Resumen de Population pharmacokinetic-pharmacodynamic modelling to optimize lenalidomide treatment in multiple myeloma patients
Anti-cancer drugs are characterized by narrow therapeutic ranges, and are often administered at a dose close to the maximum-tolerated dose. The wide variability observed in the response to anti-cancer drugs makes difficult that every patient receives the optimal dose during therapy. Several methods have been proposed for dose individualization of anti-cancer drugs, such as the use of weight or body surface area (dose/kg or dose/m2), the a priori methods (e.g. Calvert’s formula for dosing carboplatin), or the a posteriori dose revisions based on calculated pharmacokinetic exposure parameters. However, dose-response relationships represent the most extensively used method for selecting dose regimens of antineoplastic drugs in the early stages of drug development, although this probabilistic concept has certain limitations due to the presence of variability in clinical response arising from multiple factors, not only from the administered dose.
In the absence of an agreement on the best individualization method, empirical dose adjustment criteria is still used, although these criteria do not guarantee a proper individualization of antineoplastic drugs; for instance, in the event of toxicity, treatment is often delayed or the initial dose is reduced to a lower dose level that, in most cases, has been established empirically and is the same in all patients.
Nevertheless, treatment optimization of anti-cancer drugs is evolving in the recent years and there is a growing interest among researchers on this topic. It is well known that studying and quantifying the different sources of variability in the pharmacological response could allow treatment individualization in order to decrease variability in the clinical response in terms of efficacy and toxicity, leading to an optimal drug therapy.
In this context, pharmacokinetic/pharmacodynamic (PK/PD) modelling has been widely used for treatment optimization of drugs with large pharmacokinetic and pharmacodynamic variability and a narrow therapeutic range, such as anti-cancer drugs.
This conceptual framework represents the scope of this Doctoral Thesis, performed in a sample of multiple myeloma patients treated with lenalidomide in the Department of Pharmacy of Doctor Peset University Hospital of Valencia in collaboration with the Department of Pharmacy and Pharmaceutical Technology of the University of Valencia.
Multiple myeloma is a type of monoclonal gammopathy characterized by clonal proliferation of malignant plasma cells, producing monoclonal protein and causing clinical abnormalities such as anaemia, renal failure, hypercalcemia and bone lesions. Multiple myeloma is the most frequent plasma cell malignancy, representing 1% of all neoplasms and 10% of all haematological malignancies.
Until 2000, the main treatment for multiple myeloma was alkylators and corticosteroids and, in selected patients, high dose chemotherapy with autologous stem cell transplantation. Subsequently, bortezomib and oral alternatives, such as thalidomide and lenalidomide, emerged as effective agents and greatly improved clinical outcome.
Lenalidomide has shown activity both in patients who have been treated previously and in patients with previously untreated multiple myeloma that are not eligible for transplant. Even new combination regimens that include lenalidomide are being tested in order to improve the therapy outcome of multiple myeloma patients. Lenalidomide is administered in doses that range from 5 to 25 mg/daily according to renal function, and dose adjustments are performed only once patients have experienced severe toxicity, but not beforehand.
In clinical practice, a large variability in lenalidomide therapeutic and toxic response has been observed in patients treated at equivalent doses. Among the factors that may explain the different response is the inherent variability in pharmacokinetic and pharmacodynamic processes, which analysis and management is a challenge for health professionals.
For these reasons, studying the relationship between lenalidomide pharmacokinetic exposure parameters (PK) and lenalidomide therapeutic and toxic response (PD) would enable treatment optimization by individually selecting the dosing regimen associated with the greatest therapeutic benefit and the lowest undesired effects.
