast agent gadoquatrane in Japanese (Study 1) and Chinese men (Study 2). Participants and methodsIn two similarly designed single-center, randomized, single-blind, placebo-controlled, consecutive-cohort dose-escalation studies, healthy volunteers were randomly assigned to intravenous administration of gadoquatrane (0.01–0.1 mmol gadolinium/kg body weight) or placebo. Study procedures included blood sampling and collection of urine for pharmacokinetic analyses and safety assessments. ResultsTwenty-five healthy Japanese men (mean age ± standard deviation: 26±5.9 years) and 23 healthy Chinese men (31±7.6 years old) were evaluated. In both studies, the pharmacokinetic profile of gadoquatrane was characterized by rapid distribution of the drug into the extracellular space and fast renal elimination. Postdose gadolinium concentrations rapidly declined with a geometric mean effective half-life of 1.3–1.4 h. The exposure increased approximately dose-proportionally with dose. The body weight-normalized volume of distribution was constant across dose levels (0.21–0.24 L/kg). Total recovery of gadolinium in urine amounted to 82–95 % (Study 1) and 96–99 % (Study 2) of the dose administered.Only a few mild, transient adverse events were reported, none of which gave rise to any safety concerns. Exploratory drug concentration–QTc modeling indicated no risk of a clinically relevant QT/QTc prolongation at the anticipated diagnostic dose. ConclusionGadoquatrane was safe and well tolerated at all doses tested. The pharmacokinetic profile was essentially the same as that of other extracellular macrocyclic gadolinium-based contrast agents and was consequentially also similar for Japanese and Chinese participants.

The impact of different computational assumptions in 131 I dosimetry for hyperthyroidism therapy.

The goal of the current study was to investigate the impact of different computational models on 131 I dosimetry prior to hyperthyroidism therapy. It was also aimed to highlight an accurate and cost-effective method for routine dosimetry of graves and toxic adenoma patients. A cohort of 45 patients was recruited in the current study with Graves (n=30) and Toxic Adenoma (n=15) diseases. The eligibility criterion was determined using the patients' blood test, 99m Tc- pertechnetate scintigraphy, and ultrasound scan. A properly calibrated thyroid probe equipped with sodium iodide crystal [NaI(Tl)] was used to obtain the uptake measurements at 2, 24, 48, 72, and 96h following administration of 0.27-0.73MBq 131 I tracer. The absorbed radiation dose of the thyroid gland/nodule was calculated by three different methods. The calculation models were based on the time-integrated activity (recommended by MIRD), effective half-life (recommended by EANM), and ellipsoidal-shape assumption. The mean effective half-life was 138±41h and 110±48h in Graves and Toxic Adenoma patients, respectively. The mean residence time was 125±5h in Graves patients, while it was 93±55h in Toxic Adenoma. The amount of 131 I activity required to deliver 200Gy to the thyroid gland in Graves patients was calculated as 436±381MBq, 426±370MBq, and 488±455MBq according to MIRD, EANM, and ellipsoidal-shape model, respectively. However, the activity required to impart 300Gy in the toxic nodules was computed as 622±332MBq by MIRD, 907±588MBq by EANM, and 1060±639MBq by the ellipsoidal-shape model. Overall, no significant difference was found between the MIRD and both of the EANM and ellipsoidal-shape models in the Graves patients (R2 =0.99, P>0.05). In contrast, less agreement (R2 =0.86) was shown between EANM and MIRD in Toxic Adenoma patients with no statistically significant difference (P>0.05), while the difference was significant (Pvalue <0.05) between the MIRD and the ellipsoidal-shape model with moderate association (R2 =0.66). It was deduced that the effective half-life-based model (EANM model) is a successful and affordable method for performing dosimetry in Graves patients. While, unit density sphere model sounds the most appropriate approach to be used in Toxic Adenoma dosimetry. However, using the ellipsoidal-shape assumption in the thyroid gland/or nodule dose calculation leads to redundantly larger activity administration.

Safety, tolerability, and pharmacokinetics of the selective prostacyclin receptor agonist ralinepag in single and multiple dosing studies of an immediate-release oral formulation in healthy volunteers.

Ralinepag (APD811), an oral, potent, and selective prostacyclin receptor (IP) agonist is being developed for treatment of pulmonary arterial hypertension. Two, single-center, randomized, double-blind, placebo-controlled, Phase 1 studies (single ascending dose and multiple ascending dose) evaluated an oral immediate-release capsule formulation of ralinepag in healthy subjects. Blood samples assessed plasma pharmacokinetics and safety and tolerability data monitored adverse events, vital signs, laboratory findings, physical examination, and electrocardiograms. Eighty-two healthy subjects (single ascending dose (n = 32) and multiple ascending dose (n = 50)) completed the studies. No clinically significant safety issues were observed, except one serious adverse event of atrial fibrillation considered moderate in intensity. In the single ascending dose study, ralinepag was tolerated up to 100 µg (single dose), but not 200 µg due to nausea and vomiting. Dose proportional mean ralinepag plasma exposure measures were observed. Maximum plasma concentrations were reached within 1.0–1.5 h post-dose and mean terminal elimination half-life values from 20.5–26.4 h. In the multiple ascending dose study, ralinepag tolerability decreased with increasing QD or BID dose. Dose proportional steady-state plasma exposure measures were observed where evaluable, with mean steady-state peak-to-trough ratios ranging from 3.34–4.49 (QD dosing) and 1.95–2.36 (BID dosing). Mean effective half-life values ranged from 17.5–18.4 h, reflecting ∼1.7-fold (QD dosing) and ∼2.6-fold (BID dosing) accumulation in plasma exposure. Safety and tolerability of oral immediate-release ralinepag was generally consistent with expectations for this drug class, but more individualized dose escalation appears warranted. Ralinepag exhibited favorable pharmacokinetic properties, with BID dosing producing desired minimal steady-state peak-to-trough fluctuation. Overall, results supported further clinical investigation of ralinepag and guided development of an extended-release formulation to facilitate QD dosing.

Abstract P1-19-37: Pharmacokinetic assessment of ribociclib, an oral CDK4/6 inhibitor, and the interaction with endocrine therapy partners in patients with advanced breast cancer

Background: Ribociclib (RIB) is an oral CDK4/6 inhibitor used in combination with endocrine therapy (ET) to treat women with hormone receptor-positive (HR+), human epidermal growth factor receptor-2-negative locally advanced breast cancer (ABC). ET partners are aromatase inhibitors (AI), eg letrozole or anastrozole, in pre-/perimenopausal women, and AI or fulvestrant in postmenopausal women. Here we characterize the pharmacokinetics (PK) of RIB as a single agent in patients with advanced cancer, assess the potential for drug-drug interactions (DDIs) between RIB and these ET partners in patients with HR+ ABC, and estimate the in vivo potency of RIB on CDK4. Methods: The PK of RIB as a single agent was characterized in patients with advanced cancer in study CLEE011X2101 (X2101; NCT01237236). The potential for DDIs was assessed by comparing the steady-state exposures (AUC, Cmax and Ctrough) of RIB when used alone in study X2101 with those of RIB when used in combination with ET in patients with HR+ ABC (studies CLEE011X2107 [X2107; NCT01872260], MONALEESA-2 [ML-2; NCT01958021], MONALEESA-7 [ML-7; NCT02278120], and MONALEESA-3 [ML-3; NCT02422615]). The effect of RIB on the PK of ET was also assessed in these studies. The CDK4 inhibition of RIB in patients was estimated based on its steady-state exposure and in vitro potency. Results: In study X2101, RIB showed rapid absorption (median Tmax 1-4 h), mean effective half-life (t1/2,acc) of 12.0-33.1 h, and slightly over-proportional increases in exposure (Cmax and AUC) over the dose range of 50-1200 mg QD. Steady state was generally achieved by Day 8, with a geo-mean accumulation ratio of 2.51 at the dose of 600 mg. The PK of RIB in combination with letrozole in studies X2107, ML-2 and ML-7 was consistent with that of RIB in study X2101 (Table 1). Additionally, in study ML-7, exposure parameters for letrozole were similar between the letrozole + RIB 600 mg and letrozole alone arms: Ctrough geo-mean (geo-CV%) 92.7 ng/mL (50.2%) vs 96.8 ng/mL (55.9%). In study ML-7, the steady-state exposure (Ctrough) of RIB in combination with anastrozole was consistent with that in study X2101 (Table 1). Furthermore, in the same study, anastrozole Ctrough geo-mean (geo-CV%) values were broadly similar in the anastrozole + RIB 600 mg and anastrozole alone arms considering variability: 38.5 ng/mL (59.5%) and 28.4 ng/mL (70.4%). Mean plasma Ctrough of RIB in combination with fulvestrant observed in study ML-3 was consistent with the results in study X2101 (Table 1). Although PK of fulvestrant was not evaluated, it is unlikely to have a DDI with RIB because induction or inhibition of CYP3A4 have been shown to have no impact on the PK of fulvestrant. Population PK analysis suggests that concomitant use of letrozole, anastrozole, or fulvestrant has no statistically significant or clinically relevant impact on RIB exposure. Based on steady-state RIB exposure in patients, and its in vitro potency measured by inhibition of Rb phosphorylation in CDK4-dependent breast cancer cell lines, RIB is predicted to attain approximately 90% inhibition of CDK4 inhibition at steady state. Conclusion: RIB demonstrated rapid absorption and a mean t1/2,acc of 32.0 h after oral administration of 600 mg QD in patients with cancer. Concomitant use of ET partners letrozole, anastrozole, and fulvestrant appears to have no clinically relevant PK interaction with RIB in patients with ABC. Citation Format: Yan Ji, Tanay Samant, Michelle Quinlan, Abhijit Chakraborty. Pharmacokinetic assessment of ribociclib, an oral CDK4/6 inhibitor, and the interaction with endocrine therapy partners in patients with advanced breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P1-19-37.

Accuracy of kidney dosimetry performed using simplified time activity curve modelling methods: a 177Lu-DOTATATE patient study

177Lu-DOTATATE therapy has been shown to produce encouraging results in treatment of neuroendocrine tumours (NETs). Unfortunately, since dosimetry for radionuclide therapy is considered to be challenging, typically similar amount of radiopharmaceutical is administered to every patient. There is growing evidence that the efficacy of this therapy can be significantly improved by employing personalized protocols, based on the organ-at-risk dosimetry. The aim of this study is to propose a practical and accurate dosimetry protocol based on the simplified acquisition schedules.Data from fifty-three therapy cycles in thirty-nine NET patients were analyzed. Three SPECT/CT scans, acquired at 4 h (D0), 23 h (D1) and 70 h (D3) after injection, were performed. The kidney volume was determined using CT and the activity was determined from quantitative SPECT using an iterative thresholding method. For each dataset, four methods were used to model the time-activity-curves (TAC): M1—two trapezoid segments (0 to D0 and D0 to D1), followed by monoexponential fit to D1 + D3 data; M2—monoexponential fit to D0 + D1 + D3 data; M3 and M4—monoexponential fit to D0 + D3 and D1 + D3 data, respectively. Additionally, kidney doses obtained from single time point method using a monoexponential curve with the population mean effective half-life, normalized to activities at D0 or D1 or D3 points, were calculated. The accuracy of simplified dosimetry methods was assessed as the percentage difference relative to doses calculated from M1.The major contribution to the absorbed dose estimate comes from the area under the late time portion of the TAC (D1 to infinity). Therefore, information from the late scan (D3) is crucial for the determination of kidney absorbed doses. Single time point method using monoexponential TAC, with the population mean effective half-life normalized to the late data point (48–72 h for kidneys) produces <10% deviation in the absorbed dose estimation, thus is recommended for clinical use.

Phase 1 study of AG-881, an inhibitor of mutant IDH1/IDH2, in patients with advanced IDH-mutant solid tumors, including glioma.

2002 Background: Isocitrate dehydrogenase 1 and 2 mutations (mIDH1/2) occur in solid tumors including glioma, and result in production of the oncometabolite 2-hydroxyglutarate (2-HG), promoting tumorigenesis. AG-881 is an oral, potent, brain-penetrant inhibitor of mIDH1/2 that reduces 2-HG by up to 98% in glioma models. Methods: Patients (pts) with recurrent/progressive mIDH1/2 glioma (G) and non-glioma (NG) solid tumors were eligible to receive AG-881 daily in continuous 28-day cycles. Dose escalation cohorts for G and NG solid tumors enrolled using a Bayesian logistic regression model (BLRM) escalation guided by the overdose control (EWOC). Blood and tumor samples were evaluated for pharmacokinetics (PK)/pharmacodynamics (PD). Dose-limiting toxicity (DLT) was defined as a Grade (Gr) ≥3 AG-881-related event in Cycle 1 or by sponsor designation. Results: As of 1Dec2017, 93 pts had received AG-881 (G: 52; NG: 41) and 20 remain on AG-881 (G: 19, NG: 1). Demographics: M/F = 40/53; median age = 51; median no. prior systemic therapies = 3 (range 1–7). Seven initial dose levels were tested: 25mg QD (n = 10); 50mg QD (n = 12); 100mg QD (n = 21); 200mg QD (n = 22); 200mg BID (n = 5); 300mg QD (n = 5) and 400mg QD (n = 6). To further assess safety and PK in the G cohort, a 10mg dose level was tested (n = 6) and 6 additional pts enrolled in the 50mg cohort. PK showed less than dose-proportional plasma exposure with a mean effective half-life of 71±54 hrs. Common adverse events (AEs) across all pts regardless of attribution: fatigue (38.7%), nausea (35.5%), ALT/AST increase (34.4% each). Elevated ALT/AST AEs were dose-dependent (n = 0 at 10mg, n = 7 at ≤50mg, n = 10 at 100mg, n = 20 at > 100mg). Five G pts experienced DLTs at 100mg and above: Gr ≥2 ALT/AST which resolved to Gr ≤1 with dose modification (n = 4) or discontinuation (n = 1). The MTD or RP2D were not reached by BLRM with EWOC. Conclusions: AG-881 was associated with a favorable safety profile at doses < 100mg in pts with glioma and non-glioma solid tumors. No ALT/AST AEs Gr > 2 were observed at 10mg and 50mg. These doses are being explored in an ongoing perioperative glioma study. Updated safety, PK/PD, and efficacy data will be presented. Clinical trial information: NCT02481154.

External radiation exposure, excretion, and effective half-life in 177Lu-PSMA-targeted therapies

BackgroundProstate-specific membrane antigen (PSMA)-targeted therapy with 177Lu-PSMA-617 is a therapeutic option for patients with metastatic castration-resistant prostate cancer (mCRPC). To optimize the therapy procedure, it is necessary to determine relevant parameters to define radiation protection and safety necessities. Therefore, this study aimed at estimating the ambient radiation exposure received by the patient. Moreover, the excreted activity was quantified.ResultsIn total, 50 patients with mCRPC and treated with 177Lu-PSMA-617 (mean administered activity 6.3 ± 0.5 GBq) were retrospectively included in a bi-centric study. Whole-body dose rates were measured at a distance of 2 m at various time points after application of 177Lu-PSMA-617, and effective half-lives for different time points were calculated and compared. Radiation exposure to the public was approximated using the dose integral. For the estimation of the excreted activity, whole body measurements of 25 patients were performed at 7 time points.Unbound 177Lu-PSMA-617 was rapidly cleared from the body. After 4 h, approximately 50% and, after 12 h, approximately 70% of the administered activity were excreted, primarily via urine. The mean dose rates were the following: 3.6 ± 0.7 μSv/h at 2 h p. i., 1.6 ± 0.6 μSv/h at 24 h, 1.1 ± 0.5 μSv/h at 48 h, and 0.7 ± 0.4 μSv/h at 72 h. The mean effective half-life of the cohort was 40.5 ± 9.6 h (min 21.7 h; max 85.7 h). The maximum dose to individual members of the public per treatment cycle was ~ 250 ± 55 μSv when the patient was discharged from the clinic after 48 h and ~ 190 ± 36 μSv when the patient was discharged after 72 h.ConclusionsIn terms of the radiation exposure to the public, 177Lu-PSMA is a safe option of radionuclide therapy. As usually four (sometimes more) cycles of the therapy are performed, it must be conducted in a way that ensures that applicable legal requirements can be followed. In other words, the radiation exposure to the public and the concentration of activity in wastewater must be sub-marginal. Therefore, in certain countries, hospitalization of these patients is mandatory.

Biokinetic and dosimetric aspects of 64CuCl2 in human prostate cancer: possible theranostic implications

BackgroundThe aim of the present study is to evaluate the kinetics and dosimetry of 64CuCl2 in human prostate cancer (PCa) lesions.We prospectively evaluated 50 PCa patients with biochemical relapse after surgery or external beam radiation therapy. All patients underwent 64CuCl2-PET/CT to detect PCa recurrence/metastases. Volumes of interest were manually drawn for each 64CuCl2 avid PCa lesion with a diameter > 1 cm on mpMRI in each patient. Time-activity curves for all lesions were obtained. The effective and biological half-life and the standard uptake values (SUVs) were calculated. Tumour/background ratio (TBR) curves as a function of time were considered. Finally, the absorbed dose per lesion was estimated.ResultsThe mean effective half-life of 64CuCl2 calculated in the lymph nodes (10.2 ± 1.7 h) was significantly higher than in local relapses (8.8 ± 1.1 h) and similar to that seen in bone metastases (9.0 ± 0.4 h). The mean 64CuCl2 SUVmax calculated 1 h after tracer injection was significantly higher in the lymph nodes (6.8 ± 4.3) and bone metastases (6.8 ± 2.9) than in local relapses (4.7 ± 2.4). TBR mean curve of 64CuCl2 revealed that the calculated TBRmax value was 5.0, 7.0, and 6.2 in local relapse and lymph node and bone metastases, respectively, and it was achieved about 1 h after 64CuCl2 injection. The mean absorbed dose of the PCa lesions per administrated activity was 6.00E-2 ± 4.74E-2mGy/MBq. Indeed, for an administered activity of 3.7 GBq, the mean dose absorbed by the lesion would be 0.22 Gy.ConclusionsDosimetry showed that the dose absorbed by PCa recurrences/metastases per administrated activity was low. The dosimetric study performed does not take into account the possible therapeutic effect of the Auger electrons. Clinical trials are needed to evaluate 64Cu internalization in the cell nucleus that seems related to the therapeutic effectiveness reported in preclinical studies.

Pharmacokinetics and safety of indacaterol and glycopyrronium (IND/GLY) following repeated once daily inhalation from a fixed-dose combination in healthy Chinese subjects .

Indacaterol/glycopyrronium (IND/GLY) is a once-daily fixed-dose combination of two long-acting bronchodilators: indacaterol 110µg (long-acting β₂-adrenergic agonist, LABA) and glycopyrronium 50µg (long-acting muscarinic antagonist, LAMA). This study assessed the pharmacokinetics of IND/GLY 110/50 µg following multiple once-daily inhaled administrations in healthy Chinese subjects. This was a single-centre, open-label, multiple-dose study of inhaled IND/GLY delivered via the Breezhaler^® device. Pharmacokinetic samples were collected on day 1 after first dose, on days 5, 7, 10, and 12 (predose (trough)) and on day 14 (steady state) after last dose for pharmacokinetic analysis using non-compartmental analysis. Both IND and GLY were absorbed rapidly after inhalation of IND/GLY (t_max: IND, 15 minutes; GLY, 5 minutes). Accumulation through systemic exposure of both IND and GLY from day 1 to day 14 was observed (mean accumulation ratio (R_acc) of AUC_0-24h (day 14/day 1): IND, 3.02; GLY 2.94; estimated accumulation ratio of C_max: IND 1.56; GLY 1.33). Mean effective half-life (t_1/2,acc) was 41.3h and 40.0h for IND and GLY, respectively. Pharmacokinetic steady states were reached after 12 and 10 days of daily dosing for IND and GLY, respectively. There was one mild adverse event (AE) not related to the study drug. No discontinuations due to treatment related AEs/SAEs (adverse event/serious adverse event) were reported. In healthy Chinese subjects, multiple once-daily inhaled doses of IND/GLY 110/50 µg were rapidly absorbed and were safe and well tolerated. The comparison of systemic exposure data following inhalation of IND/GLY 110/50 µg in Chinese vs. the non-Chinese populations did not indicate any clinically relevant differences across ethnicities. .

Abstract B31: A Phase I study of single-agent ribociclib in Japanese patients with advanced solid tumors

Abstract Background: Ribociclib (LEE011), an orally bioavailable, highly specific cyclin-dependent kinase (CDK) 4/6 inhibitor, causes cell cycle arrest and tumor growth inhibition in multiple preclinical models with intact retinoblastoma protein (pRb+). During a Phase I dose escalation study in the US and Europe, preliminary signs of clinical activity were observed when patients with pRb+ advanced solid tumors and lymphomas were treated with single-agent ribociclib (NCT01237236). Here we report on a Phase I dose escalation study in Japanese patients with advanced solid tumors (NCT01898845). Methods: Patients with pRb+ advanced solid tumors were treated with escalating doses of ribociclib on a 21-of-28-day schedule. Dose escalation decisions were based on the synthesis of relevant data, guided by a Bayesian Logistic Regression Model and escalation with overdose control principle. The primary objective was to establish the maximum tolerated dose and/or recommended dose for expansion (RDE) of ribociclib. Secondary objectives included assessment of the safety, pharmacokinetics, and preliminary antitumor activity of ribociclib. Results: As of January 28, 2015, 17 patients (median age 57 years [range 33-73]) were treated with 400 mg (n = 4) and 600 mg (n = 13) ribociclib. Primary sites of cancer were breast (n = 4), esophagus (n = 9), peritoneum (n = 3), and soft tissue (n = 1). Patients were heavily pretreated: 71% (n = 12) received ≥3 prior antineoplastic regimens. Median durations of treatment were 54.5 days (400 mg) and 59.0 days (600 mg). The mean relative dose intensities were 100% (400 mg) and 98% (600 mg). Six dose-limiting toxicities were reported: one at 400 mg (Grade [G]3 febrile neutropenia) and five at 600 mg (G3 febrile neutropenia [n = 1]; G4 neutropenia [n = 1]; G4 thrombocytopenia [n = 1]; G3 QTc prolongation [n = 2]). The RDE was declared as 600 mg/day on a 21-of-28-day schedule. Ribociclib was absorbed rapidly (the median Tmax on Cycle 1 Day 1 was 3.12 h [range 1.97-6.00] at 400 mg and 2.97 h [range 1.92-5.87] at 600 mg), and dose-dependent increases in exposure (AUC) were observed. The geometric mean effective half-life on Cycle 1 Day 21 was 63.6 h at 400 mg, and 53.6 h at 600 mg. The most frequent study drug-related adverse events (all-grade, &amp;gt;35% of patients) were (all-grade; G3/4): leukopenia (100%; 82%), neutropenia (94%; 77%), lymphopenia (82%; 53%), thrombocytopenia (71%; 24%), QTc prolongation (41%; 12%), increased creatinine (41%; 0%), nausea (41%; 0%), vomiting (41%; 0%), and anemia (35%; 6%). Four patients had stable disease as best overall response. Conclusions: Single-agent ribociclib demonstrated an acceptable safety and tolerability profile in Japanese patients with advanced solid tumors. The RDE was declared as 600 mg/day on a 21-of-28-day schedule. Ribociclib was absorbed rapidly and showed a dose-dependent plasma exposure. Ribociclib is currently being studied at lower doses in combination with other agents in Japanese patients, including in patients with breast cancer. Citation Format: Yasuhide Yamada, Norifumi Ishikawa, Tomoyuki Kakizume, Takeshi Tajima, Becker Hewes, Toshihiko Doi. A Phase I study of single-agent ribociclib in Japanese patients with advanced solid tumors. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr B31.

Pharmacokinetics of Glycopyrronium Following Repeated Once-Daily Inhalation in Healthy Chinese Subjects.

Glycopyrronium is a once-daily long-acting muscarinic antagonist for the maintenance treatment of patients with chronic obstructive pulmonary disease. This study assessed the pharmacokinetics of inhaled glycopyrronium 50µg once-daily for 14days in healthy Chinese subjects. In this open-label study, 12 Chinese healthy subjects (six males and six females; mean age 23.1years [range 18-26years]) were enrolled and completed the study. Glycopyrronium in plasma was determined using validated liquid chromatography-mass spectrometry method with a lower limit of quantification of 1.5pg/mL. Plasma pharmacokinetic parameters were determined on Day 1 after first dose and on Day 14 (steady state) after last dose using non-compartmental analysis. Trough pharmacokinetic samples (Days 5, 7, 10 and 12) were collected. Safety was also assessed. Glycopyrronium was rapidly absorbed into the systemic circulation after inhalation and its plasma concentrations decreased rapidly thereafter. Median time to reach maximum concentration (T max) was reached within 5min after inhalation on both Days 1 and 14. Accumulation in the systemic exposure to glycopyrronium was observed from the time of first dose administration on Day 1 up to Day 14 and the observed accumulation ratio (R acc) values of area under the plasma drug concentration-time curve [AUC] from time 0 to 24h post-dose (AUC0-24h) and maximum plasma drug concentration (C max) (Day 14/Day 1) were 2.77 and 1.59, respectively. The elimination half-life (T 1/2) was not reported. Mean effective half-life (T 1/2,acc) was 37.7h. Pharmacokinetic steady state was reached after 5days of daily dosing. One subject experienced dry mouth; otherwise glycopyrronium was well tolerated. Comparison of systemic exposure to glycopyrronium in Chinese versus the non-Chinese population did not indicate clinically relevant ethnic differences. Multiple inhaled doses of glycopyrronium were safe and well tolerated.

Dosimetry of bone metastases in targeted radionuclide therapy with alpha-emitting (223)Ra-dichloride.

Ra-dichloride is an alpha-emitting radiopharmaceutical used in the treatment of bone metastases from castration-resistant prostate cancer. Image-based dosimetric studies remain challenging because the emitted photons are few. The aim of this study was to implement a methodology for in-vivo quantitative planar imaging, and to assess the absorbed dose to lesions using the MIRD approach. The study included nine Caucasian patients with 24 lesions (6 humeral head lesions, 4 iliac wing lesions, 2 scapular lesions, 5 trochanter lesions, 3 vertebral lesions, 3 glenoid lesions, 1 coxofemoral lesion). The treatment consisted of six injections (one every 4weeks) of 50kBq per kg body weight. Gamma-camera calibrations for (223)Ra included measurements of sensitivity and transmission curves. Patients were statically imaged for 30min, using an MEGP collimator, double-peak acquisition, and filtering to improve the image quality. Lesions were delineated on (99m)Tc-MDP whole-body images, and the ROIs superimposed on the (223)Ra images after image coregistration. The activity was quantified with background, attenuation, and scatter correction. Absorbed doses were assessed deriving the S values from the S factors for soft-tissue spheres of OLINDA/EXM, evaluating the lesion volumes by delineation on the CT images. In 12 lesions with a wash-in phase the biokinetics were assumed to be biexponential, and to be monoexponential in the remainder. The optimal timing for serial acquisitions was between 1 and 5h, between 18 and 24h, between 48 and 60h, and between 7 and 15days. The error in cumulated activity neglecting the wash-in phase was between 2% and 12%. The mean effective half-life (T 1/2eff) of (223)Ra was 8.2 days (range 5.5-11.4days). The absorbed dose (D) after the first injection was 0.7Gy (range 0.2-1.9Gy. Considering the relative biological effectiveness (RBE) of alpha particles (RBE = 5), D RBE = 899mGy/MBq (range 340-2,450mGy/MBq). The percent uptake of (99m)Tc and (223)Ra (activity extrapolated to t = 0) were significantly correlated. The feasibility of in vivo quantitative imaging in (223)Ra therapy was confirmed. The lesion uptake of (223)Ra-dichloride was significantly correlated with that of (99m)Tc-MDP. The D RBE to lesions per unit administered activity was much higher than that of other bone-seeking radiopharmaceuticals, but considering a standard administration of 21MBq (six injections of 50kBq/kg to a 70-kg patient), the mean cumulative value of D RBE was about 19Gy, and was therefore in the range of those of other radiopharmaceuticals. The macrodosimetry of bone metastases in treatments with (223)Ra-dichloride is feasible, but more work is needed to demonstrate its helpfulness in predicting clinical outcomes.

The Influence of Early Measurements Onto the Estimated Kidney Dose in [(177)Lu][DOTA(0),Tyr(3)]Octreotate Peptide Receptor Radiotherapy of Neuroendocrine Tumors.

Multiple measurements have been required to estimate the radiation dose to the kidneys resulting from [(177)Lu]DOTATATE therapy for neuroendocrine tumors. The aim of this study was to investigate the influence of early time-point measurement in the renal dose calculation. Anterior/posterior whole-body planar scintigraphy images were acquired at approx. 1, 24, 48, and 72 h after administration of [(177)Lu]DOTATATE. Furthermore, we acquired planar 1-bed dynamic recordings in 12 frames (5 min each) during the first hour. We assessed kidney exposure with a three-phase model consisting of a linear increase to the maximum within the initial minutes p.i., followed a bi-exponential decline. This three-phase-model served as reference for evaluating accuracy of dose estimates in 105 kidneys calculated by conventional mono-exponential fitting of the final three and four whole-body images. Mean effective half-life times for the reference model were 25.8 ± 12.0 min and 63.9 ± 17.6 h, predicting a mean renal dose of 5.7 ± 2.1 Gy. The effective half-life time was 46.3 ± 15.4 h for the last four and 63.3 ± 17.0 h for the last three data points. The mean start of the first whole-body measurement was 1.2 ± 0.1 h p.i. The ratio of fast to slow phases was 28.1 ± 23.9% at this time point, which caused a mean absolute percentage dose deviation of 12.4% for four data points, compared to 3.1% for three data points. At a mean time of 2.4 h p.i. (max 5.1 h), the ratio of fast to slow phase declined below 5%. Kinetic analysis of renal uptake using dynamic planar scans from the first hour after injection revealed a fast and a slow washout phase. Although the fast phase did not contribute substantially to the estimated renal dose, it could influence planar measurements performed within the first hours. We found that the presence of two clearance phases can hamper accurate dose estimation based on a single-phase model, resulting in approximately 12.4% dose underestimation, thus potentially resulting in overtreatment. In the absence of dynamic initial recordings, the first dosimetry measurements should therefore be obtained later than 3-5 h after [(177)Lu]DOTATATE injection. Omitting the early whole-body image reduced the dose estimation error to 3.1%.

Single- and multiple-dose pharmacokinetics of inhaled indacaterol in healthy Chinese volunteers

Indacaterol is an inhaled, ultra–long-acting β2-agonist that provides 24-h bronchodilation with once-daily dosing in patients with chronic obstructive pulmonary disorder. This study evaluated the pharmacokinetics, safety, and tolerability of multiple daily inhaled doses of indacaterol 150 or 300 μg once daily in healthy Chinese volunteers. This was a single-center, randomized, double-blind, multiple-dose, parallel-group study, placebo-controlled trial including two doses of indacaterol: 150 and 300 μg. Serum indacaterol was quantified using high-performance liquid chromatography-mass spectrometry with a lower limit of quantification of 0.01 ng/mL. The pharmacokinetic parameters were analyzed using non-compartmental analysis and included C max, T max, and AUC0–24h on Day 1 and AUC0–24h,ss, C max,ss, C min,ss, C av,ss, T max,ss, T 1/2, T 1/2,acc, CL/F, V z/F, and R acc on Day 14 (after repeated once-daily doses). Safety analyses were recorded using physical examination, biochemical tests, and ECG. Indacaterol steady state was achieved after 12–14 days of daily dosing. The mean effective half-life of indacaterol (based on drug accumulation at steady state) was 33.9 and 35.8 h for 150 and 300 μg, respectively. Systemic exposure to indacaterol increased 1.27 and 1.34-fold between the 150- and 300-μg doses on Day 1 (first dose) and Day 14 (repeated dose), respectively. Indacaterol 150 and 300 μg were safe and well tolerated in these volunteers. The pharmacokinetics of multiple inhaled doses of indacaterol 150 and 300 μg (for 14 days) were consistent with moderate systemic accumulation at steady state after repeated once-daily inhalation in healthy Chinese volunteers.

Examining recombinant human TSH primed 131I therapy protocol in patients with metastatic differentiated thyroid carcinoma: comparison with the traditional thyroid hormone withdrawal protocol

Purpose Recombinant human thyroid-stimulating hormone (rhTSH)-based protocol is a promising recent development in the management of differentiated thyroid carcinoma (DTC). The objectives of this prospective study were: (1) to assess the feasibility and efficacy of the rhTSH primed 131I therapy protocol in patients with DTC with distant metastatic disease, (2) to perform lesional dosimetry in this group of patients compared to the traditional protocol, (3) to document the practical advantages (patient symptoms and hospital stay) of the rhTSH protocol compared to the traditional thyroid hormone withdrawal protocol, (4) to document and record any adverse effect of this strategy, (5) to compare the renal function parameters, and (6) to compare the serum TSH values achieved in either of the protocols in this group of patients.

Long-term behaviour of 137Cs in spruce bark in coniferous forests in the Czech Republic

Activity concentrations of 137Cs were detected in more than 400 outer spruce bark samples collected at sites variably affected by Chernobyl fallout across the Czech Republic in 1995 and 2010. The temporal changes in the 137Cs activities were found. The mean effective half-life (TEF) for 137Cs in spruce bark was 9.6 years, and the mean environmental half-life (TE) was 14 years. The effective half-lives were significantly higher in areas with higher long-term annual precipitation sums. Coefficient a in linear regression y = ax + b of half-lives on precipitation sums was 0.015 y mm−1 for TEF and 0.036 y mm−1 for TE. The aggregated transfer factor of 137Cs from soil to bark was determined and the pre-Chernobyl bark contamination related to year 2010 was estimated.

Personalized Dosimetry of 131I-Rituximab Radioimmunotherapy of Non-Hodgkin Lymphoma Defined by Pharmacokinetics in Bone Marrow and Blood

To report a comparison of SPECT/CT technique with standard blood-based dosimetry methodology in a cohort of non-Hodgkin lymphoma (NHL) patients treated with 131I-rituximab anti-CD20 chimeric monoclonal antibody. Red marrow uptake was measured directly using serial quantitative whole-body imaging in conjunction with SPECT/CT in a cohort of 23 patients undergoing routine 131I-rituximab radioimmunotherapy of NHL. Absorbed dose measurements were then compared with radiation doses calculated using standard peripheral blood counting methodology. Activity clearance from whole body of 88.7 hours measured by imaging 131I-rituximab was significantly slower (p<0.001) than the mean effective half-life clearance of 60.8 hours calculated from the sampling peripheral blood. The mean activity concentrations in bone marrow measured using SPECT/CT, and by blood sampling, extrapolated to the time of administration, were, however, concordant. The absorbed self-dose in red marrow, measured using imaging, was 1.02 Gy compared with the dose (0.81 Gy) calculated from blood sampling. Neutrophil toxicity correlated with absorbed dose by SPECT/CT imaging (p=0.01), whereas the blood sampling method demonstrated no correlation with any parameters of hematological toxicity. Radiation dose to red marrow from 131I-rituximab is inherently underestimated by standard indirect peripheral blood counting methods. Personalized marrow dosimetry by quantitative gamma imaging more accurately predicts of hemopoietic myelotoxicity by direct measurement of the bone marrow activity concentration of 131I-rituximab.

Safety and Efficacy of 188-Rhenium-Labeled Antibody to Melanin in Patients with Metastatic Melanoma

There is a need for effective “broad spectrum” therapies for metastatic melanoma which would be suitable for all patients. The objectives of Phase Ia/Ib studies were to evaluate the safety, pharmacokinetics, dosimetry, and antitumor activity of 188Re-6D2, a 188-Rhenium-labeled antibody to melanin. Stage IIIC/IV metastatic melanoma (MM) patients who failed standard therapies were enrolled in both studies. In Phase Ia, 10 mCi 188Re-6D2 were given while unlabeled antibody preload was escalated. In Phase Ib, the dose of 188Re-6D2 was escalated to 54 mCi. SPECT/CT revealed 188Re-6D2 uptake in melanoma metastases. The mean effective half-life of 188Re-6D2 was 12.4 h. Transient HAMA was observed in 9 patients. Six patients met the RECIST criteria for stable disease at 6 weeks. Two patients had durable disease stabilization for 14 weeks and one for 22 weeks. Median overall survival was 13 months with no dose-limiting toxicities. The data demonstrate that 188Re-6D2 was well tolerated, localized in melanoma metastases, and had antitumor activity, thus warranting its further investigation in patients with metastatic melanoma.

Two phase I studies of PTI-188, a radiolabeled murine antimelanin antibody, in patients with metastatic melanoma (MM).

8555 Background: Two completed single-dose Phase I studies explored the feasibility of treating MM by targeting melanin with a 188-Rhenium-labeled IgM mAb (PTI-188) to deliver high energy β radiation to tumors. This strategy is attractive because it does not rely on patients’ genotype or immune status, and thus has potential to be used alone or in combination with other therapies in a wide pt population. The objectives of these Phase I studies were to evaluate the safety, pharmacokinetics, dosimetry and anti-tumor activity of a single dose of PTI-188. Methods: Pts with stage IIIC/IV MM who progressed after chemotherapy, immunotherapy, radiotherapy or surgery were enrolled in both studies, at least 3 pts/cohort. In Phase IA, pts were given the same dose of PTI-188 (10 mCi/10 mg) while a cold antibody pre-load was escalated from 0-50 mg in 4 cohorts. In Phase IB, pts were assigned to cohort 1 (20-30 mCi/20mg) or cohort 2 (40-60mCi/50mg). Whole body planar and tomographic (SPECT/CT) scintigraphy were performed post-infusion to determine tumor targeting and dosimetry. Toxicity and efficacy were evaluated at weeks 2 and 6 post-treatment, and monthly thereafter. Results: No dose limiting toxicities or clinically meaningful effects in safety lab tests were seen in the 13 pts dosed in Phase IA and 7 pts in Phase IB, suggesting the MTD was not met. No treatment related serious AEs occurred. Transient human anti-murine Abs were observed in 9 pts. Tomographic imaging revealed PTI-188 uptake in melanoma tumor deposits mostly in the soft tissues. The highest radiation absorbed dose to normal organs was in the kidney (13% of the allowable dose to kidney at the highest dose level of PTI-188). The mean effective half-life of PTI-188 was 12.4 hr across cohorts. Although no therapeutic benefit was expected in a single dose Phase I study, 6 pts met the RECIST criteria for stable disease at 6 weeks. 2 pts had durable disease stabilization for 14 weeks and 1 for 22 weeks. Preliminary ad-hoc analysis indicates a median overall survival of 20 months (n=17). Conclusions: The data demonstrate that a single dose of PTI-188 was well tolerated, localized in melanoma metastases and suggest antitumor activity.

The “Warfarin Window” in Pregnancy: The Importance of Half-life

Anticoagulation therapy during pregnancy in women with prosthetic cardiac valves is a therapeutic challenge. The use of vitamin K antagonists such as warfarin during pregnancy carries the potential for serious risks to the fetus, especially if these drugs are administered during the first trimester or at term. Between 6 and 12 weeks’ gestation, fetal synthesis of proteins crucial for bone and cartilage formation may be impaired by warfarin, resulting in the well-defined “warfarin embryopathy.” One of the most commonly suggested regimens involves the substitution of heparin for warfarin between 6 and 12 weeks’ gestation to minimize the risk of warfarin embryopathy. Warfarin has a long half-life; following a single dose, the terminal elimination half-life is about one week, with a mean effective half-life of 40 hours. To date, all existing guidelines have ignored this long elimination half-life. If a policy of substituting heparin for warfarin between 6 and 12 weeks’ gestation is followed, we suggest that substitution should begin at a much earlier gestational age. Substitution starting at 6 weeks’ gestation may be too late to avoid embryopathy.