Pharmacokinetics, metabolism and safety of deuterated L-DOPA (SD-1077)/carbidopa compared to L-DOPA/carbidopa following single oral dose administration in healthy subjects.

AIMS: SD-1077, a selectively deuterated precursor of dopamine (DA) structurally related to L-3,4-dihydroxyphenylalanine (L-DOPA), is under development for treatment of motor symptoms of Parkinson's disease. Preclinical models have shown slower metabolism of central deuterated DA. The present study investigated the peripheral pharmacokinetics (PK), metabolism and safety of SD-1077. METHODS: Plasma and urine PK of drug and metabolites and safety after a single oral 150 mg SD-1077 dose were compared to 150 mg L-DOPA, each in combination with 37.5 mg carbidopa (CD) in a double-blind, two-period, crossover study in healthy volunteers (n = 16). RESULTS: Geometric least squares mean ratios (GMRs) and 90% confidence intervals (90% CI) of SD-1077 vs. L-DOPA for Cmax , AUC0-t , and AUC0-inf were 88.4 (75.9-103.1), 89.5 (84.1-95.3), and 89.6 (84.2-95.4), respectively. Systemic exposure to DA was significantly higher after SD-1077/CD compared to that after L-DOPA/CD, with GMRs (90% CI) of 1.8 (1.45-2.24; P = 0.0005) and 2.06 (1.68-2.52; P < 0.0001) for Cmax and AUC0-t and a concomitant reduction in the ratio of 3,4-dihydroxyphenylacetic acid/DA confirming slower metabolic breakdown of DA by monoamine oxidase (MAO). There were increases in systemic exposures to metabolites of catechol O-methyltransferase (COMT) reaction, 3-methoxytyramine (3-MT) and 3-O-methyldopa (3-OMD) with GMRs (90% CI) for SD-1077/CD to L-DOPA/CD for 3-MT exposure of 1.33 (1.14-1.56; P = 0.0077) and 1.66 (1.42-1.93; P < 0.0001) for Cmax and AUC0-t , respectively and GMRs (90% CI) for 3-OMD of 1.19 (1.15, 1.23; P < 0.0001) and 1.31 (1.27, 1.36; P < 0.0001) for Cmax and AUC0-t . SD-1077/CD exhibited comparable tolerability and safety to L-DOPA/CD. CONCLUSIONS: SD-1077/CD demonstrated the potential to prolong exposure to central DA at comparable peripheral PK and safety to the reference L-DOPA/CD combination. A single dose of SD-1077 is safe for further clinical development in Parkinson's disease patients.

The safety of bendamustine in patients with chronic lymphocytic leukemia or non-Hodgkin lymphoma and concomitant renal impairment: a retrospective electronic medical record database analysis.

Abstract This retrospective study compared adverse-event rates in patients with chronic lymphocytic leukemia (CLL) or non-Hodgkin lymphoma (NHL), with and without renal impairment, receiving bendamustine alone or with rituximab. Patients (n = 940) were stratified into a renally impaired group (creatinine clearance [CrCL] < 40 mL/min) and two comparator groups (CrCL ≥ 40 mL/min and CrCL ≥ 60 mL/min). Renally impaired patients with NHL had a significantly greater incidence of grade 3-4 thrombocytopenia compared with the CrCL ≥ 60 mL/min group (hazard ratio [HR], 2.57; p = 0.025). For CLL and NHL together, grade 3-4 increased blood urea nitrogen was significantly higher in the renally impaired group than in the CrCL ≥ 40 mL/min (HR, 2.36; p = 0.02) and CrCL ≥ 60 mL/min (HR, 4.46; p = 0.001) groups. Based on these results, monitoring blood counts (including platelets) and renal function would be prudent in the management of patients with renal dysfunction and NHL or CLL who receive bendamustine-based regimens.

Demographics, treatment patterns, safety, and real-world effectiveness in patients aged 70 years and over with chronic lymphocytic leukemia receiving bendamustine with or without rituximab: a retrospective study.

OBJECTIVES: Bendamustine is a unique cytotoxic agent active against various human malignancies, including chronic lymphocytic leukemia (CLL). In vitro studies suggest that cytotoxic activity of bendamustine on CLL-derived cells is synergized by rituximab. A retrospective chart review was conducted to characterize treatment-naïve outpatients and those with relapsed disease aged 70 years and over with CLL receiving bendamustine (with or without rituximab) and to evaluate real-world patterns of care, safety, and effectiveness. METHODS: Using McKesson Specialty Care/US Oncology Network iKnowMed databases, 91 outpatients with at least two recorded visits and at least two cycles of bendamustine monotherapy or bendamustine-rituximab combination therapy were identified and included. Mean age at diagnosis and start of first therapy was 70.3 and 77.4 years respectively, and 63.7% of patients were men. RESULTS: Observed overall response rate was 56.3% in pooled treatment-naïve patients [n = 9; complete response (CR) 18.8%; partial response (PR) 37.5%; nodular partial response (nPR) 0%] and 58.7% in pooled patients with relapsed disease (n = 44; CR 13.3%; PR 44.0%; nPR 1.3%). Median time to progressive disease has not been reached for the 16 treatment-naïve patients (median follow up 15.1 months), and was 18.4 months for those with relapsed disease (n = 73). No unexpected toxicities were observed. Overall rate of blood/bone marrow toxicities (all grades) was 40.7%; grade 3/4 rates were 18.8% in treatment-naïve patients and 25.3% in those with relapsed disease. Most frequent nonhematologic adverse events were fatigue and rash. CONCLUSION: In this retrospective chart review of 91 outpatients with CLL aged 70 years and over, bendamustine (with or without rituximab) was an effective therapeutic option with manageable toxicity.