Renal safety of zoledronic acid with thalidomide in patients with myeloma: a pharmacokinetic and safety sub-study

BACKGROUND: Cases of impaired renal function have been reported in patients who had been treated with both zoledronic acid and thalidomide for myeloma. Hence, we conducted a safety study of zoledronic acid and thalidomide in myeloma patients participating in a trial of maintenance therapy. METHODS: Twenty-four patients who were enrolled in a large randomized trial of thalidomide vs no thalidomide maintenance therapy for myeloma, in which all patients also received zoledronic acid, were recruited to a pharmacokinetic and renal safety sub-study, and followed for up to 16 months. RESULTS: No significant differences by Wilcoxon rank-sum statistic were found in zoledronic acid pharmacokinetics or renal safety for up to 16 months in patients randomized to thalidomide or not. CONCLUSION: In myeloma patients receiving maintenance therapy, the combination of zoledronic acid and thalidomide appears to confer no additional renal safety risks over zoledronic acid alone

Compartmental pharmacokinetic analysis of oral amprenavir with secondary peaks

Amprenavir is a protease inhibitor that has been shown to have secondary peaks postulated to be due to enterohepatic recycling. We propose a model to describe the pharmacokinetics of amprenavir which accommodates the secondary peak(s). A total of 82 healthy human immunodeficiency virus (HIV)-seronegative subjects were administered a single 600-mg dose of amprenavir as part of adult AIDS Clinical Trials Group protocol A5043. Serial blood samples were obtained over 24 h. Samples were analyzed for amprenavir and fit to a compartmental model using ADAPT II software, with all relevant parameters conditional with respect to bioavailability. The model accommodated secondary peaks by incorporating clearance out of the central compartment with delayed instantaneous release back into the gut compartment. The data were weighted by the inverse of the estimated measurement error variance; model discrimination was determined using Akaike's Information Criteria. A total of 76 subjects were evaluable in the study analysis. The data were best fit by a two-compartment model, with 98.7% of the subjects demonstrating a secondary peak. Amprenavir had a mean total clearance of 1.163 liters/h/kg of body weight (0.7), a central volume of distribution of 1.208 liters/kg (0.8), a peripheral volume of distribution of 8.2 liters/kg (0.81), and distributional clearance of 0.04 liters/h/kg (0.81). The time to the secondary peak was 7.86 h (0.17), and clearance into a recycling compartment was 0.111 liters/kg/h (0.74). Amprenavir pharmacokinetics has been well described using a two-compartment model with clearance to a recycling compartment and release back into the gut. The nature of the secondary peaks may be an important consideration for the interpretation of amprenavir plasma concentrations during therapeutic drug monitoring

Unexpected Hepatotoxicity in a Phase I Study of TAS266, a Novel Tetravalent Agonistic Monoclonal Nanobody® Targeting the DR5 Receptor

ABSTRACT Purpose: TAS266 is a novel agonistic tetravalent Nanobody® targeting the DR5 receptor. In preclinical studies, TAS266 was more potent than a cross-linked DR5 antibody or TRAIL. This first-in-human study was designed to evaluate the safety and tolerability, maximum tolerated dose, pharmacokinetics, pharmacodynamics, immunogenicity and preliminary efficacy of TAS266. Methods: Adult patients with advanced solid tumors were to receive assigned doses of TAS266 (3, 10, 15, or 20 mg/kg) intravenously on days 1, 8, 15, and 22 of a 28-day treatment cycle. Results: Grade ≥3 elevations in aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) levels, occurring during cycle 1 in 3 of 4 patients at the 3 mg/kg dose level, were attributed to TAS266 and led to early study termination. Liver enzyme levels quickly returned to grade ≤1 following TAS266 discontinuation. Evidence of pre-existing antibodies able to bind to TAS266 was found in the 3 patients who experienced these dose-limiting toxicities. Immunogenic responses remained elevated and strengthened at end-of-treatment (EOT). In the 1 patient who did not develop hepatotoxicity, no evidence of immunogenicity was observed at baseline or following administration of 4 TAS266 doses; however, incipient positive immunogenicity was observed at the EOT visit. Conclusion: TAS266 was associated with unexpected, significant but reversible hepatotoxicity. Although the underlying mechanism is not fully elucidated, factors including the molecule’s high potency, immunogenicity to TAS266 and possibly increased DR5 expression on hepatocytes further enhancing the activity of the Nanobody®, may have contributed to enhanced DR5 clustering and activation of hepatocyte apoptosis

Safety, Pharmacokinetics, and Pharmacodynamics of the DR5 Antibody LBY135 Alone and in Combination with Capecitabine in Patients with Advanced Solid Tumors

Purpose: We evaluated the safety, maximum tolerated dose (MTD), pharmacokinetics, pharmacodynamics, biologic activity, and antitumor efficacy of the DR5 antibody, LBY135 ± capecitabine. Experimental design: Escalating LBY135 was administered every 21 days, alone (Arm1) or with capecitabine (Arm2), to patients with advanced solid tumors. Results: In Arm1 (n=40), LBY135 (0.3–40 mg/kg) resulted in no dose-limiting toxicities; adverse events (AEs) included fatigue, hypotension, abdominal pain, dyspnea, and nausea. Stable disease (SD) was observed in 21/38 (55.3%) patients. In Arm2 (n=33), LBY135 (1–40 mg/kg) plus capecitabine resulted in 3 DLTs (each grade 3): dehydration and mucosal inflammation (1 mg/kg), colitis (20mg/kg), and diarrhea (40 mg/kg). AEs included fatigue, nausea, dyspnea, and vomiting. Partial response was observed in 2 patients (rectal and breast cancer) and SD in 12/27 (44.4%) patients. Mean elimination half-life of LBY135 ± capecitabine at saturation of clearance (≥10 mg/kg) ranged between 146–492 hours. Immunogenicity was detected in 16/73 (22%) patients, of which 6 patients experienced reduced LBY135 exposure with repeat dosing. M30/M65 levels were not predictive for LBY135 response. FDG-PET responses were not consistently associated with RECIST responses. Conclusions: LBY135 was well tolerated up to 40mg/kg, the maximal dose administered; no MTD for LBY135 ± capecitabine was defined. Clearance was saturated at doses ≥10 mg/kg

Unexpected Hepatotoxicity in a Phase I Study of TAS266, a Novel Tetravalent Agonistic Monoclonal Nanobody® Targeting the DR5 Receptor

SUMMARY Purpose: This first-in-human study was designed to evaluate the safety and tolerability, maximum tolerated dose, pharmacokinetics, pharmacodynamics, immunogenicity, and preliminary efficacy of TAS266, a novel agonistic tetravalent Nanobody® targeting the DR5 receptor. Experimental design: Adult patients with advanced solid tumors were to receive assigned doses of TAS266 (3, 10, 15, or 20 mg/kg) intravenously on days 1, 8, 15, and 22 of a 28-day treatment cycle. Results: Grade ≥ 3 elevations in aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) levels occurring during cycle 1 in 3 of 4 patients enrolled at the 3 mg/kg dose level were attributed to TAS266 and led to early study termination. Liver enzyme levels quickly returned to grade ≤ 1 following TAS266 discontinuation. Evidence of antidrug antibodies, indicating pre-existing immunogenicity to TAS266, was found in the 3 patients who experienced these dose-limiting toxicities (DLTs). Immunogenic responses remained elevated and strengthened at the end of treatment. In the 1 patient who did not develop hepatotoxicity, no evidence of immunogenicity was observed at baseline or following administration of 4 doses of TAS266; however, incipient positive immunogenicity was observed at the end of treatment visit. TAS266 had a mean total systemic clearance of 0.47 L/hr and a median terminal phase half-life of 14.29 hours. Conclusion: TAS266 was associated with unexpected, significant but reversible hepatotoxicity. Although the underlying mechanism is not fully elucidated, immunogenicity to TAS266 may have contributed to enhanced DR5 clustering and activation of hepatocyte apoptosis

New Insights in Tissue Distribution, Metabolism and Excretion of [3H]-labeled Antibody Maytansoid Conjugates in Female Tumor Bearing Nude Rats

For antibody drug conjugates (ADCs), the fate of the cytotoxic payload in vivo needs to be well understood in order to mitigate toxicity risks and properly design the first in patient studies. Therefore, a DME study with a rat cross reactive ADC (LNL897) targeting the p-cadherin receptor was conducted in female tumor bearing nude rats. Although multiple components needed to be monitored in the DME study (total radioactivity, conjugated ADC, total ADC, payload DM1 and catabolites) with different technologies (LSC, LC-MS, ELISA, SEC), the pharmacokinetic data were nearly superimposable. LNL897 was cleared in the rat with half-lives of 51-62 h and LNL897 related radioactivity showed a minor extent of tissue distribution. The highest tissue concentrations of LNL897 related radioactivity were measured in tumor tissue. Complimentary LESA-µLC-MS/MS data proved that the LYS-MCC-DM1 catabolite was the only detectable component distributed evenly in the tumor and liver tissue. The mass balance was complete with up to 13.8+0.482% of the administered radioactivity remaining in carcass 168 h post dose. LNL897 derived radioactivity was mainly excreted via feces (84.5+3.12%) and through urine only to a minor extent (4.15+ 0.462%). In serum, the major part of radioactivity could be attributed to ADC while small molecule disposition products were the predominant species in excreta. We showed that there is a difference in metabolite profiles depending if derivatization methods for DM1 were applied and got more insights into metabolic disposition as a cysteine conjugate of DM1 and maysine could be identified in serum and excreta besides previously published LYS-MCC-DM1 and MCC-DM1

Safety, pharmacokinetics, and pharmacodynamics of the DR5 antibody LBY135 alone and in combination with capecitabine in patients with advanced solid tumors

Purpose We evaluated the safety, maximum tolerated dose (MTD), pharmacokinetics, pharmacodynamics, biologic activity, and antitumor efficacy of the DR5 antibody, LBY135 +/- capecitabine. Experimental design Escalating LBY135 was administered every 21 days, alone (Arm1) or with capecitabine (Arm2), to patients with advanced solid tumors. Results In Arm1 (n = 40), LBY135 (0.3-40 mg/kg) resulted in no dose-limiting toxicities (DLTs); adverse events (AEs) included fatigue, hypotension, abdominal pain, dyspnea, and nausea. Stable disease (SD) was observed in 21/38 (55.3 %) patients. In Arm2 (n = 33), LBY135 (1-40 mg/kg) plus capecitabine resulted in 3 DLTs (each grade 3): dehydration and mucosal inflammation (1 mg/kg), colitis (20 mg/kg), and diarrhea (40 mg/kg). AEs included fatigue, nausea, dyspnea, and vomiting. Partial response was observed in 2 patients (rectal and breast cancer) and SD in 12/27 (44.4 %) patients. Mean elimination half-life of LBY135 +/- capecitabine at saturation of clearance (a parts per thousand yen10 mg/kg) ranged between 146 h and 492 h. Immunogenicity was detected in 16/73 (22 %) patients, of which 6 patients experienced reduced LBY135 exposure with repeat dosing. M30/M65 levels were not predictive for LBY135 response. FDG-PET responses were not consistently associated with RECIST responses. Conclusions LBY135 was well tolerated up to 40 mg/kg, the maximal dose administered; no MTD for LBY135 +/- capecitabine was defined. Clearance was saturated at doses a parts per thousand yen10 mg/kg