Randomized, Parallel Group, Open-Label Bioequivalence Trial of Intramuscular Pegaspargase in Patients With Relapsed Acute Lymphoblastic Leukemia

Abstract

<jats:sec><jats:title>PURPOSE</jats:title><jats:p> Pegylated asparaginase is comparatively safer than native asparaginase in the management of acute lymphoblastic leukemia (ALL). However, the high price and nonavailability in low- and middle-income countries limits its use. In 2014, the first generic of pegaspargase (Hamsyl) was approved in India for use as a second-line treatment option for ALL. The aim of this study was to assess whether the generic pegaspargase (the test product) was bioequivalent with the reference product (Oncaspar). </jats:p></jats:sec><jats:sec><jats:title>PATIENTS AND METHODS</jats:title><jats:p> This study was an open-label, parallel-group, comparative pharmacokinetic study in pediatric patients with relapsed ALL receiving their first dose (1,000 IU/m<jats:sup>2</jats:sup>) of pegaspargase administered intramuscularly. Patients were randomly assigned 1-to-1 to either the test or the reference product. The 2 formulations were considered equivalent if the 90% CIs for area under the plasma asparaginase activity–time curve (AUC<jats:sub>0-t</jats:sub>) geometric mean test-to-reference ratio was within 75% to 133%. </jats:p></jats:sec><jats:sec><jats:title>RESULTS</jats:title><jats:p> Twenty-nine patients (6-18 years of age) were enrolled in this study, of whom 24 completed the study criteria and were considered for safety analysis (5 patients were ineligible for the assessment). Three patients were excluded from analysis, because of presence of anti-asparaginase antibodies, leaving 21 patients who were considered for bioequivalence pharmacokinetics data. The point estimate of AUC<jats:sub>0-t</jats:sub> for the test-to-reference ratio was 95.05 (90% CI, 75.07% to 120.33%). Maximum plasma concentration, trough concentrations (day 14), half-life, volume of distribution, drug clearance, and changes in the asparagine and glutamine levels were not significantly different between products. Adverse events were comparable in both groups. </jats:p></jats:sec><jats:sec><jats:title>CONCLUSION</jats:title><jats:p> Generic and reference pegaspargase had equivalent pharmacokinetics with comparable safety. This could be a safe and cost-effective alternative for patients with ALL, especially in low- and middle-income countries. </jats:p></jats:sec>

Pharmacological and clinical monitoring in children with acute lymphoblastic leukemia treated with a biogeneric PEG‐l‐asparaginase product

“…Recently, two studies regarding a comparison between the reference PEG‐ASP product and the first GEN‐PEG‐ASP product approved in India were published. Both studies, in contrast to our findings, demonstrated equivalent pharmacokinetics and comparable safety of the two products 18,19 …”

“…Both studies, in contrast to our findings, demonstrated equivalent pharmacokinetics and comparable safety of the two products. 18,19 The discrepancy observed across data and reports further highlights the complexity of the production of biogeneric drugs, making the exact replication of the innovator drug very difficult and sophisticated, especially when considering highly complex molecule such as the native and pegylated E. coli ASP. 20 The pharmacological and clinical data reported for the biogeneric native E. coli ASP products and the data reported in our experience for a GEN-PEG-ASP product raise some concrete concerns about the quality, the toxicity, and efficacy profiles of both native and pegylated E. coli ASP biogeneric products.…”

Reply to: Comment on: Unsatisfactory quality of E. coli asparaginase biogenerics in India—Implications for clinical outcomes in acute lymphoblastic leukaemia

“…This requires companies to recognise the long-term advantages of such a partnership, which includes developing the evidence base for product use in clinical practice and identifying opportunities for innovation. 6 The third approach is to engage patient advocacy groups to raise awareness and support for clinical studies that evaluate generic medicines and to identify generic products suitable for therapeutic use. This latter approach has received a fillip with launch of the World Health Organisation's Global Initiative for Childhood Cancer in 2018.…”

Experience with Generic Pegylated L-asparaginase in Children with Acute Lymphoblastic Leukemia from a Tertiary Care Oncology Center in South India

“…Patients treated with generic pegylated-L-asparaginase (Hamsyl) or innovator pegasparagase achieved more than the recommended asparaginase levels at day 14. 15 Following a single intramuscular injection of pegaspargase, the peak asparaginase activity (%1 IU/mL) was reached by day 5, and the half-life was 1.7 days. Similarly, following a single intravenous injection, the peak asparaginase activity of 1.6 IU/mL was reached within 1.25 hours.…”

“…13,14-Pegylated L-asparaginase is formed by the covalent linking of polyethylene glycol to E. coli L-asparaginase. 15 Oncaspar (pegaspargase), an innovator preparation available in the USA and Europe, is costly, and patients from middle-to-low-income group might not be able to afford it. Moreover, it is also difficult to import the drug, so its use in India is limited.…”